Avelumab (Bavencio)
Number: 0916
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Note: Requires Precertification:
Precertification of avelumab (Bavencio) is required of all Aetna participating providers and members in applicable plan designs. For precertification of avelumab (Bavencio), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.
Note: Site of Care Utilization Management Policy applies. For information on site of service for avelumab (Bavencio), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.
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Exclusions
Aetna will not provide coverage for members who have experienced disease progression while on PD-1 or PD-L1 inhibitor therapy (e.g., nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi)).
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Criteria for Initial Approval
Aetna considers avelumab (Bavencio) medically necessary for the following indications:
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Merkel Cell Carcinoma
As a single agent for the treatment of Merkel cell carcinoma in members with metastatic disease; or
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Renal Cell Carcinoma
For the treatment of advanced, relapsed, or stage IV renal cell carcinoma with clear cell histology when given in combination with axitinib as first-line treatment for the disease; or
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Urothelial Carcinomas
As a single agent for the treatment of any of the following:
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Bladder Cancer
When either of the following criteria is met:
- Used as subsequent therapy; or
- Used as maintenance therapy if there is no progression on first-line platinum-containing chemotherapy; or
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Primary Carcinoma of the Urethra
When either of the following criteria is met:
- Used as subsequent systemic therapy for recurrent, locally advanced, or metastatic disease; or
- Used as maintenance therapy if there is no progression on first-line platinum-containing chemotherapy; or
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Upper Genitourinary (GU) Tract Tumors or Urothelial Carcinoma of the Prostate
When either of the following criteria is met:
- Used as subsequent therapy for locally advanced or metastatic disease; or
- Used as maintenance therapy if there is no progression on first-line platiunum-containing chemotherapy; or
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Gestational Trophoblastic Neoplasia
As a single agent for treatment of gestational trophoblastic neoplasia for multiagent chemotherapy-resistant disease when either of the following criteria is met:
- Member has recurrent or progressive intermediate trophoblastic tumor (placental site trophoblastic tumor or epithelioid trophoblastic tumor) following treatment with a platinum-based regimen; or
- Member has high-risk disease; or
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Endometrial Carcinoma
As a single agent for subsequent treatment of recurrent or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors.
Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).
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Continuation of Therapy
Aetna considers continuation of avelumab (Bavencio) therapy medically necessary for members requesting reauthorization for an indication listed in Section II when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.
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Related Policies
Dosage and Administration
Avelumab (Bavencio) is available as a 200 mg/10 mL (20 mg/mL) solution in single-dose vial for intravenous infusion.
- Merkel cell carcinoma: Avelumab (Bavencio) 800 mg administered as an intravenous infusion (IV) over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
- Urothelial carcinoma: Avelumab (Bavencio) 800 mg administered as an IV infusion over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
- Kidney cancer (renal cell carcinoma): Avelumab (Bavencio) 800 mg administered IV infusion over 60 minutes every 2 weeks in combination with axitinib 5 mg orally taken twice daily (12 hours apart) with or without food until disease progression or unacceptable toxicity.
Source: EMD Serono, 2022
Experimental and Investigational
Aetna considers avelumab (Bavencio) experimental and investigational for the treatment of all other indications, including the following (not an all-inclusive list) because its effectiveness for these indications has not been established:
- Adenoid cystic carcinoma
- Adrenocortical cancer
- Acute myeloid leukemia
- Biliary tract cancer
- Breast cancer
- Chordoma
- Colorectal cancer
- Gastro-intestinal cancers (e.g., colorectal, esophageal, gastric cancers, and small bowel adenocarcinoma)
- Head and neck cancer
- Hodgkin lymphoma
- Large-cell lung neuroendocrine carcinoma
- Leiomyosarcoma
- Liposarcoma
- Mesothelioma (including pleural mesothelioma)
- Multiple myeloma
- Neuroendocrine cancer
- Non-small cell lung cancer
- Ovarian cancer
- Pancreatic cancer
- Prostate cancer
- Spindle cell cancer.
Background
U.S. Food and Drug Administration (FDA)-Approved Indications
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Metastatic Merkel Cell Carcinoma (MCC)
Treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma.
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Locally Advanced or Metastatic Urothelial Carcinoma (UC): First-line maintenance treatment of urothelial carcinoma
Maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma that has not progressed with first-line platinum-containing chemotherapy
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Locally Advanced or Metastatic Urothelial Carcinoma (UC): Previously-treated urothelial carcinoma
Treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy
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Advanced Renal Cell Carcinoma (RCC)
First-line treatment of patients with advanced renal cell carcinoma in combination with axitinib.
Compendial Uses
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Urothelial carcinoma
- Bladder cancer
- Primary carcinoma of the urethra
- Upper genitourinary (GU) tract tumors
- Urothelial carcinoma of the prostate
- Merkel cell carcinoma
- Renal cell carcinoma
- Gestational trophoblastic neoplasia
- Endometrial carcinoma
Avelumab is available as Bavencio (EMD Serono) and is a programmed death ligand-1 (PD-L1) blocking antibody. Avelumab binds to PD-L1 and blocks the interaction between PD-L1 and its receptors PD-1 and B7.1, This interaction releases the inhibitory effects of PD-L1 on the immune response and resultant restoration of immune responses, including anti-tumor immune responses (EMD Serono, 2020).
Per the prescribing information, avelumab (Bavencio) carries the following warnings and precautions:
- Immune-mediated adverse reactions
- Infusion-related reactions
- Complications of allogeneic hematopoietic stem cell transplantation (HSCT)
- Major adverse cardiovascular events
- Embryo-fetal toxicity.
Per the prescribing information, the most common adverse reactions (≥ 20%) included the following:
- For Merkel cell carcinoma: fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reaction, rash, decreased appetite, and peripheral edema.
- For urothelial carcinoma:
- Maintenance treatment: fatigue, musculoskeletal pain, urinary tract infection, and rash
- Previously-treated: fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite, and urinary tract infection
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For renal cell carcinoma with axitinib: diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.
Acute Myeloid Leukemia
Assi and co-workers (2018) discussed the rationale, efficacy, and toxicity of a variety of immune approaches being evaluated in the therapy of acute myeloid leukemia (AML) including naked and conjugated monoclonal antibodies, bispecific T-cell engager antibodies, and immune checkpoint blockade via antibodies targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1. The stellar success of immune therapies that harness the power of T cells in solid tumors and an improved understanding of the immune system in patients with hematologic malignancies have resulted in major efforts to develop immune therapies for the treatment of patients with AML. Monoclonal antibodies in AML therapy include naked antibodies against AML surface antigens such as CD33 (e.g., lintuzumab) or CD38 (e.g., daratumumab), antibodies conjugated to toxins in various anti-CD33 (gemtuzumab ozogamicin, SGN33A, IMGN779) and anti-CD123 (SL-401, SGN-CD123A) formulations, and antibodies conjugated to radioactive particles such as I or Ac-labeled anti-CD33 or anti-CD45 antibodies. Additional antigenic targets of interest in AML include CLL1, CD38, CD25, TIM3, FLT3, and others. Approaches to harness the body's own T cells against AML include antibodies that recruit and induce cytotoxicity of tumor cells by T cells (bi-specific T-cell engager [BiTE] such as CD33 x CD3 (e.g., AMG 330) or CD123 x CD3 (e.g., flotetuzumab, JNJ-63709178) or antibodies that block immune checkpoint receptors CTLA4 (e.g., ipilimumab) or PD1/PD-L1 (e.g., nivolumab, pembrolizumab, avelumab) on T cells, unleashing the patients' T cells against leukemic cells. The authors concluded that ongoing trials and well-designed correlative interrogation of the immune system in patients treated on such trials will further enhance the understanding and clinical application of immune therapies as single-agent and combination approaches for the treatment of AML.
Saxena and colleagues (2021) noted that patients with relapsed/refractory (R/R) AML have limited therapeutic options. In pre-clinical models of AML, inhibition of the PD-1/PD-L1 axis exhibited anti-leukemic activity. In a phase-Ib/II clinical trial, these researchers examined the safety and efficacy of azacitidine with avelumab in patients with R/R AML. Patients aged greater than or equal to 18 years who had R/R AML received azacitidine 75 mg/m2 on days 1 through 7 and avelumab on days 1 and 14 of 28-day cycles. A total of 19 patients were treated. The median age was 66 years (range of 22 to 83 years), 100 % had European LeukemiaNet 2017 adverse-risk disease, and 63 % had prior exposure to a hypo-methylating agent. Avelumab was dosed at 3 mg/kg for the first 7 patients and at 10 mg/kg for the subsequent 12 patients. The most common grade greater than or equal to 3 treatment-related AEs were neutropenia and anemia in 2 patients each; 2 patients experienced immune-related AEs of grade-2 and grade-3 pneumonitis, respectively. The overall CR rate was 10.5 %, and both were complete remission with residual thrombocytopenia. The median OS was 4.8 months. Bone marrow blasts were analyzed for immune-related markers by mass cytometry and demonstrated significantly higher expression of PD-L2 compared with PD-L1 both pre-therapy and at all time-points during therapy, with increasing PD-L2 expression on therapy. The authors concluded that although the combination of azacitidine and avelumab was well-tolerated, clinical activity was limited. High expression of PD-L2 on bone marrow blasts may be an important mechanism of resistance to anti-PD-L1 therapy in AML.
Adenoid Cystic Carcinoma
In a phase-II clinical trial, Ferrarotto et al (2023) examined the effectiveness of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC). Eligible patients had R/M ACC with progression within 6 months before enrollment. Treatment consisted of axitinib and avelumab. The primary endpoint was ORR per RECIST 1.1; secondary endpoints included PFS, OS, as well as toxicity. Simon's optimal 2-stage design tested the null hypothesis of ORR less than or equal to 5 % versus ORR greater than or equal to 20% at 6 months; greater than or equal to 4 responses in 29 patients would reject the null hypothesis. A total of 40 patients enrolled from July 2019 to June 2021; 28 were evaluable for efficacy (6 screen failures; 6 evaluable for safety only). The confirmed ORR was 18 % (95 % CI: 6.1 % to 36.9 %); there was 1 unconfirmed PR. Two patients achieved PR after 6 months; therefore, the ORR at 6 months was 14 %. The median follow-up time for surviving patients was 22 months (95 % CI: 16.6 to 39.1 months). The median PFS was 7.3 months (95 % CI: 3.7 months to 11.2 months), 6-month PFS rate was 57 % (95 % CI: 41 % to 78 %), and median OS was 16.6 months (95 % CI: 12.4 months to not reached months). Most common TRAEs included fatigue (62 %), hypertension (32 %), and diarrhea (32 %); 10 (29 %) patients had serious TRAEs, all grade-3; 4 patients (12 %) discontinued avelumab, and 9 patients (26 %) underwent axitinib dose reduction. The authors concluded that this study reached its primary endpoint with 4 or more PRs in 28 evaluable patients (confirmed ORR of 18 %). Moreover, these researchers stated that the potential added benefit of avelumab to axitinib in ACC needs further investigation.
Biliary Tract Cancer
Cousin et al (2022) stated that regorafenib has demonstrated marked clinical activity in patients with advanced biliary tract cancers (BTCs). Pre-clinical data suggested that this drug modulates anti-tumor immunity and is synergistic with immune checkpoint inhibition. In a multi-centric, single-arm, phase-II clinical trial, these researchers examined combined regorafenib-avelumab therapy for the treatment of in patients with BTC. Regorafenib was administered 3 weeks/4, 160 mg once-daily (QD); avelumab 10 mg/kg IV was given every 2 weeks, beginning at C1D15 until progression or unacceptable toxicity. The primary endpoint was the confirmed ORR under treatment, as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. The secondary endpoints included 1-year non-progression rate, PFS, and OS; safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1. A total of 34 patients were enrolled in 4 centers; 29 patients were assessable for effectiveness after central radiological review. The best response was PR for 4 patients (13.8 %), SD for 11 patients (37.9 %) and progressive disease for 14 patients (48.3 %). The median PFS and OS were 2.5 months (95 % CI: 1.9 to 5.5) and 11.9 months (95 % CI: 6.2 to NA), respectively. The most common grade-3 or grade-4 clinical AEs related to treatment were hypertension (17.6 %), fatigue (14.7 %) and maculopapular rash (11.8 %). High baseline levels of programmed cell death ligand 1 and of indoleamine 2, 3-dioxygénase expression were associated with improved outcomes. The authors concluded that regorafenib combined with avelumab exhibited anti-tumor activity in a subset of heavily pre-treated BTC population. Moreover, these researchers stated that more studies are needed in patients selected based on tumor micro-environment features.
Bladder Cancer and Other Urothelial Carcinomas
Bladder cancer makes up approximately 90% of urothelial carcinomas and is the sixth most common cancer in the US. When the disease has metastasized, the five-year survival rate is approximately 5%.
Bellmunt and colleagues (2017) noted that the treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guerin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins. Several checkpoint targets PD-L1, PD-1, and cytotoxic T-lymphocyte associated protein 4 [CTLA4]) have received the most attention in the treatment of bladder cancer, and have inhibitor agents either approved or in late-stage development. These researchers described the most recent data on agents that inhibit PD-L1 and PD-1. Atezolizumab is the only member of this class currently approved for the treatment of bladder cancer, but nivolumab, pembrolizumab, durvalumab, and avelumab all have positive results for this indication, and approvals are anticipated in the near future. The authors stated that research is ongoing to further categorize responses, define ideal patient populations, and examine combinations of checkpoint inhibitors to address multiple pathways in immune system functioning.
The FDA approved avelumab injection for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication was approved under accelerated approval based on tumor response and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
The efficacy and safety of avelumab was demonstrated in the urothelial carcinoma cohorts (N=242) of the JAVELIN Solid Tumor trial, a Phase I, open-label, single-arm, multicenter study of avelumab in the treatment of various solid tumors. The urothelial carcinoma cohorts enrolled patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen.
Patients with active or a history of central nervous system metastasis; other malignancies within the last five years; an organ transplant; conditions requiring therapeutic immune suppression; or active infection with HIV, hepatitis B or C were excluded. Patients with autoimmune disease, other than type 1 diabetes, vitiligo, psoriasis, or thyroid disease that did not require immunosuppressive treatment, were excluded. Patients were included regardless of their PD-L1 status. Patients received avelumab at a dose of 10 mg/kg intravenously over 60 minutes every two weeks until disease progression or unacceptable toxicity. Tumor response assessments were performed every six weeks, as assessed by an Independent Endpoint Review Committee (IERC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Efficacy outcome measures included confirmed overall response rate, (ORR) and duration of response (DOR). Efficacy measures were evaluated in patients who were followed for a minimum of both 13 weeks and 6 months at the time of data cut-off.
Out of the total 226 patients evaluable for efficacy, 44% had non-bladder urothelial carcinoma, including 23% of patients with upper tract disease; 83% of patients had visceral metastases; 34% of patients had liver metastases. Nine patients (4%) had disease progression following prior platinum-containing neoadjuvant or adjuvant therapy only. Forty-seven percent of patients only received prior cisplatin-based regimens, 32% received only prior carboplatin-based regimens, and 20% received both cisplatin and carboplatin-based regimens.
The most common adverse reactions (reported in at least 20% of patients) in patients with locally advanced or metastatic urothelial carcinoma were fatigue (41%), infusion-related reaction (30%), musculoskeletal pain (25%), nausea (24%), decreased appetite/hypophagia (21%) and urinary tract infection (21%).
In June 2020, the FDA approved Bavencio (avelumab) for the maintenance treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) that has not progressed with first-line platinum-containing chemotherapy. FDA approval was based on results from a phase 3, multicenter, multinational, randomized, open-label, parallel-arm study (JAVELIN Bladder 100) evaluating first-line maintenance treatment with avelumab plus best supportive care (BSC) versus BSC alone in patients with locally advanced or metastatic UC that did not progress with first-line platinum-containing chemotherapy as per RECIST v1.1. A total of 700 patients were randomly assigned to receive either avelumab (10 mg/kg intravenous infusion every 2 weeks) plus BSC (n=350) or BSC alone (n=350). The primary endpoint was overall survival (OS) in the two primary populations of all randomized patients and patients with PD-L1+ tumors defined by the Ventana SP263 assay. Secondary endpoints included progression- free survival, anti-tumor activity, safety, pharmacokinetics, immunogenicity, predictive biomarkers and patient-reported outcomes in the two primary populations. All primary and secondary endpoints are measured from the time of randomization, after completion of four to six cycles of chemotherapy. Patients with autoimmune disease or a medical condition that required immunosuppression were excluded. In PD-L1+ patients (n=358, 51%), the risk of death was reduced by 44% in the avelumab arm versus the control arm (p = <0.001). Consistent results were observed across the pre-specified subgroups of complete or partial response versus stable disease to first-line chemotherapy.1 In an exploratory analysis of patients with PD-L1-negative tumors (n=271, 39%), the OS hazard ratio was 0.85 (95% CI: 0.62, 1.18). A fatal adverse reaction (sepsis) occurred in one (0.3%) patient receiving avelumab plus BSC. Serious adverse reactions occurred in 28% of patients receiving avelumab plus BSC. Serious adverse reactions in ≥1% of patients included urinary tract infection (including kidney infection, pyelonephritis, and urosepsis) (6.1%), pain (including abdominal, back, bone, flank, extremity, and pelvic pain) (3.2%), acute kidney injury (1.7%), hematuria (1.5%), sepsis (1.2%), and infusion-related reaction (1.2%). The most common adverse reactions (≥20%) in patients receiving BAVENCIO plus BSC were fatigue, musculoskeletal pain, urinary tract infection, and rash (Pfizer, 2020).
Results from the Phase III JAVELIN Bladder 100 study, demonstrated a significant 7.1-month improvement in median OS with avelumab (Bavencio) as first-line maintenance plus best supportive care (BSC) compared with BSC alone: 21.4 months (95% CI: 18.9 to 26.1) vs. 14.3 months (95% CI: 12.9 to 17.9).This statistically significant improvement in OS represents a 31% reduction in the risk of death in the overall population (p = 0.001). OS was measured from the time of randomization, after patients were treated with four to six cycles of gemcitabine plus cisplatin or carboplatin over a period of approximately four months (Pfizer, 2020).
Breast Cancer
In a phase-Ib clinical trial, Dirix and associates (2018) evaluated the activity of avelumab in patients with metastatic breast cancer (MBC). Patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1; AEs were graded by NCI-CTCAE v4.0; membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx). A total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2 to 50 weeks and followed for 6 to 15 months. Patients were heavily pre-treated with a median of 3 prior therapies for metastatic or locally advanced disease. Grade greater than or equal to 3 treatment-related AEs (TRAEs) occurred in 13.7 % of patients, including 2 treatment-related deaths. The confirmed ORR was 3.0 % overall (1 CR and 4 PRs) and 5.2 % in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1- tumor-associated immune cells in the overall population (16.7 % versus 1.6 %) and in the TNBC subgroup (22.2 % versus 2.6 %). The authors concluded that the findings of this phase-I study showed that the anti-PD-L1 antibody avelumab has a safety profile that is considered generally manageable and tolerable, and showed modest clinical activity in a heavily pre-treated population of patients with MBC. Collectively, these data and those of other studies suggested that durable clinical benefit can be achieved with anti-PD-1/PD-L1 monotherapy in a subset of patients with MBC, particularly TNBC. Based on the results from single-agent immunotherapy in patients with MBC, studies of combination therapy that might increase the probability of treatment benefit are needed, and promising clinical activity in TNBC has been reported for a treatment regimen of atezolizumab administered in combination with taxane chemotherapy and of pembrolizumab in combination with eribulin mesylate in preliminary studies. These researchers noted that an ongoing phase-Ib/II clinical trial (JAVELIN Medley; NCT02554812), which includes a TNBC cohort, is currently examining the use of avelumab in combination with novel immunotherapies.
Chordoma
Fujii and colleagues (2016) noted that chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. These researchers examined avelumab as a potential therapy for chordoma. They investigated 4 chordoma cell lines, first for expression of PD-L1, and in-vitro for ADCC killing using natural killer (NK) cells and avelumab. PD-L1 expression was markedly up-regulated by interferon-gamma (IFN-γ) in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant up-regulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. The authors concluded that these findings suggested that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.
Colorectal Cancer
Cousin and colleagues (2021) noted that regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer (CRC) pre-clinical models. In a single-arm, multi-centric, phase-II clinical trial, regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed ORR under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year non-progression rate, PFS, and OS, safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1. A total of 48 patients were enrolled in 4 centers; 43 were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5 %) and progressive disease for 17 patients (39.5 %). The median PFS and OS were 3.6 months [95 % CI: 1.8 to 5.4] and 10.8 months (95 % CI: 5.9 to NA), respectively. The most common grade-3 or grade-4 AEs were palmar-plantar erythrodysesthesia syndrome (n = 14, 30% ), hypertension (n = 11, 23 %), and diarrhea (n = 6, 13 %). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 versus 3.7 months; p = 0.002) and OS (3.7 months versus not reached; p = 0.002). Increased tumor infiltration by CD8+ T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome. The authors concluded that these findings showed modest efficacy indicating that further studies are needed to establish successful immunotherapy strategies for CRC. A new cohort in the REGOMUNE study will examine the combination of regorafenib with avelumab in patients with CRC selected on the basis of the tumor-associated macrophages infiltration level. Moreover, these researchers stated that the main drawback of this study was its non-randomized design.
Martini et al (2023) noted that the re-challenge strategy is based on the concept that a subset of patients with RAS wild-type (WT) metastatic CRC (mCRC) could still benefit of epidermal growth factor receptor (EGFR) inhibition, after progression to an anti-EGFR based-therapy. These investigators carried out a pooled analysis of 2 prospective, phase-II clinical trials to examine the role of re-challenge in 3d-line mCRC patients with RAS/BRAF WT baseline circulating tumor DNA (ctDNA). Individual data of 33 and 13 patients from the CAVE Trial and the CRICKET Trial that received as 3rd-line therapy cetuximab re-challenge were collected. OS, PFS, ORR, stable disease (SD) of greater than 6 months were calculated; AEs were reported. For the whole 46 patient population, median PFS (mPFS) was 3.9 months (95 % CI: 3.0 to 4.9 months) with median OS (mOS) of 16.9 months (95 % CI: 11.7 to 22.1 months). For CRICKET patients, mPFS was 3.9 months (95 % CI: 1.7 to 6.2 months); mOS was 13.1 months (95 % CI: 7.3 to 18.9 months) with OS rates at 12, 18, and 24 months of 62 %, 23 %, and 0 %, respectively. For CAVE patients, mPFS was 4.1 months (95 % CI: 3.0 to 5.2 months); mOS was 18.6 months (95 % CI: 11.7 to 25.4 months) with OS rates at 12, 18, 24 months of 61 %, 52 %, 21 %, respectively. Skin rash was more frequently reported in the CAVE Trial (87.9 % versus 30.8 %; p = 0.001), whereas a increased incidence of hematological toxicities was observed in the CRICKET Trial (53.8 % versus 12.1 %; p = 0.003). The authors concluded that 3rd-line cetuximab re-challenge in combination with either irinotecan or avelumab in RAS/BRAF WT ctDNA mCRC patients represents a promising therapy. Furthermore, these researchers stated that a randomized phase-II clinical trial, which compares cetuximab single agent or in combination with avelumab as re-challenge therapy in mCRC patients with plasma RAS/BRAF WT ctDNA, has been recently started (the CAVE‐2 GOIM Trial).
The authors stated that this study had several drawbacks. First, the small sample sizes (n = 33 in the CAVE Trial and n = 13 in the CRICKET Trial) rendered these findings as hypothesis-generating. Second, while the inclusion criteria of the 2 studies and the patients' characteristics were similar, there was an imbalance in the number of patients treated with cetuximab plus avelumab (n = 33) compared with cetuximab plus irinotecan (n = 13). Third, since these results were derived from subgroup analysis of 2 single-arm, phase-II clinical trials, larger, prospective studies are needed.
Endometrial Cancer
Maiorano et al (2022) noted that endometrial cancer (EC) represents the 6th most common female tumor. In the advanced setting, the prognosis is dismal with limited therapeutic options. Platinum-based chemotherapy represents the actual standard of care (SOC) in 1st-line chemotherapy; however, no standard 2nd-line chemotherapy is approved, with less than 25 % of patients responding to 2nd-line chemotherapy. In the past decade, immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many solid tumors. These investigators carried out a review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. They searched Embase, Medline, Cochrane database, and conference abstracts from international societies, up to November 2021. Clinical trials employing ICIs in advanced EC, written in English, were included. Reviews, letters, and commentaries were excluded. The ORR, PFS, OS, and safety (number and grade of TRAEs) were evaluated. A total of 15 studies (1,627 patients) were included: 14 non-randomized phase I/II clinical trials and 1 randomized phase III clinical trial. Anti-PD1 (pembrolizumab, nivolumab, dostarlimab) and anti-PD-L1 agents (avelumab, atezolizumab, durvalumab) were administered as single agents; pembrolizumab and nivolumab were combined with the tyrosine-kinase inhibitors (TKI) lenvatinib and cabozantinib, respectively; and durvalumab was associated with anti-CTLA4 tremelimumab. A total of 4 studies selected only MSI patients. Single agents determined an ORR from 26.7 % to 58 % among MSI patients, from 3 % to 26.7 % among microsatellite stable (MSS) patients. DCR ranged from 53.5 % to 88.9 % in MSI, 31.4 % to 35.2 % in MSS patients. The combination of TKI and ICIs determined 32 % to 63.6 % of ORR in all-comers, 32 % to 36.2 % in MSS patients; 54.2 % to 76 % of patients developed TRAEs. The combination of ICIs and TKI achieved a higher toxicity rate than single agents (G3 or higher TRAEs 88.9 %). The authors concluded that ICIs represented an effective option for pre-treated advanced EC patients with a tolerable profile. Given the encouraging results in MSI patients, every woman diagnosed with EC should be examined for MS status. In MSS women, the combination of ICIs and TKI was more effective than monotherapy, notwithstanding safety concerns. PD-L1 could not predict ICI response, whereas other biomarkers such as MSI and tumor mutational burden appeared more accurate. Moreover, these researchers stated that ongoing randomized trials will further clarify the role of these therapeutic options.
The authors stated that this analysis had several drawbacks. First was the heterogeneity of the included trials, in terms of treated patients, biomarker selection, and endpoints. Second, these researchers did not carry out a quantitative comparative meta-analysis due to the non-comparative design of the almost totality of included trials; thus, the conclusions drawn regarding the safety and effectiveness of ICIs in EC from this study were only descriptive. Third, OS data were incomplete: a longer follow-up is needed to clarify the real impact on survival of ICIs for EC patients. Fourth, in many studies, safety data were partially reported. Data from randomized trials comparing ICIs with other treatments are needed to validate safety and effectiveness outcomes.
Pignata et al (2023) noted that the addition of immunotherapy to 1st-line chemotherapy might improve outcomes for patients with advanced or recurrent endometrial cancer. In a randomized, open-label, phase-II clinical trial (the MITO END-3 Trial), these researchers compared carboplatin and paclitaxel versus avelumab plus carboplatin and paclitaxel as 1st-line treatment with avelumab given concurrent to chemotherapy and as maintenance after the end of chemotherapy. This trial was carried out at 31 cancer centers, hospitals, and universities in Italy. Eligible patients were aged 18 years or older with histologically confirmed advanced (FIGO stage III to IV) or recurrent endometrial cancer, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1, and no previous systemic anti-cancer therapy as primary treatment for advanced or metastatic disease. Subjects were randomly assigned (1:1) using a computerized minimization procedure stratified by center, histology, and stage at study entry, to either receive carboplatin (area under the curve [AUC] 5 mg/ml × min) and paclitaxel (175 mg/m2; standard group) intravenously every 3 weeks for 6 to 8 cycles or avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel (experimental group) every 3 weeks and then every 2 weeks as a single maintenance treatment after the end of chemotherapy until disease progression or unacceptable toxicity. Patients, treating clinicians, and those evaluating radiological examinations were not masked to study treatment. The primary endpoint was investigator-assessed PFS, measured in the ITT population. Patients who received at least 1 dose of study drug were included in the safety analysis. Experimental group superiority was tested with 80 % power and 1-tailed α 0.20. From April 9, 2018, to May 13, 2021, a total of 166 women were examined for eligibility and 39 were excluded; 125 eligible patients were randomly assigned to receive carboplatin and paclitaxel (n = 62) or avelumab plus carboplatin and paclitaxel (n = 63) and included in the ITT population. The median follow-up was 23.3 months (inter-quartile range [IQR] 13.2 to 29.6) and was similar between the 2 groups; 91 PFS events were reported, with 49 events in 62 patients in the standard group and 42 events in 63 patients in the experimental group. The median PFS was 9.9 months (95 % CI: 6.7 to 12.1) in the standard group and 9.6 months (7.2 to 17.7) in the experimental group (HR of progression or death 0.78 [60 % CI: 0.65 to 0.93]; 1-tailed p = 0·085). Serious AEs were reported more frequently in the experimental group (24 versus 7 AEs in the standard group); neutrophil count decrease was the most frequent grade 3 to 4 AE (19 [31 %] of 61 patients in the experimental group versus 26 [43 %] of 61 patients in the standard group); 2 deaths occurred in the experimental group during treatment (1 respiratory failure following severe myositis [possibly related to treatment] and 1 cardiac arrest [not related to treatment]). The authors concluded that the addition of avelumab to 1st-line chemotherapy deserves further testing in patients with advanced or recurrent endometrial cancer, although consideration of mismatch repair status is needed.
Gastro-Intestinal Cancers
Alsina and colleagues (2016) noted that gastric cancer (GC) is a major world-wide health problem. It is the 3rd leading cause of death from cancer. The treatment of advanced GC by chemotherapy has limited efficacy. The addition of some targeted therapies like trastuzumab and ramucirumab have added a modest benefit, but only in human epidermal growth factor receptor 2 (ERBB2 or HER2)-positive patients and in the 2nd-line setting, respectively. The development of new and effective therapeutic strategies must consider the genetic complexity and heterogeneity of GC; prognostic and predictive biomarkers should be identified for clinical implementation. Immune deregulation has been associated with some GC subtypes, especially those that are associated with virus infection and those with a high mutational rate. Different mechanisms to prevent immunologic escape have been characterized during the past few years; especially the PD-1/PD-L1 inhibitors pembrolizumab, avelumab, durvalumab and atezolizumab have shown early sign of efficacy. The authors concluded that immunotherapeutic strategies may provide new opportunities for GC patients.
Bilgin and co-workers (2017) noted that EGFR, HER2, and vascular endothelial growth factor (VEGF) targeted agents are currently used in gastric, esophageal and colorectal cancers. However, treatment outcomes are still poor in most gastro-intestinal (GI) cancers. Immune checkpoints are one of the most promising immunotherapy approaches. These researchers examined the safety and effectiveness of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancers in published or reported recent studies. They performed a literature search from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: "nivolumab", "pembrolizumab", "avelumab", "GI cancers" "anti-PD1 therapy" and "anti-PD-L1 therapy". The last search was on November 2, 2016. The most important limitation of this review was that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relied on phase I and II clinical trials. Currently, there are 2 anti-PD-1 (nivolumab and pembrolizumab) and 1 anti-PDL1 (atezolizumab) agents approved by FDA. After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer and non-squamous lung cancer, trials which evaluate immune checkpoint blockade in GI cancers are ongoing. Early results of trials have been promising and encouraging for patients with advanced stage gastro-esophageal cancer. According to early results of published trials, response to anti-PD1/PD-L1 agents appeared to be associated with tumor PD-L1 levels. According to 2 recently published phase II clinical trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI) positive advanced colorectal cancer. However, several phase II/III trials are still ongoing. The authors concluded that both pembrolizumab and nivolumab showed promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic colorectal cancer.
Bang and colleagues (2018) stated that there currently are no internationally recognized treatment guidelines for patients with advanced gastric cancer/gastro-esophageal junction cancer (GC/GEJC) in whom 2 prior lines of therapy have failed. The randomized, phase-III clinical trial (JAVELIN Gastric 300) compared avelumab versus physician's choice of chemotherapy as 3rd-line therapy in patients with advanced GC/GEJC. Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomized to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care (BSC). The primary end-point was OS; secondary end-points included PFS, ORR, and safety. A total of 371 patients were randomized. The trial did not meet its primary end-point of improving OS (median of 4.6 versus 5.0 months; hazard ratio [HR] = 1.1 [95 % CI: 0.9 to 1.4]; p = 0.81); or the secondary end-points of PFS (median of 1.4 versus 2.7 months; HR = 1.73 [95 % CI: 1.4 to 2.2]; p > 0.99) or ORR (2.2 % versus 4.3 %) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9 %) and 131 patients (74.0 %) in the avelumab and chemotherapy arms, respectively. Grade greater than or equal to 3 TRAEs occurred in 17 patients (9.2 %) in the avelumab-arm and in 56 patients (31.6 %) in the chemotherapy-arm. The authors concluded that treatment of patients with GC/GEJC with single-agent avelumab in the 3rd-line setting did not result in an improvement in OS or PFS compared to chemotherapy; avelumab showed a more manageable safety profile than chemotherapy.
Head and Neck Cancer
Merlano and colleagues (2018) noted that 2nd-line treatment of platinum-resistant relapsed/metastatic (R/M) head and neck cancer (HNC) is a currently unmet clinical need. Clinical trials showed improvement in OS and quality of life (QOL) of R/M-HNC patients treated with anti-PD-1 regardless of the number of prior chemotherapy lines; however, the percentage of long-term survivors remains limited. These researchers tested the hypothesis that attacking the tumor micro-environment at multiple levels can increase immunogenicity of R/M-HNC without worsening the safety profile of immune checkpoint inhibitors. In this open-label, multi-center, single-arm, phase Ib/II clinical trial, R/M-HNC patients pre-treated with at least 1 line of chemotherapy containing platinum, fluorouracil, and cetuximab will receive a daily metronomic dose of 50 mg cyclophosphamide without a drug-free break, 10 mg/kg avelumab on day 1 and every other week until progression, and a single fraction of 8 Gy radiotherapy on day 8. The authors concluded that the treatment protocol aims to reverse immune evasion of the tumor through a radiotherapy-induced self-vaccination effect, suppression of CD4+ CD25+ FoxP3+ regulatory T-cell function by metronomic cyclophosphamide, and effector T-cell re-activation owing to the inhibition of the PD-1-PD-L1 axis by avelumab. The immunologic interplay induced by the proposed combined treatment may theoretically improve the activity of avelumab without increasing its toxicity profile. Finally, an ancillary translational study will be extended to all the patients' population.
In a randomized, double-blind, placebo-controlled, multi-center, phase-III clinical trial, Lee and colleagues (2021) examined if the addition of avelumab (anti-PD-L1) to chemoradiotherapy could improve treatment outcomes for patient with unresected locally advanced squamous cell carcinoma (SCC) of the head and neck. Subjects were recruited from 196 hospitals and cancer treatment centers in 22 countries. Patients aged 18 years or older, with histologically confirmed, previously untreated, locally advanced squamous cell carcinoma of the oropharynx, hypopharynx, larynx, or oral cavity (unselected for PD-L1 status), an ECOG performance status score of 0 or 1, and who could receive chemoradiotherapy were eligible. Patients were randomly assigned (1:1) centrally by means of stratified block randomization with block size 4 (stratified by human papillomavirus [HPV] status, tumor stage, and nodal stage, and performed by an interactive response technology system) to receive 10 mg/kg avelumab intravenously every 2 weeks plus chemoradiotherapy (100 mg/m2 cisplatin every 3 weeks plus intensity-modulated radiotherapy [IMRT] with standard fractionation of 70 Gy [35 fractions during 7 weeks]; avelumab group) or placebo plus chemoradiotherapy (placebo group). This was preceded by a single 10 mg/kg avelumab or placebo lead-in dose given 7 days previously and followed by 10 mg/kg avelumab or placebo every 2 weeks maintenance therapy for up to 12 months. The primary endpoint was PFS by investigator assessment per modified RECIST, version 1.1, in all randomly assigned patients; and AEs were evaluated in patients who received at least 1 dose of avelumab or placebo. Between December 12, 2016, and January 29, 2019, from a total of 907 patients screened, 697 patients were randomly assigned to the avelumab group (n = 350) or the placebo group (n = 347). Median follow-up for PFS was 14.6 months (inter-quartile range 8.5 to 19.6) in the avelumab group and 14.8 months (11.6 to 18.8) in the placebo group. Median PFS was not reached (95 % CI: 16.9 months to not estimable) in the avelumab group and not reached (23.0 months to not estimable) in the placebo group (stratified HR 1.21 [95 % CI: 0.93 to 1.57] favoring the placebo group; 1-sided, p = 0·92). The most common grade-3 or worse treatment-related AEs were neutropenia (57 [16 %] of 348 patients in the avelumab group versus 52 [15 %] of 344 patients in the placebo group), mucosal inflammation (50 [14 %] versus 45 [13 %]), dysphagia (49 [14 %] versus 47 [14 %]), and anemia (41 [12 %] versus 44 [13 %]). Serious treatment-related AEs occurred in 124 (36 %) patients in the avelumab group and in 109 (32 %) patients in the placebo group. Treatment-related deaths occurred in 2 (1 %) patients in the avelumab group (due to general disorders and site conditions, and vascular rupture) and 1 (less than 1 %) in the placebo group (due to acute respiratory failure). The authors concluded that the primary objective of prolonging PFS with avelumab plus chemoradiotherapy followed by avelumab maintenance in patients with locally advanced SCC of the head and neck was not met. These findings may help inform the design of future trials examining the combination of immune checkpoint inhibitors plus chemoradiation.
Poulose and Kainickal (2022) noted that the outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal. A relatively new therapeutic option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using ICIs. The safety profile and anti-tumor activity of these agents showed in early phase clinical trials paved the way to the initiation of several promising phase-III clinical trials in the field. In a systematic review, these investigators examined the evidence on the effectiveness of ICIs in HNSCC, based on published phase-III clinical trials. They searched PubMed, Cochrane Library, Embase, and Scopus to identify studies examining immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC). These researchers employed a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-3 clinical trial. A sensitive search filter was used to limit their findings to randomized controlled trials (RCTs). A total of 5 phase-III clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: 4 in R/M HNSCC and 1 in LAHNSCC. In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the 2nd-line treatment setting compared to the SOC (standard single-agent systemic therapy). While the net gain in OS with nivolumab was 2.4 months (HR = 0.69, p = 0.01), that with pembrolizumab was 1.5 months (HR = 0.80 nominal p = 0.0161). The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes. In the 1st-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 months (HR = 0.77, p = 0.0034) in the overall population and a net gain in OS of 4.2 months in the PD-L1 positive (combined positive score greater than 20) population compared to SOC (EXTREME regime). In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also showed statistically significant improvement in survival compared to EXTREME. In LAHNSCC, immunotherapy using avelumab along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy. Moreover, these researchers noted that in REACH, the superiority of avelumab in combination with RT-cetuximab compared to cisplatin -RT and/or to RT-cetuximab alone is being investigated. In addition, EACH, a randomized phase-II clinical trial among R/M HNSCC is examining the superiority of avelumab and cetuximab combination compared to avelumab monotherapy. The authors concluded that ongoing clinical trials may better define the role of ICIs in R/M HNSCC and LAHNSCC in the future.
Hodgkin Lymphoma
Desai and Ansell (2021) noted that classic Hodgkin lymphoma (cHL) is curable with chemotherapy but relapses occur in approximately 30 % of cases. Novel agents, including brentuximb vedotin (BV) and PD-1 inhibitors, alone or in combination with chemotherapy, have encouraging activity in newly diagnosed and relapsed/refractory cHL, confirming that the use of agents that target tumor cells or the tumor micro-environment are promising strategies to improve patient outcomes. The field of immunotherapy in cHL is now moving toward combinations of PD-1 inhibitors with other immunological agents such as cytotoxic T- lymphocyte associated protein-4 (CTLA-4) inhibitors, newer PD-1 inhibitors such as sintilimab, tislelizumab, avelumab and camrelizumab, bi-specific antibodies such as AFM-13, cellular therapies using CD30 chimeric antigen T-cells (CD30.CART) and anti-CD25 antibody-drug conjugates such as camidanlumab tesirine (cami-T).
Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Hodgkin lymphoma” (Version 4.2021) does not mention avelumab as a therapeutic option.
Kidney Cancer (Renal Cell Carcinoma)
In an open-label, dose-finding and dose-expansion, phase-Ib clinical trial, Choueiri and colleagues (2018) reported preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for 2nd-line treatment of advanced renal cell carcinoma (RCC), in treatment-naive patients with advanced RCC. The JAVELIN Renal 100 study is an ongoing open-label, multi-center, dose-finding, and dose-expansion, phase-Ib clinical trial, done in 14 centers in the USA, UK, and Japan. Eligible patients were aged 18 years or older (greater than or equal to 20 years in Japan) and had histologically or cytologically confirmed advanced RCC with clear-cell component, life expectancy of at least 3 months, an ECOG performance status of 1 or less, received no previous systemic treatment for advanced RCC, and had a resected primary tumor. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice-daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice-daily. Based on the pharmacokinetic data from the dose-finding phase, 10 additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary end-point was dose-limiting toxicities (DLTs) in the first 4 weeks (2 cycles) of treatment with avelumab plus axitinib. Safety and anti-tumor activity analyses were done in all patients who received at least 1 dose of avelumab or axitinib. Between October 30, 2015, and September 30, 2016, these investigators enrolled 6 patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One DLT of grade 3 proteinuria due to axitinib was reported among the 6 patients treated during the dose-finding phase. At the cut-off date (April 13, 2017), 6 (100 %, 95 % CI: 54 to 100) of 6 patients in the dose-finding phase and 26 (53 %, 38 to 68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58 %, 44 to 71] of all 55 patients); 32 (58 %) of 55 patients had grade 3 or worse TRAEs, the most frequent being hypertension in 16 (29 %) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysesthesia syndrome in 4 (7 %) patients each; 6 (11 %) of 55 patients died before data cut-off, 5 (9 %) due to disease progression and 1 (2 %) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose (MTD) established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice-daily. The authors concluded that the safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced RCC appeared to be manageable and consistent with that of each drug alone, and the preliminary data on anti-tumor activity are encouraging. These researchers noted that a phase-III clinical trial is assessing avelumab and axitinib compared with sunitinib monotherapy.
In May 2019, the FDA approved Bavencio (avelumab) plus Inlyta (axitinib) combination for the first-line treatment of advanced renal cell carcinoma (RCC), independent of programmed death ligand 1 (PD-L1) expression. FDA approval was based on outcomes from the Phase III JAVELIN Renal 101 study (NCT02684006), in which the combination significantly lowered risk of disease progression or death by 31% and extended progression-free survival (PFS) by 5.4 months for patients in the intent-to-treat (ITT) population with advanced RCC compared with sunitinib. The ITT population included patients regardless of PD-L1 expression and across IMDC (International Metastatic Renal Cell Carcinoma Database) prognostic risk groups (favorable 21%, intermediate 62% and poor 16%) (Motzer et al, 2019; Pfizer, 2019).
The JAVELIN Renal 101 study is a randomized (1:1), multicenter, open-label, Phase III study which compared the safety and efficacy of avelumab in combination with axitinib to the standard-of-care sunitinib in 886 patients with untreated advanced RCC regardless of tumor PD-L1 expression [intent-to-treat (ITT) population]. Patients with autoimmune disease or conditions requiring systemic immunosuppression were excluded. Patients were randomized to receive avelumab (10 mg/kg of body weight) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily (n=442) or sunitinib (50 mg) orally once daily for 4 weeks followed by 2 weeks off (6-week cycle) (n=444) until radiographic or clinical progression or unacceptable toxicity occurred. The two independent primary end points were progression-free survival (PFS) and overall survival (OS) among patients with PD-L1-positive tumors. A key secondary end point was PFS in the overall population; other end points included objective response and safety. The major efficacy outcome measures of PFS was assessed by a Blinded Independent Central Review (BICR) using RECIST v1.1 and OS in patients with PD-L1-positive tumors using a clinical trial assay (PD-L1 expression level ≥1%). If PFS was statistically significant in patients with PD-L1-positive tumors, it was then tested in the ITT population. Assessment of tumor status was performed at baseline, after randomization at 6 weeks, then every 6 weeks thereafter up to 18 months after randomization, and every 12 weeks thereafter until documented confirmed disease progression by BICR. The outcomes of the study found that among the 560 patients with PD-L1-positive tumors (63.2%), the median PFS was 13.8 months with avelumab plus axitinib, as compared with 7.2 months with sunitinib (p<0.001); in the overall population, the median PFS was 13.8 months, as compared with 8.4 months (p<0.001). Among the patients with PD-L1-positive tumors, the objective response rate was 55.2% with avelumab plus axitinib and 25.5% with sunitinib; at a median follow-up for overall survival of 11.6 months and 10.7 months in the two groups, 37 patients and 44 patients had died, respectively. Adverse events during treatment occurred in 99.5% of patients in the avelumab-plus-axitinib group and in 99.3% of patients in the sunitinib group; these events were grade 3 or higher in 71.2% and 71.5% of the patients in the respective groups. Patients who tolerated axitinib 5 mg twice daily without Grade 2 or greater axitinib-related adverse events for 2 consecutive weeks could increase to 7 mg and then subsequently to 10 mg twice daily. Axitinib could be interrupted or reduced to 3 mg twice daily and subsequently to 2 mg twice daily to manage toxicity. Since PFS was found to be statistically significant in patients with PD-L1-positive tumors, it was then tested in the ITT population, to which a statistically significant improvement in PFS in the ITT population was also demonstrated. The conclusion of the JAVELIN Renal 101 study was that PFS was significantly longer with avelumab plus axitinib than with sunitinib among patients who received these agents as first-line treatment for advanced renal cell carcinoma (Motzer et al, 2019; Pfizer, 2019, EMD Serono, 2020).
Adverse reactions (greater than or equal to 20%) for avelumab with axitinib in RCC include diarrhea, fatigue, hypertension, musculoskeletal pain, nausea, mucositis, palmar-plantar erythrodysesthesia, dysphonia, decreased appetite, hypothyroidism, rash, hepatotoxicity, cough, dyspnea, abdominal pain, and headache.
Leiomyosarcoma and Liposarcoma
Wagner et al (2022) stated that leiomyosarcoma and liposarcoma frequently express PD-L1 but are generally resistant to PD-1/PD-L1 inhibition (immune checkpoint inhibitor). Trabectedin is FDA-approved for leiomyosarcoma and liposarcoma. In an open-label, single-arm, phase I/II clinical trial, these researchers examined the safety and effectiveness of trabectedin with anti-PD-L1 antibody avelumab in patients with advanced leiomyosarcoma and liposarcoma. The phase I portion examined safety and feasibility of trabectedin (1, 1.2, and 1.5 mg/m2) with avelumab at standard dosing. Primary endpoint of the phase II portion was ORR by RECIST 1.1. Correlative studies included T-cell receptor sequencing (TCRseq), multiplex IHC, and tumor gene expression. A total of 33 patients were evaluable: 24 with leiomyosarcoma (6 uterine and 18 non-uterine) and 11 with liposarcoma. In the phase 1 portion, DLT were observed in 2 of 6 patients at both trabectedin 1.2 and 1.5 mg/m2. The recommended phase 2 dose (RP2D) was 1.0 mg/m2 trabectedin and 800-mg avelumab. Of 23 patients evaluable at RP2D, 3 (13 %) had PR and 10 (43 %) had SD as best response. Six-month PFS was 52 %; median PFS was 8.3 months. Patients with PR had higher Simpson Clonality score on TCRseq from peripheral blood mononuclear cells versus those with SD (0.182 versus 0.067, p = 0.02) or progressive disease (0.182 versus 0.064, p = 0.01). The authors concluded that although the trial did not meet the primary ORR endpoint, PFS compared favorably with prior studies of trabectedin warranting further investigation.
Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer, with fewer than half of patients surviving more than one year and fewer than 20% surviving beyond five years. While early-stage disease can be cured with surgical resection and radiotherapy (RT), patients with advanced MCC usually have poor prognosis. Adjuvant radiation therapy (RT) to the primary excision site and regional lymph node bed may improve loco-regional control. However, newer studies reported that patients with biopsy-negative sentinel lymph nodes (SLNs) may not benefit from regional RT. Advanced MCC currently lacks an effective treatment as responses to chemotherapy are not durable. Recent research suggested that immunotherapy targeting the programmed cell death receptor 1 [PD-1] (found on activated T and B cells and macrophages)/programmed cell death ligand 1 [PD-L1] (found on the surface of tumor cells) checkpoint holds promise in treating advanced MCC and may provide durable responses in a portion of patients. In addition, high-throughput sequencing studies have demonstrated significant differences in the mutational profiles of tumors with and without the Merkel cell polyomavirus (MCPyV). An important secondary end-point in the ongoing immunotherapy clinical studies for MCC will be examining if there is a response difference between the virus-positive MCC tumors that typically lack a large mutational burden and the virus-negative tumors that have a large number of somatic mutations and predicted tumor neo-antigens. Sequencing studies have failed to identify a highly recurrent activated driver pathway in the majority of MCC tumors. This may explain why targeted therapies could demonstrate exceptional responses in case reports; but failed when treating all comers with MCC. Stratification of patients in future clinical trials based on tumor viral status should be considered since virus-negative tumors are more likely to harbor activating driver mutations (Cassler et al, 2016).
In a multi-center, international, prospective, single-group, open-label, phase II clinical trial, Kaufman and colleagues (2016) evaluated treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV MCC that had progressed after cytotoxic chemotherapy. Patients with stage IV chemotherapy-refractory, histologically confirmed MCC (aged greater than or equal to 18 years) were enrolled from 35 cancer treatment centers and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate hematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, hematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or MCPyV status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary end-point was confirmed objective response (complete response [CR] or partial response [PR]) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least 1 dose of study drug (the modified intention-to-treat population). Between July 25, 2014, and September 3, 2015, a total of 88 patients were enrolled and received at least 1 dose of avelumab. Patients were followed-up for a median of 10.4 months (IQR 8.6 to 13.1). The proportion of patients who achieved an objective response was 28 (31.8 % [95.9 % confidence interval [CI]: 21.9 to 43.1]) of 88 patients, including 8 CRs and 20 PRs. Responses were ongoing in 23 (82 %) of 28 patients at the time of analysis; 5 grade-3 treatment-related adverse events (AEs) occurred in 4 (5 %) patients: lymphopenia in 2 patients, blood creatine phosphokinase increase in 1 patient, aminotransferase increase in 1 patient, and blood cholesterol increase in 1 patient; there were no treatment-related grade-4 AEs or treatment-related deaths. Serious treatment-related AEs were reported in 5 patients (6 %): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n = 1 each). The authors concluded that avelumab was associated with durable responses, most of which are still ongoing, and was well-tolerated; hence, avelumab represents a new therapeutic option for advanced MCC.
Terheyden and Becker (2017) stated that patients with stage IIIB und IV metastatic MCC (mMCC), who are not suitable candidates for surgery or RT, are unlikely to achieve lasting remission or tumor control by chemo- or targeted-therapy. In the majority of cases, the tumor arises from viral carcinogenesis associated with the MCPyV. In MCPyV-negative tumors with a presumable ultra-violet carcinogenesis, a high mutational burden resulting in neo-antigens was discovered. In 2 phase II clinical trials in either the 1st- or 2nd-line setting, a high response rate was observed for immunotherapies with antibodies blocking the PD-1 and PD-L1 immune checkpoints. The response rate was 56 % with the anti-PD-1 inhibitor pembrolizumab as a 1st-line and 32 % with the anti-PD-L1 antibody avelumab used as 2nd-line therapy. Both treatments were well-tolerated. Treatment response was rapid and in most cases maintained during follow-up, which, however, is still rather short. Whether the MCPyV or the PD-L1 status is predictive for treatment response and progression-free survival (PFS) is still ambiguous. Additionally, clinical criteria for patient selection for immunotherapy of mMCC have not yet been defined. The authors concluded that PD-1/PD-L1 inhibition can be regarded as new 1st-line therapy for patients with mMCC not amendable by surgery and/or RT.
The U.S. Food and Drug Administration (FDA) approved avelumab (Baencio) injection, a human anti-PD-1 antibody, for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (mMCC) (Pfizer, 2017). This indication was approved under accelerated approval based on tumor response and duration of response. The FDA states that continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
By binding to PD-L1, avelumab is thought to prevent tumor cells from using PD-L1 for protection against lymphocytes, exposing them to anti-tumor responses. Avelumab has been shown to induce antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.
The efficacy and safety of avelumab was demonstrated in the JAVELIN Merkel 200 trial, an open-label, single-arm, multi-center study conducted in 88 patients with histologically confirmed metastatic MCC whose disease had progressed on or after chemotherapy administered for distant metastatic disease (Pfizer, 2017) (Kaufman, et al., 2016, described above). Sixty-five percent of patients were reported to have had one prior anti-cancer therapy for metastatic MCC and 35% had two or more prior therapies. The major efficacy outcome measures were confirmed overall response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 as assessed by a blinded independent central review committee (IRC) and IRC-assessed duration of response.
The trial excluded patients with autoimmune disease; medical conditions requiring systemic immunosuppression; prior organ or allogenic stem cell transplantation; prior treatment with anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibodies; CNS metastases; infection with HIV, hepatitis B or hepatitis C; or ECOG performance score greater than or equal to two (Pfizer, 2017). Patients received avelumab 10 mg/kg as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.
The overall response rate (ORR) was 33% (95% confidence interval [CI]: 23.3–43.8%) (Pfizer, 2017). Eleven percent of patients experienced a complete response (95% CI: 6.6-19.9%) and 22% of patients experienced a partial response (95% CI: 13.5-31.7%). Tumor responses were durable, with 86% of responses lasting for at least six months (n=25). Forty-five percent of responses lasted at least 12 months (n=13).1 Duration of response ranged from 2.8 to over 23.3 months.
The most common adverse reactions (reported in at least 20% of patients) included fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reactions (22%), rash (22%), decreased appetite (20%) and peripheral edema (20%) (Pfizer, 2017).
The warnings and precautions for avelumab include immune-mediated adverse reactions (such as pneumonitis, hepatitis, colitis, endocrinopathies, nephritis and renal dysfunction, and other adverse reactions), infusion-related reactions and embryo-fetal toxicity (Pfizer, 2017).
Avelumab can cause immune-mediated pneumonitis, including fatal cases (Pfizer, 2017). The product labeling recommends monitoring patients for signs and symptoms of pneumonitis and evaluate suspected cases with radiographic imaging. Corticosteroids should be administered for Grade 2 or greater pneumonitis. Avelumab should be withheld for moderate (Grade 2) and permanently discontinued for severe (Grade 3), life-threatening (Grade 4), or recurrent moderate (Grade 2) pneumonitis. Pneumonitis occurred in 1.2% (21/1738) of patients, including one (0.1%) patient with Grade 5, one (0.1%) with Grade 4, and five (0.3%) with Grade 3.
Avelumab can cause immune-mediated hepatitis, including fatal cases (Pfizer, 2017). The labeling recommends monitoring patients for abnormal liver tests prior to and periodically during treatment. Corticosteroids should be administered for Grade 2 or greater hepatitis. Avelumab should be withheld for moderate (Grade 2) immune-mediated hepatitis until resolution and permanently discontinued for severe (Grade 3) or life-threatening (Grade 4) immune-mediated hepatitis. Immune-mediated hepatitis was reported in 0.9% (16/1738) of patients, including two (0.1%) patients with Grade 5 and 11 (0.6 %) with Grade 3.
Avelumab can cause immune-mediated colitis (Pfizer, 2017). Patients should be monitored for signs and symptoms of colitis. Corticosteroids should be administered for Grade 2 or greater colitis. Avelumab should be withheld until resolution for moderate or severe (Grade 2 or 3) colitis and permanently discontinued for life-threatening (Grade 4) or recurrent (Grade 3) colitis upon re-initiation of avelumab. Immune-mediated colitis occurred in 1.5% (26/1738) of patients, including seven (0.4%) with Grade 3.
Avelumab can cause immune-mediated endocrinopathies, including adrenal insufficiency, thyroid disorders, and type 1 diabetes mellitus (Pfizer, 2017). The labeling recommends monitoring patients for signs and symptoms of adrenal insufficiency during and after treatment and administering corticosteroids as appropriate. Avelumab should be withheld for severe (Grade 3) or life-threatening (Grade 4) adrenal insufficiency. Adrenal insufficiency was reported in 0.5% (8/1738) of patients, including one (0.1%) with Grade 3.
The labeling states that thyroid disorders can occur at any time during treatment (Pfizer, 2017). Patients should be monitored for changes in thyroid function at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation. Hypothyroidism should be managed with hormone replacement therapy and hyperthyroidism with medical management. Avelumab should be withheld for severe (Grade 3) or life threatening (Grade 4) thyroid disorders. Thyroid disorders including hypothyroidism, hyperthyroidism, and thyroiditis were reported in 6% (98/1738) of patients, including three (0.2%) with Grade 3.
Type 1 diabetes mellitus, including diabetic ketoacidosis: patients should be monitored for hyperglycemia or other signs and symptoms of diabetes (Pfizer, 2017). Avelumab should be withheld and anti-hyperglycemics or insulin administered in patients with severe or life-threatening (Grade 3 or greater) hyperglycemia and treatment resumed when metabolic control is achieved. Type 1 diabetes mellitus without an alternative etiology occurred in 0.1% (2/1738) of patients, including two cases of Grade 3 hyperglycemia.
Avelumab can cause immune-mediated nephritis and renal dysfunction (Pfizer, 2017). Patients should be monitored for elevated serum creatinine prior to and periodically during treatment. Corticosteroids should be administered for Grade 2 or greater nephritis. Avelumab should be withheld for moderate (Grade 2) or severe (Grade 3) nephritis until resolution to Grade 1 or lower. Avelumab should be permanently discontinued for life-threatening (Grade 4) nephritis. Immune-mediated nephritis occurred in 0.1% (1/1738) of patients.
Avelumab can result in other severe and fatal immune-mediated adverse reactions involving any organ system during treatment or after treatment discontinuation (Pfizer, 2017). For suspected immune-mediated adverse reactions evaluate to confirm or rule out an immune-mediated adverse reaction and to exclude other causes. Depending on the severity of the adverse reaction, withhold or permanently discontinue avelumab, administer high-dose corticosteroids, and initiate hormone replacement therapy if appropriate. Resume avelumab when the immune-mediated adverse reaction remains at Grade 1 or lower following a corticosteroid taper. Permanently discontinue avelumab for any severe (Grade 3) immune-mediated adverse reaction that recurs and for any life-threatening (Grade 4) immune-mediated adverse reaction. The following clinically significant immune-mediated adverse reactions occurred in less than 1% of 1738 patients treated with avelumab: myocarditis with fatal cases, myositis, psoriasis, arthritis, exfoliative dermatitis, erythema multiforme, pemphigoid, hypopituitarism, uveitis, Guillain-Barré syndrome, and systemic inflammatory response.
Avelumab can cause severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions (Pfizer, 2017). Patients should be premedicated with an antihistamine and acetaminophen prior to the first 4 infusions and for subsequent doses based upon clinical judgment and presence/severity of prior infusion reactions. Monitor patients for signs and symptoms of infusion-related reactions, including pyrexia, chills, flushing, hypotension, dyspnea, wheezing, back pain, abdominal pain, and urticaria. Interrupt or slow the rate of infusion for mild (Grade 1) or moderate (Grade 2) infusion-related reactions. Permanently discontinue avelumab for severe (Grade 3) or life-threatening (Grade 4) infusion-related reactions. Infusion-related reactions occurred in 25% (439/1738) of patients, including three (0.2%) patients with Grade 4 and nine (0.5%) with Grade 3.
Avelumab can cause fetal harm when administered to a pregnant woman (Pfizer, 2017). Advise patients of the potential risk to a fetus including the risk of fetal death. Advise females of childbearing potential to use effective contraception during treatment with avelumab and for at least one month after the last dose of avelumab. It is not known whether avelumab is excreted in human milk. Advise a lactating woman not to breastfeed during treatment and for at least one month after the last dose of avelumab due to the potential for serious adverse reactions in breastfed infants.
The most common adverse reactions (all grades, greater than or equal to 20%) in patients with metastatic MCC were fatigue (50%), musculoskeletal pain (32%), diarrhea (23%), nausea (22%), infusion-related reactions (22%), rash (22%), decreased appetite (20%), and peripheral edema (20%). The most common adverse reaction requiring dose interruption was anemia (Pfizer, 2017).
Selected treatment-emergent laboratory abnormalities (all grades, greater than or equal to 20%) in patients with metastatic MCC were lymphopenia (49%), anemia (35%), increased aspartate aminotransferase (34%), thrombocytopenia (27%). and increased alanine aminotransferase (20%) (Pfizer, 2017). Selected treatment-emergent Grade 3-4 laboratory abnormalities (greater than or equal to 2%) were lymphopenia (19%), anemia (9%), hyperglycemia (7%), increased alanine aminotransferase (5%), and increased lipase (4%).
Mesothelioma (Including Pleural Mesothelioma)
Khanna and associates (2016) studied the functional aspects of PD-1 and PD-L1 immune checkpoints in malignant mesothelioma. Tumor samples from 65 patients with mesothelioma were evaluated for PD-L1 expression by immunohistochemistry, and its prognostic significance was examined. Malignant effusions from patients with pleural and peritoneal mesothelioma were evaluated for PD-1-positive and PD-L1-positive infiltrating lymphocytes and their role in inducing PD-L1 expression in tumor cells; ADCC of avelumab against primary mesothelioma cell lines was evaluated in presence of autologous and allogeneic NK cells. Of 65 pleural and peritoneal mesothelioma tumors examined, 41 (63 %) were PD-L1-positive, which was associated with slightly inferior overall survival (OS) compared to patients with PD-L1-negative tumors (median of 23.0 versus 33.3 months, p = 0.35). The frequency of PD-L1 expression was similar in patients with pleural and peritoneal mesothelioma, with 62 % and 64 % of samples testing positive, respectively. In 9 mesothelioma effusion samples evaluated, the fraction of cells expressing PD-L1 ranged from 12 % to 83 %. In 7 patients with paired malignant effusion and peripheral blood mononuclear cell (PBMC) samples, PD-L1 expression was significantly higher on CD3-positive T cells present in malignant effusions as compared with PBMCs (p = 0.016). In addition, the numbers of CD14-positive PD-1-positive cells were increased in malignant effusions compared with PBMCs (p = 0.031). The lymphocytes present in malignant effusions recognized autologous tumor cells and induced IFN-γ-mediated PD-L1 expression on the tumor cell surface. Of the 3 primary mesothelioma cell lines tested, 2 were susceptible to avelumab-mediated ADCC in the presence of autologous NK cells. The authors concluded that most pleural as well as peritoneal mesotheliomas express PD-L1. Malignant effusions in this disease were characterized by the presence of tumor cells and CD3-positive T cells that highly express PD-L1. In addition, mesothelioma tumor cells were susceptible to ADCC by the anti-PD-L1 antibody avelumab.
Rimner et al (2022) noted that single-agent monoclonal antibody therapy against PD-L1 has modest effects in malignant pleural mesothelioma. Radiation therapy can enhance the anti-tumor effects of immunotherapy. Nevertheless, the safety of combining anti-PD-L1 therapy with stereotactic body radiation therapy (SBRT) is unknown. In a single-arm, investigator-initiated, phase-I clinical trial, these researchers examined the safety of avelumab plus SBRT in patients with malignant pleural mesothelioma. This study included patients who progressed on prior chemotherapy. Avelumab was delivered every other week, and SBRT was delivered to 1 lesion in 3 to 5 fractions (minimum of 30 Gy) followed by continuation of avelumab up to 24 months or until disease progression. The primary endpoint of the study was safety on the basis of grade 3+ non-hematologic AEs within 3 months of SBRT. A total of 13 evaluable patients received a median of 7 cycles (range of 2 to 26 cycles) of avelumab. There were 27 grade-1, 17 grade-2, 4 grade-3, and no grade-4 or grade-5 avelumab-related AEs. The most common AEs were infusion-related allergic reactions (n = 6), anorexia or weight loss (n = 6), fatigue (n = 6), thyroid disorders (n = 5), diarrhea (n = 3), and myalgia or arthralgias (n = 3). There were 10 grade-1, 4 grade-2, 1 grade-3, and no grade-4 or grade-5 SBRT-related AEs. The most common AEs were diarrhea (n = 3), chest pain/myalgia (n = 2), fatigue (n = 2), cough (n = 2), dyspnea (n = 2), and nausea/vomiting (n = 2). The authors concluded that combined avelumab and SBRT appeared tolerable on the basis of the pre-specified toxicity endpoints of the 1st stage of this Simon 2-stage design phase-I clinical trial. These researchers stated that further research is needed to optimize the combination with immunotherapy and maximize the immunologic effects.
The authors stated that this study had several drawbacks. First, although there was no signal of excessive toxicity and the combination of avelumab and SBRT appeared safe, the sample size was small (n = 13) as the study was stopped following completion of accrual to the 1st planned stage of this phase-I trial; therefore, a larger study is needed for a more robust toxicity assessment. Second, the small sample size limited these investigators in examining the oncologic effects of avelumab plus SBRT. Although the effects appeared additive rather than synergistic, a larger study may detect a subset of patients who may particularly benefit from this combination therapy. Third, correlative analyses were limited by only 1 patient having responded to avelumab. Analysis of a larger cohort may allow these researchers to detect differences in the baseline immune phenotype or response of immune biomarkers to the combination therapy that would allow selection of patients with a greater response to therapy. Nevertheless, even the ability to find safety and tolerability of this regimen with additive effects of avelumab and SBRT is worthwhile and assuring.
Multiple Myeloma
Kazandjian and colleagues (2021) stated that despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma (MM), subsequent clinical studies have been disappointing. Pre-clinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, RT with checkpoint inhibition did not appear to activate the anti-tumor immune response. This was a single-arm, phase-II Simon 2-stage, single-center study that was prematurely terminated because of the COVID-19 pandemic after enrolling 4 patients. Key eligibility included patients with relapsed/refractory MM (RRMM) who had exhausted or were not candidates for standard therapy and had at least 1 lesion amenable to RT. Subjects received avelumab until progression or intolerable toxicity and hypo-fractionated RT to a focal lesion in cycle 2; RT was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect. At a median potential follow-up of 10.5 months, there were no objective responses, 1 minimal response, and 2 stable disease as best response. The median PFS was 5.3 months (95 % CI: 2.5 to 7.1 months), and no deaths occurred; and there were no grade greater than or equal to 3 and 5 grade-1 to grade-2 treatment-related AEs. The authors concluded that avelumab in combination with RT for patients with RRMM and extra-medullary disease was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local RT. Furthermore, the combination was very well-tolerated compared with historical RRMM treatment regimens. The authors stated that a main drawback of this study was the small sample size (n = 4), and the question remains whether one would observe deep responses in a small subset of patients if these researchers had enrolled more patients. Given their and others’ findings, it is unclear if immune checkpoint inhibitor combination regimens would synergize to produce meaningful clinical benefit; thus, excluding clinical trials, PD‐1/L1 inhibitors are unlikely to have a role in the MM clinic in the near future.
Neuroendocrine Neoplasia
Weber and Fottner (2018) stated that well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by anti-proliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, therapeutic options for patients with advanced/metastatic high-grade NENs remain limited. These investigators reviewed the literature and international congress abstracts on the safety and efficacy of immunotherapy by checkpoint inhibition in advanced/metastatic NENs. Evidence pointed to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastro-entero-pancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs. The authors concluded that immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.
Chan et al (2022) stated that higher grade NENs continues to pose a treatment dilemma, with the optimal treatment undefined. Although immunotherapy has revolutionized the treatment of many cancers, its role in NENs remains unclear. These investigators examined the safety and effectiveness of avelumab in patients with advanced unresectable/metastatic higher grade NENs. NET001 and NET002 are phase-II clinical trials examining avelumab (NCT03278405 and NCT03278379). Eligible patients had unresectable and/or metastatic WHO G2-3 NENs from a gastro-entero-pancreatic (GEP) source or a bronchial primary (excluding typical carcinoid) and 0 to 2 prior lines of systemic therapy (excluding somatostatin analogs [SSAs]). Patients were treated with avelumab 10 mg/kg intravenously every 2 weeks for 26 cycles. NET001 examined G3 poorly differentiated GEP neuroendocrine carcinomas (NECs) and bronchial small/large cell NEC, whereas NET002 examine G2-G3 well-differentiated GEPNETs and bronchial atypical carcinoids. The primary endpoint in both trials was ORR by RECIST v1.1; secondary endpoints included PFS, OS, disease control rate (DCR) at 6 months and toxicity. A total of 27 patients were enrolled (21 GEP, 6 lungs; 10 in NET-001, 17 in NET-002); median age of 64 years (range of 37 to 80), 30 % ECOG PS 1-2 and 78 % received 1+ lines of prior therapy. The median Ki-67 index was 35 % (range of 10 to 100); 12 of the 27 patients had died at the time of data lock. The median time on treatment was 85 days (7 cycles); no objective responses were observed. Stable disease was achieved in 33 % of patients, and the DCR at 6 months was 21 %. The median PFS was 3.3 months (range of 1.2 to 24.6), and the median OS was 14.2 months. Treatment-related AEs (all grades) occurred in 58 % of patients; 3 patients had treatment-related grade-3 to grade-4 AEs leading to treatment discontinuation (immune-related hepatitis n = 2 and infusion-related reaction n = 1). The authors concluded that single-agent PD-L1 blockade with avelumab showed limited anti-tumor activity in patients with G2-G3 NENs; correlative studies are underway. These researchers stated that further studies are needed to examine the role of dual immunotherapy and other combinations in this population with few treatment alternatives.
Non-Small Cell Lung Cancer
Valecha and colleagues (2017) stated that advanced non-small cell lung cancer (NSCLC) has been conventionally treated with cytotoxic chemotherapy with short-lived responses and significant toxicities. Monoclonal antibodies to PD-1 and PD-L1 have shown tremendous promise in the treatment of advanced NSCLC in various clinical trials. These researchers reviewed the outcomes of various trials of anti-PD-1/anti-PD-L1 antibodies (e.g., atezolizumab, avelumab, durvalumab, and nivolumab) in the treatment of NSCLC. They also discussed their mechanism of action and toxicities. The authors noted that anti-PD-1/PD-L1 antibodies offer several advantages including significant anti-tumor activity, induction of long lasting responses, and favorable safety profile. Several trials are now being conducted to evaluate their effectiveness as 1st-line agents as well as in combination with other agents. They also stated that more research is needed to identify other biomarkers, in addition to PD-L1 expression, that could more reliably predict response to these drugs, and aid in better patient selection.
In an open-label, phase-II clinical trial, Galffy et al (2023) hypothesized that avelumab plus axitinib could improve clinical outcomes in patients with advanced NSCLC or UC. These investigators enrolled previously treated patients with advanced or metastatic NSCLC, or untreated, cisplatin-ineligible patients with advanced or metastatic UC. Patients received avelumab 800 mg every 2 weeks (Q2W) and axitinib 5 mg orally twice-daily. The primary endpoint was ORR. Immunohistochemistry was used to examine PD-L1 expression (SP263 assay) and the presence of CD8+ T cells (clone C8/144B). Tumor mutational burden (TMB) was evaluated by whole-exome sequencing (WES). A total of 61 patients were enrolled and treated (NSCLC, n = 41; UC, n = 20); 5 remained on treatment at data cut-off (February 26, 2021). The confirmed ORR was 31.7 % in the NSCLC cohort and 10.0 % in the UC cohort (all PRs). Anti-tumor activity was observed irrespective of PD-L1 expression. In exploratory subgroups, ORRs were higher in patients with higher (greater than or equal to median) CD8+ T cells in the tumor. ORRs were higher in patients with lower TMB (less than median) in the NSCLC cohort and higher TMB (greater than or equal to median) in the UC cohort. TRAEs occurred in 93.4 % of patients, including grade-3 or higher TRAEs in 55.7 %. Avelumab exposures with 800 mg Q2W dosing were similar to those observed with 10 mg/kg Q2W dosing. The authors concluded that the combination of avelumab plus axitinib in patients with advanced or metastatic platinum-treated NSCLC or cisplatin-ineligible UC showed acceptable safety and anti-tumor activity. In the NSCLC cohort, the ORR and OS compared favorably with prior studies of single-agent ICIs, irrespective of PD-L1 status, whereas in the UC cohort, the ORR was lower than expected, potentially limited by small patient numbers.
Andric et al (2023) presented the results of a phase-IIa clinical trial of 1st-line avelumab plus cetuximab in patients with advanced squamous NSCLC. Patients with recurrent or metastatic squamous NSCLC received avelumab 800 mg (Days 1 and 8), cetuximab 250 mg/m2 (Day 1) and 500 mg/m2 (Day 8), cisplatin 75 mg/m2 (Day 1), and gemcitabine 1,250 mg/m2 (Days 1 and 8) for four 3-week cycles, followed by avelumab 800 mg and cetuximab 500 mg/m2 every 2 weeks. The primary endpoint was the best overall response; the secondary endpoints were PFS, duration of response, OS, and safety. Effectiveness analyses were reported from an updated data cut-off. A total of 43 patients were enrolled. The median follow-up was 6.6 months for the primary analyses and 9.2 months for the effectiveness analyses. In the effectiveness analyses, 15 patients had a confirmed PR (ORR, 34.9 % [95 % CI: 21.0 % to 50.9 %]), and the median duration of response was 7.1 months (95 % CI: 4.2 months to 12.5 months). The median PFS and OS were 6.1 months and 10.0 months, respectively. In the safety analyses (primary analysis), 38 patients (88.4 %) had a treatment-related AE, of whom 24 (55.8 %) had a grade-3 or higher treatment-related AE. The authors concluded that the combination of avelumab + cetuximab and chemotherapy showed anti-tumor activity and tolerable safety; however, on the basis of a pre-defined statistical threshold, the combination did not achieve a clinically meaningful treatment effect; the ORR was not improved compared with those reported for current SOC.
Ovarian Cancer
Pujade-Lauraine and colleagues (2021) stated that most patients with ovarian cancer will relapse after receiving front-line platinum-based chemotherapy and eventually develop platinum-resistant or platinum-refractory disease. In a randomized, open-label, parallel-group, 3-arm, phase-III clinical trial, these investigators reported results of avelumab alone or avelumab plus pegylated liposomal doxorubicin (PLD) compared with PLD alone in patients with platinum-resistant or platinum-refractory ovarian cancer. The JAVELIN Ovarian 200 Trial was carried out at 149 hospitals and cancer treatment centers in 24 countries. Eligible patients were aged 18 years or older with epithelial ovarian, fallopian tube, or peritoneal cancer (maximum of 3 previous lines for platinum-sensitive disease, none for platinum-resistant disease) and an ECOG performance status of 0 or 1. Patients were randomly assigned (1:1:1) via interactive response technology to avelumab (10 mg/kg intravenously every 2 weeks), avelumab plus PLD (40 mg/m2 intravenously every 4 weeks), or PLD and stratified by disease platinum status, number of previous anti-cancer regimens, and bulky disease. Primary endpoints were PFS by blinded independent central review and OS in all randomly assigned patients, with the objective to show whether avelumab alone or avelumab plus PLD was superior to PLD. Safety was examined in all patients who received at least 1 dose of study treatment. Between January 5, 2016, and May 16, 2017, a total of 566 patients were enrolled and randomly assigned (combination, n = 188; PLD, n = 190, and avelumab, n = 188). At data cut-off (September 19, 2018), median duration of follow-up for OS was 18.4 months (inter-quartile range 15.6 to 21.9) for the combination group, 17.4 months (15.2 to 21.3) for the PLD group, and 18.2 months (15.8 to 21.2) for the avelumab group. Median PFS by blinded independent central review was 3.7 months (95 % CI: 3.3 to 5.1) in the combination group, 3.5 months (2.1 to 4.0) in the PLD group, and 1.9 months (1.8 to 1.9) in the avelumab group (combination versus PLD: stratified HR 0.78 [repeated 93.1 % CI: 0.59 to 1.24], 1-sided, p = 0.030; avelumab versus PLD: 1.68 [1.32 to 2.60], 1-sided, p > 0.99). Median OS was 15.7 months (95 % CI: 12.7 to 18.7) in the combination group, 13.1 months (11.8 to 15.5) in the PLD group, and 11.8 months (8.9 to 14.1) in the avelumab group (combination versus PLD: stratified HR 0.89 [repeated 88.85 % CI: 0.74 to 1.24], 1-sided p = 0.21; avelumab versus PLD: 1.14 [0.95 to 1.58], 1-sided p = 0.83]). The most common grade-3 or worse treatment-related AEs were palmar-plantar erythron-dysesthesia syndrome (18 [10 %] in the combination group versus 9 [5 %] in the PLD group versus 0 in the avelumab group), rash (11 [6 %] versus 3 [2 %] versus 0), fatigue (10 [5 %] versus 3 [2 %] versus 0), stomatitis (10 [5 %] versus 5 [3 %] versus 0), anemia (6 [3 %] versus 9 [5 %] versus 3 [2 %]), neutropenia (9 [5 %] versus 9 [5 %] versus 0), and neutrophil count decreased (8 [5 %] versus 7 [4 %] versus 0). Serious treatment-related AEs occurred in 32 (18 %) patients in the combination group, 19 (11 %) in the PLD group, and 14 (7 %) in the avelumab group. Treatment-related AEs resulted in death in 1 patient each in the PLD group (sepsis) and avelumab group (intestinal obstruction). The authors concluded that neither avelumab plus PLD nor avelumab alone significantly improved PFS or OS versus PLD. These findings provided insights for patient selection in future studies of immune checkpoint inhibitors in platinum-resistant or platinum-refractory ovarian cancer.
Other Types of Cancers
Donahue and associates (2017) examined the effect on immune cell subsets in the peripheral blood of cancer patients prior to and following multiple administrations of avelumab. A total of 123 distinct immune cell subsets in the peripheral blood of cancer patients (n = 28) in a phase I clinical trial were analyzed by flow cytometry prior to and following 1, 3, and 9 cycles of avelumab. The 28 patients exhibited 12 different types of solid tumors: adrenocortical (n = 2), breast (n = 3), chordoma (n = 1), GI (n = 7), lung (n = 1), mesothelioma (n = 3), neuroendocrine (n = 1), ovarian (n = 1), pancreatic (n = 4), prostate (n = 1), renal cell (n = 3), and spindle cell (n = 1) cancer. Changes in soluble (s) CD27 and sCD40L in plasma were also evaluated. In-vitro studies were also performed to determine if avelumab would mediate ADCC of PBMC. No statistically significant changes in any of the 123 immune cell subsets analyzed were observed at any dose level, or number of doses, of avelumab. Increases in the ratio of sCD27:sCD40L were observed, suggesting potential immune activation. Controlled in-vitro studies also showed lysis of tumor cells by avelumab versus no lysis of PBMC from 5 donors. The authors concluded that these studies demonstrated the lack of any significant effect on multiple immune cell subsets, even those expressing PD-L1, following multiple cycles of avelumab. These findings complemented previous studies showing anti-tumor effects of avelumab and comparable levels of AEs with avelumab versus other anti-PD-1/PD-L1 MAbs. They stated that the findings of these studies provided the rationale to further exploit the potential ADCC mechanism of action of avelumab as well as other human IgG1 checkpoint inhibitors.
Prostate Cancer
Madan et al (2023) stated that therapeutic cancer vaccines including sipuleucel-T , a prostatic acid phosphatase (PAP) targeted vaccine that improves survival in metastatic castration-resistant prostate cancer (mCRPC), can produce immune responses that translate to clinical benefit. The effects of sequential checkpoint inhibitors after therapeutic vaccine on immune responses are unknown. Avelumab is an anti-PD-L1 monoclonal antibody evaluated in patients with mCRPC in the JAVELIN solid tumor phase-I clinical trial expansion cohort, enriched for patients with a previous therapeutic prostate cancer-targeted vaccine. Patients with mCRPC received intravenous avelumab 10 mg/kg every 2 weeks with imaging every 6 weeks. Peripheral blood T-cell responses to PAP and to PA2024, the peptide containing PAP utilized by the vaccine, were evaluated pre- and post-treatment. A total of 18 patients were enrolled in this trial, and previous treatments included abiraterone or enzalutamide in 14 (78 %), therapeutic cancer vaccine in 14 (78 %), and chemotherapy in 4 (22 %). Avelumab had a manageable safety profile. There were no sustained prostate specific antigen (PSA) decreases. Of 17 patients evaluable for best overall response by RECISTv1.1, 12 had SD and 5 had progressive disease; 7 patients had SD for more than 24 weeks post-treatment; 14 patients had previously received therapeutic cancer vaccines; 11 patients (79 %) had SD as the best overall response. Of these 14 patients, 9 had previously received sipuleucel T. Analysis of antigen-specific T-cell responses pre- and post-avelumab treatment did not show changes in IFN-γ production or proliferation in response to PAP or PA2024. The authors concluded that data from this small study suggested that although tumor-targeted vaccine and immune checkpoint inhibition may each be components of immune-mediated anti-tumor activity, they were insufficient when a vaccine was given as monotherapy before immune checkpoint blockade monotherapy. These researchers noted that this should be a consideration for future investigations, regardless of tumor type. They stated that regimens that optimize timing and employ other immune-enhancing treatments (e.g., cytokines) may be needed to produce clinically meaningful anti-tumor responses in mCRPC patients.
The authors stated that his analysis had several drawbacks. First, this was not a pre-planned analysis of the sequential use of vaccine and avelumab. The vaccine treatment was not an eligibility requirement for the protocol. In addition, the timing of the vaccine before avelumab was not uniform (median = 6 months). Given that the effects of vaccines could be delayed relative to pharmacologic interventions, this may have fewer implications; but it was noteworthy, nonetheless. Even when vaccines were used, both sipuleucel-T and PROSTVAC were considered equivalent in their ability to work sequentially with avelumab despite different levels of proven efficacy and potential mechanisms of immune activation. Second, the small sample size and a lack of follow-up to include survival were also limitations of this analysis. Third, a small minority of patients were co-treated with enzalutamide, which has been shown to perhaps increase systemic steroids; thus, affecting the potential for immune responses as well. These investigators noted that the lack of any evidence of confirmed radiographic or PSA responses was noteworthy and contributed to the body of evidence that does not support tumor-targeted vaccine sequentially followed by immune checkpoint blockade.
Small Bowel Adenocarcinoma
Cardin et al (2022) noted that small bowel adenocarcinomas (SBAs) are rare and frequently treated like large intestinal adenocarcinomas; however, SBAs have a very different micro-environment and could respond differently to the same therapies. Previous data from these researchers suggested that SBAs might benefit from targeting the PD-1/PD-L1 axis based on PD-L1 staining in almost 50 % of SBA tissue samples tested. In a phase-II clinical trial, these investigators examined the safety and effectiveness of avelumab in SBA. Patients with advanced or metastatic disease were enrolled; ampullary tumors were considered part of the duodenum and allowed; however, prior PD-1/PD-L1 inhibition was not allowed. Avelumab (10 mg/kg) was administered every 2 weeks, and imaging was carried out every 8 weeks. Primary endpoint was response rate. A total of 8 patients (ampullary, n= 3; small intestine, n= 5) were enrolled, with a majority (88 %) being men and a median age of 61 years. Of 7 effectiveness-evaluable patients, 2 (29 %) experienced partial responses (PRs); stable disease (SD) occurred in 3 additional patients (71 %); and median PFS was 3.35 months. Most frequent, related toxicities were anemia, fatigue, and infusion-related reaction (25 % each), mostly grade-2 or lower; grade-3 hypokalemia and hyponatremia occurred in 1 patient, and another reported grade-4 diabetic ketoacidosis. The authors concluded that despite the observed benefit, accrual was slower than expected and the study was closed early due to feasibility. These researchers stated that a general clinic observation was that patients were receiving immunotherapy off-label as the availability of these agents increased; off-label availability and disease rarity were likely drivers of insufficient accrual.
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