Avelumab (Bavencio)

Number: 0916

Policy

Note: REQUIRES PRECERTIFICATION

Precertification of avelumab is required of all Aetna participating providers and members in applicable plan designs.  For precertification of avelumab, call (866) 752-7021 or fax (866) 267-3277.

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.

  1. Aetna considers avelumab (Bavencio) medically necessary for the following indications:

    1. Merkel Cell Carcinoma - for the treatment of metastatic Merkel cell carcinoma; or
    2. Kidney Cancer - for the treatment of advanced, relapsed, or stage IV kidney cancer including renal cell carcinoma when avelumab is given in combination with axtinib as first-line treatment for the disease; or
    3. Urothelial Carcinomas - as a single agent for the treatment of any of the following:

      1. Bladder Cancer - when either of the following criteria is met:

        1. Used as subsequent therapy following platinum-containing chemotherapy for any of the following: 

          1. locally advanced or metastatic disease; or
          2. metastatic or local recurrence post-cystectomy; or
          3. muscle invasive local recurrence or persistent disease in a preserved bladder; or
        2. Used as maintenance therapy if there is no progression on first-line platinum-containing chemotherapy; or

      2. Primary Carcinoma of the Urethra - when either of the following is met:

        1. Used as subsequent systemic therapy for recurrent, locally advanced, or metastatic disease following platiunum-containing chemotherapy; or
        2. Used as maintenance therapy if there is no progression on first-line platinum-containing chemotherapy; or
      3. Upper Genitourinary (GU) Tract Tumors or Urothelial Carcinoma of the Prostate - when either of the following criteria is met: 

        1. Used as subsequent therapy following platinum-containing chemotherapy for locally advanced or metastatic disease; or
        2. Used as maintenance therapy if there is no progression on first-line platiunum-containing chemotherapy.
  2. Aetna considers continuation of avelumab (Bavencio) medically necessary for members requesting reauthorization for an indication listed above when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. 

  3. Aetna considers avelumab experimental and investigational for members who have experienced disease progression while on anti-PD-1/PDL1 therapy (e.g., nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), and durvalumab (Imfinzi)).

  4. Aetna considers avelumab 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:

    1. Adrenocortical cancer
    2. Acute myeloid leukemia
    3. Breast cancer
    4. Chordoma
    5. Gastro-intestinal cancers (e.g., colorectal, esophageal, and gastric cancers)
    6. Head and neck cancer
    7. Large-cell lung neuroendocrine carcinoma
    8. Mesothelioma
    9. Neuroendocrine cancer
    10. Non-small cell lung cancer
    11. Ovarian cancer
    12. Pancreatic cancer
    13. Prostate cancer
    14. Spindle cell cancer.

Dosing Recommendations

Bavencio (avelumab) injection, for intravenous use, is available as a 200 mg/10 mL (20 mg/mL) solution in single-dose vial.

  • Merkel cell carcinoma - avelumab 800 mg administered as an intravenous infusion (IV) over 60 minutes every 2 weeks until disease progression or unacceptable toxicity.
  • Urothelial carcinoma - avelumab 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 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: Pfizer, 2020a

Background

Avelumab (Bavencio) is a programmed death ligand-1 (PD-L1) blocking antibody.

U.S. Food and Drug Administration (FDA)-Approved Indications (Pfizer, 2020a)

  • Merkel Cell Carcinoma (MCC)

    Adults and pediatric patients 12 years and older with metastatic MCC. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

  • Urothelial Carcinoma (UC)

    • Maintenance treatment of patients with locally advanced or metastatic UC that has not progressed with first-line platinum-containing chemotherapy
    • Patients with locally advanced or metastatic UC who:

      • Have disease progression during or following platinum-containing chemotherapy 
      • Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

  • Renal Cell Carcinoma (RCC)

    First-line treatment, in combination with axitinib, of patients with advanced RCC

Compendial Uses (NCCN, 2020)

Urothelial carcinoma

  • Bladder cancer (including muscle invasive local recurrence or persistent disease in a preserved bladder, metastatic or local recurrence post-cystectomy)
  • Primary carcinoma of the urethra
  • Upper genitourinary (GU) tract tumors
  • Urothelial carcinoma of the prostate

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.

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, 2020b).

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, 2020b).

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.

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.

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, 2019b).

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, 2019a, Pfizer, 2019b).

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.

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

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.

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.

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.

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.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :

Other CPT codes related to the CPB:

96413 - 96417 Chemotherapy administration, intravenous infusion technique

HCPCS codes covered if selection criteria are met:

J9023 Injection, avelumab, 10 mg

Other HCPCS codes related to the CPB:

Axitinib (Inlyta) - no specific code:

J9022 Injection, atezolizumab, 10 mg
J9045 Injection, carboplatin, 50 mg
J9060 Injection, cisplatin, powder or solution, 10 mg
J9173 Injection, durvalumab, 10 mg
J9263 Injection, oxaliplatin, 0.5 mg
J9271 Injection, pembrolizumab, 1 mg
J9299 Injection, nivolumab, 1 mg

ICD-10 codes covered if selection criteria are met:

C4A.10 - C4A.9 Merkel cell carcinoma
C61 Malignant neoplasm of prostate
C64.1 - C64.9 Malignant neoplasm of kidney, except renal pelvis
C65.1 - C65.9 Malignant neoplasm of renal pelvis
C66.1 - C66.9 Malignant neoplasm of ureter
C67.0 - C67.9 Malignant neoplasm of bladder
C68.0 Malignant neoplasm of urethra

ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):

C15.3 - C26.9 Malignant neoplasms of digestive organs
C34.00 - C34.92 Malignant neoplasm of bronchus and lung
C45.0 - C45.9 Mesothelioma
C50.011 - C50.929 Malignant neoplasm of breast
C56.1 - C56.9 Malignant neoplasm of ovary
C74.00 - C74.92 Malignant neoplasm of adrenal gland
C7A.00 - C7A.8 Malignant neuroendocrine tumors
C76.0 Malignant neoplasm of head, face, and neck
C80.1 Malignant neoplasm without specification of site [Spindle cell cancer]
C92.00 - C92.02, C92.40 - C92.A2 Acute myeloid leukemia (AML)
D16.00 - D16.9 Benign neoplasm of bone and articular cartilage (chondroma)

The above policy is based on the following references:

  1. Alsina M, Moehler M, Hierro C, et al. Immunotherapy for gastric cancer: A focus on immune checkpoints. Target Oncol. 2016;11(4):469-477.
  2. Assi R, Kantarjian H, Ravandi F, Daver N. Immune therapies in acute myeloid leukemia: A focus on monoclonal antibodies and immune checkpoint inhibitors. Curr Opin Hematol. 2018;25(2):136-145.
  3. Bang YJ, Ruiz EY, Van Cutsem E, et al. Phase 3, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment for patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300. Ann Oncol. 2018;29(10):2052-2060.
  4. Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treat Rev. 2017;54:58-67.
  5. Bilgin B, Sendur MA, Bulent Akıncı M, et al. Targeting the PD-1 pathway: A new hope for gastrointestinal cancers. Curr Med Res Opin. 2017;33(4):749-759.
  6. Cassler NM, Merrill D, Bichakjian CK, Brownell I. Merkel cell carcinoma therapeutic update. Curr Treat Options Oncol. 2016;17(7):36.
  7. Choueiri TK, Larkin J, Oya M, et al. Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): An open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol. 2018;19(4):451-460.
  8. Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2018;167(3):671-686.
  9. Donahue RN, Lepone LM, Grenga I, et al. Analyses of the peripheral immunome following multiple administrations of avelumab, a human IgG1 anti-PD-L1 monoclonal antibody. J Immunother Cancer. 2017;5:20.
  10. EMD Serono and Pfizer. FDA grants Bavencio (avelumab) approval for a common type of advanced bladder cancer. Press Release. Rockland, MA and New York, NY: EMD Serono and Pfizer; May 9, 2017.
  11. Fujii R, Friedman ER, Richards J, et al. Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab. Oncotarget. 2016;7(23):33498-33511.
  12. Kaufman HL, Russell J, Hamid O, et al. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial. Lancet Oncol. 2016;17(10):1374-1385.
  13. Khanna S, Thomas A, Abate-Daga D, et al. Malignant mesothelioma effusions are infiltrated by CD3+ T cells highly expressing PD-L1 and the PD-L1+ tumor cells within these effusions are susceptible to ADCC by the anti-PD-L1 antibody avelumab. J Thorac Oncol. 2016;11(11):1993-2005.
  14. Merlano MC, Merlotti AM, Licitra L, et al. Activation of immune responses in patients with relapsed-metastatic head and neck cancer (CONFRONT phase I-II trial): Multimodality immunotherapy with avelumab, short-course radiotherapy, and cyclophosphamide. Clin Transl Radiat Oncol. 2018;12:47-52.
  15. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. N Engl J Med. 2019;380(12):1103-1115.
  16. National Comprehensive Cancer Network (NCCN). Avelumab. NCCN Drugs and Biologics Compendium. Fort Washington, PA: NCCN; 2020.
  17. National Comprehensive Cancer Network (NCCN). Bladder cancer. NCCN Clinical Practice Guidelines in Oncology, version 5.2018. Fort Washington, PA: NCCN; 2018.
  18. Pfizer Inc and EMD Serono Inc. Bavencio (avelumab) injection, for intravenous use. Prescribing Information. Reference ID: 4074145. New York, NY: Pfizer; revised March 2017. 
  19. Pfizer Inc and EMD Serono Inc. Bavencio (avelumab) injection, for intravenous use. Prescribing Information. Reference ID: 4095102. New York, NY: Pfizer; revised May 2017. 
  20. Pfizer Inc. Bavencio (avelumab) injection, for intravenous use. Prescribing Information. New York, NY: Pfizer; revised May 2019a.
  21. Pfizer Inc. Bavencio (avelumab) injection, for intravenous use. Prescribing Information. New York, NY: Pfizer; revised June 2020a.
  22. Pfizer Inc. FDA approves Bavencio (avelumab) plus Inlyta (axitinib) combination for patients with advanced renal cell carcinoma. Press Release. New York, NY: Pfizer; May 14, 2019b.
  23. Pfizer Inc. FDA approves Bavencio as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma. Press Release. New York, NY: Pfizer; June 2020b.
  24. Pfizer Inc. FDA grants approval for Bavencio (avelumab), the first immunotherapy approved for metastatic Merkel cell carcinoma. Press Release. New York, NY: Pfizer; March 23, 2017.
  25. Pujade-Lauraine E, Fujiwara K, Dychter SS, et al. Avelumab (anti-PD-L1) in platinum-resistant/refractory ovarian cancer: JAVELIN Ovarian 200 Phase III study design. Future Oncol. 2018;14(21):2103-2113.
  26. Terheyden P, Becker JC. New developments in the biology and the treatment of metastatic Merkel cell carcinoma. Curr Opin Oncol. 2017;29(3):221-226.
  27. U.S. Food and Drug Administration (FDA). FDA approves first treatment for rare form of skin cancer. Press Release. Silver Spring, MD: FDA; March 23, 2017.
  28. Valecha GK, Vennepureddy A, Ibrahim U, et al. Anti-PD-1/PD-L1 antibodies in non-small cell lung cancer: The era of immunotherapy. Expert Rev Anticancer Ther. 2017;17(1):47-59.
  29. Weber MM, Fottner C. Immune checkpoint inhibitors in the treatment of patients with neuroendocrine neoplasia. Oncol Res Treat. 2018;41(5):306-312.