Durvalumab (Imfinzi)

Number: 0917

Policy

Note: Requires Precertification.

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

Note: Site of Care Utilization Management Policy applies. For information on site of service for durvalumab (Imfinzi), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

1. Criteria for Initial Approval

   Aetna considers durvalumab (Imfinzi) medically necessary for the following indications:

   1. Non-small cell lung cancer (NSCLC) - for treatment of unresectable, Stage II or III NSCLC that has not progressed following concurrent platinum-based chemotherapy and radiation therapy;
   2. Extensive-stage small cell lung cancer (ES-SCLC) - for first-line treatment in combination with etoposide and either carboplatin or cisplatin followed by single agent maintenance. 

2. Continuation of Therapy

   Aetna considers continuation of durvalumab therapy medically necessary for the following indications:

   1. NSCLC - for continued treatment (up to 12 months total) in members requesting reauthorization for NSCLC when there is no evidence of unacceptable toxicity or disease progression while on the current regimen;
   2. All Other Indications - for continued treatment in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. 

3. Other

   Aetna considers the VENTANA PD-L1 (SP263) Assay (Ventana Medical Systems, Inc.) medically necessary for the assessment of the PD-L1 protein in formalin-fixed, paraffin-embedded urothelial carcinoma tissue to determine individuals who are more likely to respond to durvalumab therapy.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Dosage and Administration

The following information includes dosing recommendations as per the FDA-approved prescribing information. 

Durvalumab (Imfinzi) is available for injection as 500 mg/10 mL (50 mg/mL) or 120 mg/2.4 mL (50 mg/mL) solution in a single-dose vial. Imfinzi is administered as an intravenous (IV) infusion over 60 minutes. Duration of therapy is until disease progression or unacceptable toxicity, unless otherwise specified.

Unresectable Stage III NSCLC

• For persons with a body weight of less than 30 kg: 10 mg/kg every 2 weeks, for a maximum of 12 months
• For persons with a body weight of 30 kg and more: 10 mg/kg every 2 weeks, or 1500 mg every 4 weeks, for a maximum of 12 months

ES-SCLC

• For persons with a body weight of less than 30 kg: with etoposide and either carboplatin or cisplatin, administer Imfinzi 20 mg/kg every 3 weeks (21 days) for 4 cycles in combination with chemotherapy, followed by 10 mg/kg every 2 weeks as a single agent
• For persons with a body weight of 30 kg and more: with etoposide and either carboplatin or cisplatin, administer Imfinzi 1500 mg every 3 weeks (21 days) for 4 cycles in combination with chemotherapy, followed by 1500 mg every 4 weeks as a single agent

Source: AstraZeneca, 2021a

Background

U.S. Food and Drug Administration (FDA)-Approved Indications

• Unresectable, Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy
• As first-line treatment of extensive-stage small cell lung cancer (ES-SCLC) in combination with etoposide and either carboplatin or cisplatin

Compendial Uses

• Non-small cell lung cancer - unresectable stage II disease

Durvalumab is available as Imfinzi (AstraZeneca Pharmaceuticals LP), which is a programmed death-ligand 1 (PD-L1) blocking antibody. Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of PD-L1 with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases the inhibition of immune responses, without inducing antibody dependent cellmediated cytotoxicity (ADCC) (AstraZeneca, 2020).

Durvalumab carries the following warnings and precautions: immune-mediated adverse reactions, which may be severe or fatal (includes immune-mediated pneumonitis, immune-mediated colitis, immune-mediated hepatits, immune-mediated endocrinopathies, immune-mediated dermatologic adverse reactions, immune-mediated nephritis and renal dysfunction, and solid organ transplant rejection); infusion-related reactions; complications of allogeneic HSCT; and embryo-fetal toxicity. 

The most common adverse reactions (20 percent or more of patients with unresectable, stage III NSCLC) were cough, fatigue, pneumonitis / radiation pneumonitis, upper respiratory tract infections, dyspnea, and rash. The most common adverse reaction (20 percent or more of patients with extensive-stage SCLC) were nausea, fatigue / asthenia, and alopecia. 

Alveolar Soft-Part Sarcoma

Lewin and colleagues (2018) stated that alveolar soft-part sarcoma (ASPS) is a morphologically distinctive mesenchymal tumor characterized by a canonical ASPL-TFE3 fusion product.  In the metastatic setting, standard cytotoxic chemotherapies are typically ineffective.  Studies have suggested modest clinical response to multi-targeted receptor tyrosine kinase inhibitors.  These investigators reported sustained partial responses (PRs) in 2 patients with immune checkpoint inhibition treated with either durvalumab (anti-PD-L1) alone or in combination with tremelimumab (anti-CTLA-4), which appeared unrelated to tumor immune infiltrates or mutational burden.  Genomic analysis of these patients, and other cases of ASPS, demonstrated molecular mismatch-repair deficiency signatures.  The authors concluded that these findings suggested that immune checkpoint blockade may be a useful therapeutic strategy for ASPS.

Bladder Cancer - Urothelial

Bellmunt (2017) noted that immunotherapy has a well-defined role in the management of bladder cancer patients who have progressed during or after platinum-based chemotherapy.  Research into immunotherapy has led to important advances in the treatment of melanoma, non-small cell lung cancer (NSCLC), and other malignancies using checkpoint inhibition, particularly with antibodies directed against the programmed cell death-1 protein (PD-1) or its ligand (PD-L1).  These agents (e.g., durvalumab) have also been shown to exhibit clinically important activity in advanced urothelial bladder carcinoma (UBC), and are being evaluated in clinical trials in patients with advanced UBC.

In a phase I/II multi-center, open-label, clinical trial, Massard and colleagues (2016) examined the safety and effectiveness of durvalumab, a human monoclonal antibody that binds PD-L1, and the role of PD-L1 expression on clinical response in patients with advanced UBC.  This study was being conducted in patients with inoperable or metastatic solid tumors.  These investigators reported the findings from the UBC expansion cohort.  Durvalumab (10 mg/kg every 2 weeks) was administered intravenously for up to 12 months.  The primary end-point was safety, and objective response rate (ORR, confirmed) was a key secondary end-point.  An exploratory analysis of pre-treatment tumor biopsies led to defining PD-L1-positive as greater than or equal to 25 % of tumor cells or tumor-infiltrating immune cells expressing membrane PD-L1.  A total of 61 patients (40 PD-L1-positive, 21 PD-L1-negative), 93.4 % of whom received 1 or more prior therapies for advanced disease, were treated (median duration of follow-up, 4.3 months).  The most common treatment-related adverse events (AEs) of any grade were fatigue (13.1 %), diarrhea (9.8 %), and decreased appetite (8.2 %).  Grade-3 treatment-related AEs occurred in 3 patients (4.9 %); there were no treatment-related grade-4 or grade-5 AEs.  One treatment-related AE (acute kidney injury) resulted in treatment discontinuation.  The ORR was 31.0 % (95 % confidence interval [CI]: 17.6 to 47.1) in 42 response-evaluable patients, 46.4 % (95 % CI: 27.5 to 66.1) in the PD-L1-positive subgroup, and 0 % (95 % CI: 0.0 to 23.2) in the PD-L1-negative subgroup.  Responses were ongoing in 12 of 13 responding patients, with median duration of response not yet reached (range of 4.1+ to 49.3+ weeks).  The authors concluded that durvalumab demonstrated a manageable safety profile and evidence of meaningful clinical activity in PD-L1-positive patients with UBC, many of whom were heavily pre-treated.

Bellmunt and associates (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 for 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, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages.  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.

On May 1, 2017, the Food and Drug Administration (FDA) granted accelerated approval to durvalumab (Imfinzi).  Imfinzi is indicated for the treatment of patients with locally advanced or metastatic UBC who have disease progression during or following platinum-containing chemotherapy, or whose disease has progressed within 12 months of receiving platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery.  The FDA also approved the VENTANA PD-L1 (SP263) Assay (Ventana Medical Systems, Inc.) as a complementary diagnostic for the assessment of the PD-L1 protein in formalin-fixed, paraffin-embedded urothelial carcinoma tissue.  The FDA approval was based on 1 single-arm clinical trial of 182 patients with locally advanced or metastatic UBC whose disease progressed after prior platinum-containing chemotherapy.  Durvalumab, 10 mg/kg intravenously, was administered every 2 weeks.  Confirmed ORR as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, was 17.0 % (95 % CI: 11.9 to 23.3).  At the data cut-off for the ORR analysis, median response duration was not reached (range of 0.9+ to 19.9+ months); ORR was also analyzed by PD-L1 expression status as measured by VENTANA PD-L1 (SP263) Assay.  In the 182 patients, the confirmed ORR was 26.3 % (95 % CI: 17.8 to 36.4) in 95 patients with a high PD-L1 score and 4.1 % (95 % CI: 0.9 to 11.5) in 73 patients with a low or negative PD-L1 score.  The most common AEs in at least 15 % of patients were fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema, and urinary tract infection.  Grade-3 to grade-4 AEs were seen in 43 % of patients.  Infection and immune-related AEs such as pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency, and diabetes were also seen with durvalumab.

On February 22, 2021, AstraZenca announced the voluntary withdrawal of Imfinzi for the indication of advanced bladder cancer in the U.S. This decision was made in consultation with the Food and Drug Administration (FDA). "In May 2017, Imfinzi was granted accelerated approval in the US based on promising tumour response rates and duration of response data from Study 1108, a Phase I/II trial that evaluated the safety and efficacy of Imfinzi in advanced solid tumours, including previously treated bladder cancer. Continued approval was contingent on results from the DANUBE Phase III trial in the 1st-line metastatic bladder cancer setting, which did not meet its primary endpoints in 2020. The withdrawal is aligned with FDA guidance for evaluating indications with accelerated approvals that did not meet post-marketing requirements, as part of a broader industry-wide evaluation. This withdrawal does not impact the indication outside the US and does not impact other approved Imfinzi indications within or outside the US" (AstraZeneca, 2021b).

Breast Cancer

McArthur and Page (2016) noted that immunotherapy encompasses both vaccines that direct immune responses to tumor-associated antigens, and checkpoint blocking antibodies that inhibit immune system suppression by targeting key pathways mediated by CTLA-4, PD-1, and PD-L1.  Both of these approaches are currently being explored as potential strategies for the treatment of breast cancer.  Recent studies suggested that immunotherapy is poised to change the therapeutic landscape for some breast cancers.  Specifically, ORR of 19 % with PD-1/PD-L1-directed antibodies have been reported in 2 small studies of women with PD-L1-positive, heavily pre-treated advanced triple-negative breast cancer.  In combination with nab-paclitaxel, confirmed response rates were 46 % in a PD-L1-unselected population in the first-line metastatic triple-negative breast cancer setting.  Checkpoint-blocking antibodies also have been evaluated in small studies of women with hormone receptor-positive metastatic breast cancer, and in women whose breast cancers lack PD-L1 expression, with more modest response rates.  It has been hypothesized that some breast cancers are not inherently recognized by the immune system; however, pre-clinical and preliminary clinical data suggested that inherently modest immunogenicity may be overcome with novel vaccination strategies, as well as strategies that combine immune checkpoint blockade with methods of optimizing antigen presentation, such as tumor ablation, radiation, chemotherapy, or other approaches.  If ongoing registrational trials support the use of immunotherapy, it could revolutionize the care of early-stage and metastatic breast cancer, and ideally improve cure rates.

Colorectal Cancer

Basile and colleagues (2017) stated that in the last few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC).  The development of new drugs that target the immune response to cancer cells seems very promising and has already been established for other tumor types.  In particular, the use of immune checkpoint inhibitors appears to be an encouraging immuno-therapeutic strategy.  The authors provided an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC.  To understand the key role of immunotherapy in CRC, the authors discussed the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment.  Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy.  Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary.  Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed.  As expected, additional studies are needed to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response.  One of the keywords in this study was PD-L1.

Esophageal Cancer

Iams and Villaflor (2017) stated that locally advanced esophageal carcinoma has a poor prognosis, and epidemiologic trends show that more patients are being diagnosed with locally advanced esophageal carcinoma and with adenocarcinoma histology.  This prompts a review and evaluation of the field regarding standard of care treatment for patients with locally advanced esophageal carcinoma, both adenocarcinoma and squamous cell carcinoma.  These investigators reviewed the evidence showing the moderate benefit of neoadjuvant chemo-radiation followed by esophagectomy compared to peri-operative chemotherapy plus esophagectomy in patients who are good surgical candidates.  Also, these researchers summarized the emerging clinical trial landscape in the peri-operative setting primarily seeking to apply targeted therapies against HER2 (trastuzumab or pertuzumab) or immune checkpoint inhibitors against PD-1 (pembrolizumab and nivolumab) or PD-L1 (durvalumab).

Gastric Cancer

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.  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 last years; in particular the PD-1/PD-L1 inhibitors pembrolizumab, avelumab, durvalumab and atezolizumab have shown early sign of efficacy.  Thus, immunotherapeutic strategies may provide new opportunities for GC patients.

Glioblastoma

In a review on “Safety and efficacy of durvalumab (MEDI4736) in various solid tumors”, Yang and colleagues (2018) noted that available evidence included a phase II clinical trial on the use of durvalumab for the treatment of glioblastoma.

Head and Neck Squamous Cell Carcinoma

Rebelatto and associates (2016) noted that a high-quality PD-L1 diagnostic assay may help predict which patients are more likely to respond to anti-PD-1/PD-L1 antibody-based cancer therapy.  These researchers describe a PD-L1 immunohistochemical (IHC) staining protocol developed by Ventana Medical Systems Inc. and key analytical parameters of its use in formalin-fixed, paraffin-embedded (FFPE) samples of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC).  An anti-human PD-L1 rabbit monoclonal antibody (SP263) was optimized for use with the VENTANA OptiView DAB IHC Detection Kit on the automated VENTANA BenchMark ULTRA platform.  The VENTANA PD-L1 (SP263) Assay was validated for use with FFPE NSCLC and HNSCC tissue samples in a series of studies addressing sensitivity, specificity, robustness, and precision.  Samples from a subset of 181 patients from a phase I/II clinical trial of durvalumab were analyzed to determine the optimal PD-L1 staining cut-off for enriching the probability of responses to treatment.  The scoring algorithm was defined using statistical analysis of clinical response data from this clinical trial and PD-L1 staining parameters in HNSCC and NSCLC tissue.  Inter-reader agreement was established by 3 pathologists who evaluated 81 NSCLC and 100 HNSCC samples across the range of PD-L1 expression levels.  The VENTANA PD-L1 (SP263) Assay met all pre-defined acceptance criteria.  For both cancer types, a cut-off of 25 % of tumor cells with PD-L1 membrane staining of any intensity best discriminated responders from non-responders.  Samples with staining above this value were deemed to have high PD-L1 expression, and those with staining below it were deemed to have low or no PD-L1 expression.  Inter-reader agreement on PD-L1 status was 97 and 92 % for NSCLC and HNSCC, respectively.  The authors concluded that these results highlighted the robustness and reproducibility of the VENTANA PD-L1 (SP263) Assay and support its suitability for use in the evaluation of NSCLC and HNSCC FFPE tumor samples using the devised greater than or equal to 25 % tumor cell staining cut-off in a clinical setting.  The clinical utility of the PD-L1 diagnostic assay as a predictive biomarker will be further validated in ongoing durvalumab studies.

Hepatocellular Carcinoma

In a review on “Safety and efficacy of durvalumab (MEDI4736) in various solid tumors”, Yang and colleagues (2018) noted that available evidence included phase I/II clinical trials on the use of durvalumab for the treatment of hepatocellular carcinoma (HCC).

Locally Advanced and Unresectable or Metastatic Gastro-Intestinal or Thoracic Malignancies

In a review on “Safety and efficacy of durvalumab (MEDI4736) in various solid tumors”, Yang and colleagues (2018) noted that available evidence included a phase Ia clinical trial on the use of durvalumab for the treatment of locally advanced and unresectable or metastatic gastro-intestinal or thoracic malignancies.

Melanoma

Mahoney and colleagues (2015) stated that blocking the interaction between the PD-1 protein and its ligands PD-L1 has been reported to have impressive anti-tumor responses.  Therapeutics targeting this pathway are currently in clinical trials.  Pembrolizumab and nivolumab were the first of this anti-PD-1 pathway family of checkpoint inhibitors to gain accelerated approval from the FDA for the treatment of ipilimumab-refractory melanoma.  Nivolumab has been associated with improved overall survival (OS) compared with dacarbazine in patients with previously untreated wild-type serine/threonine-protein kinase B-raf proto-oncogene BRAF melanoma.  Although the most mature data are in the treatment of melanoma, the FDA has granted approval of nivolumab for squamous cell lung cancer and the breakthrough therapy designation to immune checkpoint inhibitors for use in other cancers: nivolumab for Hodgkin lymphoma, and MPDL-3280A for bladder cancer and NSCLC.  These investigators reviewed the literature on PD-1 and PD-L1 blockade and focused on the reported clinical studies that have included patients with melanoma.  PubMed was searched to identify relevant clinical studies of PD-1/PD-L1-targeted therapies in melanoma.  A review of data from the current trials on clinicaltrial.gov was incorporated, as well as data presented in abstracts at the 2014 annual meeting of the American Society of Clinical Oncology, given the limited number of published clinical trials on this topic.  The anti-PD-1 and anti-PD-L1 agents have been reported to have impressive anti-tumor effects in several malignancies, including melanoma.  The greatest clinical activity in unselected patients has been seen in melanoma.  Tumor expression of PD-L1 is a suggestive, but inadequate, biomarker predictive of response to immune-checkpoint blockade.  However, tumors expressing little or no PD-L1 are less likely to respond to PD-1 pathway blockade.  Combination checkpoint blockade with PD-1 plus CTLA-4 blockade appeared to improve response rates in patients who are less likely to respond to single-checkpoint blockade.  Toxicity with PD-1 blocking agents is less than the toxicity with previous immunotherapies (e.g., interleukin 2, CTLA-4 blockade).  Certain AEs can be severe and potentially life-threatening, but most can be prevented or reversed with close monitoring and appropriate management.  The authors concluded that this family of immune-checkpoint inhibitors benefited not only patients with metastatic melanoma but also those with historically less responsive tumor types.  Although a subset of patients responded to single-agent blockade, the initial trial of checkpoint-inhibitor combinations has reported a potential to improve response rates.  Combination therapies appeared to be a means of increasing response rates, albeit with increased immune-related AEs.  As these treatments become available to patients, education regarding the recognition and management of immune-related effects of immune-checkpoint blockade will be essential for maximizing clinical benefit.

Mesothelioma

In an open-label, non-randomized, phase-II clinical trial, Calabro and colleagues (2018) examined the safety and efficacy of 1st-line or 2nd-line tremelimumab combined with durvalumab in patients with malignant mesothelioma.  Patients with unresectable pleural or peritoneal mesothelioma received intravenous tremelimumab (1 mg/kg body weight) and durvalumab (20 mg/kg body weight) every 4 weeks for 4 doses, followed by maintenance intravenous durvalumab at the same dose and schedule for 9 doses.  The primary end-point was the proportion of patients with an immune-related objective response according to the immune-related modified RECIST (for pleural mesothelioma) or immune-related RECIST version 1.1 (for peritoneal mesothelioma).  The primary analysis was done by intention-to-treat (ITT), whereas the safety analysis included patients who received at least 1 dose of study drug.  From October 30, 2015 to October 12, 2016, a total of 40 patients with mesothelioma were enrolled and received at least 1 dose each of tremelimumab and durvalumab.  Patients were followed-up for a median of 19.2 months (IQR 13.8 to 20.5); 11 (28 %) of 40 patients had an immune-related objective response (all PRs; confirmed in 10 patients), with a median response duration of 16.1 months (IQR 11.5 to 20.5); 26 (65 %) patients had immune-related disease control and 25 (63 %) had disease control.  Median immune-related PFS was 8.0 months (95 % CI: 6.7 to 9.3), median PFS was 5.7 months (1.7 to 9.7), and median OS was 16.6 months (13.1 to 20.1).  Baseline tumor PD-L1 expression did not correlate with the proportion of patients who had an immune-related objective response or immune-related disease control, with immune-related PFS, or with OS; 30 (75 %) patients experienced treatment-related AEs (TRAEs) of any grade, of whom 7 (18 %) had grade 3 to 4 TRAEs.  Treatment-related toxicity was generally manageable and reversible with protocol guidelines.  The authors concluded that the combination of tremelimumab and durvalumab appeared active, with a good safety profile in patients with mesothelioma, warranting further exploration.

Multiple Myeloma

Jelinek and Hajek (2016) stated that the introduction of PD-1/PD-L1 pathway inhibitors has marked a significant milestone in the treatment of various types of solid tumors.  The current situation in multiple myeloma (MM) is rather unclear, as distinct research groups have reported discordant results.  This discrepancy dominantly concerns the expression of PD-1/PD-L1 molecules as well as the identification of the responsible immune effector cell population.  The results of monotherapy with PD-1/PD-L1 inhibitors have been unsatisfactory in MM, suggesting that a combination approach is needed.  The most logical partners are immunomodulatory agents as they possess many synergistic effects.  The authors also proposed other rational and promising combinations that warrant further investigation.

Neuroendocrine Neoplasms

Weber and Fottner (2018) noted 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 clinical trials examine 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

In a multi-center, non-randomized, open-label, phase Ib clinical trial carried out at 5 cancer centers in the US, Antonia and colleagues (2016) evaluated durvalumab plus tremelimumab in patients with advanced squamous or non-squamous NSCLC.  These researchers enrolled immunotherapy-naive patients aged 18 years or older with confirmed locally advanced or metastatic NSCLC.  They gave patients durvalumab in doses of 3 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg every 4 weeks, or 10 mg/kg every 2 weeks, and tremelimumab in doses of 1 mg/kg, 3 mg/kg, or 10 mg/kg every 4 weeks for 6 doses, then every 12 weeks for 3 doses.  The primary end-point of the dose-escalation phase was safety.  Safety analyses were based on the as-treated population.  The dose-expansion phase of the study is ongoing.  Between October 28, 2013, and April 1, 2015, a total of 102 patients were enrolled into the dose-escalation phase and received treatment.  At the time of analysis (June 1, 2015), median follow-up was 18.8 weeks (interquartile range [IQR] 11 to 33).  The maximum tolerated dose (MTD) was exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg, with 2 (30 %) of 6 patients having a dose-limiting toxicity (1 grade-3 increased aspartate aminotransferase and alanine aminotransferase and 1 grade-4 increased lipase).  The most frequent treatment-related grade-3 and grade-4 AEs were diarrhea (11 [11 %]), colitis (9 [9 %]), and increased lipase (8 [8 %]).  Discontinuations attributable to treatment-related AEs occurred in 29 (28 %) of 102 patients.  Treatment-related serious AEs occurred in 37 (36 %) of 102 patients; 22 patients died during the study, and 3 deaths were related to treatment.  The treatment-related deaths were due to complications arising from myasthenia gravis (durvalumab 10 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), pericardial effusion (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg), and neuromuscular disorder (durvalumab 20 mg/kg every 4 weeks plus tremelimumab 3 mg/kg).  Evidence of clinical activity was noted both in patients with PD-L1-positive tumors and in those with PD-L1-negative tumors.  Investigator-reported confirmed objective responses were achieved by 6 (23 %, 95 % CI: 9 to 44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising 2 (22 %, 95 % CI: 3 to 60) of 9 patients with PD-L1-positive tumors and 4 (29 %, 95 % CI: 8 to 58) of 14 patients with PD-L1-negative tumors, including those with no PD-L1 staining (4 [40 %, 95 % CI: 12 to 74] of 10 patients).  The authors concluded that durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg showed a manageable tolerability profile, with anti-tumor activity irrespective of PD-L1 status, and was selected as the dose for phase III studies, which are ongoing.

On July 31, 2017, AstraZeneca and MedImmune announced that the FDA granted Breakthrough Therapy designation for Imfinzi (durvalumab), an anti-PD-L1 monoclonal antibody, for patients with locally advanced, unresectable non-small cell lung cancer (NSCLC) who do not relapse after platinum-based chemoradiation therapy. This Breakthrough Therapy designation was based on interim results from the Phase III PACIFIC trial (AstraZeneca, 2017).

The PACIFIC trial is a phase III, randomized, double-blinded, placebo-controlled, multi-center study that compared consolidation therapy with durvalumab versus placebo in patients with stage III NSCLC (PS 0-1) who had not progressed after 2 or more cycles of platinum-based chemoradiotherapy. The co-primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary end points included 12-month and 18-month progression-free survival (PFS) rates, the objective response rate, the duration of response, the time to death or distant metastasis, and safety. Of  the 713 patients who underwent randomization, 709 received consolidation therapy (473 received durvalumab and 236 received placebo). Most patients were current or former smokers and did not have EGFR mutations. Their PD-L1 status was typically less than 25% or unknown. Patients were randomly assigned to receive durvalumab (at a dose of 10 mg/kg intravenously) or placebo every 2 weeks for up to 12 months. Durvalumab was administered 1 to 42 days after the patients had received chemoradiotherapy. The median PFS was 16.8 months (95% confidence interval [CI], 13.0 to 18.1) with durvalumab versus 5.6 months (95% CI, 4.6 to 7.8) with placebo (stratified hazard ratio for disease progression or death, 0.52; 95% CI, 0.42 to 0.65; P<0.001); the 12-month PFS rate was 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0%. The response rate was higher with durvalumab than with placebo (28.4% vs. 16.0%; P<0.001), and the median duration of response was longer (72.8% vs. 46.8% of the patients had an ongoing response at 18 months). The median time to death or distant metastasis was longer with durvalumab than with placebo (23.2 months vs. 14.6 months; P<0.001). Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo; the most common adverse event of grade 3 or 4 was pneumonia (4.4% and 3.8%, respectively). A total of 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events. Investigators concluded that PFS was significantly longer with durvalumab than with placebo, and that the secondary end points also favored durvalumab. The safety was noted to be similar between the groups (Antonia et al, 2017).

Small-Cell Lung Cancer

Reck and colleagues (2016) noted that treatment for small-cell lung cancer (SCLC) has changed little over the past few decades; available therapies have failed to extend survival in advanced disease.  In recent years, immunotherapy with treatments such as interferons, tumor necrosis factors (TNFs), vaccines and immune checkpoint inhibitors has advanced and shown promise in the treatment of several tumor types.  Immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab, durvalumab, tremelimumab and ulocuplumab are at the forefront of immunotherapy and have achieved approvals for certain cancer types, including melanoma (ipilimumab, nivolumab and pembrolizumab), NSCLC (nivolumab and pembrolizumab) and RCC (nivolumab).  Clinical trials are investigating different immunotherapies in patients with other solid and hematologic malignancies, including SCLC.

In March 2020, the U.S. FDA approved durvalumab (Imfinzi, AstraZeneca) in combination with etoposide and either carboplatin or cisplatin as first-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC).

FDA approval was based on positive results from the phase III CASPIAN trial, in which Paz-Ares and colleagues (2019) found that durvalumab in combination with standard-of-care (SoC) platinum-etoposide demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) versus SoC alone. The CASPIAN trial was a randomized, multicenter, active-controlled, open-label, phase III trial that assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone (268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group). All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m² on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m² (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The phase III CASPIAN trial had two primary endpoints comparing experimental arms to SoC. The investigators found that in the durvalumab plus SoC arm, the risk of death was reduced by 27% (p=0.0047), with median overall survival (OS) of 13.0 months versus 10.3 months for SoC alone. Results also showed an increased confirmed objective response rate (ORR) in the durvalumab plus SoC arm (68% versus 58% for SoC alone). The safety and tolerability for durvalumab plus SoC was consistent with the known safety profiles of these medicines. The most common adverse reactions (≥20%) in patients with ES-SCLC were nausea, fatigue/asthenia, and alopecia. The investigators concluded that first-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group (AstraZeneca, 2020; FDA, 2020; Paz-Ares et al., 2019).

Durvalumab is also being tested following concurrent chemoradiation therapy in patients with limited-stage SCLC in the phase III ADRIATIC trial with data anticipated in 2021 (AstraZeneca, 2020).

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 "+" :
CPT codes covered if selection criteria are met:
VENTANA PD-L1 (SP263) Assay - no specific code :
Other CPT codes related to the CPB:
96413 - 96417	Chemotherapy administration; intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9173	Injection, durvalumab, 10 mg
Other HCPCS codes related to the CPB:
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9181	Injection, etoposide, 10 mg
J9263	Injection, oxaliplatin, 0.5 mg
ICD-10 codes covered if selection criteria are met:
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [non-small lung cancer (NSCLC) only] [extensive-stage small cell lung cancer (ES-SCLC) only]
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
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
C00.0 - C00.9, C01, C02.0 - C02.9, C03.0 - C03.9, C05.0 - C05.1, C06.0 - C06.9, C09.0 - C09.9, C10.3, C11.0 - C11.9, C12, C13.0 - C13.9, C14.0 - C14.8, C30.0, C31.0 - C31.9, C32.0 - C32.9, C76.0	Squamous cell carcinoma of head and neck
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach [gastric cancer]
C18.0 - C20	Malignant neoplasm of colon, rectosigmoid junction and rectum
C22.0	Liver cell carcinoma [hepatocellular carcinoma]
C37	Malignant neoplasm of thymus
C43.0 - C43.9	Malignant neoplasm of skin
C45.0	Mesothelioma of pleura
C45.1	Mesothelioma of peritoneum
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue [alveolar soft-part sarcoma]
C50.011 - C50.929	Malignant neoplasm of breast
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
C7A.00 - C7A.8	Malignant neuroendocrine tumors
C7B.00 - C7B.8	Secondary malignant neuroendocrine tumors
C90.00 - C90.02	Multiple myeloma
D15.0	Benign neoplasm of thymus
D3A.00 - D3A.8	Benign neuroendocrine tumors

The above policy is based on the following references: