Durvalumab (Imfinzi)

Number: 0917

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses durvalumab (Imfinzi) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

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 (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

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

1. Exclusions

   Aetna considers members not eligible for Imfinzi when they have experienced disease progression while on PD-1 or PD-L1 inhibitor therapy.

2. Criteria for Initial Approval

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

   1. Non-small cell lung cancer (NSCLC) - for treatment of NSCLC when any of the following criteria are met:

      1. The member has unresectable stage II or III NSCLC that has not progressed following concurrent platinum-based chemotherapy and radiation therapy; or
      2. The member has recurrent, advanced or metastatic NSCLC and meets all of the following criteria:
         
         
         1. The requested medication will be used in combination with tremelimumab-actl (Imjudo) and platinum-based chemotherapy; and
         2. The tumor is negative for EGFR exon 19 deletion and exon 21 L858R mutations and ALK rearrangements; or

      3. The member has resectable NSCLC and meets all of the following criteria:

         1. The requested medication will be used as neoadjuvant treatment in combination with platinum-containing chemotherapy and continued as adjuvant treatment after surgery as a single agent; and
         2. The tumor is negative for EGFR exon 19 deletion and exon 21 L858R mutations and ALK rearrangements;

   2. Small cell lung cancer (SCLC) - treatment of small cell lung cancer when either of the following criteria is met:

      1. The requested medication will be used for first-line treatment of extensive-stage small cell lung cancer in combination with etoposide and either carboplatin or cisplatin followed by single agent maintenance; or
      2. The requested medication will be used for adjuvant consolidation therapy as a single agent for treatment of limited stage small cell lung cancer and the member did not experience disease progression after systemic therapy with concurrent radiation therapy;
   3. Biliary tract cancer - for treatment of biliary tract cancer when the requested medication will be used in combination with cisplatin and gemcitabine to treat locally advanced, locoregionally advanced, unresectable or resected gross residual (R2) disease, or metastatic biliary tract cancer (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer) or for disease recurrence after surgery and adjuvant therapy;
   4. Cervical cancer - for treatment of persistent, recurrent or metastatic small cell neuroendocrine carcinoma of the cervix (NECC) when used in combination with etoposide and either cisplatin or carboplatin and continued as single agent maintenance therapy;
   5. Ampullary adenocarcinoma - for first-line treatment of unresectable or metastatic ampullary adenocarcinoma when both of the following criteria are met:
      
      
      1. The disease is pancreatobiliary or mixed type; and
      2. The requested medication will be used in combination with cisplatin and gemcitabine.
   6. Pleural mesothelioma - for first-line treatment of unresectable pleural mesothelioma when used in combination with pemetrexed and either cisplatin or carboplatin;
   7. Hepatocellular carcinoma - for first-line treatment of hepatocellular carcinoma as a single agent or in combination with tremelimumab-actl (Imjudo) when both of the following criteria are met:
      
      
      1. Disease is unresectable or extrahepatic/metastatic; and
      2. The member is ineligible for transplant.

   8. Esophageal, esophagogastric junction and gastric cancer - for treatment of esophageal, esophagogastric junction or gastric cancer (for a total of 3 doses) when all of the following criteria are met:

      1. The requested medication will be used in combination with tremelimumab (Imjudo) for neoadjuvant treatment; and
      2. The tumor is microsatellite instability-high (MSI-H) or deficient mismatch repair (dMMR); and
      3. The member is medically fit for surgery.

   9. Endometrial cancer - for treatment of advanced or recurrent endometrial cancer when all of the following criteria are met:

      1. The requested medication will be used in combination with carboplatin and paclitaxel followed by use as a single agent; and
      2. The tumor is deficient mismatch repair (dMMR).

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

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

   1. NSCLC - for continued treatment in members requesting reauthorization for NSCLC when any of the following criteria are met:

      1. The member has unresectable stage II or III NSCLC and there is no evidence of unacceptable toxicity or disease progression while on the current regimen (up to 12 months total); or
      2. The member has recurrent, advanced or metastatic NSCLC and there is no evidence of unacceptable toxicity or disease progression while on the current regimen; or
      3. The member has resectable NSCLC and there is no evidence of unacceptable toxicity or disease progression while on the current regimen (up to 12 cycles after surgery);
   2. Limited stage SCLC - for continued treatment in members requesting reauthorization for limited stage SCLC when there is no evidence of unacceptable toxicity or disease progression while on the current regimen (up to 24 months total);
   3. Esophageal, esophagogastric junction and gastric cancer - for treatment of esophageal, esophagogastric junction or gastric cancer (for a total of 3 doses). Reauthorization is considered medically necessary only when the member did not receive a total of 3 doses from the initial approval;
   4. All other indications - for continued treatment in members requesting reauthorization for an indication listed in Section II when there is no evidence of unacceptable toxicity or disease progression while on the current regimen. 

4. 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.

5. Related Policies

   1. CPB 0890 - Pembrolizumab (Keytruda)
   2. CPB 0892 - Nivolumab (Opdivo)
   3. CPB 0909 - Atezolizumab (Tecentriq)

Dosage and Administration

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

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

Neoadjuvant and Adjuvant Treatment of Resectable Non-small Cell Lung Cancer (NSCLC):

• For persons with a body weight of 30 kg and more:

  • Neoadjuvant: Imfinzi 1,500 mg in combination with chemotherapy every 3 weeks for up to 4 cycles prior to surgery
  • Adjuvant: Imfinzi 1,500 mg as a single agent every 4 weeks for up to 12 cycles after surgery

• For persons with a body weight of less than 30 kg:

  • Neoadjuvant: Imfinzi 20 mg/kg every 3 weeks in combination with chemotherapy for up to 4 cycles prior to surgery
  • Adjuvant: Imfinzi 20 mg/kg every 4 weeks as a single agent for up to 12 cycles after surgery

Unresectable Stage III NSCLC, Following Concurrent Platinum-based Chemotherapy and Radiation Therapy

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

Metastatic NSCLC

• For persons with a body weight of 30 kg or more: Administer Imfinzi 1,500 mg every 3 weeks in combination with tremelimumab-actl 75 mg and platinum-based chemotherapy for 4 cycles, and then administer Imfinzi 1,500 mg every 4 weeks as a single agent with histology-based pemetrexed maintenance therapy every 4 weeks, and a fifth dose of tremelimumab-actl 75 mg in combination with Imfinzi dose 6 at week 16. 
• For persons with a body weight of less than 30 kg: Administer Imfinzi 20 mg/kg every 3 weeks in combination with tremelimumab-actl 1 mg/kg and platinum-based chemotherapy, and then administer Imfinzi 20 mg/kg every 4 weeks as a single agent with histology-based pemetrexed therapy every 4 weeks, and a fifth dose of tremelimumab-actl 1 mg/kg in combination with Imfinzi dose 6 at week 16.

Limited Stage-Small Cell Lung Cancer (LS-SCLC), Following Concurrent Platinum-based Chemotherapy and Radiation Therapy

• For persons with a body weight of 30 kg or more: With etoposide and either carboplatin or cisplatin, administer Imfinzi 1,500 mg every 3 weeks in combination wiht chemotherapy, and then 1,500 mg every 4 weeks as a single agent.
• 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 in combination with chemotherapy, and then 10 mg/kg every 2 weeks as a single agent.

Extensive-stage Small Cell Lung Cancer (ES-SCLC)

• 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
• 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

Biliary Tract Cancer (BTC)

• For persons with a body weight of 30 kg or more: Administer Imfinzi 1,500 mg every 3 weeks in combination with chemotherapy, and then 1,500 mg every 4 weeks as a single agent.
• For persons with a body weight of less than 30 kg : Administer Imfinzi 20 mg/kg every 3 weeks in combination with chemotherapy, and then 20 mg/kg every 4 weeks as a single agent.

Unresectable Hepatocellular Carcinoma

• For persons with a body weight of 30 kg and more: Administer Imfinzi 1,500 mg in combination with tremelimumab-actl 300 mg as a single dose at day 1 of cycle 1, followed by Imfinzi as a single agent every 4 weeks.
• For persons with a body weight of less than 30 kg: Administer Imfinzi 20 mg/kg in combination with tremelimumab-actl 4 mg/kg as a single dose at day 1 of cycle 1, followed by Imfinzi as a single agent every 4 weeks.

Mismatch Repair Deficient Endometrial Cancer

• For persons with a body weight of 30 kg and more: Administer Imfinzi 1,120 mg in a combination with carboplatin and paclitaxel every 3 weeks (21 days) for 6 cycles, followed by Imfinzi 1,500 mg every 4 weeks as a single agent. Administer Imfinzi prior to chemotherapy on the same day.
• For persons with a body weight of less than 30 kg: Administer Imfinzi 15 mg/kg in combination with carboplatin and paclitaxel every 3 weeks (21 days) for 6 cycles, followed by Imfinizi 20 mg/kg every 4 weeks as a single agent. Administer Imfinzi prior to chemotherapy on the same day.

Source: AstraZeneca, 2024

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
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:
J9022	Injection, atezolizumab, 10 mg
J9023	Injection, avelumab, 10 mg
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9119	Injection, cemiplimab-rwlc, 1 mg
J9181	Injection, etoposide, 10 mg
J9196	Injection, gemcitabine hydrochloride (accord), not therapeutically equivalent to j9201, 200 mg
J9198	Injection, gemcitabine hydrochloride, (infugem), 100 mg
J9201	Injection, gemcitabine hydrochloride, not otherwise specified, 200 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9271	Injection, pembrolizumab, 1 mg
J9299	Injection, nivolumab, 1 mg
J9305	Injection, pemetrexed, not otherwise specified, 10 mg
J9347	Injection, tremelimumab-actl, 1 mg
ICD-10 codes covered if selection criteria are met:
C15.3 - C15.9	Malignant neoplasm of esophagus
C16.0 - C16.9	Malignant neoplasm of stomach [gastric cancer]
C22.0 – C22.9	Malignant neoplasm of liver and intrahepatic bile ducts
C23	Malignant neoplasm of gallbladder
C24.0 – C24.9	Malignant neoplasm of other and unspecified parts of biliary tract
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [Recurrent, advanced non-small lung cancer (NSCLC) only] [extensive-stage small cell lung cancer (ES-SCLC) only]
C45.0	Mesothelioma of pleura
C53.0 - C53.9	Malignant neoplasm of cervix uteri
C54.1	Malignant neoplasm of endometrium
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
C18.0 - C20	Malignant neoplasm of colon, rectosigmoid junction and rectum
C37	Malignant neoplasm of thymus
C43.0 - C43.9	Malignant neoplasm of skin
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

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Background

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

• Imfinzi, as a single agent, is indicated for the treatment of adult patients with unresectable, Stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.
• Imfinzi, in combination with etoposide and either carboplatin or cisplatin, is indicated for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).
• Imfinzi, in combination with gemcitabine and cisplatin, is indicated for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC).
• Imfinzi, in combination with tremelimumab-actl, is indicated for the treatment of adult patients with unresectable hepatocellular carcinoma (uHCC).
• Imfinzi, in combination with tremelimumab-actl and platinum-based chemotherapy, is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) genomic tumor aberrations.
• Imfinizi, in combination with carboplatin and paclitaxel followed by Imfinzi as a single agent, is indicated for the treatment of adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR).
• Imfinzi, in combination with platinum-containing chemotherapy as neoadjuvant treatment, followed by Imfinzi continued as a single agent as adjuvant treatment after surgery, is indicated for the treatment of adult patients with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements.
• Imfinzi, as a single agent, is indicated for the treatment of adult patients with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy.

Compendial Uses

• Ampullary adenocarcinoma
• Cervical cancer
• Biliary tract cancer
  
  
  • Intrahepatic cholangiocarcinoma
  • Extrahepatic cholangiocarcinoma
  • Gallbladder cancer
    
    
• Esophageal and esophagogastric junction cancer
• Gastric cancer
• Hepatocellular carcinoma
• Non-small cell lung cancer
• Pleural mesothelioma
• Small cell lung cancer

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 cell mediated 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 hepatitis, 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.

Biliary Tract Cancer

On September 2, 2022, the U.S. Food and Drug Administration (FDA) approved Imfinzi (durvalumab) in combination with gemcitabine and cisplatin for the treatment of adult patients with locally advanced or metastatic biliary tract cancer (BTC). The FDA approval was based on supporting data from the TOPAZ-1 study. (FDA, 2022a).

In the TOPAZ-1 study, a randomized, double-blind, placebo-controlled, multicenter trial, investigators evaluated the efficacy of Imfinzi (durvalumab) in patients (n =685) with histologically confirmed locally advanced unresectable metastatic BTC who had not previously received systemic therapy for advanced disease. Patients were randomized 1:1 to receive: Imfinzi 1,500 mg on day 1 + gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 of each 21-day cycle up to 8 cycles, followed by Imfinzi 1,500 mg every 4 weeks or placebo on day 1 + gemcitabine 1,000 mg/m2 and cisplatin 25 mg/m2 on days 1 and 8 of each 21-day cycle up to 8 cycles, followed by placebo every 4 weeks. The major efficacy outcome endpoint was overall survival (OS). Tumor assessments were performed every 6 weeks for the first 24 weeks, then every 8 weeks until confirmed objective disease progression. A statistically significant improvement in OS was noted in patients randomized to receive Imfinzi with gemcitabine and cisplatin versus those randomized to receive placebo with gemcitabine and cisplatin. Median OS was 12.8 months (95% confidence interval [CI]: 11.1, 14) and 11.5 months (95% CI; 10.1, 12.5) in the Imfinzi and placebo arms, respectively (hazard ratio 0.80; 95% CI: 0.66, 0.97, p = 0.021). The median progression-free survival was 7.2 months (95% CI: 6.7, 7.4) and 5.7 months (95% CI: 5.6, 6.7) in the Imfinzi and placebo arms, respectively. Investigator-assessed overall response rate was 27% (95% CI: 22%-32%) and 19% (95% CI: 15%-23%) in the Imfinzi and placebo arms, respectively (AstraZeneca, 2022; FDA, 2022a).

Bladder Cancer - Urothelial

In the UpToDate review of "Treatment of metastatic urothelial cancer of the bladder and urinary tract", Bellmunt (2023) noted "We do not offer durvalumab to patients with metastatic urothelial carcinoma who are either treatment-naïve or refractory to platinum-based chemotherapy. While durvalumab was initially granted accelerated regulatory approval by the FDA based on clinical activity in early phase I/II clinical trials as second-line therapy, a phase III trial (DANUBE) in treatment-naïve patients did not confirm an OS benefit over platinum-based chemotherapy, either as a single agent or in combination with the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitor tremelimumab. Based on these data, regulatory approval for durvalumab in second-line was voluntarily withdrawn in the United States only, specifically for advanced or metastatic urothelial carcinoma that has progressed on platinum-based chemotherapy.

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).

Deininger et al (2022) stated that in Bacillus Calmette-Guerin (BCG) refractory non-muscle-invasive bladder cancer (NMIBC), radical cystectomy is the gold standard.  The advent of immune checkpoint inhibitors (CPIs) has permanently changed the therapy landscape of BC.  These researchers presented a systematic review of immune-modulating (IM) therapies (CPIs and others) in BCG-refractory NMIBC.  A total of 406 studies were identified via data bank research in PubMed/Medline, with data cut-off in October 2021; 4 full-text articles and 4 additional congress abstracts were included in the review.  Durvalumab plus oportuzumab monatox, pembrolizumab, and nadofaragene firadenovec (NF) showed complete response (CR) rates of 41.6 %, 40.6 %, and 59.6 % after 3 months, with a long-lasting effect, especially for NF (12-month CR rate of 30.5 %).  Instillations with oncolytic viruses such as NF and CG0070 showed good effectiveness without triggering significant immune-mediated systemic AEs.  Recombinant BCG VPM1002BC could prove to be valid as an alternative to BCG in the future.  The recombinant pox-viral vector vaccine PANVAC is not convincing in combination with BCG.  Interleukin (IL)-mediating therapies, such as ALT-803, are currently being investigated.  The authors concluded that CPIs and other IM agents now offer an increasing opportunity for bladder-preserving strategies; studies on different substances are ongoing and will yield new findings.

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.

Huo et al (2021) noted that one of the main therapeutic regimens for the treatment of metastatic triple-negative breast cancer (mTNBC) is with PD-1 or PD-L1 blockade combined with chemotherapy; however, the results of such studies have been controversial.  These investigators searched PubMed, Embase, Cochrane Library, and the proceedings of the last 5 years of several meetings until February 18, 2021.  The primary endpoint was the PFS of PD-L1-positive patients treated with PD1/PD-L1 blockade plus chemotherapy compared with chemotherapy.  A total of 4 studies (3,007 mTNBC patients) were analyzed in this meta-analysis.  PFS was significantly improved in the PD1/PD-L1 blockade plus chemotherapy group compared with the chemotherapy group in PD-L1-positive mTNBC patients (hazard ratios [HR], 0.69; 95 % CI: 0.59 to 0.80; p < 0.001), also in ITT population (HR, 0.82; 95 % CI: 0.74 to 0.90; p < 0.001).  However, no significant benefit in OS was observed regardless of PD-L1 status or ITT population.  The immunotherapy plus chemotherapy had higher AEs compared with chemotherapy (all AEs, odds ratios [ORs], 2.33; 95 % CI: 1.50 to 3.62; p < 0.001; grade 3 to 5 AEs, OR, 1.27; 95 % CI: 1.04 to 1.55; p = 0.019).  The authors concluded that this meta-analysis showed that the addition of PD1/PD-L1 blockade to chemotherapy improved PFS in PD-L1 positive mTNBC patients, also in the ITT population.  However, no significant benefit in OS was observed in patients of PD-L1 positive or in the ITT population after adding PD1/PD-L1 blockade.  These investigators found a higher rate of AEs with the addition of PD1/PD-L1 blockers to chemotherapy.  Durvalumab is one of the key words listed in this trial.

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.

Endometrial Cancer

Maiorano et al (2022) noted that endometrial cancer (EC) represents the 6th most common female tumor.  In the advanced setting, the prognosis is dismal with limited therapeutic options.  Platinum-based chemotherapy represents the actual SoC in 1st-line chemotherapy, but no standard 2nd-line chemotherapy is approved, with less than 1/4 of patients responding to 2nd-line chemotherapy.  In the past decade, immune checkpoint inhibitors (ICIs) have changed the treatment landscape of many solid tumors.  This systematic review was carried out according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.  These investigators searched Embase, Medline, Cochrane Database, and conference abstracts from international societies, up to November 2021.  Clinical trials using ICIs in advanced EC, written in English, were included.  Reviews, letters, and commentaries were excluded.  The ORR, PFS, OS, and safety (number and grade of TRAEs) were evaluated.  A total of 15 studies (1,627 patients) were included: 14 non-randomized phase-I/II clinical trials and 1 randomized phase-III clinical trial.  Anti-PD1 (pembrolizumab, nivolumab, dostarlimab) and anti-PD-L1 agents (avelumab, atezolizumab, durvalumab) were administered as single agents; pembrolizumab and nivolumab were combined with the tyrosine-kinase inhibitors (TKI) lenvatinib and cabozantinib, respectively; and durvalumab was associated with anti-CTLA4 tremelimumab; 4 studies selected only MSI patients.  Single agents determined an ORR from 26.7 % to 58 % among MSI patients, from 3 % to 26.7 % among MSS patients.  Disease control rate (DCR) ranged from 53.5 % to 88.9 % in MSI, 31.4 % to 35.2 % in MSS patients.  The combination of TKI and ICIs determined 32 % to 63.6 % of ORR in all-comers, 32 % to 36.2 % in MSS patients. 54.2 % to 76 % of patients developed TRAEs.  The combination of ICIs and TKI achieved a higher toxicity rate than single agents (grade-3 or worse TRAEs 88.9 %).  The authors concluded that ICIs represent an effective option for pre-treated advanced EC patients with a tolerable profile.  Given the encouraging results in MSI patients, every woman diagnosed with EC should be examined for MS status.  In MSS women, the combination of ICIs and TKI was more effective than monotherapy, notwithstanding safety concerns.  PD-L1 could not predict ICI response, whereas other biomarkers such as MSI and tumor mutational burden appeared more accurate.  These researchers stated that ongoing randomized trials will further clarify the role of these therapeutic options.

On June 14, 2024, the U.S. Food and Drug Administration approved Imfinzi (durvalumab) with carboplatin plus paclitaxel followed by single-agent Imfinzi for adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR). The FDA approval was based on supporting data from the DUO-E study, a randomized, multicenter, double-blind, placebo-controlled trial in patients with advanced or recurrent endometrial cancer (FDA, 2024b).

The DUO-E study enrolled patients with newly diagnosed Stage III disease (with measurable disease per Response Evaluation Criteria in Solid Tumors [RECIST] v1.1), or newly diagnosed Stage IV disease and patients with recurrent disease with a low potential for cure by radiation therapy or surgery. Patient randomization was stratified by tumor mismatch repair (MMR) status (proficient or deficient), disease status (recurrent or newly diagnosed), and geographic region (Asia or rest of the world). Investigators used an immunohistochemistry tumor tissue test to assess MMR status. Patients were randomized (1:1:1) to one of the following treatment arms (AstraZeneca, 2024):

• Imfinzi 1120 mg with carboplatin plus paclitaxel every 3 weeks for a maximum of 6 cycles. Following completion of chemotherapy, patients received Imfinzi 1500 mg every 4weeks as maintenance until disease progression.
• Placebo with carboplatin and paclitaxel every 3 weeks for a maximum of 6 cycles. Following completion of chemotherapy, patients received placebo every 4 weeks until disease progression.
• An additional investigational combination regimen.

Investigators determined progression-free survival (PFS), the major efficacy outcome measure, by assessment using RECIST v1.1. While improvement in PFS was statistically significant in the overall population for Imfinzi with carboplatin plus paclitaxel compared to carboplatin and paclitaxel alone, the improvement in the overall population was mainly due to patients with dMMR tumors based on an exploratory analysis by tumor MMR status (FDA, 2024b).

In 95 patients with dMMR tumors, median PFS was not reached (NR) (95% confidence interval [CI]: NR, NR) in the Imfinzi arm and was 7 months (95% CI: 6.7, 14.8) in the placebo arm (hazard ratio: 0.42 [95% CI: 0.22, 0.80]). Overall survival, an additional efficacy outcome measure, was immature at the PFS analysis (FDA, 2024b).

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.

Poulose and Kainickal (2022) stated that the outcomes of patients diagnosed with head and neck squamous cell carcinoma (HNSCC) who are not candidates for local salvage therapy and of those diagnosed with recurrent or metastatic disease are dismal.  A relatively new systemic therapy option that emerged in recent years in the treatment of advanced HNSCC is immunotherapy using ICIs.  The safety profile and anti-tumor activity of these agents demonstrated in early phase clinical trials paved the way to the initiation of several promising phase-III clinical trials in the field.  In a systematic review, these investigators examined the evidence on the effectiveness of ICIs in HNSCC, based on published phase-III clinical trials.  They searched PubMed, Cochrane Library, Embase, and Scopus to identify published literature evaluating immunotherapy using ICIs in recurrent or metastatic HNSCC (R/M HNSCC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC).  These researchers used a combination of standardized search terms and keywords including head and neck squamous cell carcinoma, recurrent, metastatic, locally advanced, immunotherapy, immune checkpoint inhibitors, monoclonal antibodies, programmed cell death protein-1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T- lymphocyte associated protein-4 (CTLA-4), and phase-III clinical trial.  A sensitive search filter was used to limit their results to RCTs.  A total of 5 phase-III clinical trials have reported the data on the effectiveness of immunotherapy in HNSCC so far: 4in R/M HNSCC and 1 in LAHNSCC.  In patients with R/M HNSCC, anti-PD-1 agents nivolumab and pembrolizumab demonstrated improved survival benefits in the 2nd-line treatment setting compared to the SoC (standard single-agent systemic therapy).  While the net gain in OS with nivolumab was 2.4 months (hazard ratio [HR] = 0.69, p = 0.01), that with pembrolizumab was 1.5 months (HR = 0.80 nominal p = 0.0161).  The anti-PD-L1 agent durvalumab with or without the anti-cytotoxic T- lymphocyte associated protein-4 agent tremelimumab did not result in any beneficial outcomes.  In the 1st-line setting, in R/M HNSCC, pembrolizumab plus platinum-based chemotherapy resulted in significant improvement in survival with a net gain in OS of 2.3 months (HR = 0.77, p = 0.0034) in the overall population and a net gain in OS of 4.2 months in the PD-L1 positive (combined positive score of greater than 20) population compared to SoC (EXTREME regime).  In patients with PD-L1 positive R/M HNSCC, monotherapy with pembrolizumab also demonstrated statistically significant improvement in survival compared to EXTREME.  In LAHNSCC, immunotherapy using avelumab (an anti-PD-L1 agent) along with standard chemoradiation therapy did not result in improved outcomes compared to placebo plus chemoradiation therapy.  The authors concluded that anti-PD-1 agents provided survival benefits in R/M HNSCC in the 1st and 2nd-line settings, with acceptable toxicity profiles compared to standard therapy.  There is no proven effectiveness in the curative setting to-date.

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).

On October 21, 2022, the U.S. Food and Drug Administration (FDA) approved tremelimumab (Imjudo) in combination with durvalumab for adult patients with unresectable hepatocellular carcinoma (uHCC). The FDA approval was based on supporting data from the HIMALAYA study for efficacy assessment comparing 782 patients randomized to tremelimumab plus durvalumab (n=393) versus sorafenib (n=389) (FDA, 2022c).

The efficacy of tremelimumab in combination with durvalumab was evaluated in the HIMALAYA study, a randomized (1:1:1), open-label, multicenter study consisting of patients confirmed with unresectable hepatocellular carcinoma (uHCC) who had not received prior systemic treatment for HCC. Patient randomization was to one of three arms: tremelimumab 300 mg as a one-time single intravenous (IV) infusion plus durvalumab 1500 mg IV on the same day, followed by durvalumab 1500 mg IV every 4 weeks; durvalumab 1500 mg IV every 4 weeks; or sorafenib 400 mg orally twice daily until disease progression or unacceptable toxicity. The major efficacy outcome measure was overall survival (OS). Additional outcome measures included: investigator-assessed progression-free survival (PFS), objective response rate (ORR) and duration of response (DoR) according to RECIST v1.1. The results demonstrated statistical significance and clinically meaningful improvement in OS in the tremelimumab plus durvalumab arm compared to the sorafenib arm (stratified hazard ratio [HR] of 0.78 [95% Confidence Interval (CI): 0.66, 0.92], 2-sided p value = 0.0035); median OS was 16.4 months (95% CI: 14.2, 19.6) versus 13.8 months (95% CI: 12.3,16.1). Median PFS was 3.8 months (95% CI: 3.7, 5.3) and 4.1 months (95% CI: 3.7, 5.5) for the tremelimumab plus durvalumab and sorafenib arms, respectively (stratified HR 0.90; 95% CI: 0.77, 1.05). ORR was 20.1% (95% CI:16.3, 24.4) in the tremelimumab plus durvalumab arm and 5.1% (95% CI: 3.2, 7.8) for those treated with sorafenib (FDA, 2022c).

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.

Lower Gastro-Intestinal Cancers

Wilson et al (2021) stated that limited therapy options exist for patients with treatment-refractory metastatic colorectal or anal cancers, prompting investigation into alternative therapies.  Immunotherapy in the form of immune checkpoint blockade is one such emerging treatment that has shown promising results in other types of tumors.  In a systematic review, these investigators examined the current use of immune checkpoint blockade in patients with lower gastro-intestinal (GI) tumors.  They searched Embase, Medline and Cochrane databases for included studies.  Clinical trials published in English and using immune checkpoint blockade for primary tumors situated in the lower GI tract were included.  Databases were searched for studies reporting on at least one of the following: OS, PFS or response to therapy.  A total of 972 abstracts were screened, with 10 studies included in the final review; 8 studies (833 patients) examined immune checkpoint blockade in the setting of CRCs.  These included pembrolizumab, nivolumab, durvalumab, atezolizumab, tremelimumab and ipilimumab.  A total of 20 patients across all studies achieved a CR, and 111 patients achieved a PR to treatment; 2 trials (62 patients) assessed immune checkpoint blockade in anal cancer, using nivolumab and pembrolizumab; 2 patients across both studies achieved a CR, and 11 patients achieved a PR.  The authors concluded that a number of patients with advanced lower GI tumors achieved a CR to treatment for what would otherwise be considered palliative disease.  These researchers stated that presented data highlighted that select patients may benefit from 1st-line or combination immunotherapy; thus, further investigation is needed to individualize treatment.

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).

On November 10, 2022, the U.S. Food and Drug Administration (FDA) approved tremelimumab (Imjudo) in combination with durvalumab (Imfinzi) and platinum-based chemotherapy for adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Efficacy was evaluated in the POSEIDON study, a randomized (1:1:1), multicenter, active-controlled, open-label study in patients with metastatic NSCLC who had not received prior systemic treatment. Patients were randomized to one of three treatment arms: (1) tremelimumab, durvalumab, and platinum-based chemotherapy for 4 cycles, followed by durvalumab and maintenance chemotherapy every 4 weeks. Patients were treated with a fifth tremelimumab dose at week 16; (2) durvalumab plus platinum-based chemotherapy for 4 cycles followed by durvalumab and maintenance chemotherapy; or (3) platinum-based chemotherapy for 6 cycles followed by maintenance chemotherapy. Treatment was continued until disease progression or unacceptable toxicity. This approval was based on an efficacy comparison of treatment arm 1 (n=338) and 3 (n=337). The major efficacy endpoint measures were progression-free survival (PFS) and overall survival (OS). Tremelimumab plus durvalumab and platinum-based chemotherapy exhibited a statistically significant and clinically meaningful improvement in OS compared to platinum-based chemotherapy (hazard ratio [HR] of 0.77 [95% CI: 0.65, 0.92], 2-sided p-value = 0.00304); median OS was 14 months (95% CI: 11.7, 16.1) and 11.7 months (95% CI: 10.5, 13.1) in the treatment arm 1 and 3, respectively. Median PFS was 6.2 months (95% CI: 5.0, 6.5) and 4.8 months (95% CI 4.6, 5.8) in the treatment arms, respectively (HR 0.72 [95% CI: 0.60, 0.86], 2-sided p-value = 0.00031). Overall response rate was 39% (95% CI: 34,44) in and 24% (95% CI: 20, 29) in the treatment arm 1 and 3, respectively. Median duration of response was 9.5 months (95% CI: 7.2, not reached) and 5.1 months (95% CI: 4.4, 6.0) in the two treatment arms (AstraZeneca, 2022; FDA, 2022b).

On August 15, 2024, the FDA approved durvalumab (Imfinzi) with platinum-containing chemotherapy as neoadjuvant treatment, followed by single-agent durvalumab as adjuvant treatment after surgery for adults with resectable (tumors ≥ 4 cm and/or node positive) non-small cell lung cancer (NSCLC) and no known epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements. The FDA approval was based on supporting data from the AEGEAN study (FDA, 2024c),

In the AEGEAN study, a randomized, double-blind, placebo-controlled, multicenter trial, Heymach et al. (2023), evaluated the efficacy and safety of durvalumab (Imfinzi) in combination with neoadjuvant chemotherapy, followed by surgery and continued adjuvant treatment of Imfinzi as a single agent in 802 patients with previously untreated and resectable squamous or non-squamous NSCLC (Stage IIA to select Stage IIIB [AJCC Cancer Staging Manual, 8th edition]). Patients were randomized 1:1 to receive either durvalumab or placebo, with platinum-based chemotherapy, every 3 weeks for up to 4 cycles (neoadjuvant treatment) followed by either continued single-agent agent durvalumab (n = 400) or placebo (n = 402), every 4 weeks for up to 12 cycles (adjuvant treatment). Patients were randomized to one of the following treatment arms (Genentech, 2024):

• Arm 1: Neoadjuvant Imfinzi 1500 mg once every 3 weeks for up to 4 cycle in combination with:

  • Squamous tumor histology: carboplatin AUC 6 and paclitaxel 200 mg/m² on Day1 of each 3-week cycle, or cisplatin 75 mg/m² on Day 1 and gemcitabine 1250 mg/m² on Day 1 and Day 8 of each 3-week cycle, for 4 cycles
  • Non-squamous tumor histology: pemetrexed 500 mg/m² and cisplatin 75 mg/m² on Day 1 of each 3-week cycle, for 4 cycles OR pemetrexed 500 mg/m² and carboplatin AUC 5 on Day 1 of each 3-week cycle, for 4 cycles.

Followed by adjuvant Imfinzi 1500 mg as a single agent for up to 12 cycles post-surgery.

• Arm 2: Neoadjuvant placebo in combination with 4 cycles of chemotherapy (refer to full prescribing information) prior to surgery.

  Followed by placebo for up to 12 cycles post-surgery.

The primary efficacy outcome measures were event-free survival (EFS) by blinded independent central review assessment and pathological complete response (pCR) by blinded central pathology review. Median EFS was not reached (95% Confidence Interval [CI]: 31.9, not estimable [NE]) in the the Imfinzi arm and 25.9 months (95% CI: 18.9, NE) in the placebo arm (hazard ratio 0.68 [95% CI: 0.53, 0.88]; p = 0.0039). The pCR rate was 17.2% (95% CI: 13.5, 21.5) and 4.3% (95% CI: 2.5, 6.8) in the durvalumab and placebo arms, respectively. At the time of the prespecified interim analyses, overall survival (OS) was not formally tested for statistical significance. Nevertheless, a descriptive analysis revealed no clear detriment (FDA, 20224b).

The most common adverse reactions (≥ 20%) were anemia, nausea, constipation, fatigue, musculoskeletal pain, and rash. In the neoadjuvant Imfinzi arm, 1.7% of the patients were unable to undergo surgery due to adverse reactions compared with 1% in the placebo arm (FDA, 2024c).

Ovarian Cancer

Barve et al (2022) noted that gemogenovatucel-T (Vigil) is a triple-function autologous tumor cell immunotherapy that expresses granulocyte-macrophage colony-stimulating factor and decreases expression of furin and down-stream TGF-β1 and TGF-β2.  Vigil has suggested survival benefit in front-line maintenance of ovarian cancer (OC) patients who are BRCA-wt.  Furthermore, Vigil demonstrated relapse-free survival (RFS) and OS advantage in homologous recombination-proficient patients with OC.  Further evidence of clinical benefit and safety has been demonstrated in combination with atezolizumab.  In a pilot study, these researchers examined the combined use of durvalumab and Vigil for the treatment of advanced BRCA-wt relapsed TNBC patients and stage III to IV recurrent/refractory (R/R) OC patients.  Patients received the combination regimen of Vigil (1 × 10e6-10e7 cells/dose intradermally, up to 12 doses) and durvalumab (1,500 mg/dose intravenous infusion, up to 12 months) once every 4 weeks.  The primary objective was to evaluate safety of this combination.  This trial included 13 BRCA-wt patients (TNBC, n = 8; OC, n = 5).  The most common treatment-emergent adverse events (TEAEs of 20 % or worse) in all patients included injection-site reaction (92.3 %), myalgia (38.5 %), bruise at injection site (23.1 %), and pruritus (23.1 %); 3 grade-3 TEAES were observed and related to durvalumab.  There were no grade 4/5 TEASEs.  Median PFS was 7.1 months; and the median OS was not reached.  Prolonged PFS was improved in patients with PD-L1+ tumors (n = 8, HR = 0.304, 95 % CI: 0.0593 to 1.56, 1-sided p = 0.04715) compared with those with PD-L1- tumors.  The authors concluded that Vigil plus durvalumab was well-tolerated and showed promising clinical activity in advanced BRCA-wt TNBC and stage III-IV recurrent/refractory OC patients.

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).

On December 4, 2024, the U.S. Food and Drug Administration (FDA) approved durvalumab (Imfinzi) for the treatment of adults with limited-stage small cell lung cancer (LS-SCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. The FDA approval was based on supporting data from the ADRIATIC study (FDA, 2024a).

In the ADRIATIC study, a randomized, double-blind, placebo-controlled, multicenter study, Cheng et al. (2024) evaluated the efficacy of durvalumab (Imfinzi) in 730 patients with histologically or cytologically confirmed (Stage I to III according to American Joint Committee on Cancer [AJCC], 8th edition) whose disease had not progressed following concurrent chemoradiation therapy (cCRT). Patients with active or prior documented autoimmune disease within 5 years of initiation into the study; a history of active primary immunodeficiency; a history of Grade ≥ 2 pneumonitis or active tuberculosis or hepatitis B or C or HIV infection; active interstitial lung disease were not eligible. Additionally patients with mixed small cell lung cancer and non-small cell lung cancer history were also not eligible. Patients were randomized 1:1:1 to receive Imfinzi 1500 mg, as a single agent (n=264), Imfinzi plus tremelimumab 75 mg (four doses only) (n=200), or Imfinzi plus placebo (n=266) every 4 weeks until disease progression, until acceptable toxicity, or for a maximum of 24 months. Randomization was stratified by disease stage (I or II versus III) and receipt of prophylactic cranial irradiation (yes versus no).

All study medications were given intravenously. Efficacy evaluation for LS-SCLC was based on a comparison between (AstraZeneca, 2024):

• Arm 1: Imfinzi 1,500 mg in combination with placebo every 4 weeks for 4 cycles, followed by Imfinzi 1,500 mg every 4 weeks.
• Arm 2: Placebo in combination with a second placebo every 4 weeks for 4 cycles, followed by a single placebo every 4 weeks.

Tumor assessments were performed every 8 weeks for the first 72 weeks, then every 12 weeks up to 96 weeks and then every 24 weeks thereafter (AstraZeneca, 2024).

The primary efficacy outcome measures were overall survival (OS) and progression-free survival (PFS) assessed by blinded independent clentral review (BICR) according to the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) for the comparison of Imfinzi as a single agent and placebo. Imfinzi demonstrated a statistically significant OS improvement compared to placebo with a hazard ratio (HR) of 0.73 (95% Confidence Interval [CI]: 0.57, 0.93; p=0.0104). The medion OS was 55.9 months (95% CI: 37.3, not reached) in the Imfinzi arm and 33.4 months (95% CI: 25.5, 39.9) in the placebo arm. Imfinzi also demonstrated a statistically significant PFS improvement compared to placebo with HR of 0.76 (95% CI: 0.61, 0.95; p=0.0161). The median PFS was 16.6 months (95% CI: 10.2, 28.2) and 9.2 months (95% CI: 7.4, 12.9) in the Imfinzi and placebo arms, respectively (AstraZeneca, 2024; FDA, 2024a).

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