| Coverage Policy Manual | |
| Policy #: | 2016005 |
| Category: | Pharmacy |
| Initiated: | February 2016 |
| Last Review: | August 2023 |
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| Anti-PD-1 (programmed death receptor-1) Therapy (e.g., Nivolumab) (e.g., Durvalumab) (e.g., Cemiplimab) | |
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| Description: |
The programmed death 1 protein (PD1) is an immune checkpoint receptor expressed by activated T cells. PD-1 binds to its ligands Pd1-L1 and PD1-L2 which are expressed on tumor cells, causing immunosuppression and preventing the immune system from rejecting the tumor.
PD-1 inhibition has been studied in clinical trials in metastatic melanoma, non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, head and neck cancer and urothelial cancer.
Regulatory Status
Nivolumab was originally approved in December 2014 by the U.S. Food and Drug Administration under an accelerated approval for the treatment of individuals with unresectable or metastatic melanoma and disease progression following ipilimumab and if BRAF V600 mutation positive, a BRAF inhibitor. In September 2015, the FDA granted approval for the treatment of metastatic squamous non-small cell lung cancer in individuals with progression on or after platinum-based chemotherapy as well as in combination with ipilimumab in individuals with BRAF V600 wild-type melanoma. In November 2015, FDA approval was granted for the use as a single agent in the treatment of individuals with BRAF V600 wild-type unresectable or metastatic melanoma. In January 2016, the FDA granted expansion of the indication as a single agent for the treatment of individuals with BRAF V600 mutation positive, unresectable or metastatic melanoma to remove the restriction that such individuals should have disease progression following ipilimumab and a BRAF inhibitor. Additionally, the approval expanded the indication for the combined use with ipilimumab for the treatment of individuals with unresectable or metastatic melanoma to remove the restriction for the treatment of only patients with BRAF wild-type melanoma.
On May 17, 2016, the FDA granted accelerated approval to nivolumab (e.g., Opdivo, marketed by Bristol-Myers Squibb) for the treatment of individuals with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin (Adcetris) (FDA, 2016).
On November 10, 2016, the FDA approved nivolumab (e.g., OPDIVO Injection, Bristol-Myers Squibb Company), for the treatment of individuals with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy (FDA, 2016).
On February 2, 2017, the U.S. Food and Drug Administration granted accelerated approval to nivolumab (e.g., OPDIVO, Bristol-Myers Squibb Company) for treatment of individuals with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy (FDA, 2017).
A new “Warning and Precaution” was issued for complications of allogeneic HSCT after nivolumab. Transplant-related deaths have occurred, and health care professionals should follow individuals closely for early evidence of transplant-related complications, such as hyperacute graft-versus-host disease (GVHD), severe acute GVHD, steroid-requiring febrile syndrome, hepatic veno-occlusive disease, and other immune-mediated adverse reactions. FDA has required the manufacturer to further study the safety of allogeneic HSCT after nivolumab.
Durvalumab (e.g., Imfinzi™) was FDA-approved in May 2017 for the treatment of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. (U.S. Food and Drug Administration 2017).
Cemiplimab-rwlc is a monoclonal antibody that belongs to the class of drugs that bind to the PD-1 receptor, blocking the PD-1/PD-L1 pathway and removes the inhibition response with the potential for breaking of peripheral tolerance and induction of immune-mediated adverse reactions.
On September 28, 2018 the FDA granted approval for Cemiplimab-rwlc for the treatment of individuals with metastatic cutaneous squamous cell carcinoma (CSCC) or locally advanced CSCC who are not candidate for curative surgery or curative radiation.
On March 10, 2020, Nivolumab (e.g., Opdivo) was approved by the FDA in combination with ipilimumab, for the treatment of individuals with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
On March 27, 2020, Durvalumab (e.g., Imfinzi™) was approved by the FDA in combination with etoposide and either carboplatin or cisplatin, for the first-line treatment of adult individuals with extensive-stage small cell lung cancer (ESSCLC).
On May 15, 2020, Nivolumab (e.g., Opdivo) was approved by the FDA in combination with ipilimumab, for the first-line treatment of adult individuals with metastatic or recurrent non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (≥1%) as determined by an FDA-approved test with no EGFR or ALK genomic tumor aberrations.
On May 26, 2020, the Food and Drug Administration approved Nivolumab in combination with ipilimumab and 2 cycles of platinum-based chemotherapy, for the first-line treatment of adult individuals with metastatic or recurrent non-small cell lung cancer with no EGFR or ALK genomic tumor aberrations.
On June 10, 2020, the FDA approved nivolumab (e.g., Opdivo) for the treatment of unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma (ESCC) after prior therapy with fluoropyrimidine-and platinum-based chemotherapy.
On October 2, 2020, the Food and Drug Administration approved Nivolumab in combination with ipilimumab, for the treatment of adult individuals with unresectable malignant pleural mesothelioma.
On February 19, 2021, the following indication, previously approved under FDA accelerated approval for Durvalumab (e.g., Imfinzi) was removed for the treatment of locally advanced or metastatic urothelial carcinoma who:
On February 9, 2021, the Food and Drug Administration approved Cemiplimab (e.g., Libtayo) for the treatment of individuals with locally advanced or metastatic basal cell carcinoma (BCC) previously treated with a hedgehog pathway inhibitor, into the following two supplements:
On February 22, 2021, the Food and Drug Administration approved Cemiplimab (e.g., Libtayo) for the first-line treatment of individuals with non-small cell lung cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) >50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations, and is:
On April 16, 2021, the Food and Drug Administration approved Nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for the treatment of individuals with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.
On May 20, 2021, the Food and Drug Administration approved Nivolumab for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease, in individuals who have received neoadjuvant chemoradiotherapy CRT.
On July 23, 2021, the Food and Drug Administration withdrew approval (previously approved under accelerated approval) of Nivolumab (e.g., OPDIVO), as a single agent, for the treatment of individuals with hepatocellular carcinoma who have been previously treated with sorafenib.
On January 22, 2021, the Food and Drug Administration approved the combination of nivolumab (e.g., Opdivo) and cabozantinib (e.g., Caboetyx, Exelixis) as first-line treatment for individuals with advanced renal cell carcinoma (RCC).
Coding
See CPT/HCPCS Code secion below.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize an oncology benefits management program, Prior Approval is required for this service and is managed through the oncology benefits management program.
Please refer to policy 2019005 for Pembrolizumab (Keytruda).
Effective August 23, 2023
Nivolumab (e.g., Opdivo®)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nivolumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA label
Recommended dosage based upon each indication:
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Nivolumab for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, nivolumab for any indication or circumstance other than those described above is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Durvalumab (e.g., Imfinzi®)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Durvalumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
Administer Durvalumab IV over 60 minutes.
Recommended dosage based upon each indication:
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Durvalumab, for any indication or circumstance other than those described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, durvalumab for any indication or circumstance other than those described aboce is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Cemiplimab (e.g., Libtayo)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Cemiplimab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following indications:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing per FDA Guidelines
The recommended dosage of Cemiplimab-rwlc is 350 mg IV over 30 minutes every 3 weeks.
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Cemiplimab-rwlc, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, cemiplimab-rwlc, for any indication or circumstance not described above, is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective January 12, 2023 to August 22, 2023
Nivolumab (e.g., Opdivo®)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nivolumab meets member benefit certificate primary coverage criteria and is covered for the following indications:
2. For the treatment of adults with NON-SMALL CELL LUNG CANCER (NSCLC):
3. For the treatment of adults with advanced RENAL CELL CARCINOMA and one of the following:
4. For the treatment of CLASSICAL HODGKIN LYMPHOMA that has relapsed or progressed after one of the following:
5. For the treatment of individuals with recurrent or metastatic HEAD AND NECK SQUAMOUS-CELL CARCINOMA with disease progression on or after a platinum-based therapy (NCCN 1).
6. For the treatment of individuals with UROTHELIAL CARCINOMA for one of the following:
7. For the treatment of adult and pediatric (12 years and older) individuals with COLORECTAL CANCER that is microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, given as a single agent or in combination with ipilimumab (NCCN 2A).
8. For the treatment of individuals with HEPATOCELLULAR CARCINOMA who have previously been treated with sorafenib or in combination with ipilimumab. (Effective May 2020 in combination with ipilimumab) (NCCN 2A).
9. For the treatment of ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC) in individuals with:
10. For the treatment of adults with unresectable MALIGNANT PLEURAL MESOTHELIOMA, as first-line treatment in combination with ipilimumab. (FDA Oct 2020; Lancet, Bass Jan 2021) (NCCN 1).
11. For the treatment of individuals with advanced or metastatic GASTRIC CANCER, GASTROESOHPAGEAL JUNCTION CANCER, and ESOPHAGEAL ADENOCARCINOMA in combination with fluoropyrimidine- and platinum-containing chemotherapy. (FDA Apr 2021; Lancet, Janjigian, July 2021) (NCCN 1).
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing in accordance with FDA recommended guidelines
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Nivolumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:
For members with contracts without primary coverage criteria, nivolumab is considered investigational including the following:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Durvalumab (e.g., Imfinzi®)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Durvalumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
4. First-line treatment for Hepatobiliary Cancers-Hepatocellular Carcinoma (NCCN 2A) as a single agent for individuals who:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Durvalumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:
For members with contracts without primary coverage criteria, durvalumab is considered investigational including the following:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Cemiplimab (e.g., Libtayo)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Cemiplimab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
2. Treatment of individuals with Basal Cell Carcinoma (BCC) (NCCN 2A):
3. First-line treatment of individuals with Non-Small Cell Lung Cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) >50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations (NCCN 1), and is:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Cemiplimab-rwlc does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for or any circumstance or indication other than those outlined above, including but not limited to the following:
For members with contracts without primary coverage criteria, cemiplimab-rwlc is considered investigational including the following:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective July 27, 2022 to January 11, 2023
Nivolumab (e.g., Opdivo®)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Nivolumab meets member benefit certificate primary coverage criteria and is covered for the following indications:
2. For the treatment of adults with NON-SMALL CELL LUNG CANCER (NSCLC):
3. For the treatment of adults with advanced RENAL CELL CARCINOMA and one of the following:
4. For the treatment of CLASSICAL HODGKIN LYMPHOMA that has relapsed or progressed after one of the following:
5. For the treatment of patients with recurrent or metastatic HEAD AND NECK SQUAMOUS-CELL CARCINOMA with disease progression on or after a platinum-based therapy (NCCN 1).
6. For the treatment of patients with UROTHELIAL CARCINOMA for one of the following:
7. For the treatment of adult and pediatric (12 years and older) patients with COLORECTAL CANCER that is microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, given as a single agent or in combination with ipilimumab (NCCN 2A).
8. For the treatment of patients with HEPATOCELLULAR CARCINOMA who have previously been treated with sorafenib or in combination with ipilimumab. (Effective May 2020 in combination with ipilimumab) (NCCN 2A).
9. For the treatment of ESOPHAGEAL SQUAMOUS CELL CARCINOMA (ESCC) in patients with:
10. For the treatment of adults with unresectable MALIGNANT PLEURAL MESOTHELIOMA, as first-line treatment in combination with ipilimumab. (FDA Oct 2020; Lancet, Bass Jan 2021) (NCCN 1).
11. For the treatment of patients with advanced or metastatic GASTRIC CANCER, GASTROESOHPAGEAL JUNCTION CANCER, and ESOPHAGEAL ADENOCARCINOMA in combination with fluoropyrimidine- and platinum-containing chemotherapy. (FDA Apr 2021; Lancet, Janjigian, July 2021) (NCCN 1).
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Dosing in accordance with FDA recommended guidelines
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Nivolumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for for the following:
For members with contracts without primary coverage criteria, nivolumab is considered investigational including the following:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Durvalumab (e.g., Imfinzi®)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Durvalumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
4. First-line treatment for Hepatobiliary Cancers-Hepatocellular Carcinoma (NCCN 2A) as a single agent for patients who:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Durvalumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following:
For members with contracts without primary coverage criteria, durvalumab is considered investigational including the following:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Cemiplimab (e.g., Libtayo)
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Cemiplimab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for the following indications:
2. Treatment of patients with Basal Cell Carcinoma (BCC) (NCCN 2A):
3. First-line treatment of patients with Non-Small Cell Lung Cancer (NSCLC) whose tumors have high PD-L1 expression [Tumor Proportion Score (TPS) >50%] as determined by an FDA-approved test, with no EGFR, ALK or ROS1 aberrations (NCCN 1), and is:
The use of this drug is covered if a FDA-approved oncologic indication exists (not listed as an indication above) with the member meeting all of the additional requirements of the prescribing information (package insert listed in the “Indications and Usage”) AND/OR a NCCN category 1 or 2A recommendation is recognized in the NCCN Drugs and Biologics Compendium with the member meeting specified criteria (See policy #2000030).
Dosage and Administration
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Cemiplimab-rwlc does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness for or any circumstance or indication other than those outlined above, including but not limited to the following:
For members with contracts without primary coverage criteria, cemiplimab-rwlc is considered investigational including the following:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Due to the detail of the policy statement, the document containing the coverage statements for dates July 27, 2022 and prior are not online. If you would like a hardcopy print, please email: codespecificinquiry@arkbluecross.com
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| Rationale: |
Nivolumab
The advanced melanoma indication for nivolumab received accelerated biologics license application approval based on tumor response rate and durability of response in one open-label, Phase III trial of nivolumab in adults with unresectable or metastatic melanoma following progression on ipilimumab and, if BRAF V600 mutation‒positive, a BRAF inhibitor (dabrafenib or vemurafenib). An improvement in survival or disease-related symptoms has not yet been established. Phase III trials are to be submitted by end of 2016. CheckMate-372 was a randomized (2:1), open-label trial in which 370 patients with unresectable or metastatic melanoma received nivolumab 3 mg/kg every 2 weeks (n=268) or investigator’s choice of chemotherapy (n=102), either dacarbazine or carboplatin plus paclitaxel. Primary end points were ORR, by independent radiology review committee, and overall survival (OS). Secondary end points included progression-free survival (PFS); PD-L1 expression; and health-related quality of life (HRQOL).
Efficacy was assessed in a single-arm, noncomparative, preplanned interim analysis in the first 120 patients who received nivolumab in Trial 1 and in whom the minimum duration of follow-up was 6 months. Data are unpublished and taken from the label. ORR in the efficacy subset was 32% (95% confidence interval [CI], 23 to 41), consisting of 4 complete responses and 34 partial responses in nivolumab-treated patients. Of the 38 patients with responses, 33 patients (87%) had ongoing responses with durations ranging from 2.6+ to 10+ months, which included 13 patients with ongoing responses of 6 months or longer. There were objective responses in patients with and without BRAF V600 mutation‒positive melanoma. Data on quality of life were not reported at this time. Because of the uncontrolled, observational nature of the interim efficacy subset in the first 120 patients who received nivolumab in and in whom the minimum duration of follow-up was 6 months.
Warnings and precautions are generally related to the development of moderate-to-severe immune-mediated reactions in a small number of patients; this results in administration of corticosteroids and either withholding the drug (in the majority of cases) or discontinuation of the drug. Such reactions included immune-mediated pneumonitis (2.2%), colitis (2.2%), hepatitis (1.1%), nephritis or renal dysfunction (0.7%), hyperthyroidism (3%) or hypothyroidism (8%), or other immune-mediated events (<1%). Nivolumab was discontinued for adverse reactions in 9% of patients, while 26% of patients receiving nivolumab had a drug delay for an adverse reaction. Serious adverse reactions occurred in 41% of patients receiving nivolumab. The most frequent grade 3 and 4 adverse reactions reported in 2% to less than 5% of patients receiving nivolumab were abdominal pain, hyponatremia, increased aspartate aminotransferase, and increased lipase. The most common adverse reaction was rash (> 20%).
July 2016 Update
On May 17, 2016, the FDA granted accelerated approval to nivolumab for the treatment of patients with classical Hodgkin lymphoma. The approval was based on two single-arm, multicenter trials of nivolumab in adults with relapsed or refractory cHL (FDA, 2016). The trials enrolled patients regardless of PD-L1 expression status on Reed-Sternberg cells. The primary efficacy endpoint was objective response rate (ORR) as determined by an independent radiographic review committee. Additional outcome measures included duration of response (DOR).
Efficacy was evaluated in 95 patients previously treated with autologous HSCT and post-transplantation brentuximab vedotin. Patients had a median of 5 prior systemic regimens (range: 3, 15) and received a median of 17 doses of nivolumab (range: 3, 48). Single-agent nivolumab produced a 65% ORR (95% CI: 55%, 75%), with 58% partial remission and 7% complete remission. The median time-to-response was 2.1 months (range: 0.7 to 5.7 months). The estimated median DOR was 8.7 months.
Safety was evaluated in 263 patients with relapsed or refractory cHL. Ninety-eight per cent of patients had received autologous HSCT. Patients received a median of 10 doses of nivolumab (range: 1, 48) at the approved dose-schedule. The most common (reported in at least 20%) adverse reactions of any grade were fatigue, upper respiratory tract infection, cough, pyrexia, and diarrhea. Additional common adverse reactions (reported in at least 10%) included rash, pruritus, musculoskeletal pain, nausea, vomiting, abdominal pain, headache, peripheral neuropathy, arthralgia, dyspnea, infusion-related reactions, and hypothyroidism or thyroiditis.
Other immune-mediated adverse reactions, occurring in 1% to 5% of patients, included rash, pneumonitis, hepatitis, hyperthyroidism, and colitis. Serious adverse reactions were reported in 21% of patients. The most common SAEs, reported in 1% to 3% of patients, were pneumonia, pleural effusion, pneumonitis, pyrexia, infusion-related reaction, and rash.
AUGUST 2017 UPDATE
Durvulumab
The safety and efficacy of durvalumab for urothelial cancer has been evaluated in one multicenter open-label study, in which 182 patients with locally advanced or metastatic disease were enrolled. Patients had progressed on or after platinum-based therapy. Patients with immunodeficiency, medical conditions that required immunosuppression (defined as greater than or equal to 10mg of prednisone or equivalent), severe autoimmune disease, untreated CNS metastatses, HIV, active TB, hepatitis B or hepatitis C were excluded. Enrolled patients had a median age of 67, with 72% being male. Of the enrolled patients, 70% had received cisplatin, 30% had received carboplatin, and 35% had received two or more prior lines of therapy. Tumor assessments were subsequently performed. Of the 182 patients, 5 had a complete response and 26 had a partial response.
2018 Update
A literature search conducted through November 2018 did not reveal any new literature that would prompt a change in the coverage statement.
Update July 2019
The efficacy of cemiplimab-rwlc (Libtayo) for the treatment of metastatic or locally advanced CSCC in patients who are not candidates for curative surgery or curative radiation was evaluated in two open-label, multicenter, non-randomized, multicohort studies, NCT02383212, a phase 1 study with 26 patients and NCT02760498, a phase 2 study with 82 patients. Of the 108 patients, 33 had locally advanced disease and 75 had metastatic CSCC (69% with distant metastases and 31% only nodal metastases). Half of the patients had received at least one prior anti-cancer systemic therapy, 58% had received prior cancer-related surgery and 77% had received prior radiotherapy. The primary outcome was overall response rate (ORR), as measured by independent central review and/or Response Evaluation Criteria In Solid Tumors (RECIST). Patients received cemiplimab 3mg/kg intravenously every 2 weeks with response assessment every 8 weeks, for up to 48 weeks in the phase 1 trial and up to 96 weeks in the phase 2 trial. Treatment was given until disease progression, unacceptable toxicity or completion of planned treatment. The efficacy analysis was conducted after all patients had at least 6 months of follow-up. The ORR (95% confidence interval) for the 108 patients was 47.2% (37.5-57.1%). The partial response rate was 43.5% and complete response rate 3.7%. The duration of response ranged from 1 to 15+ months, with 61% of patients having a duration of response of ≥6 months. Adverse events in the phase 2 study included diarrhea, fatigue, nausea, constipation and rash; four patients (7%) discontinued treatment due to an adverse event.
June 2020 Update
A randomized, open-label, phase 3 trial was done at 209 sites across 23 countries. 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. 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 primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment.
Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.
First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. (Paz-Ares L, Dvorkin M, Chen Y, et al., 2019)
A multicenter, multiple cohort, open-label trial (CHECKMATE-040) conducted in patients with HCC who progressed on or were intolerant to sorafenib to assess safety and efficacy. Additional eligibility criteria included histologic confirmation of HCC and Child-Pugh Class A cirrhosis. The trial excluded patients with active autoimmune disease, brain metastasis, a history of hepatic encephalopathy, clinically significant ascites, infection with HIV, or active co-infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) or HBV and hepatitis D virus (HDV); however, patients with only active HBV or HCV were eligible.
The efficacy of YERVOY 3 mg/kg in combination with nivolumab 1 mg/kg was evaluated in Cohort 4 of CHECKMATE-040. A total of 49 patients received the combination regimen, which was administered every 3 weeks for four doses, followed by single-agent nivolumab at 240 mg every 2 weeks until disease progression or unacceptable toxicity.
The median age was 60 years (range: 18 to 80); 88% were male; 74% were Asian, and 25% were White. Baseline ECOG performance status was 0 (61%) or 1 (39%). Fifty-seven percent (57%) of patients had active HBV infection, 8% had active HCV infection, and 35% had no evidence of active HBV or HCV. The etiology for HCC was alcoholic liver disease in 16% and non-alcoholic liver disease in 6% of patients. Child-Pugh class and score was A5 for 82% and A6 for 18%; 80% of patients had extrahepatic spread; 35% had vascular invasion; and 51% had alfa-fetoprotein (AFP) levels ≥400 μg/L. Prior treatment history included surgery (74%), radiotherapy (29%), or local treatment (59%). All patients had received prior sorafenib, of whom 10% were unable to tolerate sorafenib; 29% of patients had received 2 or more prior systemic therapies. (El-Khoueiry AB, Sangro B, Yau T, et al., 2017)
In an open-label, phase 3 trial (CheckMate 227), patients with stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The patients who had a PD-L1 expression level of less than 1% were randomly assigned in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy alone. All the patients had received no previous chemotherapy. The primary end point reported here was overall survival with nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1 expression level of 1% or more.
Among the patients with a PD-L1 expression level of 1% or more, the median duration of overall survival was 17.1 months (95% confidence interval [CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7 to 16.7) with chemotherapy (P=0.007), with 2-year overall survival rates of 40.0% and 32.8%, respectively. The median duration of response was 23.2 months with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall survival benefit was also observed in patients with a PD-L1 expression level of less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with chemotherapy. Among all the patients in the trial, the median duration of overall survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy.
The percentage of patients with grade 3 or 4 treatment-related adverse events in the overall population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.
First-line treatment with nivolumab plus ipilimumab resulted in a longer duration of overall survival than did chemotherapy in patients with NSCLC, independent of the PD-L1 expression level. No new safety concerns emerged with longer follow-up. (Hellmann MD, Paz-Ares L, Bernabe Caro R, et al., 2019)
2020 Update
A multicenter, randomized, open-label, phase 3 trial (ATTRACTION-3) at 90 hospitals and cancer center in Denmark, Germany, Italy, Japan, South Korea, Taiwan, the UK, and the USA. We enrolled patients aged 20 years and older with unresectable advanced or recurrent esophageal squamous cell carcinoma (regardless of PD-L1 expression), at least one measurable or non-measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, a baseline Eastern Cooperative Oncology Group performance status of 0–1, and who were refractory or intolerant to one previous fluoropyrimidine-based and platinum-based chemotherapy and had a life expectancy of at least 3 months. Patients were randomly assigned (1:1) to either nivolumab (240 mg for 30 min every 2 weeks) or investigator's choice of chemotherapy (paclitaxel 100 mg/m 2 for at least 60 min once per week for 6 weeks then 1 week off; or docetaxel 75 mg/m 2 for at least 60 min every 3 weeks), all given intravenously. Treatment continued until disease progression assessed by the investigator per RECIST version 1.1 or unacceptable toxicity. Randomization was done using an interactive web response system with a block size of four and stratified according to geographical region, number of organs with metastases, and PD-L1 expression. Patients and investigators were not masked to treatment allocation. The primary endpoint was overall survival, defined as the time from randomization until death from any cause, in the intention-to-treat population that included all randomly assigned patients. Safety was assessed in all patients who received at least one dose of the assigned treatment.
Between Jan 7, 2016, and May 25, 2017, 419 patients were assigned to treatment: 210 to nivolumab and 209 to chemotherapy. At the time of data cutoff on Nov 12, 2018, median follow-up for overall survival was 10·5 months (IQR 4·5–19·0) in the nivolumab group and 8·0 months (4·6–15·2) in the chemotherapy group. At a minimum follow-up time (ie, time from random assignment of the last patient to data cutoff) of 17·6 months, overall survival was significantly improved in the nivolumab group compared with the chemotherapy group (median 10·9 months, 95% CI 9·2–13·3 vs 8·4 months, 7·2–9·9; hazard ratio for death 0·77, 95% CI 0·62–0·96; p=0·019). 38 (18%) of 209 patients in the nivolumab group had grade 3 or 4 treatment-related adverse events compared with 131 (63%) of 208 patients in the chemotherapy group. The most frequent grade 3 or 4 treatment-related adverse events were anemia (four [2%]) in the nivolumab group and decreased neutrophil count (59 [28%]) in the chemotherapy group. Five deaths were deemed treatment-related: two in the nivolumab group (one each of interstitial lung disease and pneumonitis) and three in the chemotherapy group (one each of pneumonia, spinal cord abscess, and interstitial lung disease).
Nivolumab was associated with a significant improvement in overall survival and a favorable safety profile compared with chemotherapy in previously treated patients with advanced esophageal squamous cell carcinoma, and might represent a new standard second-line treatment option for these patients. (Kato K, Cho BC, Takahashi M, et al., 2019)
In a randomized, open-label trial (CHECKMATE-9LA (NCT03215706)) in patients with metastatic or recurrent NSCLC. The trial included patients (18 years of age or older) with histologically confirmed Stage IV or recurrent NSCLC (per the 7th International Association for the Study of Lung Cancer classification [IASLC]), ECOG performance status 0 or 1, and no prior anticancer therapy (including EGFR and ALK inhibitors) for metastatic disease. Patients were enrolled regardless of their tumor PD-L1 status. Patients with known EGFR mutations or ALK translocations sensitive to available targeted inhibitor therapy, untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. Patients with stable brain metastases were eligible for enrollment.
Patients were randomized 1:1 to receive either:
Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) and pemetrexed 500 mg/mg2, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 for non-squamous NSCLC; or carboplatin (AUC 6) and paclitaxel 200 mg/m2 for squamous NSCLC. Patients with non-squamous NSCLC in the control arm could receive optional pemetrexed maintenance therapy. Stratification factors for randomization were tumor PD-L1 expression level (≥1% versus <1% or non-quantifiable), histology (squamous versus non-squamous), and sex (male versus female). Study treatment continued until disease progression, unacceptable toxicity, or for up to 2 years. Treatment could continue beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit by the investigator. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue OPDIVO as a single agent as part of the study. Tumor assessments were performed every 6 weeks from the first dose of study treatment for the first 12 months, then every 12 weeks until disease progression or study treatment was discontinued. The primary efficacy outcome measure was OS. Additional efficacy outcome measures included PFS, ORR, and duration of response as assessed by BICR.
A total of 719 patients were randomized to receive either OPDIVO in combination with ipilimumab and platinum-doublet chemotherapy (n=361) or platinum-doublet chemotherapy (n=358). The median age was 65 years (range: 26 to 86) with 51% of patients >65 years and 10% of patients >75 years. The majority of patients were White (89%) and male (70%). Baseline ECOG performance status was 0 (31%) or 1 (68%), 57% had tumors with PD-L1 expression <1% and 37% had tumors with PD-L1 expression that was <1%, 32% had tumors with squamous histology and 68% had tumors with non-squamous histology, 17% had CNS metastases, and 86% were former or current smokers.
The study demonstrated a statistically significant benefit in OS, PFS, and ORR. With an additional 4.6 months of follow-up, the hazard ratio for overall survival was 0.66 (95% 0.55, 0.80) and median survival was 15.6 months (95% CI: 13.9, 20.0) and 10.9 months (95% 9.5, 12.5) for patients receiving OPDIVO and ipilimumab and platinum-doublet chemotherapy or platinum-doublet chemotherapy, respectively. (FDA, 2020)
2021 Update
DANUBE is an open label, randomized, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced, or metastatic urothelial carcinoma, conducted at 224 academic research centers, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomization was done through an interactive voice-web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24.
Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9-43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4-17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4-15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71-1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1-18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9-14·0) in the chemotherapy group (0·85, 95% CI 0·72-1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (<1%) patient in the chemotherapy group (acute kidney injury).
This study did not meet either of its coprimary endpoints. Further research to identify the patients with previously untreated metastatic urothelial carcinoma who benefit from treatment with immune checkpoint inhibitors, either alone or in combination regimens, is warranted. (Powles T, van der Heijden MS, Castellano D, et. al., 2020)
An open-label, multicenter, single-arm, phase 2 trial was conducted across 38 outpatient clinics, primarily at academic medical centers, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants.
Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumor assessments before the data cutoff and were confirmed by tumor assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths.
Cemiplimab exhibited clinically meaningful antitumor activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. (Stratigos AJ, Sekulic A, Peris K, et.al., 2021).
In EMPOWER-Lung 1, a multicenter, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing.
Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9-not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2-17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42-0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1-8·8) with cemiplimab versus 5·7 months (4·5-6·2) with chemotherapy (HR 0·54 [0·43-0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3-4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy.
Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population. (Sezer A, Kilickap S, Gümüş M, et.al., 2021)
An open-label, randomized, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable malignant pleural mesothelioma (MPM), and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299.
Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).
Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. (Baas P, Scherpereel A, Nowak AK, 2021)
In a multicenter, randomized, open-label, phase 3 trial (CheckMate 649), adults (≥18 years) with previously untreated, unresectable, non-HER2-positive gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma, regardless of PD-ligand 1 (PD-L1) expression were enrolled from 175 hospitals and cancer centers in 29 countries. Patients were randomly assigned (1:1:1 while all three groups were open) via interactive web response technology (block sizes of six) to nivolumab (360 mg every 3 weeks or 240 mg every 2 weeks) plus chemotherapy (capecitabine and oxaliplatin every 3 weeks or leucovorin, fluorouracil, and oxaliplatin every 2 weeks), nivolumab plus ipilimumab, or chemotherapy alone. Primary endpoints for nivolumab plus chemotherapy versus chemotherapy alone were OS or progression-free survival (PFS) by blinded independent central review, in patients whose tumours had a PD-L1 combined positive score (CPS) of five or more. Safety was assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT02872116.
From March 27, 2017, to April 24, 2019, of 2687 patients assessed for eligibility, we concurrently randomly assigned 1581 patients to treatment (nivolumab plus chemotherapy [n=789, 50%] or chemotherapy alone [n=792, 50%]). The median follow-up for OS was 13·1 months (IQR 6·7-19·1) for nivolumab plus chemotherapy and 11·1 months (5·8-16·1) for chemotherapy alone. Nivolumab plus chemotherapy resulted in significant improvements in OS (hazard ratio [HR] 0·71 [98·4% CI 0·59-0·86]; p<0·0001) and PFS (HR 0·68 [98 % CI 0·56-0·81]; p<0·0001) versus chemotherapy alone in patients with a PD-L1 CPS of five or more (minimum follow-up 12·1 months). Additional results showed significant improvement in OS, along with PFS benefit, in patients with a PD-L1 CPS of one or more and all randomly assigned patients. Among all treated patients, 462 (59%) of 782 patients in the nivolumab plus chemotherapy group and 341 (44%) of 767 patients in the chemotherapy alone group had grade 3-4 treatment-related adverse events. The most common any-grade treatment-related adverse events (≥25%) were nausea, diarrhea, and peripheral neuropathy across both groups. 16 (2%) deaths in the nivolumab plus chemotherapy group and four (1%) deaths in the chemotherapy alone group were considered to be treatment-related. No new safety signals were identified.
Nivolumab is the first PD-1 inhibitor to show superior OS, along with PFS benefit and an acceptable safety profile, in combination with chemotherapy versus chemotherapy alone in previously untreated patients with advanced gastric, gastro-oesophageal junction, or oesophageal adenocarcinoma. Nivolumab plus chemotherapy represents a new standard first-line treatment for these patients. (Janjigian YY, Shitara K, Moehler M, 2021)
July 2022 Update
In an open label, randomized, phase 3 trial was done in 125 hospitals and cancer centers across 18 countries. We included patients aged 18 years or older with previously untreated advanced or metastatic clear-cell renal cell carcinoma, a Karnofsky performance status of 70% or higher, measurable disease according to Response Evaluation Criteria in Solid Tumors version 1.1 assessed by the investigator, any International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk category, and available tumor tissue for PD-L1 testing. Patients were randomly assigned (1:1) to nivolumab (240 mg) intravenously every 2 weeks plus cabozantinib (40 mg) orally once daily or sunitinib (50 mg orally) once daily (4 weeks per 6-week cycle). Randomization, stratified by IMDC risk status, tumor PD-L1 expression, and geographical region, was done by permuted block within each stratum using a block size of four, via an interactive response system. The primary endpoint was progression-free survival by blinded independent central review. Overall survival was a secondary endpoint (reported here as the preplanned final analysis according to the protocol). Efficacy was assessed in all randomly assigned patients; safety was assessed in all patients who received at least one dose of any study drug.
Between Sept 11, 2017, and May 14, 2019, 323 patients were randomly assigned to the nivolumab plus cabozantinib group and 328 to the sunitinib group. With an extended follow-up (data cutoff of June 24, 2021; median 32·9 months [IQR 30·4-35·9]), median overall survival was 37·7 months (95% CI 35·5-not estimable) in the nivolumab plus cabozantinib group and 34·3 months (29·0-not estimable) in the sunitinib group (hazard ratio [HR] 0·70 [95% CI 0·55-0·90], p=0·0043) and updated median progression-free survival was 16·6 months (12·8-19·8) versus 8·3 months (7·0-9·7; HR 0·56 [95% CI 0·46-0·68], p<0·0001). Grade 3-4 treatment-related adverse events occurred in 208 (65%) of 320 patients with nivolumab plus cabozantinib versus 172 (54%) of 320 with sunitinib. The most common grade 3-4 treatment-related adverse events were hypertension (40 [13%] of 320 patients in the nivolumab plus cabozantinib group vs 39 [12%] of 320 in the sunitinib group), palmar-plantar erythrodysesthesia (25 [8%] vs 26 [8%]), and diarrhea (22 [7%] vs 15 [5%]). Grade 3-4 treatment-related serious adverse events occurred in 70 (22%) of 320 patients in the nivolumab plus cabozantinib group and 31 (10%) of 320 in the cabozantinib group. One additional treatment-related death occurred with sunitinib (sudden death).
With extended follow-up and preplanned final overall survival analysis per protocol, nivolumab plus cabozantinib demonstrated improved efficacy versus sunitinib, further supporting the combination in the first-line treatment of advanced renal cell carcinoma. (Motzer RJ, Powles T, Burotto M, et.al., 2022)
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through August 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
The efficacy of LIBTAYO in combination with platinum-based chemotherapy was evaluated in Study 16113 (NCT03409614), a randomized, multi-center, double-blind, active-controlled trial in 466 patients with locally advanced NSCLC who were not candidates for surgical resection or definitive chemoradiation or with metastatic NSCLC who had not previously received systemic treatment for metastatic NSCLC. Patients were eligible regardless of tumor PD-L1 expression status.
Patients with EGFR, ALK or ROS1 genomic tumor aberrations; a medical condition that required systemic immunosuppression; or ongoing or recent autoimmune disease that required systemic therapy were ineligible. Patients with a history of brain metastases were eligible if they had been adequately treated and had neurologically returned to baseline for at least 2 weeks prior to randomization.
Randomization was stratified by histology (non-squamous vs squamous) and PD-L1 expression according to the VENTANA PD-L1 (SP263) assay. Patients were randomized (2:1) to receive either:
Platinum-based chemotherapy in either arm consisted of carboplatin AUC of 5 or 6 and paclitaxel 200 mg/m2 ; cisplatin 75 mg/m2 and paclitaxel 200 mg/m2 ; carboplatin AUC of 5 or 6 and pemetrexed 500 mg/m2 ; or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 . Maintenance pemetrexed was mandatory for patients with non-squamous NSCLC who received a pemetrexed containing chemotherapy regimen in the first 4 treatment cycles.
Study treatment continued until RECIST 1.1-defined progressive disease, unacceptable toxicity, or 108 weeks. Assessment of tumor status was performed every 9 weeks during year 1 and every 12 weeks after year 1. The major efficacy outcome measure was overall survival (OS). Additional efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) as assessed by blinded independent central review (BICR).
The study population characteristics were: median age of 63 years (range: 25 to 84), 40% age 65 or older; 84% male; 87% White, 13% Asian. Fifteen percent had Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 and 84% had ECOG PS 1; 85% had metastatic disease and 15% had stage IIIB or IIIC disease and were not candidates for surgical resection or definitive chemoradiation per investigator assessment; 57% had non-squamous and 43% had squamous histology; and 7% had history of treated brain metastases at baseline.
The trial demonstrated a statistically significant improvement in OS for patients randomized to LIBTAYO in combination with chemotherapy compared with placebo in combination with chemotherapy. (FDA, 2023)
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