| Coverage Policy Manual | |
| Policy #: | 2011006 |
| Category: | Pharmacy |
| Initiated: | April 2011 |
| Last Review: | August 2023 |
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| Ipilimumab (e.g., Yervoy™) | |
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| Description: |
Melanoma is a cancer that begins in skin cells called melanocytes. Melanomas can occur anywhere on the skin, but are more likely to start in certain locations. The trunk (chest and back) is the most common site in men. The legs are the most commonly affected site in women. The neck and face are other common sites. Melanomas can also form in other parts of your body such as the eyes, mouth, and vagina, but these are much less common than melanoma of the skin. Melanoma is much less common than basal cell and squamous cell skin cancers, but it is far more dangerous. Like basal cell and squamous cell cancers, melanoma is almost always curable in its early stages. But it is much more likely than basal or squamous cell cancer to spread to other parts of the body if not caught early. Melanoma accounts for less than 5% of skin cancer cases but causes a large majority of skin cancer deaths.
Treatment of melanoma may include surgery, chemotherapy, immunotherapy or radiation therapy. Surgery is the main treatment option for most stages of melanoma. However, once the melanoma has metastasized to other organs it is very unlikely to be cured by surgery. Several chemotherapy drugs have been used to treat metastatic melanoma including dacarbazine, cisplatin, temozolomide and paclitaxel. However, no therapy has been proven to improve overall survival (Hodi, 2010).
Regulatory Status
In March, 2011, the FDA approved ipilimumab (Yervoy™) for the treatment of unresectable or metastatic melanoma. Ipilimumab (e.g., Yervoy™) is a recombinant monoclonal antibody that blocks a molecule known as cytotoxic T-lymphocyte antigen (CTLA-4), a down regulator of T-cell activation. Blockade of CTLA-4 has been shown to augment T-cell activation and proliferation. The proposed mechanism of action of ipilimumab is by blocking CTLA-4, T-cells may be allowed to proliferate and attack melanoma cancer cells.
In March 2020, the U.S. Food and Drug Administration granted approval under accelerated approval based on overall response rate and duration of response a new indication for Yervoy in combination with nivolumab, for the treatment of individuals with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib.
On May 15, 2020, the FDA approved a new indication for Yervoy in combination with nivolumab, 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 FDA approved a new indication for the use of ipilimumab, in combination with nivolumab 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.
The FDA approved ipilimumab (e.g., Yervoy™) with a Risk Evaluation and Mitigation Strategies (REMS) and included a “black box warning” in the labeling, indicating that ipilimumab (e.g., Yervoy™) can result in sever and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. These immune-mediated reactions may involve any organ system. Thirteen percent of individuals in the Yervoy trial had severe or fatal autoimmune reactions (allergic). Other common side effects included diarrhea, skin rash, fatigue and colitis. These severe side effects led to the FDA’s requirement of a REMS program consisting of a communication plan to inform potential prescribers and supportive healthcare providers about serious adverse reactions associated with Yervoy.
On October 2, 2020, the Food and Drug Administration approved for a new indication for Ipilimumab, in combination with nivolumab, for the first-line treatment of adult individuals with unresectable malignant pleural mesothelioma.
On May 27, 2022, the Food and Drug Administration approved ipilimumab (e.g., Yervoy) in combination with nivolumab, for the first-line treatment of individuals with unresectable advanced or metastatic esophageal squamous cell carcinoma.
Coding
See CPT/HCPCS Code section 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.
Effective August 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of the following listed 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 by intravenous infusion based upon recommended infusion rate for each indication.
Ipilimumab is available as 50 mg/10 mL (5 mg/mL) and 200 mg/40 ml (5 mg/mL) in a single-dose vial.
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
Ipilimumab for any indication or circumstance not described above, does not meet member benefit certificate coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, Ipilimumab 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 August 24, 2022 to July 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed 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
Administer by intravenous infusion based upon recommended infusion rate for 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
Ipilimumab does not meet member benefit certificate coverage criteria that there be scientific evidence of effectiveness for any indication or circumstance other than those listed above.
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (e.g., Yervoy™) and vemurafenib (e.g., Zelboraf) for the treatment of melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab (e.g., Yervoy™) and vemurafenib (e.g., Zelboraf) for the treatment of melanoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 1, 2021 to August 23, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed 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
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
Any other use of Ipilimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 2021 to October 31, 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
NCCN 1, 2A and 2B Recommendations in accordance with Coverage 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
Any other use of Ipilimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective August 2020 to July 2021
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
Dosing Guidelines in accordance with FDA labeling:
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
Any other use of Ipilimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of
melanoma does not meet member benefit certificate primary coverage criteria that there be scientific
evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab
(Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of
coverage.
Effective June 2020 to July 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
Dosing Guidelines in accordance with FDA labeling:
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
Any other use of Ipilimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of
melanoma does not meet member benefit certificate primary coverage criteria that there be scientific
evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab
(Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of
coverage.
Effective August 2019 to May 2020
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
NCCN 1, 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
Dosing Guidelines in accordance with FDA labeling:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Any other use of Ipilimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of
melanoma does not meet member benefit certificate primary coverage criteria that there be scientific
evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab
(Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational.
Investigational services are specific contract exclusions in most member benefit certificates of
coverage.
Effective July 2018 to July 2019
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Ipilimumab meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in the treatment of the following listed indications:
5.NCCN 2A and 2B Recommendations in accordance with Coverage Policy #2000030.
Dosing Guidelines:
Dosing Guidelines in accordance with FDA labeling
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Any other use of Ipilimumab does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, any other use of Ipilimumab is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of
melanoma does not meet member benefit certificate primary coverage criteria that there be scientific
evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective April 2013
Therapy with the human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, ipilimumab (Yervoy™) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of patients with unresectable or metastatic melanoma.
Therapy with ipilimumab (Yervoy™) is being studied in clinical trials to determine effectiveness in conditions other than metastatic melanoma and does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any indication other than unresectable or metastatic melanoma.
For members with contracts without primary coverage criteria, therapy with ipilimumab (Yervoy™) in conditions other than metastic melanoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness.
For members with contracts without primary coverage criteria, combination therapy of ipilimumab (Yervoy™) and vemurafenib (Zelboraf) for the treatment of melanoma is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective prior to April 2013
Therapy with the human cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, ipilimumab (Yervoy™) meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in the treatment of patients with unresectable or metastatic melanoma.
Therapy with ipilimumab (Yervoy™) is being studied in clinical trials to determine effectiveness in conditions other than metastatic melanoma and does not meet primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in any indication other than unresectable or metastatic melanoma.
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| Rationale: |
The FDA approval of ipilimumab was based on a phase 3 randomized controlled trial assessing the safety and effectiveness of ipilimumab (3mg/kg) with or without the tumor vaccine (gp100) or gp100 alone (Hodi, 2010). Gp100 was used as an active control in lieu of an accepted standard of care following first-line treatment of stage III-IV melanoma.
A total of 676 patients with unresectable stage III or IV melanoma whose disease progressed while on therapy were randomized to receive one of the three treatments every 3 weeks for up to four treatments. The primary endpoint was overall survival. The median overall survival was 10.0 months for patients who received ipilimumab plus gp100 compared with 6.4 months among patients who received gp100 alone. There was no difference in overall survival in the group that received ipilimumab plus gp100 and the ipilimumab alone group.
Ten to 15% of patients that received treatment with ipilimumab experienced grade 3 or 4 immune-related events, including 7 out of 14 study treatment related deaths.
The data from the phase III study is consistent with the results of the phase II studies in the same population ( Weber, 2009) (Wolchok, 2010) (O’Day, 2010). Wolchok and colleagues published results of a phase II, randomized, double-blind, multicenter dose-ranging trial. In this study, 217 patients were assigned to receive ipilimumab 10mg/kg, 3mg/kg or 0.3mg/kg every 3 weeks for four cycles. The primary endpoint was best overall response ( the percentage of patients with a complete or partial response). The best overall response was 11.1% for the 10mg/kg group, 4.2% for 3 mg/kg group and 0% for the 0.3 mg/kg group.
O’Day and colleagues reported on the phase II study evaluating the safety and efficacy of ipilimumab monotherapy (10mg/k every 3 weeks for four cycles) in patients with unresectable stage III/IV melanoma. Induction treatment was followed by maintenance therapy every 3 months. The primary end point was best overall response rate (BORR) using modified World Health Organization criteria. BORR was 5.8% with a disease control rate of 27%. One and two year survival rates were 47.2% and 32.8%, respectively. The authors reported that immune-related events were manageable and generally reversible with corticosteroids.
In another phase II study, investigators randomized both previously treated and treatment-näive patients with unresectable stage III or IV melanoma to receive ipilimumab 10mg/kg every 3 weeks for four doses with either budesonide or placebo Weber, 2009). The trial was conducted to determine whether budesonide reduced the rate of immune-related adverse events. Prophylactic treatment with budesonide did not affect the rate of grade 2 or greater diarrhea. The median overall survival rate in the group treated with ipilimumab plus prophylactic budesonide was 17.7 months compared with 19.3 months in the group treated with ipilimumab plus placebo. In this study there were no treatment related deaths.
Studies are currently being conducted on ipilimumab for the treatment of various other cancers including prostate, small cell lung cancer, non-small cell lung cancer, advanced or refractory solid tumors, recurrent or refractory lymphoma, colon cancer and renal cell cancer (clinicaltrials.gov). There is insufficient evidence that ipilimumab improves health outcomes in any form of cancer other than the FDA approved indication of unresectable or metastatic melanoma.
2013 Update
Ribas and colleagues in a letter to the editor of the NEJM reported on a phase 1 study of the concurrent administration of vemurafenib and ipilimumab for patients with metastatic melanoma with a BRAF V600 mutation who had not received previous therapy BRAF or MEK inhibitor or with CTLA-4 or programmed cell death protein 1 (PD-1)–blocking antibodies. Two cohorts (six patients each) were enrolled. Hepatic adverse events occurred in 8 of 10 patients who received both drugs. Two patients in the 2nd cohort received only vemurafenib. The study was closed to further patient accrual due to the liver toxic effects. All hepatic adverse events in the two cohorts were asymptomatic and reversible with either temporary discontinuation of the study drugs or administration of glucocorticoids.
2014 Update
A search of the MEDLINE database conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement.
2015 Update
A literature search conducted through March 2015 did not reveal any new information that would prompt a change in the coverage statement.
2016 Update
A literature search conducted through March 2016 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update
A literature search conducted through August 2019 did not reveal any new information that would prompt a change in the coverage statement.
June 2020 Update
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)
Ongoing Trials:
A Phase 3, Randomized, Open Label Study of Nivolumab Combined with Ipilimumab Versus Sunitinib Monotherapy in Subjects with Previously Untreated, Advanced or Metastatic Renal Cell Carcinoma (CheckMate 214, NCT02231749)
A Phase 2, Nonrandomized, Open Label Study of Nivolumab in patients with metastatic DNA mismatch repair deficient/microsatellite instability–high colorectal cancer (CheckMate 142, NCT02060188)
2020 Update
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
Patients with previously untreated advanced melanoma were randomly assigned to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group.
At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted.
Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (CheckMate 067 ClinicalTrials.gov number, NCT01844505.) (Larkin J, Chiarion-Sileni V, Gonzalez R, et.al., 2019)
The EORTC 18071 enrolled patients with complete and adequate resection of stage III melanoma. Histologically confirmed melanoma had to be metastatic to lymph nodes including stage IIIA melanoma (if N1a, at least 1 metastasis >1 mm), stage IIIB or stage IIIC (no in-transit metastasis). Full details of the eligibility criteria are reported elsewhere (8). All participating patients had to provide signed informed consent which included a description of the HRQoL assessments.
This was a randomized, double-blind, placebo-controlled, Phase III trial conducted across 18 countries worldwide. The primary objective was to determine whether post-operative adjuvant therapy with ipilimumab improves RFS (defined as the time between the date of randomization and the date of first recurrence (local, regional, distant metastasis) or death due to any cause) compared to placebo.
Secondary objectives included comparisons of distant metastasis-free survival (DMFS) overall survival (OS) and safety profiles. An additional objective was to compare HRQoL between treatment arms using the EORTC QLQ-C30 instrument. Patients were randomized in a 1:1 ratio to receive either ipilimumab 10 mg/kg or placebo every 3 weeks for 4 doses, then every 3 months for up to a maximum of 3 years. Treatment was discontinued early in case of disease progression, unacceptable toxicity, withdrawal of consent, or death.
As patients receiving Ipi might experience a temporary reduction in HRQoL, the main hypothesis was that there would be no clinically relevant differences between the two arms using the global QoL scale after the induction phase. A secondary objective was to evaluate the treatment effect on the various symptoms and functioning scales as treatment related side-effects may have a (temporary) negative influence on the health related domains of QoL of these patients.
HRQoL was an important secondary endpoint in this study in which Ipilimumab and placebo were compared. Its primary selected scale, the EORTC QLQ-C30 GH/QoL score, showed no clinically relevant differences (10 points or more) between the two treatment arms at any time point, confirmed by sensitivity analyses. We observed ipi-induced clinically relevant worsening for diarrhea and fatigue at week 10, and ipi-induced clinically relevant treatment differences for diarrhea and insomnia at week 10. After induction, no relevant treatment differences are observed. This study shows that Ipilimumab can achieve an improvement in RFS with little impairment in HRQoL as measured by the QLQ-C30 despite severe side effects. (ClinicalTrials.gov NCT00636168) (Coens C, Suciu S, Chiarion-Sileni V,et.al., 2017)
Updated analyses of the phase III CheckMate 214 trial with extended minimum follow-up assessing long-term outcomes with first-line nivolumab plus ipilimumab (NIVO+IPI) versus (vs) sunitinib (SUN) in patients with advanced renal cell carcinoma (aRCC) were reported.
Patients with aRCC with a clear cell component were stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk and randomized to NIVO (3 mg/kg) plus IPI (1 mg/kg) every three weeks ×4 doses, followed by NIVO (3 mg/kg) every two weeks; or SUN (50 mg) once per day ×4 weeks (6-week cycle). Efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) per independent radiology review committee in patients with intermediate/poor-risk disease (I/P; primary), intent-to-treat patients (ITT; secondary) and in patients with favorable-risk disease (FAV; exploratory).
Overall, 1096 patients were randomized (ITT: NIVO+IPI, n=550, SUN, n=546; I/P: NIVO+IPI, n=425, SUN, n=422; FAV: NIVO+IPI, n=125, SUN, n=124). After 4 years minimum follow-up, OS (HR; 95% CI) remained superior with NIVO+IPI vs SUN in ITT (0.69; 0.59 to 0.81) and I/P patients (0.65; 0.54 to 0.78). Four-year PFS probabilities were 31.0% vs 17.3% (ITT) and 32.7% vs 12.3% (I/P), with NIVO+IPI vs SUN. ORR remained higher with NIVO+IPI vs SUN in ITT (39.1% vs 32.4%) and I/P (41.9% vs 26.8%) patients. In FAV patients, the HRs (95% CI) for OS and PFS were 0.93 (0.62 to 1.40) and 1.84 (1.29 to 2.62); ORR was lower with NIVO+IPI vs SUN. However, more patients in all risk groups achieved complete responses with NIVO+IPI: ITT (10.7% vs 2.6%), I/P (10.4% vs 1.4%) and FAV (12.0% vs 6.5%). Probability (95% CI) of response ≥4 years was higher with NIVO+IPI vs SUN (ITT, 59% (0.51 to 0.66) vs 30% (0.21 to 0.39); I/P, 59% (0.50 to 0.67) vs 24% (0.14 to 0.36); and FAV, 60% (0.41 to 0.75) vs 38% (0.22 to 0.54)) regardless of risk category. Safety remained favorable with NIVO+IPI vs SUN.
After long-term follow-up, NIVO+IPI continues to demonstrate durable efficacy benefits vs SUN, with manageable safety. (ClinicalTrials.gov identifier: NCT02231749) (Albiges L, Tannir NM, Burotto M, et.al., 2020)
Purpose Nivolumab provides clinical benefit (objective response rate [ORR], 31%; 95% CI, 20.8 to 42.9; disease control rate, 69%; 12-month overall survival [OS], 73%) in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); nivolumab plus ipilimumab may improve these outcomes. Efficacy and safety results for the nivolumab plus ipilimumab cohort of CheckMate-142, the largest single-study report of an immunotherapy combination in dMMR/MSI-H mCRC, are reported. Patients and Methods Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. Primary end point was investigator-assessed ORR. Results Of 119 patients, 76% had received ≥ two prior systemic therapies. At median follow-up of 13.4 months, investigator-assessed ORR was 55% (95% CI, 45.2 to 63.8), and disease control rate for ≥ 12 weeks was 80%. Median duration of response was not reached; most responses (94%) were ongoing at data cutoff. Progression-free survival rates were 76% (9 months) and 71% (12 months); respective OS rates were 87% and 85%. Statistically significant and clinically meaningful improvements were observed in patient-reported outcomes, including functioning, symptoms, and quality of life. Grade 3 to 4 treatment-related adverse events (AEs) occurred in 32% of patients and were manageable. Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population. Conclusion Nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Indirect comparisons suggest combination therapy provides improved efficacy relative to anti-programmed death-1 monotherapy and has a favorable benefit-risk profile. Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC. (ClinicalTrials.gov NCT02060188) (Overman MJ, Lonardi S, Wong KYM, et.al., 2018)
A phase I/II, open-label, non-comparative, multicenter trial (27 centers) included patients with Child-Pugh B (B7-B8) aHCC. Patients received intravenous nivolumab 240 mg every 2 weeks until unacceptable toxicity or disease progression. Primary endpoints were objective response rate (ORR) by investigator assessment (using Response Evaluation Criteria in Solid Tumors v1.1) and duration of response. Safety was assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.
Twenty-five sorafenib-naive and 24 sorafenib-treated patients began treatment between November 2016 and October 2017 (median follow-up, 16.3 months). Investigator-assessed ORR was 12% (95% CI 5-25%) with 6 patients responding; disease control rate was 55% (95% CI 40-69%). Median time to response was 2.7 months (interquartile range, 1.4-4.2), and median duration of response was 9.9 months (95% CI 9.7-9.9). Treatment-related adverse events (TRAEs) were reported in 25 patients (51%) and led to discontinuation in 2 patients (4%). The most frequent grade 3/4 TRAEs were hypertransaminasemia (n = 2), amylase increase (n = 2), and aspartate aminotransferase increase (n = 2). The safety of nivolumab was comparable to that in patients with Child-Pugh A aHCC.
Nivolumab showed clinical activity and favorable safety with manageable toxicities, suggesting it could be suitable for patients with Child-Pugh B aHCC.
In patients with advanced hepatocellular carcinoma, almost all systemic therapies require very good liver function, i.e. Child-Pugh A status. The evidence from this study suggests that nivolumab shows clinical activity and an acceptable safety profile in patients with hepatocellular carcinoma with Child-Pugh B status who have mild to moderate impairment of liver function or liver decompensation that might rule out other therapies. Further studies are warranted to assess the safety and efficacy of nivolumab in this patient population. (ClinicalTrials.gov NCT01658878) (Kudo M, Matilla A, Santoro A, et.al., 2021)
In CheckMate 227 (NCT02477826), patients with treatment-naive stage IV or recurrent NSCLC and 1% or greater tumor programmed death ligand 1 expression had significantly improved overall survival with nivolumab plus ipilimumab versus chemotherapy.
Patients (N = 1189) were randomized to nivolumab plus ipilimumab, nivolumab, or chemotherapy. Patient-reported outcomes (PRO) were exploratory. Changes in Lung Cancer Symptom Scale (LCSS) average symptom burden index, LCSS 3-item global index, EQ-5D visual analog scale (VAS), and EQ-5D utility index were analyzed descriptively. Mixed-effect model repeated measures and time-to-first deterioration and improvement analyses were conducted.
PRO completion rates were generally greater than 80%. On-treatment improvements from baseline in LCSS measures of symptom burden and global health status with nivolumab plus ipilimumab generally met or exceeded the minimal important difference (smallest clinically meaningful change) from weeks 24 and 30, respectively; improvements with chemotherapy generally remained below the minimal important difference. Mean on-treatment EQ-5D VAS scores for both treatments approached the U.K. population norm at week 24, remaining so throughout the treatment period. Mixed-effect model repeated measures analyses revealed numerically greater improvements from baseline with nivolumab plus ipilimumab versus chemotherapy across LCSS average symptom burden index and 3-item global index, and EQ-5D VAS and utility index. Nivolumab plus ipilimumab had delayed time-to-first deterioration (hazard ratio [95% confidence interval] 0.74 [0.56 to 0.98]) and a trend for more rapid time-to-first improvement (1.24 [0.98 to 1.59]) versus chemotherapy.
Nivolumab plus ipilimumab revealed delayed deterioration and numerical improvement in symptoms and health-related quality of life versus chemotherapy in patients with advanced NSCLC and 1% or greater programmed death ligand 1 expression. (Reck M, Ciuleanu TE, Lee JS, et.al., 2021)
First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC).
This randomized, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomization was stratified by tumor histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analyzed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis.
Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anemia (21 [6%] vs 50 [14%]), diarrhea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related.
Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favorable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC. (ClinicalTrials.gov, number NCT03215706) (Paz-Ares L, Ciuleanu TE, Cobo M, et.al., 2021)
Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumor types, including first-line non-small-cell lung cancer. We hypothesized that this regimen would improve overall survival in MPM.
This 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 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,
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. (ClinicalTrials.gov, NCT02899299) (Baas P, Scherpereel A, Nowak AK, et.al., 2021)
2022 Update
In an open-label, phase 3 trial, adults with previously untreated, unresectable advanced, recurrent, or metastatic esophageal squamous-cell carcinoma were randomly assigned in a 1:1:1 ratio to receive nivolumab plus chemotherapy, nivolumab plus the monoclonal antibody ipilimumab, or chemotherapy. The primary end points were overall survival and progression-free survival, as determined by blinded independent central review. Hierarchical testing was performed first in patients with tumor-cell programmed death ligand 1 (PD-L1) expression of 1% or greater and then in the overall population (all randomly assigned patients).
A total of 970 patients underwent randomization. At a 13-month minimum follow-up, overall survival was significantly longer with nivolumab plus chemotherapy than with chemotherapy alone, both among patients with tumor-cell PD-L1 expression of 1% or greater (median, 15.4 vs. 9.1 months; hazard ratio, 0.54; 99.5% confidence interval [CI], 0.37 to 0.80; P<0.001) and in the overall population (median, 13.2 vs. 10.7 months; hazard ratio, 0.74; 99.1% CI, 0.58 to 0.96; P = 0.002). Overall survival was also significantly longer with nivolumab plus ipilimumab than with chemotherapy among patients with tumor-cell PD-L1 expression of 1% or greater (median, 13.7 vs. 9.1 months; hazard ratio, 0.64; 98.6% CI, 0.46 to 0.90; P = 0.001) and in the overall population (median, 12.7 vs. 10.7 months; hazard ratio, 0.78; 98.2% CI, 0.62 to 0.98; P = 0.01). Among patients with tumor-cell PD-L1 expression of 1% or greater, a significant progression-free survival benefit was also seen with nivolumab plus chemotherapy over chemotherapy alone (hazard ratio for disease progression or death, 0.65; 98.5% CI, 0.46 to 0.92; P = 0.002) but not with nivolumab plus ipilimumab as compared with chemotherapy. The incidence of treatment-related adverse events of grade 3 or 4 was 47% with nivolumab plus chemotherapy, 32% with nivolumab plus ipilimumab, and 36% with chemotherapy alone.
Both first-line treatment with nivolumab plus chemotherapy and first-line treatment with nivolumab plus ipilimumab resulted in significantly longer overall survival than chemotherapy alone in patients with advanced esophageal squamous-cell carcinoma, with no new safety signals identified. (Doki Y, Ajani JA, Kato K, 2022)
2023 Update
5-year results from CheckMate 227 Part 1, in which nivolumab plus ipilimumab improved overall survival (OS) versus chemotherapy in patients with metastatic non-small-cell lung cancer, regardless of tumor programmed death ligand 1 (PD-L1) status.
Adults with stage IV/recurrent non-small-cell lung cancer without EGFR mutations or ALK alterations and with tumor PD-L1 ≥ 1% or < 1% (n = 1739) were randomly assigned. Patients with tumor PD-L1 ≥ 1% were randomly assigned to first-line nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. Patients with tumor PD-L1 < 1% were randomly assigned to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy. End points included exploratory 5-year results for efficacy, safety, and quality of life.
At a minimum follow-up of 61.3 months, 5-year OS rates were 24% versus 14% for nivolumab plus ipilimumab versus chemotherapy (PD-L1 ≥ 1%) and 19% versus 7% (PD-L1 < 1%). The median duration of response was 24.5 versus 6.7 months (PD-L1 ≥ 1%) and 19.4 versus 4.8 months (PD-L1 < 1%). Among patients surviving 5 years, 66% (PD-L1 ≥ 1%) and 64% (PD-L1 < 1%) were off nivolumab plus ipilimumab without initiating subsequent systemic anticancer treatment by the 5-year time point. Survival benefit continued after nivolumab plus ipilimumab discontinuation because of treatment-related adverse events, with a 5-year OS rate of 39% (combined PD-L1 ≥ 1% and < 1% populations). Quality of life in 5-year survivors treated with nivolumab plus ipilimumab was similar to that in the general US population through the 5-year follow-up. No new safety signals were observed.
With all patients off immunotherapy treatment for ≥ 3 years, nivolumab plus ipilimumab increased 5-year survivorship versus chemotherapy, including long-term, durable clinical benefit regardless of tumor PD-L1 expression. These data support nivolumab plus ipilimumab as an effective first-line treatment for patients with metastatic non-small-cell lung cancer. (Brahmer JR, Lee JS, Ciuleanu TE, 2023)
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