The combination of nivolumab and ipilimumab was recently approved by the U.S. Food and Drug Administration (FDA) for the treatment of patients with non–small cell lung cancer (NSCLC) in two different regimens: On May 15, 2020, the two-drug combination was approved for first-line treatment in metastatic NSCLC with tumors that have PD-L1 expression ≥ 1%, as determined by an FDA-approved test, and with no EGFR or ALK genomic tumor mutations.1-3 And on May 26, 2020, nivolumab/ipilimumab was approved for use with two cycles of platinum-doublet chemotherapy, again as first-line treatment for patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor mutations.1,2,4
Also on May 15, with the indication not including chemotherapy, the FDA simultaneously approved the PD-L1 IHC 28-8 pharmDx assay as a companion diagnostic device for selecting patients with NSCLC for treatment with nivolumab plus ipilimumab.
Supporting Efficacy Data: CheckMate 227
The May 15 Approval was based on findings in the phase III open-label, multipart CheckMate 227 trial (ClinicalTrials.gov identifier NCT02477826) in patients with metastatic or recurrent NSCLC and no prior anticancer therapy for advanced disease.2,3,5 In part 1a of the trial, 793 patients with PD-L1 tumor expression ≥ 1% were randomly assigned to receive nivolumab at 3 mg/kg every 2 weeks plus ipilimumab at 1 mg/kg every 6 weeks (n = 396) or platinum-doublet chemotherapy every 3 weeks for four cycles (n = 397). Patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study. The primary endpoint was overall survival.
Chemotherapy consisted of pemetrexed plus either cisplatin or carboplatin for nonsquamous NSCLC and gemcitabine plus either cisplatin or carboplatin for squamous NSCLC. Nivolumab/ipilimumab treatment continued until disease progression, unacceptable toxicity, or for up to 24 months. Treatment was continued beyond disease progression if a patient was clinically stable and was considered to be deriving clinical benefit. Patients who discontinued combination therapy due to an adverse event attributed to ipilimumab were permitted to continue nivolumab as monotherapy.
OF NOTE
Ipilimumab has a boxed warning for severe and fatal immune-mediated adverse reactions. Such reactions may involve any organ system.
Among the patients in part 1a, the median age was 64 years (range = 26–87 years; 49% aged ≥ 65 years and 10% aged ≥ 75 years). Of these patients, 76% were white, 65% were male, and their Eastern Cooperative Oncology Group (ECOG) performance status was 0 (34%) or 1 (65%). In addition, 50% had PD-L1 expression ≥ 50%, 29% had squamous and 71% nonsquamous histology, 10% had treated brain metastases, and 85% were former or current smokers.
Median overall survival was 17.1 months (95% confidence interval [CI] = 15–20.1 months) in the nivolumab/ipilimumab group vs 14.9 months (95% CI = 12.7–16.7 months) in the chemotherapy group (hazard ratio [HR] = 0.79, 95% CI = 0.67–0.94, P = .0066).
Median progression-free survival on blinded independent central review was 5.1 months (95% CI = 4.1–6.3 months) vs 5.6 months (95% CI = 4.6–5.8 months, HR = 0.82, 95% CI = 0.69–0.97). Confirmed overall response rate on blinded review was 36% vs 30%. Median response duration was 23.2 months vs 6.2 months.
Supporting Efficacy Data: CheckMate 9LA
The May 26 Approval was based on findings from the open-label, phase III CheckMate 9LA trial (NCT03215706).2,3 In the trial, 719 patients with recurrent or metastatic disease were randomly assigned to receive nivolumab at 360 mg every 3 weeks with ipilimumab at 1 mg/kg every 6 weeks and platinum-doublet chemotherapy every 3 weeks for two cycles (n = 361) or platinum-doublet chemotherapy every 3 weeks for four cycles (n = 358). Platinum-doublet chemotherapy consisted of either carboplatin (AUC 5 or 6) or cisplatin at 75 mg/m2 plus pemetrexed at 500 mg/mg2 for nonsquamous NSCLC, and carboplatin (AUC 6) and paclitaxel at 200 mg/m2 for squamous NSCLC. Patients with nonsquamous NSCLC in the control group could receive pemetrexed maintenance therapy.
Nivolumab/ipilimumab was 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. Patients who discontinued combination therapy because of an adverse reaction attributed to ipilimumab were permitted to continue receiving nivolumab as a single agent.
Patients were enrolled regardless of tumor PD-L1 status. Those with stable brain metastases were eligible for enrollment. Patients with untreated brain metastases, carcinomatous meningitis, active autoimmune disease, or medical conditions requiring systemic immunosuppression were excluded from the study.
The median patient age was 65 years (range = 26–86 years; 51% were at least 65 and 10% were at least 75). Overall, 89% were white and 70% were male, and ECOG performance status was 0 in 31% and 1 in 68%. In addition, 57% had tumors with PD-L1 expression ≥ 1% and 37% < 1%; 32% had squamous histology and 68% had nonsquamous histology; 17% had central nervous system metastases; and 86% were former or current smokers.
The primary efficacy outcome measure was overall survival. Additional efficacy outcome measures included progression-free survival, overall response rate, and duration of response according to blinded independent central review.
At prespecified interim analysis for overall survival (when 351 events had been observed, representing 87% of the planned number of events for final analysis), the median overall survival was 14.1 months (95% CI = 13.2–16.2 months) with nivolumab/ipilimumab plus chemotherapy vs 10.7 months (95% CI = 9.5–12.5 months) with chemotherapy (HR = 0.69, 96.71% CI = 0.55–0.87, P = .0006). After an additional 4.6 months of follow-up, the hazard ratio for overall survival was 0.66 (95% CI = 0.55–0.80), with a median overall survival of 15.6 months (95% CI = 13.9–20.0 months) vs 10.9 months (95% CI = 9.5–12.5 months).
Median progression-free survival was 6.8 months (95% CI = 5.6–7.7 months) with nivolumab/ipilimumab plus chemotherapy vs 5.0 months (95% CI = 4.3–5.6 months) with chemotherapy (HR = 0.70, 95% CI = 0.57–0.86). The confirmed overall response rate was 38% vs 25% (P = .0003), with median response durations of 10.1 months vs 5.1 months.
How It Is Used
FOR the INDICATION approved without chemotherapy, the recommended doses for the combination are nivolumab at 3 mg/kg via 30-minute intravenous infusion every 2 weeks, and ipilimumab at 1 mg/kg via 30-minute intravenous infusion every 6 weeks until disease progression, unacceptable toxicity, or for up to 2 years in patients without disease progression. Patients must be selected for treatment based on PD-L1 expression ≥ 1%.
For the indication approved with chemotherapy, the recommended dosages are nivolumab at 360 mg every 3 weeks, with ipilimumab at 1 mg/kg every 6 weeks, and histology-based platinum-doublet chemotherapy every 3 weeks for two cycles. Nivolumab and ipilimumab are continued until disease progression, unacceptable toxicity, or up to 2 years in patients without disease progression.
For management of adverse reactions with both regimens, if either agent is withheld, the other should also be withheld. For both agents, infusion should be interrupted or slowed in patients with mild or moderate infusion-related reactions and discontinued in patients with severe or life-threatening infusion-related reactions.
KEY POINTS
- The combination of nivolumab plus ipilimumab was approved for first-line treatment of patients with metastatic NSCLC whose tumors have PD-L1 expression ≥ 1%, as determined by an FDA-approved test, and with no EGFR or ALK genomic tumor aberrations.
- Recommended doses for the combination are nivolumab at 3 mg/kg via 30-minute intravenous infusion every 2 weeks, and ipilimumab at 1 mg/kg via 30-minute intravenous infusion every 6 weeks.
- The combination of nivolumab plus ipilimumab was also approved for use with two cycles of platinum-doublet chemotherapy as first-line treatment for patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations.
- The recommended dosages in the indication with chemotherapy are nivolumab at 360 mg every 3 weeks, with ipilimumab at 1 mg/kg every 6 weeks, and histology-based platinum-doublet chemotherapy every 3 weeks for two cycles.
Nivolumab prescribing information provides instructions on dose modification, including withholding or discontinuing treatment for colitis, pneumonitis, hepatitis/nonhepatocellular carcinoma, hepatitis/hepatocellular carcinoma, hypophysitis, adrenal insufficiency, type 1 diabetes, nephritis and renal dysfunction, skin toxicity (including Stevens-Johnson syndrome and toxic epidermal necrolysis), and encephalitis. Additional indications for dose modification include persistent grade 2 or 3 adverse reactions, other grade 3 adverse reactions, life-threatening or grade 4 adverse reactions, grade 3 myocarditis, and requirement for ≥ 10 mg/d of prednisone or equivalent for more than 12 weeks. There are no recommended dose modifications for hypothyroidism or hyperthyroidism.
Ipilimumab prescribing information provides instructions on dose modification, including withholding or discontinuing treatment for endocrine adverse reactions, ophthalmologic adverse reactions, grade 2 and persistent grade 2 adverse reactions, inability to reduce the corticosteroid dose to 7.5 mg of prednisone or equivalent per day, and grade 3 or 4 adverse reactions.
Safety Profile
In clinical trials of nivolumab/ipilimumab, the most common adverse events of any grade (≥ 20% of patients) have been fatigue, diarrhea, rash, pruritus, nausea, musculoskeletal pain, pyrexia, cough, decreased appetite, vomiting, abdominal pain, dyspnea, upper respiratory tract infection, arthralgia, headache, hypothyroidism, decreased weight, and dizziness.
Safety data for the indication without chemotherapy were derived from the total of 576 patients receiving nivolumab/ipilimumab and 570 patients receiving platinum-doublet chemotherapy in CheckMate 227. The median duration of therapy in patients receiving nivolumab/ipilimumab was 4.2 months (range = 1 day to 25.5 months), with 39% of patients receiving treatment for more than 6 months and 23%, for more than 1 year. The most common adverse events of any grade in patients receiving nivolumab/ipilimumab were fatigue (44% vs 42% in the chemotherapy group), rash (34% vs 10%), decreased appetite (31% vs 26%), musculoskeletal pain (27% vs 16%), diarrhea/colitis (26% vs 16%), dyspnea (26% vs 16%), cough (23% vs 13%), pruritus (21% vs 3%), nausea (21% vs 42%), and hepatitis (21% vs 10%). The most common grade 3 or 4 adverse events included hepatitis (9% vs 1%), pneumonia (7% vs 4%), fatigue (6% vs 4%), and rash (5% vs < 1%). The most common grade 3 or 4 laboratory abnormalities were increased lipase (14% vs 3%), hyponatremia (12% vs 5%), increased amylase (9% vs 2%), increased alanine transaminase (7% vs 1%), increased aspartate transaminase (5% vs < 1%), and lymphopenia (5% vs 15%). Serious adverse events occurred in 58% of patients receiving nivolumab/ipilimumab, with the most common (≥ 2% of patients) consisting of pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and hypophysitis. Adverse events led to withholding of at least one dose of treatment in 53% of patients and to permanent treatment discontinuation in 24%. Fatal adverse events occurred in 1.7% of patients, including pneumonitis, myocarditis, acute kidney injury, shock, hyperglycemia, multisystem organ failure, and renal failure.
In CheckMate 9LA, the median duration of therapy with nivolumab/ipilimumab plus chemotherapy was 6 months, with 50% of patients receiving nivolumab/ipilimumab for more than 6 months and 13% for more than 1 year. The most common adverse events of any grade with nivolumab/ipilimumab plus chemotherapy were fatigue (49% vs 40% with chemotherapy alone), musculoskeletal pain (39% vs 27%), nausea (32% vs 41%), diarrhea (31% vs 18%), rash (30% vs 10%), decreased appetite (28% vs 22%), constipation (21% vs 23%), and pruritus (21% vs 3%). The most common grade 3 or 4 adverse events included diarrhea (6% vs 1.7%), fatigue (5% vs 4.9%), rash (4.7% vs 0.3%), dyspnea (4.7% vs 3.2%), and musculoskeletal pain (4.5% vs 2.0%). The most common grade 3 or 4 laboratory abnormalities were neutropenia (15% vs 15%), leukopenia (10% vs 9%), and hyponatremia (10% vs 7%). Serious adverse events occurred in 57% of patients with nivolumab/ipilimumab plus chemotherapy, with the most common (more than 2%) being pneumonia, diarrhea, febrile neutropenia, anemia, acute kidney injury, musculoskeletal pain, dyspnea, pneumonitis, and respiratory failure. Adverse events led to withholding at least one component of treatment in 56% and to permanently discontinuing treatment in 24%. Fatal adverse events occurred in seven patients (2%) and included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.
Nivolumab has warnings/precautions for immune-mediated adverse reactions, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis; infusion-related reactions; complications of allogeneic hematopoietic stem cell transplantation; and embryofetal toxicity. Patients should be advised not to breastfeed while receiving nivolumab.
Ipilimumab has warnings/precautions for immune-mediated adverse reactions, including hepatitis, endocrinopathies, pneumonitis, nephritis and renal dysfunction, and encephalitis; infusion-related reactions; and embryofetal toxicity. Patients should be advised not to breastfeed while taking ipilimumab. Ipilimumab also has a boxed warning for severe and fatal immune-mediated adverse reactions. Such reactions may involve any organ system, with the most common reactions consisting of enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy. The majority of reactions have onset during treatment; however, a minority have occurred weeks to months after discontinuation of treatment. Ipilimumab should be permanently discontinued and systemic high-dose corticosteroid therapy administered for severe immune-mediated reactions.
REFERENCES
1. U.S. Food and Drug Administration: FDA approves nivolumab plus ipilimumab for first-line mNSCLC (PD-L1 tumor expression ≥ 1%). Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-first-line-mnsclc-pd-l1-tumor-expression-1. Accessed May 21, 2020.
2. U.S. Food and Drug Administration: Highlights of prescribing information for Opdivo (nivolumab) injection. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125554s082lbl.pdf. Accessed June 2, 2020.
3. U.S. Food and Drug Administration: Highlights of prescribing information for Yervoy (ipilimumab) injection. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125377s110lbl.pdf. Accessed June 2, 2020.
4. U.S. Food and Drug Administration: FDA approves nivolumab plus ipilimumab and chemotherapy for first-line treatment of metastatic NSCLC. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-nivolumab-plus-ipilimumab-and-chemotherapy-first-line-treatment-metastatic-nsclc. Accessed June 2, 2020.
