Opdivo ( Nivolumab ) 3 mg/kg plus Yervoy ( Ipilimumab ) 1 mg/kg ( injections for intravenous use ) was approved by the U.S. Food and Drug Administration ( FDA ) for the first-line treatment of adult patients with metastatic non-small cell lung cancer ( NSCLC ) whose tumors express PD-L1 ( greater than or equal to 1% ) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.
This approval is based on Part 1a of the phase 3 CheckMate -227 trial in which Nivolumab + Ipilimumab ( n=396 ) demonstrated superior overall survival ( OS ) versus chemotherapy ( n=397 ) ( hazard ratio [ HR ] 0.79; 95% confidence interval [ CI ]: 0.67 to 0.94; P=0.0066 ) regardless of tumor histology with a minimum follow up of 29.3 months.
The median overall survival was 17.1 months ( 95% CI: 15.0 to 20.1 ) versus 14.9 months ( 95% CI: 12.7 to 16.7 ).
In the trial, 63% of patients treated with Nivolumab + Ipilimumab and 56% treated with chemotherapy were alive at one year, and 40% and 33% at two years, respectively.
At three years ( median 43.1 months follow up ), 33% of patients treated with Nivolumab + Ipilimumab and 22% of those treated with chemotherapy were still alive.
As assessed by BICR ( Blinded Independent Central Review ), the confirmed overall response rate ( ORR ) with a minimum follow up of 28.3 months was 36% ( 142/396, 95% CI: 31 to 41 ) with Nivolumab + Ipilimumab ( 5.8% complete response [ CR ] and 30.1% partial response [ PR ] ) and 30% ( 119/397, 95% CI: 26 to 35 ) with chemotherapy ( 1.8% CR and 28.2% PR ).
Among patients who responded, the median duration of response ( DOR ) was 23.2 months ( 95% CI: 15.2 to 32.2 ) for patients treated with Nivolumab + Ipilimumab and 6.2 months ( 95% CI: 5.6 to 7.4 ) for chemotherapy.
ORR and DOR were pre-specified descriptive analyses.
The results from the CheckMate -227 trial have shown that a dual immunotherapy approach offers a chance at long-term survival for appropriate patients with metastatic NSCLC.
CheckMate -227 is a randomized, open-label, multi-center phase 3 trial, evaluating Nivolumab + Ipilimumab versus Platinum-doublet chemotherapy in patients with previously untreated metastatic or recurrent NSCLC across non-squamous and squamous tumor histologies.
Part 1a of the trial enrolled patients whose tumors express PD-L1 ( greater than or equal to 1% ).
Tumor specimens were evaluated prospectively using the PD-L1 IHC 28-8 pharmDx assay at a central laboratory.
Key eligibility criteria included patients 18 years or older with stage IV or recurrent NSCLC, ECOG PS 0/1 and no prior systemic anticancer therapy.
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.
Three hundred ninety-six patients received Nivolumab 3 mg/kg Q2W + Ipilimumab 1 mg/kg Q6W and 397 patients received Platinum-doublet chemotherapy Q3W.
Patients randomized to chemotherapy with non-squamous histology received Pemetrexed and Cisplatin or Carboplatin with optional Pemetrexed maintenance following chemotherapy, while patients with squamous histology received Gemcitabine and either Cisplatin or Carboplatin.
Treatment continued until disease progression, unacceptable toxicity or for up to 24 months.
The primary efficacy outcome measure was overall survival. Additional descriptive efficacy outcome measures included progression-free survival, ORR and DOR as assessed by BICR.
Serious adverse reactions occurred in 58% of patients.
Nivolumab + Ipilimumab was discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.
The most frequent ( greater than or equal to 2% ) serious adverse reactions were pneumonia, diarrhea / colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency and hypophysitis.
Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis ( 4 patients ), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure and renal failure.
The most common ( greater than or equal to 20% ) adverse reactions were fatigue ( 44% ), rash ( 34% ), decreased appetite ( 31% ), musculoskeletal pain ( 27% ), diarrhea/colitis ( 26% ), dyspnea ( 26% ), cough ( 23% ), hepatitis ( 21% ), nausea ( 21% ) and pruritus ( 21% ). ( Xagena )
Source: BMS, 2020