18 May 2020 - - US-based drugmaker Bristol Myers Squibb's (NYSE: BMY) Opdivo (nivolumab) 3 mg/kg plus Yervoy (ipilimumab) 1 mg/kg (injections for intravenous use) was approved by the US Food and Drug Administration for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, the company said.

This approval is based on Part 1a of the Phase 3 CheckMate -227 trial in which Opdivo + Yervoy (n=396) demonstrated superior overall survival 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 OS 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 Opdivo + Yervoy 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 Opdivo + Yervoy and 22% of those treated with chemotherapy were still alive.

As assessed by Blinded Independent Central Review, the confirmed overall response rate with a minimum follow up of 28.3 months was 36% (142/396, 95% CI:31 to 41) with Opdivo + Yervoy (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 was 23.2 months (95% CI: 15.2 to 32.2) for patients treated with Opdivo + Yervoy and 6.2 months (95% CI: 5.6 to 7.4) for chemotherapy.

ORR and DOR were pre-specified descriptive analyses.

Opdivo is associated with the following Warnings and Precautions including immune-mediated: pneumonitis, colitis, hepatitis, endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, encephalitis, other adverse reactions; infusion-related reactions; embryo-fetal toxicity; and increased mortality in patients with multiple myeloma when Opdivo is added to a thalidomide analogue and dexamethasone, which is not recommended outside of controlled clinical trials.

Opdivo + Yervoy is a unique combination of two immune checkpoint inhibitors that features a potentially synergistic mechanism of action, targeting two different checkpoints (PD-1 and CTLA-4) to help destroy tumor cells: Yervoy helps activate and proliferate T cells, while Opdivo helps existing T cells discover the tumor.

Some of the T cells stimulated by Yervoy can become memory T cells, which may allow for a long-term immune response.

Targeting of normal cells can also occur and result in immune-mediated adverse reactions, which can be severe and potentially fatal.

CheckMate -227 is a randomised, open-label, multi-center Phase 3 trial, evaluating Opdivo + Yervoy 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-L1.1 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 Opdivo 3 mg/kg Q2W + Yervoy 1 mg/kg Q6W and 397 patients received platinum-doublet chemotherapy Q3W.

Patients randomised 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 OS. Additional descriptive efficacy outcome measures included progression-free survival, ORR and DOR as assessed by BICR.

Serious adverse reactions occurred in 58% of patients.

Opdivo + Yervoy was discontinued for adverse reactions in 24% of patients and 53% had at least one dose withheld for an adverse reaction.

The most frequent 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 adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea and pruritus.