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Nivolumab plus Ipilimumab Combination Improves Survival in Patients with Metastatic NSCLC

TOP - January 2020, Vol 13, No 1

Barcelona, Spain—The immunotherapy combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) improved overall survival (OS) compared with chemotherapy as first-line treatment in patients with advanced non–small-cell lung cancer (NSCLC) and PD-L1 expression ≥1%, according to results of CheckMate 227. The OS was also improved with nivolumab plus ipilimu­mab compared with chemotherapy in the total study population and in patients whose tumors had low (<1%) PD-L1 expression.

These late-breaking results of the final analysis of part 1 of CheckMate 227 were presented at the ESMO Congress 2019 and published online simultaneously (Hellmann MD, et al. N Engl J Med. 2019;381:2020-2031).

“CheckMate 227 met its primary end point. It is the first phase 3 trial to prove that the combination of checkpoint inhibitor and CTLA-4 inhibitor improves survival compared to chemotherapy in unselected, treatment-naïve patients with metastatic NSCLC,” said Solange Peters, MD, PhD, Head, Medical Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, who presented the results.

“In my opinion, these results are practice changing. Now that we have a number of treatment options, including chemotherapy plus an anti–PD-1 agent or an anti–PD-L1 agent alone, and now a chemotherapy-sparing option of nivolumab-ipilimumab, we have to begin the discussion of which patients should receive which treatment,” she added. “The majority of NSCLC patients do not have driver mutations.”

Other experts were more cautious about adopting nivolumab plus ipilimumab as a standard treatment.

Formal ESMO discussant Sanjay Popat, MBBS, FRCP, PhD, Consultant Thoracic Medical Oncologist, Royal Marsden Hospital NHS Foundation Trust, London, England, said, “We have many options in therapy, but I question whether nivolumab-ipilimumab is the preferred regimen in clinical practice. If we use nivolumab-ipilimumab as the preferred regimen, the combination may not be worth the benefit, because one-third of patients have grade 3 and 4 treatment-emergent adverse events,” he continued. “Nivolumab monotherapy has no role in the front-line setting with limited efficacy. Ipilimumab adds efficacy to nivolumab monotherapy, but at the meaningful cost of toxicities.”

“The hazard ratio for survival with nivolumab-ipilimumab is not better than for all other monotherapies. There is a similar survival benefit with other single-agent checkpoint inhibitors and less toxicity. Finally, if ipilimumab really does add something, it is not clear that nivolumab is the best checkpoint inhibitor to combine it with,” Dr Popat said.

Study Details

CheckMate 227 randomized patients with treatment-naïve stage IV and recurrent NSCLC and PD-L1 expression ≥1% to nivolumab plus ipilimumab versus nivolumab alone versus chemotherapy alone (part 1a, 1189 patients); and patients with PD-L1 <1% to nivolumab plus ipilimumab versus nivolumab plus chemotherapy or chemotherapy alone (part 1b, 550 patients). Treatment was continued until disease progression or unacceptable toxicity, or for 2 years for the immunotherapy regimens. No crossover was permitted.

Previously, CheckMate 227 reported improved progression-free survival with nivolumab plus ipilimumab versus chemotherapy and showed that tumor mutational burden did not identify patients who would respond to the combination.

Dr Peters’ presentation at ESMO 2019 focused on OS in patients with PD-L1 ≥1%.

Baseline characteristics were well-balanced in the 3 treatment arms. The median age was 64 years; approximately 10% were age ≥75 years. Approximately 66% of patients were male, approximately 85% were current or former smokers, approximately 30% had squamous histology, and 70% had nonsquamous cancer. The dose and frequency of ipilimumab were decreased in this trial in an effort to reduce adverse events of the combination that had been observed in studies in melanoma and renal-cell carcinoma.

Minimum follow-up was 29.3 months in patients with PD-L1 ≥1% (part 1a of the trial). In this group, the median OS was 17.1 months with nivolumab plus ipilimumab and 14.9 months with chemotherapy (P = .007). The 2-year OS rates were 40% and 32.8%, respectively. The median duration of response was 23.2 months for nivolu­mab plus ipilimumab and 6.2 months with chemotherapy.

The OS was also improved in the group with PD-L1 <1%, with a median OS of 17.2 months versus 12.2 months with chemotherapy.

Among all patients enrolled in the trial, the median OS was 17.1 months with nivolumab plus ipilimumab and 13.9 months with chemotherapy.

Grade 3 or 4 treatment-related adverse events were reported in 32.8% with the combination versus 36% with chemotherapy. Adverse events of any grade were more common with nivolumab plus ipilimumab than with chemotherapy (24.5% vs 13.9%, respectively), as were events leading to treatment discontinuation (18.1% vs 9.1%). In the combination therapy arm, skin reactions were the most common immune-mediated events (34%), followed by endocrine events (23.8%). Treatment-related deaths were reported in 8 patients in the nivolumab plus ipilimumab arm and in 6 patients in the chemotherapy arm.

The search for biomarkers that predict enhanced response to nivolumab plus ipilimumab is ongoing. Neither PD-L1 expression level nor tumor mutational burden level has panned out.

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