Combination of Nivolumab and Ipilimumab Moves Forward in NSCLC

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How best to combine new immunotherapies is a burning question in oncology. A new study in the CheckMate series suggests that nivolumab (Opdivo) and ipilimumab (Yervoy) can be safely and effectively combined as first-line treatment of advanced non–small cell lung cancer (NSCLC),1 but further study is needed. This combination is being studied in the phase III CheckMate 227 trial. For now, a platinum-containing doublet is still the standard of care.

Matthew Hellmann, MD

Matthew Hellmann, MD

“Nivolumab plus ipilimumab has promising efficacy in advanced NSCLC. The combination is well tolerated, with no treatment-related deaths. Overall response rates range from 39% to 47%, and median duration of response has not yet been reached,” said lead author Matthew Hellmann, MD, of Memorial Sloan Kettering Cancer Center, New York.

Both nivolumab and ipilimumab enhance T-cell antitumor activity. The combination of nivolumab plus ipilimumab has been approved for the treatment of melanoma by the U.S. Food and Drug Administration (FDA). Nivolumab monotherapy has been approved by the FDA for adults with locally advanced NSCLC progressing after platinum-doublet chemotherapy.

Study Details

CheckMate 012 is a phase I trial comparing nivolumab monotherapy with nivolumab and ipilimumab as first-line treatment in advanced NSCLC. At the 2016 ASCO Annual Meeting, Dr. Hellmann presented the results of the nivolumab monotherapy arm (3 mg/kg given every 2 weeks) and nivolumab plus ipilimumab given every 12 weeks (n = 38) or nivolu­mab plus ipilimumab given every 6 weeks (n = 39).1 Follow-up for the combination arms was about 12 months.

Response Rates

Overall response rates were 47% with nivolumab plus ipilimumab every 12 weeks vs 39% with nivolumab plus ipilimumab every 6 weeks, compared with 23% with first-line nivolumab monotherapy. “Responses continue to be deep and durable. Eighty percent of responses were achieved by week 11, and a majority of responses remain ongoing at the time of this datalock,” Dr. Hellmann revealed.

Nivolumab plus ipilimumab has promising efficacy in advanced NSCLC. Overall response rates range from 39% to 47%, and median duration of response has not yet been reached.
— Matthew Hellmann, MD

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Eighty percent of patients had tissue available for PD-L1 (programmed cell death ligand 1) testing. PD-L1 expression appeared to predict response to the combination in both arms. In patients with at least 1% of cells positive for PD-L1, the overall response rate was 57%, and in patients with ≥ 50% of cells expressing PD-L1, the overall response rate was 92%.

Response rates were also higher for the combination than for nivolumab monotherapy in never smokers, smokers, epidermal growth factor receptor (EGFR)-mutated cancers, and EGFR wild-type cancer.

“On a personal note, I’ll mention one remarkable case involving a 54-year-old patient of mine with metastatic NSCLC who had an excellent response to nivolu­mab plus ipilimumab over the course of a year. He had toxicity that improved with steroids but required stopping therapy. Since he had only a few lesions left, we resected the residual disease and found that there was no viable cancer. He’d had a pathologic complete response. A year and a half after his initial diagnosis of metastatic NSCLC, he is effectively cancer-free. And since then, we’ve had two other patients who have had similar pathologic complete responses to this combination,” Dr. ­Hellmann told listeners.

Combination Immunotherapy in NSCLC

  • Preliminary evidence of the CheckMate 012 trial suggests that the combination of nivolumab plus ipilimumab achieves higher response rates in advanced NSCLC than nivolumab alone, with good tolerability.
  • It seems to be preferable to give ipilimumab every 12 weeks instead of every 6 weeks in combination with nivolumab.
  • A phase III study is evaluating the combination of nivolumab and ipilimumab in NSCLC, but for now, a platinum doublet remains the standard of care for first-line treatment of advanced NSCLC.


The tolerability of the combination compared similarly with that of nivolumab monotherapy. Across all treatment arms, about 10% of patients discontinued treatment related to treatment-emergent adverse events. No treatment-related deaths were ­reported.

Treatment-related adverse events of any grade were reported in 82% and 72% with ipilimumab every 12 weeks and ipilimumab every 6 weeks, respectively. Grade 3 and 4 adverse events were 37% and 33%, respectively.

“These rates of treatment-emergent adverse events are improved compared to older arms using higher and more frequent doses of ipilimumab and compare favorably to what might be expected from chemotherapy,” Dr. Hellmann added. ■

Disclosure: The study was funded by Bristol-Myers Squibb. Dr. Hellmann has consulted for Bristol-Myers Squibb, Merck, Genentech, AstraZeneca, Neon, and Inovio and received research funding from Bristol-Myers Squibb.


1. Hellmann MD, Gettinger SN, Goldman JW, et al: CheckMate 012: Safety and efficacy of first-line nivolumab and ipilimumab in advanced NSCLC. 2016 ASCO Annual Meeting. Abstract 3001. Presented June 4, 2016.

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Expert Point of View: David R. Spigel, MD

[The relatively small improvement in progression-free survival] leads me to question whether median progression-free survival is the best endpoint for trials of combination immunotherapy.
— David R. Spigel, MD

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“These are outstanding results,” commented ...