Nivolumab/Ipilimumab: Another First-Line Option for Advanced NSCLC

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The combination of nivolumab and ipilimumab improved overall survival compared with chemotherapy as first-line therapy for patients with advanced non–small cell lung cancer (NSCLC) and programmed cell death ligand 1 (PD-L1) expression of at least 1%, according to the results of CheckMate 227. Nivolumab/ipilimumab also improved overall survival compared with chemotherapy in the total study population as well as in patients whose tumors had low expression of PD-L1 (ie, < 1%).

These results were presented at the European Society for Medical Oncology (ESMO) Congress 20191 and published online simultaneously in TheNew England Journal of Medicine.2 They represent the final analysis of part 1 of the two-part CheckMate 227 trial, which has a complex design.

“CheckMate 227 met its primary endpoint. It is the first phase III trial to prove that the combination of a checkpoint inhibitor and a CTLA-4 [cytotoxic T-lymphocyte–associated protein 4] inhibitor improve survival compared with chemotherapy in unselected, treatment-naive patients with metastatic NSCLC,” said presenting author Solange Peters, MD, PhD, Head of the Medical Oncology Service and Chair of Thoracic Oncology, Oncology Department at the Centre Hospitalier Universitaire Vaudois in Lausanne, Switzerland. Dr. Peters is President-Elect of ESMO for 2020–2021.

Nivolumab and ipilimumab have distinct but complementary mechanisms of action, and there is a strong rationale for combining these two agents.
— Solange Peters, MD, PhD

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“In my opinion, these results are practice-changing. Now that we have a number of treatment options, including chemotherapy plus an anti–PD-1 [programmed cell death protein 1] agent or an anti–PD-L1 agent alone, and a chemotherapy-sparing option of nivolumab/ipilimumab, we have to begin the discussion of which patients [without driver mutations] should receive which treatment,” she added. “The majority of patients with NSCLC do not have actionable driver mutations.”

Previously, the CheckMate 227 investigators reported improved progression-free survival with nivolumab/ipilimumab vs chemotherapy in patients with a high tumor mutational burden. They also showed at ESMO that, in contrast, tumor mutational burden could not identify patients with improved survival on nivolumab/ipilimumab. “Nivolumab and ipilimumab have distinct but complementary mechanisms of action, and there is a strong rationale for combining these two agents,” she told listeners.

Study Details

CheckMate 227 randomly assigned patients with treatment-naive stage IV and recurrent NSCLC and PD-L1 expression ≥ 1% 1:1:1 to nivolumab/ipilimumab vs nivolumab alone vs chemotherapy alone (part 1a, 1,189 patients); and patients with PD-L1 expression < 1% 1:1:1 to nivolumab/ipilimumab vs nivolumab/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. Patients provided baseline tumor tissue for analysis of PD-L1 expression and were prestratified for PD-L1 expression and for squamous and nonsquamous histology.

The main focus of Dr. Peters’ presentation was an overall survival analysis in patients with PD-L1 expression of at least 1%, one of the primary endpoints. The dose and frequency of ipilimumab were decreased in this trial in an effort to reduce the adverse events of the combination observed in early lung trials and in melanoma and renal cell carcinoma.

Baseline characteristics were well balanced in the three treatment arms for PD-L1 expression ≥ 1% and overall. The median age of patients was 64 years. About 10% were 75 years or older. About two-thirds were men, about 85% were current or former smokers, about 30% had squamous histology, and 70% had nonsquamous disease.

Part 1a and 1b Analysis

In patients with PD-L1 expression ≥ 1% (part 1a of the trial), the minimum follow-up was 29.3 months. Among this group, the median overall survival was 17.1 months with nivolumab/ipilimumab and 14.9 months with chemotherapy (P = .007). The 2-year overall survival rates were 40% and 33%, respectively. The median duration of response was 23.2 months with nivolumab/ipilimumab and 6.2 months with chemotherapy.

Overall survival was also improved in the group with PD-L1 expression < 1% (part 1b of the trial). The median duration of 17.2 months vs 12.2 months with chemotherapy.

Findings From CheckMate 227

  • The combination of nivolumab/ipilimumab improved overall survival compared with chemotherapy as first-line therapy for patients with NSCLC regardless of PD-L1 expression.
  • It is not clear whether nivolumab/ipilimumab is preferable to other options due to increased toxicity.

Among all patients enrolled in the trial, the median overall survival was 17.1 months with nivolumab/ipilimumab and 13.9 months with chemotherapy.

“The contribution of ipilimumab and CTLA-4 inhibition was probably necessary to achieve these results,” stated Dr. Peters. “When you look at the survival curves for nivolumab/ipilimumab vs nivolumab, the separation of the curves is sustained over time and is obvious. The duration of response is striking: 23 months for the nivolumab/ipilimumab combination vs 15.5 months for nivolumab alone. Almost half of patients treated with the combination are still in response at 2 years.”


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

Biomarkers for predicting an enhanced response to nivolumab are still elusive. Both PD-L1–positive and PD-L1–negative patients responded to treatment, and in an earlier analysis of these data, tumor mutational burden did not identify responders.

Additional Commentary

At a press conference, Marina Chiara Garassino, MD, of the Istituto Nazionale dei Tumori, Milan, Italy, offered some perspective on CheckMate 227. “We now have multiple options for the treatment of NSCLC. Dr. Peters presented data potentially applicable to the majority of patients with NSCLC—about 90% of them.”

Marina Chiara Garassino, MD

Marina Chiara Garassino, MD

Dr. Garassino continued: “We have three options for this group of patients: single-agent pembrolizumab, chemotherapy plus a checkpoint inhibitor, and now nivolumab and ipilimumab. The promise of CheckMate 227 is the possibility of long-lasting responses and long life for our patients with a chemotherapy-sparing regimen. We have to go back to the biology and clinical characteristics and identify the right patients for each option. We need time to understand which is the right treatment algorithm.”

The good news, according to Dr. Garassino, is that now there are multiple options for this patient population. “The voice of the patient will play a role,” she added. “We need to discuss options for first-line treatment with our patients in this time of patient empowerment.” 

DISCLOSURE: CheckMate 227 was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Peters has received educational grants, provided consultation, attended advisory boards, and/or provided lectures for AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Incyte, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Pfizer, Regeneron, Sanofi, Seattle Genetics, and Taked (from whom she has received honoraria [fees to institution]).Dr. Garassino reported financial relationships with Boehringer Ingelheim, Novartis, Pfizer, Inivata, Seattle Genetics, Daiichi Sankyo, Otsuka Pharma, Incyte, Lilly, Bristol-Myers Squibb, Roche, Celgene, Takeda, Merck Sharp & Dohme, AstraZeneca, Tiziana Sciences, Clovis, Merck Serono, Celgene, Bayer, F. Hoffmann-La Roche, Spectrum Pharmaceuticals, Exelixis, GlaxoSmithKline, and Blueprint Medicine.


1. Peters S, Ramalingam SS, Paz-Ares L, et al: Nivolumab + low-dose ipilimumab vs platinum-doublet chemotherapy as first-line treatment for advanced non-small cell lung cancer. 2019 ESMO Congress. Abstract LBA4. Presented September 28, 2019.

2. Hellmann MD, Paz-Ares L, Bernabe Caro R, et al: Nivolumab plus ipilimumab in advanced non-small-cell lung cancer. N Engl J Med. September 28, 2019 (early release online).

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