American Association for Cancer Research Annual Meeting
American Association for Cancer Research Annual Meeting
April 16, 2018
4 min read

Immunotherapy superior to chemotherapy for advanced lung cancer with high tumor mutational burden

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Matthew Hellmann

CHICAGO — Immunotherapy with nivolumab plus ipilimumab significantly prolonged PFS compared with standard chemotherapy among patients with newly diagnosed advanced non-small cell lung cancer with high tumor mutational burden, according to results of the randomized phase 3 CheckMate -227 trial presented at American Association for Cancer Research Annual Meeting.

The study offers the opportunity to introduce two new standards of care for patients with non-small cell lung cancer, according to researcher Matthew Hellmann, MD, assistant attending at Memorial Sloan Kettering Cancer Center.

“First, this study demonstrates the clinical value of nivolumab plus ipilimumab for [this patient population],” Hellmann said during a press conference. “The combination provided durable benefit, builds upon our progress in precision medicine in lung cancer, spares the use of chemotherapy in the first-line setting and allows it to be used as a second-line option if needed.

“Second, this study validates role of tumor and tissue burden as a biomarker and the effectiveness of the prespecified endpoint to identify those who receive the greatest benefit,” Hellmann added. “This establishes tumor mutational burden as a distinct and definable new subgroup of lung cancer and broadens the clinical actionability of data we can derive from routine next-generation sequencing.”

Platinum chemotherapy has long been the standard for patients with newly diagnosed NSCLC.

Although PD-1 immunotherapies have emerged as a new treatment option for this patient population, only a small percentage of patients with NSCLC respond, according to study background.

“This context has yielded two critical opportunities for improvement: to develop effective combinations of therapy that can broaden the population of patients who respond to immunotherapy, and to identify effective biomarkers to predict response,” Hellmann said.

The combination of the PD-L1 inhibitor nivolumab (Opdivo, Bristol-Myers Squibb) and the CTLA-4 inhibitor ipilimumab (Yervoy, Bristol-Myers Squibb) showed promising activity and tolerability as first-line therapy in a phase 1 trial of patients with advanced NSCLC.

The open-label CheckMate -227 study compared three experimental regimens — nivolumab plus ipilimumab, nivolumab alone, or nivolumab plus platinum doublet chemotherapy — with platinum doublet chemotherapy alone as first-line treatment for patients with advanced NSCLC.

The analysis included 1,739 patients with chemotherapy-naive, histologically confirmed stage IV or recurrent NSCLC, ECOG performance status of 0 or 1, and no known sensitizing EGFR or ALK mutations.

Researchers assigned patients with PD-L1 expression of 1% or higher (n = 1,189) to one of three regimens: nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (n = 396), nivolumab monotherapy dosed at 240 mg every 2 weeks (n = 396), or histology-based doublet chemotherapy (n = 397).


Investigators assigned patients with PD-L1 expression less than 1% (n = 550) to one of three regimens: nivolumab plus ipilimumab (n = 187), nivolumab 360 mg every 3 weeks plus histology-based chemotherapy (n = 177), or chemotherapy alone (n = 186).

Treatment continued up to 2 years, or until disease progression or unacceptable toxicity.

Researchers established two coprimary endpoints:

OS for nivolumab-ipilimumab compared with platinum doublet chemotherapy among patients with PD-L1-selected tumors; and

PFS determined by blinded central review for nivolumab-ipilimumab compared with platinum doublet chemotherapy among patients with high tumor mutational burden ( 10 mutations per megabase).

Baseline characteristics appeared similar among all patients with evaluable tumor mutational burden and among all patients randomly assigned to treatment. They also appeared balanced between the nivolumab-ipilimumab and platinum doublet chemotherapy groups.

Minimum follow-up was 11.2 months.

Among all randomly assigned patients, researchers reported an HR for PFS of 0.83 (95% CI, 0.72-0.96) with nivolumab-ipilimumab compared with chemotherapy.

Among patients with high tumor mutational burden, those assigned nivolumab plus ipilimumab achieved significantly longer PFS than those assigned chemotherapy (HR = 0.58; 97.5% CI, 0.41-0.81).

Results appeared consistent across subgroups, including those with nonsquamous histology (HR = 0.55; 95% CI, 0.38-0.8), those with squamous histology (HR = 0.63; 95% CI, 0.39-1.04), those with PD-L1 expression of 1% or higher (HR = 0.62; 95% CI, 0.44-0.88), and those with PD-L1 expression of less than 1% (HR = 0.48; 95% CI, 0.27-0.85).

The immunotherapy combination also appeared associated with a higher objective response rate (45.3% vs. 26.9%) and longer median duration of response (not reached vs. 5.4 months). Median time to response was 2.7 months with the nivolumab-ipilimumab combination and 1.5 months with chemotherapy.

The immunotherapy combination did not confer a significant PFS benefit among patients with tumor mutational burden less than 10 mutations per megabase (HR = 1.07; 95% CI, 0.84-1.35).

OS data for the PD-L1-selected coprimary population have not been released. Hellmann described them as “preliminary but encouraging.”

Among all treated patients, those assigned chemotherapy experienced a higher rate any-grade treatment-related adverse events (81% vs. 75%), as well as grade 3 to grade 4 treatment-related adverse events (36% vs. 31%). A higher percentage of patients assigned nivolumab-ipilimumab discontinued therapy due to adverse events (12% vs. 5%). One treatment-related death occurred in each group.

Hossein Borghaei
Hossein Borghaei

Hossein Borghaei, DO, MS, medical oncologist at Fox Chase Cancer Center and a researcher on Checkmate -227, described the efficacy observed so far as “very impressive.”

“You are getting up to a 42% reduction in the risk for progression or death. That is a clinically meaningful magnitude,” Borghaei told HemOnc Today. “I admit I am biased toward this regimen, but I think having a chemotherapy-sparing regimen is important. It is a good idea to have [a combination of immuno-oncology agents] as a backbone that we can build on for future studies.”

He cited previously reported results that showed 16% of patients with advanced NSCLC survived 5 years when they received nivolumab monotherapy.

“The goal is to improve long-term survival,” Borghaei said. “The question is, how do you make that 16% to become 20%, 25% or 30%? To me, it really seems having an IO-IO combination can help get to that improvement at the tail of the curve.” – by Mark Leiser



Hellmann MD, et al. Abstract CT077. Presented at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.


Disclosure: Bristol-Myers Squibb and Ono Pharmaceutical Co. sponsored the study. Hellmann reports paid consultant roles with AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Janssen, Merck, Mirati Therapeutics, Novartis and Shattuck Labs. He also reports grant/research support from Bristol-Myers Squibb. Borghaei reports consultant roles with AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech, Merck and Novartis; research funding from Bristol-Myers Squibb, Celgene, Eli Lilly, Merck and Millennium; and travel accommodations or expenses from AstraZeneca, Celgene, Eli Lilly, Genentech, Merck and Novartis. Please see the abstract for all other authors’ relevant financial disclosures.