Immunotherapy combination improves OS compared with chemotherapy in lung cancer subset
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BARCELONA, Spain — A combination of nivolumab and low-dose ipilimumab significantly improved OS compared with chemotherapy as first-line treatment for patients with advanced non-small cell lung cancer, according to results of the randomized phase 3 CheckMate 227 study presented at European Society for Medical Oncology Congress.
Researchers observed a survival benefit among patients with less than 1% PD-L1 expression, as well as those with expression of 1% or greater.
“The landscape of lung cancer has become very complex,” Solange Peters, MD, PhD, head of the thoracic malignancies program in the department of oncology at University of Lausanne in Switzerland, said during her presentation. “There are many options for front-line therapies these days. We would like to give front-line immunotherapy to as many patients as possible, very often combined with chemotherapy. In very specific patients, there is even a chemotherapy-sparing regimen. We really like if we can avoid chemotherapy in the front-line setting if possible.”
Previous results from CheckMate 227 showed nivolumab (Opdivo, Bristol-Myers Squibb), an anti-PD-1 antibody, in combination with ipilimumab (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 antibody, significantly extended PFS compared with chemotherapy alone for patients with advanced NSCLC with tumor mutational burden of at least 10 mutations per megabase.
Peters presented OS results from the final analysis of part 1 of the trial, which compared nivolumab-based regimens with chemotherapy for patients with stage IV or recurrent NSCLC and no known EGFR or ALK mutations.
In part 1, researchers randomly assigned 1,189 patients with PD-L1 expression of 1% or greater to one of three regimens: 3 mg/kg nivolumab every 2 weeks plus 1 mg/kg ipilimumab every 6 weeks (n = 396); 240 mg nivolumab every 2 weeks (n = 396); or histology-based chemotherapy (n = 397).
They also randomly assigned 550 patients with tumor PD-L1 expression of less than 1% to the nivolumab-plus-low-dose ipilimumab regimen (n = 187), 360 mg nivolumab every 3 weeks plus histology-based chemotherapy (n = 177) or chemotherapy alone (n = 186).
OS for nivolumab plus ipilimumab vs. chemotherapy among patients with tumor PD-L1 expression of at least 1% served as the primary endpoint.
Minimum follow-up for OS was 29.3 months.
Results showed patients with tumor PD-L1 expression of at least 1% achieved significantly longer median OS with the immunotherapy combination compared with chemotherapy (17.1 months vs. 14.9 months; HR = 0.79; 97.7% CI, 0.65-0.96). Patients in this subgroup who received nivolumab alone had median OS of 15.7 months (95% CI, 13.3-18.1).
PFS, objective response rate, and duration of response all appeared more favorable for patients treated with nivolumab plus ipilimumab compared with chemotherapy.
Researchers also observed longer median OS with nivolumab plus ipilimumab vs. chemotherapy among patients with PD-L1 expression of less than 1% (17.2 months vs. 12.2 months), as well as among all randomly assigned patients (17.1 months vs. 13.9 months).
Grade 3 or grade 4 treatment-related adverse events occurred among 33% of patients treated with nivolumab and ipilimumab, 19% of patients treated with nivolumab alone, and 36% of patients treated with chemotherapy.
The trial began before the approval of chemotherapy plus immunotherapy or immunotherapy alone for the front-line treatment of NSCLC, so the immunotherapy combination was not compared against the current standards of care. Researchers acknowledged this was the study’s primary limitation.
“This is interesting because it is the first phase 3 study proving this in the negative-based fashion of the combination of CTLA4 and anti-PD1 or anti-PDL1 in NSCLC,” Peters said. “The improvement was seen beyond the primary endpoint in unselected patients and to me represents a new front-line option.” – by John DeRosier
Reference:
Peters S, et al. Abstract LBA4_PR; Presented at: European Society for Medical Oncology Congress; Sept. 27-Oct. 1, 2019; Barcelona, Spain.
Disclosures: Bristol-Myers Squibb funded this study. Peters reports consultant roles with 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, Janssen, and Merck Sharp & Dohme. Please see the abstract for all other authors' relevant financial disclosures.
Perspective
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Nicholas Rohs, MD
I was pleasantly surprised to see these results, but I am not sure they are practice changing for me. Benefit was notably more pronounced for patients with high PD-L1-expressing tumors. Given these patients often have good response from a well-tolerated single-agent immunotherapy regimen, my excitement in this subpopulation is modest. Similarly, the 1% to 49% group crossing the confidence interval supports continued use of chemoimmunotherapy in this area. The most intriguing data, albeit as part of a retrospective analysis, was regarding the benefit seen in the population of patients with PD-L1 expression less than 1%. This may allude to a different biology or immune context for low PD-L1-expressing tumors that may derive more benefit from the addition of CTLA-4 checkpoint inhibition. It also speaks to the heterogeneity of these tumors with regard to immune expression. I think everyone would be interested to see data on the nivolumab-ipilimumab combination vs. chemoimmunotherapy in PD-L1-low populations. This is particularly important because we can’t overlook the real amount of grade 3/grade 4 toxicities with dual checkpoint inhibition. Although this regimen has a relatively tolerable side effect profile, particularly because the investigators thoughtfully utilized a lower dose of ipilimumab, it minimizes one of the most favored aspects of immunotherapy: improved tolerance. I look forward to seeing all of these data sets mature so we can see if one truly has more durable benefit. In the meantime, these data give us another tool in our toolbox with a different side effect profile that may be more appropriate for certain patient populations, particularly those patients who are strongly chemotherapy averse. The next step we always talk about is trying to discover better ways to predict which patients will respond best to certain therapies. This trial may have made that more difficult with tumor mutational burden showing no ability to help predict response, at least in this treatment combination and at a cutoff of 10 mutations per megabase. Either way, I think this study further cements immunotherapy as a part of all first-line options for patients with metastatic NSCLC who do not have actionable mutations, regardless of PDL-1 status.
Perspective
Back to TopMarina Garassino, MD
It’s incredible after 5 years we are here talking about multiple treatment options for NSCLC. Five years ago, we started with a single agent in the second line and observed that there were long-lasting responses for some patients. They were about 20% of the patients, and they are still alive now. The next part was the selection of patients. Three years ago, we were here in the plenary session to discuss the possibility of treating patients in the first-line setting with PD-L1 single-agent pembrolizumab (Keytruda, Merck). Last year was the year when the combination of chemotherapy and immunotherapy received attention.
Now, we are here to discuss the possibility of combining two immunotherapies in this same population.
The promise of [this trial] is the long-lasting responses that led to a longer life for patients [while also] being spared chemotherapy. At the same time, we have to go back to the bench and ask which patients are the right ones for a combination of two immunotherapies, a combination of immunotherapy and chemotherapy, or just treatment with a single agent.
I think we need time to understand which is the right treatment for specific patients, but the good news is that we now have the options for multiple possibilities.
We are in the time of patient empowerment in terms of decision-making, and I believe that patients will play a fundamental role in deciding treatment for the front-line setting.
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