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Ipilimumab-nivolumab combination safe for historically unstudied patients with lung cancer
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BARCELONA — The combination of low-dose, weight-based ipilimumab and flat-dose nivolumab demonstrated safety and efficacy as first-line treatment for patients with stage IV non-small cell lung cancer and comorbidities that traditionally preclude them from enrolling in clinical trials, according to results of the single-arm, nonrandomized CheckMate 817 study presented at International Association for the Study of Lung Cancer World Conference on Lung Cancer.
This special population of patients included those with a poor ECOG performance status, asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV infection.
Fabrice Barlesi, MD, PhD, professor of medicine at Aix-Marseille University and Assistance Publique Hôpitaux de Marseille in France, and colleagues conducted CheckMate 817 due to the limited data on safety and efficacy of immunotherapy for patients with advanced NSCLC and these comorbidities.
The study featured two cohorts. Cohort A included 391 patients with an ECOG performance score of 0 to 1. Cohort A1 included 198 patients with an ECOG performance status of 2 — which indicates a patient is ambulatory but cannot engage in most work activities — as well as patients with an ECOG performance status of 0 to 1 and either asymptomatic untreated brain metastases, hepatic or renal impairment, or HIV infection.
No patients had received prior systemic therapy, and none harbored EGFR or ALK mutations.
Patients received 240 mg IV nivolumab (Opdivo, Bristol-Myers Squibb) every 2 weeks with 1 mg/kg IV ipilimumab (Yervoy, Bristol-Myers Squibb) every 6 weeks until disease progression or unacceptability toxicity, for up to 2 years.
The occurrence of select grade 3 to grade 5 treatment-related adverse events and immune-mediated adverse events served as the primary endpoint. Secondary endpoints included PFS, overall response rate, duration of response and OS.
Results showed that 77% of patients in cohort A experienced a treatment-related adverse event of any grade, and 35% experienced a grade 3 to grade 4 event. In comparison, 67% of patients in cohort A1 experienced any treatment-related adverse event, and 28% experienced a grade 3 or grade 4 event.
Incidence of adverse events in cohort A1 appeared comparable whether patients had an ECOG performance status of 2 (any grade, 63%; grade 3-4, 26%) or an ECOG performance status of 0 to 1 and comorbidities (any grade, 78%; grade 3-4, 34%).
“These data show that for those [special cohorts of patients], this regimen is as safe as it is for the general population,” Barlesi said during a press conference. “The treatment-related adverse events leading to discontinuation also were comparable and treatment-related deaths were very low in both cohorts.”
The ORR in cohort A1 was 24%, with a median duration of response of 13.8 months (95% CI, 9.6-not reached). The response rate ranged from 19% among those with an ECOG performance status of 2 (median duration of response, 14.2 months; 95% CI, 10-not reached) to 37% among those with other comorbidities (median duration of response, 9.7 months; 95% CI, 7-not reached).
Median PFS reached 3.9 months (95% CI, 2.8-5.4) in cohort A1 overall, with 26% of patients achieving 1-year PFS. Median PFS was 3.6 months (95% CI, 2.8-5.4; 1-year PFS, 25%) in the subgroup with a poor performance status and 4.2 months (95% CI, 2.7-9.6; 1-year PFS, 27%) in the subgroup with comorbidities.
Researchers also evaluated outcomes in cohort A1 according to biomarker analyses. Results showed those with PD-L1 expression of 50% of higher had the longest median PFS, at 9.6 months (95% CI, 2.8-15.6), with a 46% 1-year PFS rate. Tumor mutational burden of at least 10 mutations/Mb also predicted for longer PFS (median, 8.3 months; 95% CI, 2.9-14.8; 1-year PFS, 42%).
“This study showed a consistent safety profile across both a general, ECOG performance status of 0-to-1 population — those who are usually included in clinical trials — and a special population, including those with ECOG performance status of 2 or comorbid conditions, patients who are usually excluded from clinical trials,” Barlesi said. “Overall, the safety profile was consistent with prior studies using weight-based nivolumab.”
The data also suggest encouraging activity among these patients, he added.
“But, as expected, unfortunately, globally the outcomes of this population were lower than those with a better ECOG performance status,” Barlesi said. “But, despite this poor performance status and comorbidities, those patients achieved durable responses with nivolumab and ipilimumab.” – by Alexandra Todak
Reference:
Barlesi F, et al. Abstract OA04.02. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer; Sept. 7-10, 2019; Barcelona.
Disclosures: Barlesi reports consultant/advisory roles with or research funding or honoraria from AbbVie, ACEA, Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eisai, Eli-Lilly, Genentech, Ignyta, Innate Pharma, Ipsen, Loxo Oncology, MedImmune, Merck, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi-Aventis and Takeda. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Tarek M. Mekhail, MD
Most patients who show up in our clinic do not have an ECOG performance status of 0 or 1, and many have comorbidities. Further, patients with an ECOG performance status of 2 are self-sufficient, but they cannot work. This reflects the majority of our patients. The study included patients with significant renal dysfunction, with creatinine clearance of 20 mg/kg to 30 mg/kg, as well as patients with poor liver function — these are very valuable data. The researchers also included patients with HIV, which does not represent a large group, and I applaud the authors for providing at least the safety data necessary to be able to provide treatment for these patients.
It is impossible to include patients with every type of comorbidity, so we must use these data and real-world data to guide our practices. Many of us have already been treating these patients; having the evidence-based comfort that there isn’t added toxicity and that these treatments are relatively well-tolerated among these patients is important.
The studies that led to the approval of immunotherapies for first- or second-line treatment included patients with an ECOG performance status of 0 or 1. Previously, when using a treatment pathway for a patient with an ECOG performance status of 2, the pathway would have recommended a more toxic treatment: chemotherapy. It does not make sense to recommend a treatment that is more toxic just because previously there weren’t data for patients with an ECOG performance status of 2. Now there are data, and one of the treatment pathways we use in the U.S. was recently amended to include patients with a performance status of 2.
I would recommend that as we develop non-chemotherapy trials for non-chemotherapy combinations, that patients with performance statuses of 0 to 2 be included, with trial stratification according to performance status. We can even go back and study regimens among patients with an ECOG performance status of 3, because these patients can show the Lazarus effect if they have a positive predictive marker suggestive of treatment benefit. If I have a patient with a performance status of 3 who has PD-L1 expression of greater than 50%, I am very tempted to treat them with immunotherapy. We don’t have an evidence base to support this decision, but real-world data suggest this is an appropriate treatment.
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