Addition of ipilimumab to pembrolizumab fails to improve outcomes for NSCLC subset
Click Here to Manage Email Alerts
The addition of first-line ipilimumab to pembrolizumab did not improve outcomes for patients with metastatic non-small cell lung cancer who had PD-L1 tumor proportion scores of 50% or greater and no targetable EGFR or ALK aberrations.
With greater toxicity also observed with the combination of ipilimumab (Yervoy, Bristol Myers Squibb) and pembrolizumab (Keytruda, Merck), pembrolizumab monotherapy remains standard of care for this group, according to results of the KEYNOTE-598 trial, presented at the virtual International Association for the Study of Lung Cancer World Conference on Lung Cancer and simultaneously published in Journal of Clinical Oncology.
“This is the first adequately powered trial that compared an anti-PD-L1 monotherapy against the combination of an anti-PD-L1 and an anti-CTLA-4 [therapy] in this population of patients,” Michael Boyer, MBBS, PhD, clinical professor of medicine at Chris O’Brien Lifehouse and Central Clinical School of the University of Sydney in Australia, said during his presentation.
Pembrolizumab is standard-of-care first-line therapy for metastatic NSCLC without sensitizing EGFR or ALK aberrations and with a PD-L1 tumor proportion score of at least 50% based on results of the KEYNOTE-024 study, which showed an improvement with pembrolizumab monotherapy compared with platinum-doublet chemotherapy.
KEYNOTE-598 evaluated whether the addition of ipilimumab to pembrolizumab further improved outcomes for these patients.
Boyer and colleagues randomly assigned 568 patients to either 200 mg pembrolizumab every 3 weeks for up to 35 doses plus 1 mg/kg ipilimumab every 6 weeks for up to 18 doses (n = 284; median age, 64 years; 71.7% men) or 200 mg pembrolizumab every 3 weeks for up to 35 doses plus placebo every 6 weeks for up to 18 doses (n = 284; median age, 65 years; 67.3% men).
OS and PFS by blinded independent central review per RECIST version 1.1 served as co-primary endpoints. Objective response rate, duration of response per RECIST version 1.1 and safety served as secondary endpoints.
Results showed median OS of 21.4 months with pembrolizumab plus ipilimumab and 21.9 months with pembrolizumab monotherapy (HR = 1.08; 95% CI, 0.85-1.37). Median PFS also was numerically shorter with the combination (8.2 months vs. 8.4 months; HR = 1.06; 95% CI, 0.86-1.3).
“The futility boundaries that were set for this study were met and, as a result, the study was stopped. Ipilimumab and placebo were then stopped, and all patients continued with pembrolizumab monotherapy,” Boyer said. “We also looked at subgroups of patients and found that for all subgroups examined, the results were consistent with the overall trial results — there were no subgroups that had particular benefit. Of note, we have not yet looked at tumor mutation burden as a subgroup.”
The ORR was 45.4% for both groups, with a slightly longer median duration of response in the pembrolizumab monotherapy group (17.3 months vs. 16.1 months).
The combination group had higher rates of grade 3 to grade 5 adverse events (62.4% vs. 50.2%) and toxicity-related deaths (13.1% vs. 7.5%) than the monotherapy group.
“The addition of ipilimumab to pembrolizumab did not improve efficacy, but it did increase toxicity,” Boyer said. “Pembrolizumab monotherapy remains a standard-of-care first-line treatment for NSCLC.”
References:
Boyer M, et al. Abstract PS01.09. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer (virtual meeting); Jan. 28-31, 2021.
Boyer M, et al. J Clin Oncol. 2021;doi:10.1200/JCO.20.03579.
Perspective
Back to Top
Results of KEYNOTE-598 demonstrate that the addition of ipilimumab to pembrolizumab does not improve outcomes among patients with metastatic NSCLC, specifically for those with PD-L1 expression of 50% or greater, compared with pembrolizumab alone.
Specifically, researchers reported no differences for PFS, ORR or duration of response. In addition to lack of efficacy, there was increased toxicity with the combination, and increases in serious adverse events and grade 3 or higher adverse events. This study was stopped for futility.
Immune checkpoint inhibition is an important component of first-line treatment for metastatic NSCLC among patients without actionable driver mutations. It is fair to say that based on the results of the study, the addition of ipilimumab to pembrolizumab should not be justified for a subset of patients with a PD-L1 score of at least 50% in the clinic.
However, many questions remain. Are there subsets of patients that would clearly benefit? This trial did not assess the role of combined PD-1 and CTLA-4 inhibition in patients with low or negative PD-L1 expression. This is a setting where we do have approval of combination nivolumab (Opdivo, Bristol Myers Squibb) and ipilimumab as front-line therapy for metastatic NSCLC with PD-L1 expression of at least 1%. Results of the CheckMate 227 trial showed improved outcomes, including survival, with this combination compared with chemotherapy.
Are there phenotypic and genotypic characteristics that we may be able to use to make therapeutic decisions? In the future, we need to emphasize development of biomarkers such as tissue or plasma tumor mutational burden either alone or in combination with gene expression profiling, and molecular signatures, including next-generation sequencing, may provide valuable information for appropriate therapeutic selection.
Reference:
Ramalingam SS, et al. Abstract 9500. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
Collapse
Boyer M, et al. Abstract PS01.09. Presented at: International Association for the Study of Lung Cancer World Conference on Lung Cancer (virtual meeting); Jan. 28-31, 2021.
Click Here to Manage Email Alerts