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Dual immunotherapy with pembrolizumab (Keytruda) and ipilimumab (Yervoy) did not improve survival outcomes over pembrolizumab alone in the treatment of metastatic non-small cell lung cancer (NSCLC) in the KEYNOTE-598 trial.
However, the combination was associated with markedly worse toxicity than pembrolizumab monotherapy, with more than twice as many serious adverse events, which resulted in the study being stopped early.
Consequently, pembrolizumab monotherapy “remains a standard of care” for the first-line treatment of NSCLC in this population, said lead author Michael Boyer, MBBS, PhD, chief clinical officer and conjoint chair of medical oncology, Chris O’Brien Lifehouse, Camperdown, Australia.
The results were presented at the 2020 World Conference on Lung Cancer on January 30, and simultaneously published in the Journal of Clinical Oncology.
Table of Contents
Hoping for Synergy
The hope behind this trial was that the combination of two immunotherapies with distinct mechanisms of action (pembrolizumab targets PD-1, whereas ipilimumab is a CTLA-4 inhibitor) would work synergistically to improve outcomes over pembrolizumab alone.
In fact, a similar combination — but with a different PD inhibitor, that of ipilimumab with nivolumab (Opdivo) — is already approved for use in metastatic NSCLC, as well as for melanoma and liver cancer.
The trial involved 560 untreated patients with stage IV NSCLC, a PD-L1 tumor proportion score (TPS) ≥50%, and no actionable EGFR or ALK alterations. These patients were randomly assigned to receive either dual immunotherapy or pembrolizumab plus placebo.
The combination did not improve either progression-free survival (median PFS was 8.2 months with the combination vs 8.4 months on monotherapy), nor overall survival (21.4 months vs 21.9 months), and did not increase overall response rates (45.4% in both groups) nor duration of response (16.1 vs 17.3 months).
However, this lack of comparative benefit came at the cost of increased rates of adverse events such as pneumonitis, elevated liver enzymes, and colitis. Serious adverse events were recorded in 27.7% on the drug combination vs 13.9% on monotherapy, and adverse events leading to treatment discontinuation were recorded in 19.1% vs 7.5% of patients, respectively.
The results show that adding ipilimumab to pembrolizumab “did not improve efficacy as a first-line therapy for NSCLC” and although the efficacy and safety in the two groups were “as expected,” dual therapy was associated with “greater toxicity” than pembrolizumab alone, Boyer reported.
The findings led to the study being “stopped for futility” on the recommendation of the steering committee, and “ipilimumab and placebo were discontinued,” leaving patients on pembrolizumab monotherapy, Boyer added.
Discussing the results on Twitter, Joshua Bauml, MD, assistant professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia, asked: “How do we align these findings with the positive results [with ipilimumab plus nivolumab] from CheckMate 227 and CheckMate 9LA?”
He said it is “important to remember” that the comparison in CheckMate 227 “was not between nivolumab/ipilimumab and nivolumab, but nivolumab/ipilimumab and chemotherapy.”
So where does this leave us? How do we align these findings with the positive results from CM227 or 9LA? Important to remember that in CM227 the comparison was not between nivo/ipi and nivo, but nivo/ipi and chemo. #LCSM #WCLC20
— Joshua Bauml, MD (@Jbauml) January 30, 2021
More fundamentally, Devika Das, MD, clinical assistant professor of hematology and oncology at the University of Alabama at Birmingham, said on Twitter that, based on the current trial results, there will be “no change in my clinical practice!!”
She added that “we really need biomarker-based decision making here.”
Keynote 598 ? Ipi + Pembro: No change in my clinical practice ‼️We really need biomarker based decision making here. #lcsm #wclc20 Dr Fan summarized it well for me ? pic.twitter.com/vYoBFf3aKS
— Devika Das, MD, MSHQS ? (@DevikaDasMD) January 30, 2021
Charu Aggarwal, MD, MPH, associate professor for lung cancer excellence, Penn Medicine, Philadelphia, agreed with Das but added that she “would like to see longer follow-up to determine if there is a tail to the curve.”
Will not change practice in my patients with #NSCLC >50%, but would like to see longer follow up to determine if there is a tail to the curve #WCLC20 @IASLC #LCSM https://t.co/jMSP6nRnjg
— Charu Aggarwal, MD, MPH (@CharuAggarwalMD) January 30, 2021
Other Combinations Under Study
Fan Yun, MD, director of thoracic oncology at Zhejiang Cancer Hospital, Hangzhou, China, was the invited discussant for the study. Despite the negative results from this trial, the idea of combination immunotherapy continues to be studied and is showing some promising results.
These include combination anti-TIGIT therapy with tiragolumab (Roche) plus atezolizumab (Tecentriq), which was recently granted a breakthrough therapy designation by the US Food and Drug Administration on the basis of the recent phase 2 CITYSCAPE trial.
Another one to watch is the ongoing phase 3 study comparing M7824 (EMD Serono) with pembrolizumab, as well as LEAP-007, which is comparing pembrolizumab plus lenvatinib (Lenvima) with pembrolizumab alone.
The study was sponsored by Merck Sharp & Dohme Corp. Boyer reports relationships with AstraZeneca, Bristol-Myers Squibb, MSD, Amgen, Ascentage, Genentech/Roche, Lilly, Merck KgA, MSD, Novartis, and Pfizer.Yun has disclosed no relevant financial relationships.
2020 World Conference on Lung Cancer Singapore: Abstract PS01.09. Presented January 30, 2021.
J Clin Oncol. Published online January 29, 2021. Full text
For more from Medscape Oncology, follow us on Twitter: @MedscapeOnc
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