Adding pembrolizumab to chemotherapy improves outcomes in metastatic NSCLC
The addition of pembrolizumab to chemotherapy provided long-term benefit to a subset of patients with advanced non-small cell lung cancer, according to study results presented during the ASCO20 Virtual Scientific Program.
The combination also induced a higher overall response rate while exhibiting a manageable toxicity profile.
“The KEYNOTE-189 study previously showed significant improvements in OS and PFS when patients are treated with pembrolizumab [in combination with] chemotherapy compared with placebo and chemotherapy in these patients without sensitizing EGFR or ALK mutations,” Delvys Rodriguez-Abreu, MD, medical oncologist at Insular University Hospital Complex in Spain, said during a presentation. “This report is the protocol-specified final analysis of this study.”
The randomized phase 3 KEYNOTE-189 study included 616 patients with previously untreated metastatic nonsquamous NSCLC.
Researchers randomly assigned them to 35 cycles of the PD-1 inhibitor pembrolizumab (Keytruda, Merck) dosed at 200 mg three times per week (n = 410) or placebo (n = 206). All patients received four cycles of pemetrexed and carboplatin/cisplatin chemotherapy followed by maintenance pemetrexed chemotherapy.
PFS and OS served as the study’s primary endpoints. ORR served as a secondary endpoint. PFS2 — defined as the time from randomization to objective tumor progression on next-line treatment or death — served as an exploratory endpoint.
Median time from randomization to data cutoff was 31 months (range, 26.5-38.8).
At the time of data cutoff May 20, 17 patients in the pembrolizumab group and one patient in the placebo group continued to receive their initially assigned treatment. Eighty-four patients in the placebo group had switched to pembrolizumab.
Researchers reported longer median OS (22 months vs. 10.6 months; HR = 0.56; 95% CI, 0.46-0.69) and longer median PFS (9 months vs. 4.9 months; HR = 0.49; 95% CI, 0.41-0.59) in the pembrolizumab group.
The pembrolizumab regimen also appeared associated with improved 2-year OS (45.7% vs. 27.3%), 2-year PFS (22% vs. 3.4%) and PFS2 (17 months vs. 9 months; HR = 0.5; 95% CI, 0.41-0.61).
ORRs were 48.3% with pembrolizumab and chemotherapy compared with 19.9% with placebo plus chemotherapy.
Fifty-six patients assigned pembrolizumab completed all 35 cycles of the treatment. ORR among those patients was 85.7%, including four complete responses, 44 partial responses and eight patients with stable disease. Median OS among those patients was not reached.
Overall, 292 patients in the pembrolizumab group and 135 patients in the placebo group experienced grade 3 to grade 5 adverse events.
“The final analysis of this study showed that patients with previously untreated metastatic nonsquamous NSCLC continued to benefit with pembrolizumab over placebo,” Rodriguez-Abreu said. “This is now a standard of care for patients with this disease.”
Perspective
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This is already a leading standard of care in a setting where there are multiple FDA-approved options.
This is not one of the most pressing questions at this point because we already have seen publications that reported follow-up data that were reassuring, so this is a good backup and not surprising.
We have newly approved options — including nivolumab plus ipilimumab (Yervoy, Bristol-Myers Squibb) with chemotherapy — and we don’t know whether that can lead to longer, more sustained responses than what we see here. The only way to know for sure is through a direct head-to-head comparison, but I don’t think we are going to see that any time soon.
There are some questions about whether there could be differences in outcomes with these regimens once you get 3 or 4 years down the road, and that may lead medical professionals to favor a newer regimen over the KENOTE-189 approach. But I think many people are overall very happy with this study.
The other thing with nivolumab and ipilimumab with chemotherapy is whether you actually need ongoing chemotherapy. This trial has ongoing pembrolizumab and chemotherapy, but it’s unclear whether that is actually needed. Some patients may do just as well with pembrolizumab alone in the maintenance setting. We have to keep pushing the question as to whether we are overtreating or undertreating our patients.
Perspective
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The abstract is an important update to what we learned from the KEYNOTE-189 trial, which ultimately led to the adoption of pembrolizumab plus pemetrexed-platinum chemotherapy as a standard of care for patients with lung cancer who do not have ALK or EGFR mutations.
This presentation shows relative stability of the survival curves seen in a paper published in May in Journal of Clinical Oncology, and it reflects maturity of the data during the past 10 months.
The most interesting thing to take away from is abstract is PFS2, or time to progression on next line of therapy for patients who received immunotherapy in the first-line setting. In KEYNOTE-189, patients randomly assigned immunotherapy first achieved longer PFS, as well as longer PFS2. This suggests the benefits of immunotherapy continue beyond when you receive it.
With the maturity of the data from KEYNOTE-189 , and the confidence that clinicians have in it, the debate now will center on how we should decide between the long-term experience we have with KEYNOTE-189 and the new findings from the CheckMate-9LA study, which showed nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) improved OS with a shorter regimen of chemotherapy. The CheckMate-9LA study presents a new alternative for patients, but the publication and mature data are not yet available. We know giving immunotherapy with chemotherapy is good. The question now is: What is the right amount of chemotherapy and immunotherapy — whether as one antibody or two— to give to patients? Those who favor longer experiences with a dataset will continue to favor the approach in KEYNOTE-189.
Reference:
Gadgeel S, et al. J Clin Oncol. 2020;doi:10.1200/JCO.19.03136.
Reck M, et al. Abstract 9501. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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Rodriguez-Abreu, et al. Abstract 9582. Presented at: ASCO20 Virtual Scientific Program; May 29-31, 2020.
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