Pembrolizumab Plus Chemotherapy Extended Survival Longer Than Chemotherapy Alone: Study

“In a review of the literature, we found that, to date, pembrolizumab has been the only PD-1 or PD-LI inhibitor to show a significant survival benefit over chemotherapy when given as monotherapy or as part of combination therapy for metastatic, squamous, or nonsquamous NSCLC [non-small cell lung cancer].”¹

That statement is from researchers writing in The New England Journal of Medicine, who also presented new data at the IASLC’s 19th World Conference on Lung Cancer in Toronto, Canada, on September 25, 2018. Based on their data, Merck Sharp & Dohme, the maker of pembrolizumab, can now add that treatment with pembrolizumab, in combination with chemotherapy, resulted in significantly longer overall survival (OS) and progression-free survival (PFS) compared with chemotherapy alone in squamous NSCLC. According to the article, Kaplan-Meier estimates of the rate of survival at 1 year were 65.2% in the pembrolizumab-combination arm and 48.3% in the placebo-combination arm.

Though the trial has not concluded (and has an estimated conclusion date of 2021), the decision to report the second interim results occurred because the “efficacy boundaries for the primary hypotheses of overall survival and progression-free survival had been met,” the investigators wrote.¹ They originally set the goalpost for interim analysis to occur after 332 events or disease progression or death occurred.

In a double-blind, phase 3 trial, researchers running the KEYNOTE-407 trial randomly assigned 559 untreated, metastatic, squamous NSCLC patients to receive either 200 mg of pembrolizumab or saline placebo for up to 35 cycles (278 patients and 281 patients, respectively). All patients were also treated with carboplatin and either paclitaxel or nanoparticle-albumin bound [nab]-paclitaxel for the first 4 cycles. Patients who received paclitaxel also received premedication with a glucocorticoid and antihistamines.

Patients were allowed to crossover in certain circumstances; 75 patients switched from placebo to pembrolizumab after disease progression, and 14 patients received a subsequent PD-1 or PD-L1 inhibitor from prescribers outside of the trial.

PD-L1 expression status was assessed using Agilent Technologies’ PD-L1 IHC 22C3 pharmDx assay, and tumor imaging was scheduled for weeks 6, 12, and 18, every 9 weeks through week 45, and then every 12 weeks thereafter. As a result of the use of this tool, patients were excluded from the trial if they could not provide a tumor sample for the determination of PD-L1 status. OS, PFS, response rate, and duration of response were calculated through the use of blinded, independent central review of radiologic images.

A PD-L1 tumor proportion score of 1% or greater was seen in 63.1% of patients — but regardless of patient PD-L1 expression level, there was an overall survival benefit observed across the pembrolizumab-combination group. In this group, median OS at follow-up was 15.9 months, compared with 11.3 months in the placebo-combination group (hazard ratio for death, 0.64; 95% confidence interval [CI], 0.49-0.85; P < .001); median PFS was 6.4 months and 4.8 months, respectively (hazard ratio for disease progression or death, .056; 95% CI, 0.45-0.70; P < .001).

“The risk of death was 36% lower and the risk of disease progression or death was 44% lower in the pembrolizumab-combination group than in the placebo-combination group,” the authors wrote. But, they added, “In patients with PD-L1-positive tumors, the currently available data do not permit the determination of whether pembrolizumab plus chemotherapy has greater efficacy than pembrolizumab alone.”¹

Response rates, however, were higher among the individuals who received the pembrolizumab-based regimen compared with the rates observed in those on the placebo regimen when the patients were placed in subgroups defined by PD-L1 tumor proportion score. And, outcomes improved across all categories of PD-L1 tumor proportion scores in the pembrolizumab/chemotherapy group, making the study authors question the usefulness of PD-L1 as a biomarker to guide drug selection.

Adverse events (AEs) were similar across treatment groups, although treatment discontinuation in the pembrolizumab-combination group occurred more frequently than in the placebo-combination group (13.3% vs 6.4%, respectively). There were 23 deaths due to AEs in the pembrolizumab-based arm and 18 AE-related deaths in the placebo-based arm.

Read more of Cancer Therapy Advisor‘s coverage of the IASLC 2018 meeting by visiting the conference page.

Reference

1. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer [published online September 25, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1810865