Study Supports Pembrolizumab Plus Chemo as Standard of Care for PD-L1-Negative Advanced NSCLC


A pooled analysis of 3 randomized controlled trials found that pembrolizumab plus chemotherapy demonstrated response and survival improvements with a manageable safety in comparison with chemotherapy alone in PD-L1‒negative advanced non-small cell lung cancer.

A pooled analysis of 3 randomized controlled trials found that pembrolizumab (Keytruda) plus chemotherapy demonstrated clinically meaningful improvements in overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) along with a manageable safety profile compared with chemotherapy alone in patients with PD-L1—negative advanced non-small cell lung cancer (NSCLC).

Pembrolizumab plus chemotherapy significantly reduced the risk of death (HR for OS, 0.63) and improved the median OS by approximately 8 months (19.0 vs 11.4 months). Additionally, it improved PFS (HR, 0.68), PFS-2 (HR, 0.57), and ORR (50.0% vs 29.8%). Patients who completed 2 years of treatment were among those who acquired a long-term benefit from pembrolizumab plus chemotherapy; ORR was high among those in this group, and all patients remained alive at the time of the individualized data cutoffs.

“Together, these results support pembrolizumab plus chemotherapy as a standard-of-care first-line treatment for patients with PD-L1‒negative advanced NSCLC without EGFR/ALK alterations,” the authors wrote.

Researchers pooled individual patient data from KEYNOTE-021 cohort G (nonsquamous; NCT02039674), KEYNOTE-189 (nonsquamous; NCT02578680 and NCT03950674), and KEYNOTE-407 (squamous; NCT02775435). Patients included in the trials were treated with either pembrolizumab plus chemotherapy, including pemetrexed and platinum for those with nonsquamous histology and carboplatin and paclitaxel/nab-paclitaxel for those with squamous histology, or chemotherapy alone.

In total, 444 of 1328 patients (33.4%) who were enrolled across the 3 trials were found to have PD-L1‒negative tumors, including 256 on pembrolizumab plus chemotherapy (nonsquamous, n = 155; squamous, n = 94; other, n = 7) and 188 on chemotherapy alone (nonsquamous, n = 83; squamous, n = 99; other, n = 6). The median time from randomization to the data cutoff was 28.0 months (range, 14.7-55.4 months).

When added to chemotherapy, pembrolizumab improved OS (HR, 0.63; 95% CI, 0.50-0.79) and PFS (HR, 0.68; 95% CI, 0.56-0.83) over chemotherapy alone. The median PFS was 6.9 months (95% CI, 6.2-8.8 months) in the pembrolizumab plus chemotherapy group and 5.8 months (95% CI, 4.8-6.2 months) in the chemotherapy alone group. The estimated 12-month PFS rates were 32.8% (95% CI, 27.0%-38.7%) and 19.3% (95% CI, 13.9%-25.3%), respectively, and the 24-month rates were 17.1% (95% CI, 12.5%-22.4%) and 8.5% (95% CI, 4.8%-13.5%), respectively.

Pembrolizumab plus chemotherapy also improved PFS-2 over chemotherapy alone (HR, 0.57; 95% CI, 0.46-0.70). The median PFS-2 was 14.5 months (95% CI, 12.6-15.9 months) in the pembrolizumab plus chemotherapy group and 9.1 months (95% CI, 7.6-10.2 months) in the chemotherapy alone group.

Of those with PD-L1‒negative tumors, the ORR was higher with pembrolizumab plus chemotherapy (50.0%; 95% CI, 43.7%-56.3%) compared with chemotherapy alone (29.8%; 95% CI, 23.4%-36.9%). The median DORs were 8.5 months (range, 1.1+ to 46.0 months) and 6.9 months (range, 1.4+ to 30.1+ months), respectively.

Moreover, 16 patients in the pembrolizumab plus chemotherapy arm completed 2 years of treatment; the ORR was 87.5% (95% CI, 61.7%-98.4%), and the 3-year OS rate was 100%.

“Importantly, our results demonstrate that pembrolizumab plus chemotherapy provides a clinically meaningful OS benefit for patients with PD-L1‒negative NSCLC, a population in need of better treatment options,” the authors wrote. “Although cross-trial comparisons should be approached with caution, the magnitude of benefit provided by pembrolizumab plus chemotherapy versus chemotherapy alone in this setting is substantially more pronounced than previously observed with other agents.”

Regarding safety, adverse events (AEs) were reported in 99.2% of the patients who received pembrolizumab plus chemotherapy and in 98.9% of the patients who received chemotherapy alone, with grade 3 or higher AEs occurring in 71.4% and 72.0%, respectively. The most common AEs in both the pembrolizumab plus chemotherapy group and the chemotherapy alone group were anemia and nausea.

Further, immune-mediated AEs and infusion reactions were experienced by 29.0% and 12.4%, respectively. The most common immune-mediated AEs in the pembrolizumab plus chemotherapy group were hypothyroidism, pneumonitis, and hyperthyroidism. Two patients (0.8%) in the pembrolizumab plus chemotherapy group had grade 5 pneumonitis; no patients in the chemotherapy group had grade 5 immune-mediated AEs or infusion reactions.

“This pooled analysis represents the largest evaluation of outcomes with an immunotherapy plus chemotherapy combination in patients with PD-L1‒negative advanced NSCLC, and the outcomes described provide an important benchmark for comparison with outcomes in future studies,” the authors wrote.


Borghaei H, Langer CJ, Paz-Ares L, et al. Pembrolizumab Plus Chemotherapy Versus Chemotherapy Alone in Patients With Advanced Non–Small Cell Lung Cancer Without Tumor PD-L1 Expression: A Pooled Analysis of 3 Randomized Controlled Trials. Cancer. doi: 10.1002/cncr.33142

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