Pembrolizumab/Chemo PFS Benefit in NSCLC Sustained With Longer Follow-Up

Vassiliki A. Papadimitrakopoulou, MD

The frontline combination of pembrolizumab (Keytruda), pemetrexed, and carboplatin reduced the risk of progression or death by 50% and nearly doubled objective response rates (ORR) compared with chemotherapy alone for patients with advanced non-squamous non—small cell lung cancer (NSCLC), according to data from cohort G of the KEYNOTE-021 trial presented at the 2017 ASCO Annual Meeting.

After 14.5 months of follow-up, the median progression-free survival (PFS) was not yet reached in the pembrolizumab arm (95% CI, 8.5-not reached) compared with 8.9 months with chemotherapy alone (95% CI, 6.2-10.3). The 12-month PFS rate was 56% in the pembrolizumab arm compared with 34% with chemotherapy alone (HR, 0.50; 95% CI, 0.29-0.84; P = .0038). The ORR with pembrolizumab was 56.7% compared with 30.2% for chemotherapy alone (P = .0016).

The 12-month OS rate with pembrolizumab was 76% compared with 69.3% for patients treated with chemotherapy alone. At the 14.5-month follow-up, there had been 16 deaths in the pembrolizumab arm and 23 in the chemotherapy group. Median OS had not yet been reached at the time of the analysis. There was a nonstatistically significant 31% reduction in the risk of death with pembrolizumab (HR, 0.69; 95% CI, 0.36-1.31; P = .13).

"Pembrolizumab plus pemetrexed and carboplatin chemotherapy improved objective response rates and progression-free survival in patients with treatment-naive advanced nonsquamous NSCLC, irrespective of PD-L1 expression," said lead author Vassiliki A. Papadimitrakopoulou, MD, from the MD Anderson Cancer Center. "The hazard ratio for OS was 0.69 favoring the pembrolizumab plus pemetrexed and carboplatin arm. A trend toward OS benefit is emerging with longer follow up in addition to the benefits in PFS and ORR first observed in the primary analysis."

Cohort G of the phase II KEYNOTE-021 study randomized 123 patients to pemetrexed and carboplatin alone (n = 63) or in combination with pembrolizumab (n = 60). In both groups, carboplatin was given at AUC 5 mg/mL per min and pemetrexed was given at 500 mg/m² every 3 weeks for 4 cycles followed by indefinite pemetrexed maintenance. In the investigational arm, pembrolizumab was continued for 24 months at a fixed 200 mg dose every 3 weeks.

Crossover to pembrolizumab was permitted following progressive disease. Seventy-five percent of those who discontinued chemotherapy alone went on to receive a PD-1 or PD-L1 inhibitor, with 22 patients receiving pembrolizumab as part of the crossover, Papadimitrakopoulou noted, while stressing that the trend in OS occurred despite this high rate of crossover.

The median age of patients was 62.5 years in the pembrolizumab group versus 66.0 years for the control arm. Fifty-eight percent of patients had an ECOG performance status of 1 in the pembrolizumab group compared with 54% with chemotherapy alone. More patients were current or former smokers in the chemotherapy alone arm (75% vs 86%) and more patients had stable brain metastases in the pembrolizumab group (15% vs 10%).

Patients with both PD-L1—positive and –negative NSCLC benefited more from the pembrolizumab combination compared with chemotherapy alone. In those with PD-L1 expression on <1% of cells, the ORR with pembrolizumab was 62% (13 of 21 patients; 95% CI, 38%-82%) versus 13% with chemotherapy alone (3 of 23; 95% CI, 3%-34%). Those with the highest level of PD-L1 expression (≥50%), had an ORR of 80% with pembrolizumab (16 of 20; 95% CI, 56%-94%) versus 41% with chemotherapy alone (7 of 17; 95% CI, 18%-67%).

Grade ≥3 treatment-related adverse events (AEs) were experienced by 39% of those in the pembrolizumab arm versus 29% of those treated with chemotherapy alone. The most common grade ≥3 AEs with pembrolizumab plus chemotherapy and chemotherapy alone, respectively, were anemia (12% vs 15%), neutrophil count decrease (7% vs 3%), fatigue (3% vs 0%), nausea (2% vs 0%), rash (2% vs 0%), vomiting (2% vs 0%), aspartate aminotransferase increase (2% vs 2%), and alanine aminotransferase increase (2% vs 2%).

"Most treatment-related adverse events were of mild to moderate severity," said Papadimitrakopoulou. "It is also important to note that median duration of therapy was more than twice as long with pembrolizumab, pemetrexed, and carboplatin than with pemetrexed and carboplatin alone, at 10.1 months versus 4.9 months, respectively."

On May 9, 2017, the FDA granted an accelerated approval to the frontline combination of pembrolizumab, pemetrexed, and carboplatin for patients with metastatic or advanced nonsquamous NSCLC, regardless of PD-L1 expression. The FDA has also approved pembrolizumab as a monotherapy for patients with PD-L1—positive NSCLC without an EGFR or ALK gene alteration.

"Pembrolizumab now has accelerated approval in combination with the standard chemotherapy combination, pemetrexed and carboplatin, in treatment-naïve non-squamous NSCLC, irrespective of PD-L1 status, based on clinically profound improvements in response rate and progression-free survival and only minimal increase in toxicity," said senior author Corey J. Langer, MD, director of Thoracic Oncology and Professor of Medicine at the Hospital of the University of Pennsylvania.

"This approval is an important milestone, but raises a number of issues since it occurred in the absence of phase III data or a proven survival advantage and was based on a relatively small phase II trial with just 120 enrollees," Langer noted. "In this regard, we await the results of the ongoing phase III trial, KEYNOTE-189, which randomizes patients 2:1 to pemetrexed/carboplatin in combination with pembrolizumab versus chemotherapy alone. Like its predecessor, KEYNOTE-021-G, the randomized phase III trial features crossover to pembrolizumab for patients on the control arm whose disease progresses. I strongly suspect the continued approval of pembrolizumab frontline with chemotherapy will depend on successful outcomes in KEYNOTE-189."

The phase III KEYNOTE-189 study has fully recruited participants. The estimated primary completion date for the primary outcome measure of PFS is September 2017. Secondary endpoints of the study are focused on ORR and OS.

Papadimitrakopoulou V, Gadgeel SM, Borghaei H, et al. First-line carboplatin and pemetrexed (CP) with or without pembrolizumab (pembro) for advanced nonsquamous NSCLC: Updated results of KEYNOTE-021 cohort G. J Clin Oncol. 2017;35 (suppl; abstr 9094).

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The median duration of response was not reached in the PD-1 arm compared with 16.2 months for chemotherapy alone. Overall, 59% of patients in the pembrolizumab arm continued to respond versus 47% with chemotherapy alone.