Tony Mok, MD

Single-agent treatment with the PD-1 inhibitor pembrolizumab (Keytruda) improved overall survival (OS) versus chemotherapy as a frontline treatment for patients with locally advanced or metastatic non—small cell lung cancer (NSCLC) and a PD-L1 expression level ≥1%.

The findings are from the phase III KEYNOTE-042 trial, which included patients with both squamous and nonsquamous histology. The study compared frontline pembrolizumab with investigator’s choice of carboplatin/paclitaxel or carboplatin/pemetrexed.

Previously, results from the phase III KEYNOTE-024 trial showed that frontline pembrolizumab more than doubled median OS compared with standard chemotherapy in patients with NSCLC and a PD-L1 expression level ≥50%.

“Improvement in overall survival is the ultimate objective in the treatment of advanced lung cancer. KEYNOTE-042 is the first randomized phase III study of a single-agent immunotherapy using overall survival as the primary endpoint that has demonstrated significant benefit as first-line therapy in NSCLC patients who tested positive for PD-L1 at 1% or higher,” Tony Mok, MD, professor in the Department of Clinical Oncology at the Chinese University of Hong Kong, said in a statement.

Under the recommendation of an independent data monitoring panel, the KEYNOTE-042 trial is continuing to assess the secondary endpoint of progression-free survival (PFS). Merck (MSD), the manufacturer of pembrolizumab, announced in a press release that the KEYNOTE-042 results will be presented at an upcoming medical meeting and submitted to regulatory agencies for review.

KEYNOTE-042 trial (NCT02220894) randomized 1274 patients in a 1:1 ratio to pembrolizumab or standard of care platinum-based chemotherapy. Patients who harbored EGFR or ALK genomic tumor aberrations were excluded from enrollment. PD-L1 levels were assessed by tumor proportion score (TPS). The primary endpoint, which the study met, was OS with TPS of ≥50%, ≥20%, and ≥1%, which were sequentially assessed. Merck noted in its statement that the safety data for pembrolizumab were similar to previous single-agent studies of the PD-1 inhibitor in advanced NSCLC.

In October 2016, the FDA approved pembrolizumab for the frontline treatment of patients with metastatic NSCLC whose tumors have ≥50% PD-L1 expression based on an FDA-approved test and who do not harbor EGFR or ALK aberrations.

The approval was based on the KEYNOTE-024 trial, which compared frontline pembrolizumab with standard platinum-based chemotherapy in patients with NSCLC without EGFR/ALK aberrations and a TPS ≥50%. The median OS with the PD-1 inhibitor was 30.2 months versus 14.2 months with chemotherapy, representing a 37% reduction in the risk of death (HR, 0.63; 95% CI, 0.47-0.86; P = .002).1

Merck announced in January 2018 that findings from the phase III KEYNOTE-189 trial met its primary endpoint of improved OS and PFS with pembrolizumab plus chemotherapy versus chemotherapy alone in the frontline setting for patients with nonsquamous NSCLC. Patients on the trial received frontline pembrolizumab or placebo in combination with pemetrexed (Alimta) and either cisplatin or carboplatin. The results are being presented as a late-breaking abstract at the 2018 American Association for Cancer Research Annual Meeting.

The approval was based on part 2 of cohort G in the KEYNOTE-021 trial, which showed that the frontline combination of pembrolizumab, pemetrexed, and carboplatin reduced the risk of progression or death compared with chemotherapy alone for patients with advanced nonsquamous NSCLC. Updated results for the study were presented at the 2017 ESMO Congress.2

At median follow-up of 18.7 months, the overall response rate was 56.7% for the pemetrexed arm compared with 31.7% with pemetrexed and carboplatin alone (95% CI, 7.2-40.9; P = .0029). The risk of progression or death was reduced by 46% with pembrolizumab (HR, 0.54; 95% CI, 0.33-0.88; P = .0067). There was also a trend toward an OS improvement with pembrolizumab (HR, 0.59; 95% CI, 0.34-1.05; P = .03).

Beyond the frontline, pembrolizumab is also approved in NSCLC as a single agent for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS ≥1%) with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved targeted therapies for these aberrations, according to the FDA label.

References

Brahmer JR, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: pembrolizumab vs platinum-based chemotherapy for advanced NSCLC with PD-L1 TPS ≥50%. Presented at: the IASLC 18th World Conference on Lung Cancer; October 15-18; Yokohama, Japan. Abstract OA 17.06 (ID 9582). Merck’s KEYTRUDA® (pembrolizumab) Plus Pemetrexed and Carboplatin (pem/carbo) Demonstrated Continued Benefit in Overall Response Rates and Progression-Free Survival Compared to Pem/Carbo Alone in Patients with First-Line Nonsquamous NSCLC. https://bit.ly/2ExmUXK . Published online September 8, 2017. Accessed April 9, 2018.



The KEYNOTE-189 study is a confirmatory trial for the accelerated approval of pembrolizumab in this setting. In May 2017, the FDA granted an accelerated approval to pembrolizumab for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced NSCLC, regardless of PD-L1 expression.