First-line pembrolizumab improves survival for PD-L1-positive non-small cell lung cancer

CHICAGO — First-line pembrolizumab conferred longer median OS than chemotherapy among patients with non-small cell lung cancer and PD-L1 expression, according to results of the phase 3 KEYNOTE-042 clinical trial presented during the plenary session at ASCO Annual Meeting.

Patients with a PD-L1 expression of 1% or greater first treated with pembrolizumab (Keytruda, Merck) lived a median of 4 to 8 months longer than patients who received chemotherapy.

“Given the overall efficacy and safety profile, pembrolizumab monotherapy is a standard-of-care, first-line therapy for PD-L1-expressing locally advanced or metastatic squamous or nonsquamous NSCLC without sensitizing EGFR mutations or ALK translocation,” Gilberto Lopes, MD, MBA, medical director of international programs at Sylvester Comprehensive Cancer Center of University of Miami Health System, said during a press conference.

Chemotherapy has been the standard of care for patients with NSCLC without driver mutations.

Findings from the smaller KEYNOTE-024 trial showed pembrolizumab is superior to chemotherapy as first-line therapy for advanced NSCLC with a PD-L1 tumor progression score of at least 50% and no sensitizing EGFR mutations and ALK translocations. FDA approved pembrolizumab in this setting based on these data.

In the KEYNOTE-042 trial, Lopes and colleagues evaluated pembrolizumab at a lower PD-L1 expression threshold, defined as a tumor proportion score of at least 1%.

Researchers randomly assigned 1,274 patients with locally advanced or metastatic NSCLC without EGFR mutations or ALK translocation to receive 200 mg pembrolizumab every 3 weeks (n = 637) or investigator’s choice of maximum six cycles of paclitaxel plus carboplatin or pemetrexed plus carboplatin (n = 637) with optional pemetrexed maintenance for nonsquamous disease.

Among the patients, 599 had tumor PD-L1 expression score of at least 50%, 818 had at least 20% PD-L1 expression, and all 1,274 patients had at least 1% PD-L1 expression.

The median follow-up was 12.8 months.

Results indicated patients who received pembrolizumab had longer median OS — regardless of level of PD-L1 expression in the tumor — than patients who received standard chemotherapy.

Pembrolizumab significantly improved OS among patients with tumor proportion score of more than 50% (median OS, 20 months vs. 12.2 months; HR = 0.69; 95% CI, 0.56-0.85), more than 20% (17.7 months vs. 12 months; HR = 0.77; 95% CI, 0.64-0.92) and more than 1% (16.7 months vs. 12.1 months; HR = 0.81; 95% CI, 0.71-0.93).

Despite the benefit observed across expression levels, researchers noted pembrolizumab conferred greater benefit when PD-L1 expression was higher.

An external data monitoring committee recommended continuing the trial to explore PFS as a secondary endpoint. At the current analysis, researchers did not observe a significant PFS benefit with pembrolizumab (PD-L1 50%, HR = 0.81; 95% CI, 0.67-0.99; PD-L1 20%, HR = 0.94; 95% CI, 0.8-1.11; PD-L1 1%, HR = 1.07; 95% CI, 0.94-1.21).

ORR was higher in the pembrolizumab arm for the 50% or greater expression cohort (39.5% vs. 32%), 20% or greater expression cohort (33.4% vs. 28.9%) and all patients (27.3% vs. 26.5%).

Median duration of response was 20.2 months with pembrolizumab compared with 8.3 months for chemotherapy.

Grade 3 to grade 5 treatment-related adverse events (17.8% vs. 41%) and any-grade treatment-related adverse event (62.7% vs. 89.9%) occurred less frequently with pembrolizumab than chemotherapy.

“We do need to do a lot more work [because] even though patients do better today, they still don’t do well enough,” Lopes said. “The vast majority of patients with advanced lung cancer will have disease progression and will succumb to lung cancer, so we need to continue doing the work.”

ASCO expert John V. Heymach, MD, PhD, professor and chair of the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, called the results of the study a “major milestone” for NSCLC.

“For the first time, we can say the vast majority of patients with non-small cell lung cancer receiving a first-line therapy can receive immune therapy with pembrolizumab instead of chemotherapy and potentially receive substantial benefit,” Heymach said during the press conference.

Questions do remain, such as whether chemotherapy is superior to immunotherapy, and whether greater benefit can be derived from combination therapies, which are being investigated in current trials.

“Those will be addressed in time but, for now, an era where chemotherapy was the only option for these patients is coming to a close,” Heymach said. “Almost all lung cancer patients can receive a nonchemotherapy regimen. Immunotherapy is here to stay as the vast majority of non-small lung cancer patients can use it as first-time treatment.” – by Melinda Stevens

Reference:

Lopes G, et al. Abstract LBA4. Presented at: ASCO Annual Meeting; June 1-5,2018; Chicago.

Disclosures: Merck funded this study. Lopes reports research funding to his institution from AstraZeneca, EMD Serono and Merck Sharp & Dohme. Please see the abstract for all other authors’ relevant financial disclosures.