Pembrolizumab Combos Showcase Promising Safety, Antitumor Activity in NSCLC

Pembrolizumab (Keytruda) has demonstrated promising activity when used in combination with chemotherapy or quavonlimab (MK-1308), according to long-term results from cohort G of the KEYNOTE-021 (NCT02039674) trial in select patients with nonsquamous non–small cell lung cancer (NSCLC) and updated data from a phase 1/2 trial (NCT03179436) in patients with advanced NSCLC, respectively.¹

Results from cohort G of KEYNOTE-021 presented during the IASLC 2020 North America Conference on Lung Cancer showed that when pembrolizumab was combined with chemotherapy in patients with advanced nonsquamous NSCLC without EGFR or ALK aberrations, it resulted to a significant improvement in objective response rate (ORR) versus pemetrexed and platinum chemotherapy alone, at 58% versus 33%, respectively.

The combination also led to an improvement in progression-free survival (PFS; HR, 0.54; 95% CI, 0.35-0.83), as well as a sustained long-term survival benefit (HR, 0.71; 95% CI, 0.45-1.12) compared with chemotherapy alone.

Additionally, updated follow-up data from a phase 1/2 trial showed that frontline pembrolizumab in combination with quavonlimab demonstrated promising antitumor activity with a satisfactory safety profile in patients with advanced NSCLC.

“Over the past 5 years, [pembrolizumab] has become foundational in the treatment of metastatic lung cancer,” said Vicki Goodman, MD, vice president of oncology clinical research at Merck Research Laboratories.¹ “The long-term data from KEYNOTE-021 (cohort G) reinforce the use of [pembrolizumab] in combination with chemotherapy in certain [patients with] advanced lung cancer, while data from our oncology pipeline reflect our commitment to exploring a number of new combinations with [pembrolizumab] that we believe could have a meaningful impact for more [patients with] lung cancer.”

“Updated data from anti–CTLA-4 antibody quavonlimab in combination with [pembrolizumab] support the continued development of this new combination and a phase 3 study of quavonlimab coformulated with [pembrolizumab] in advanced NSCLC is planned,” added Goodman.

Long-Term Data With Pembrolizumab/Chemotherapy from Cohort G of KEYNOTE-021

In the multicohort, multicenter, open-label phase 1/2 KEYNOTE-021 trial, investigators examined frontline pembrolizumab in combination with pemetrexed and platinum chemotherapy (n = 60) compared with pemetrexed and platinum chemotherapy alone (n = 63) in patients with advanced nonsquamous NSCLC without EGFR and ALK aberrations.

Results from cohort G demonstrated that half of patients who received the pembrolizumab combination were alive at 3 years compared with 37% of those who received chemotherapy alone. Pembrolizumab combined with chemotherapy also resulted in a 29% reduction in the risk of death (HR, 0.71; 95% CI, 0.45-1.12) compared with chemotherapy alone. Specifically, the median overall survival (OS) was 34.5 months in the investigational arm versus 21.1 months in the control arm. Notably, the OS benefit was seen despite a 70% effective crossover rate (n = 43/61) from chemotherapy to anti–PD-1/PD-L1 therapy; this included 28 participants who received pembrolizumab as part of the on-study crossover.

Moreover, the median PFS with the pembrolizumab combination versus chemotherapy was 24.5 months versus 9.9 months, respectively. The estimated PFS rate at 3 years was 37% for those in the investigational arm versus 16% for those in the control arm.

Additionally, the ORR for the combination was 58% compared with 33% with chemotherapy alone. The addition of pembrolizumab also led to a 46% reduction in the risk of disease progression or death (HR, 0.54; 95% CI, 0.35-0.83) compared with chemotherapy alone. The median duration of response (DOR) was also extended by 1 year with pembrolizumab versus chemotherapy alone, at 36.3 months versus 22.8 months, respectively. Approximately half, or 51% of patients who received the combination experienced responses lasting 3 years compared with 47% in those given chemotherapy alone.

The majority of participants who completed 2 years of treatment with pembrolizumab were alive at 3 years (92%; n = 11/12). All of these patients had an objective response to treatment and the estimated DOR rate at 3 years was 100%; the median DOR was not reached.

With regard to safety, the combination did not exhibit any new safety signals. Thirty-nine percent of patients who received the pembrolizumab combination versus 31% of those given chemotherapy alone experienced treatment-related toxicities that were grades 3 to 5 in severity. Grade 3-5 treatment-related adverse effects (TRAEs) that resulted in discontinuation were reported in 17% and 16% of those in the investigational and control arms, respectively. Grade 3-5 TRAEs resulted in death in 1 patient on the combination and 2 patients on chemotherapy alone.

Results With Pembrolizumab/Quavonlimab in Phase 1/2 Trial

In the first-in-human, open-label, multiarm phase 1/2 trial, investigators set out to examine pembrolizumab in combination with the CTLA-4 inhibitor quavonlimab as frontline treatment in patients with advanced NSCLC.

In the trial, patients were given quavonlimab at a dose of either 25 mg or 75 mg every 3 weeks or every 6 weeks in combination with pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles. The primary end point of the dose-confirmation phase of the trial was safety and tolerability, while key secondary end points included ORR per RECIST v1.1 criteria per blinded independent central review, PFS, OS, and DOR. Additionally, response was based on PD-L1 expression and was retrospectively assessed through the use of tumor proportion score (TPS) as a continuous variable.

Results showed that the pembrolizumab/quavonlimab combination was safe with no unacceptable toxicities; the regimen was also found to exhibit promising antitumor activity. Ninety-eight percent of patients experienced any-grade toxicities, while TRAEs were observed in 85% of participants. Thirty-six percent of patients across all treatment arms reported grade 3 or higher TRAEs, with the most common toxicities being increased alanine aminotransferase (8%), pneumonitis (8%), and increased aspartate aminotransferase (6%).

At a median follow-up of 16.9 months, the effect of the combination was observed across all secondary end points analyzed, including ORR, PFS, OS, and DOR. In the arm who received quavonlimab at 25 mg every 6 weeks plus pembrolizumab (n = 40), the ORR was 37.5%, the median PFS was 7.8 months, the OS was 18.1 months, and the median DOR had not yet been reached. In the arm that received quavonlimab at 25 mg every 3 weeks plus pembrolizumab (n = 40), the ORR was 40%, the median PFS was 6.0 months, the median OS was 18.1 months, and the median DOR was 7.9 months.

In the arm that was given quavonlimab at 75 mg every 6 weeks plus pembrolizumab (n = 40), the ORR was 27.5%, the median PFS was 6.0 months, the median OS was 17.1 months, and the median DOR was 15.9 months. In the arm that received quavonlimab at 75 mg every 3 weeks plus pembrolizumab (n = 14), the ORR was 35.7%, the median PFS was 3.4 months, the median OS was 13.7 months, and the median DOR had not yet been reached.

Notably, responses to pembrolizumab/quavonlimab were reported, irrespective of PD-L1 expression, although higher TPS was significantly linked with better response to treatment (one-sided P =.015).

The investigators concluded that the safety and efficacy findings supported 25 mg given every 6 weeks as the recommended phase 2 dose of quavonlimab when used in combination with pembrolizumab.

Reference

1. Merck presents 3-year survival data for Keytruda (pembrolizumab) in combination with chemotherapy and updated phase 1/2 data for investigational quavonlimab (MK-1308) in combination with Keytruda in advanced non-small cell lung cancer. News release. Merck. October 16, 2020. Accessed October 19, 2020. https://bit.ly/34cOdXC.