Vibostolimab Plus Pembrolizumab Coformulation ± Docetaxel Did Not Significantly Improve PFS in NSCLC

A coformulation of vibostolimab and pembrolizumab (Keytruda; MK-7684A) with or without docetaxel failed to result in a statistically significant improvement in progression-free survival (PFS) compared with docetaxel alone in patients with metastatic non­–small cell lung cancer (NSCLC), missing the primary end point of the phase 2 KeyVibe-002 trial (NCT04725188).^1,2

Data presented at the 2023 ESMO Immuno-Oncology Annual Congress indicated that vibostolimab and pembrolizumab plus docetaxel (n = 87) led to a median PFS of 5.6 months (95% CI, 3.9-6.8) vs 3.2 months (95% CI, 2.8-5.7) with docetaxel alone (n = 85; HR, 0.77; 95% CI, 0.53-1.13; P = .0910).1 Vibostolimab and pembrolizumab alone (n = 83) did not prolong median PFS vs docetaxel alone, at 2.7 months (95% CI, 1.8-4.0) vs 3.2 months (HR, 1.40; 95% CI, 0.96-2.02; P = .9622).

The 12-month PFS rates with vibostolimab/pembrolizumab plus docetaxel, vibostolimab and pembrolizumab alone, and docetaxel alone were 23.2% (95% CI, 13.4%-34.5%), 8.0% (95% CI, 2.5%-17.5%), and 12.5% (95% CI, 3.3%-28.2%), respectively.

“This study was designed to evaluate a coformulation of vibostolimab and pembrolizumab in a population of patients who are heavily pre-treated and have progressed following treatment with standard of care therapies, often leaving them with limited treatment options and a poor prognosis,” Scot Ebbinghaus, MD, vice president of global clinical development at Merck Research Laboratories, stated in a press release.² “We will leverage our evolving understanding of novel combinations and coformulations to help inform our comprehensive research program evaluating this coformulation across a wide range of tumor types.”

Patients with stage IV NSCLC who experienced disease progression following platinum-doublet chemotherapy and 1 previous PD-1 or PD-L1 inhibitor who had measurable disease by RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and tumor tissue available for PD-L1 testing.¹ They needed to be at least 18 years of age and could not have untreated or unstable brain metastasis. EGFR-, ALK-, or ROS1-targeted therapies could not be indicated.

A total of 255 patients were randomly assigned 1:1:1 to the following arms:

• Arm 1 (double-blind): Vibostolimab at 200 mg with pembrolizumab at 200 mg every 3 weeks plus docetaxel at 75 mg/m² every 3 weeks
• Arm 2 (open-label): Vibostolimab plus pembrolizumab at same dose and schedule
• Arm 3 (double-blind): Placebo every 3 weeks plus docetaxel at same dose and schedule

Randomization was stratified by performance status (0 vs 1), prior anti–PD(L)-1 monoclonal antibody (immediate vs no immediate prior treatment), and PD-L1 tumor proportion score (TPS; <50% vs ≥50%).

In addition to the primary end point of PFS by RECIST v1.1 criteria and blinded independent central review (BICR) for arm 1 vs arm 3 and arm 2 vs arm 3, secondary end points included objective response rate (ORR) and duration of response by RECIST v1.1 criteria and BICR, as well as overall survival (OS), safety, and tolerability.

The data cutoff date was January 26, 2023, and the median time to randomization was 12.3 months (range, 6.2-19.8). The median age spanning arms 1, 2, and 3 was 66.7 years (range, 39-83). More than half were male (69.0%; 72.3%; 71.8%) and had an ECOG performance status of 1 (62.1%; 63.9%; 63.5%). Most patients were current or former smokers (89.7%; 88.0%; 90.6%). In arm 1, 11.5% and 23.0% had baseline brain and liver metastasis, respectively; in arm 2, these rates were 20.5% and 30.1%, respectively, and in arm 3, these rates were 21.2% and 22.4%, respectively.

Regarding PD-L1 TPS, in arm 1, 17.2% of patients had a TPS of 50% or higher, 39.1% had a TPS ranging from 1% to 49%, and 42.5% had a TPS of less than 1%. In arm 2, these rates were 16.9%, 22.9%, and 54.2%, respectively; in arm 3, these rates were 15.3%, 41.2%, and 40.0%, respectively. More than half of patients across the arms received at least 1 prior line of therapy (66.7%; 59.0%; 61.2%); in arms 1, 2, and 3, 4.6%, 7.2%, and 8.2% of patients, respectively, received 3 or more prior lines of treatment. Anti–PD-(L)1 treatment was immediate prior therapy for 82.8% of those in arm 1, 84.3% of those in arm 2, and 84.7% of those in arm 3.

Consistent PFS data were observed across key patient subsets for arm 2 vs arm 3.

The median OS achieved with vibostolimab and pembrolizumab plus docetaxel was 10.2 months (95% CI, 8.6-14.9) vs 8.8 months (95% CI, 6.4-11.1) with docetaxel alone (HR, 0.76; 95% CI, 0.50-1.15). Vibostolimab and pembrolizumab alone led to a median OS of 7.5 months (95% CI, 5.2-13.4) vs 8.8 months with docetaxel alone (HR, 1.05; 95% CI, 0.70-1.58). The 12-month OS rates in arms 1, 2, and 3 were 47.6% (95% CI, 35.6%-58.6%), 41.0% (95% CI, 29.8%-51.8%), and 37.5% (95% CI, 25.5%-49.4%), respectively.

The combination of vibostolimab and pembrolizumab with docetaxel elicited an ORR of 29.9% (95% CI, 20.5%-40.6%), which comprised a complete response (CR) rate of 3.4%, a partial response (PR) rate of 26.4%, and a stable disease (SD) rate of 39.1%; 20.7% of patients experienced progressive disease (PD), 4.6% were not evaluable for response, and 5.7% were not assessed. The median DOR was 6.5 months (range, 2.1+ to 15.4+), and the median time to response (TTR) was 1.8 months (range, 1.2-8.2).

Vibostolimab and pembrolizumab alone induced an ORR of 6.0% (95% CI, 2.0%-13.5%), which included a 1.2% CR rate, a 4.8% PR rate, a 45.8% SD rate, and a 37.3% PD rate; 4.8% of patients were not evaluable and 6.0% were not assessed. The median DOR in this group was not yet reached (NR; range, 2.6+ to 6.2+) and the median TTR was 4.1 months (range, 1.4-12.5). Docetaxel alone led to an ORR of 15.3% (95% CI, 8.4%-24.7%), with no CRs and a PR rate of 15.3% and a SD rate of 45.9%; 23.5% of patients experienced PD, 3.5% were not evaluable for response, and 11.8% were not assessed. The median DOR was NR (range, 1.6-11.1+) and the median TTR was 1.6 months (range, 1.2-5.7).

The overall toxicity profile of vibostolimab plus pembrolizumab with or without docetaxel generally aligned with what has previously been reported with single-agent pembrolizumab or pembrolizumab paired with chemotherapy. No new safety signals were observed.

Any-grade treatment-related adverse effects (TRAEs) were experienced by 96.5% of those in arm 1, 60.2% of those in arm 2, and 89.2% of those in arm 3; these effects were grades 3 to 5 for 49.4%, 13.3%, and 32.5% of patients, respectively. In these arms, TRAEs led to drug discontinuation for 36.5%, 6.0%, and 16.9% of patients, respectively; they led to death for 4 patients in arm 1, and 1 patient each in arms 2 and 3.

In the vibostolimab/pembrolizumab and docetaxel arm, the most common TRAEs experienced by at least 10% of patients included pruritus (grade 1/2, 25.9%; grade 3 to 5, 3.5%), alopecia (28.2%; 0%), anemia (21.2%; 7.1%), diarrhea (23.5%; 3.5%), fatigue (24.7%; 1.2%), nausea (23.5%; 0%), rash (21.2%; 2.4%), asthenia (17.6%; 4.7%), decreased neutrophil count (2.4%; 16.5%), reduced appetite (17.6%; 0%), stomatitis (15.3%; 1.2%), peripheral neuropathy (14.1%; 1.2%), dysgeusia (12.9%; 0%), constipation (10.6%; 0%), and vomiting (10.6%; 0%).

In the vibostolimab and pembrolizumab alone arm, the most common TRAEs reported in 10% or more of patients comprised pruritus (grade 1/2, 13.3%; grade 3 to 5, 0%), alopecia (2.4%; 0%), anemia (1.2%; 0%), diarrhea (6.0%; 2.4%), fatigue (3.6%; 1.2%), nausea (7.2%; 0%), rash (14.5%; 1.2%), asthenia (7.2%; 2.4%), reduced appetite (7.2%; 0%), stomatitis (1.2%; 0%), and vomiting (1.2%; 0%).

Any-grade immune-mediated adverse effects (AEs) and infusion reactions were experienced by 29.4% of those in arm 1, 20.5% of those in arm 2, and 12.0% of those in arm 3; these effects were grade 3 to 5 for 15.3%, 2.4%, and 2.4% of patients, respectively. They resulted in death for 2 patients in arm 1.

In arm 1, immune-mediated AEs and infusion reactions to occur in at least 1 patient included adrenal insufficiency (grade 1/2, 2.4%; grade 3 to 5, 0%), colitis (0%; 2.4%), hyperthyroidism (4.7%; 0%), hypophysitis (0%; 1.2%), hypothyroidism (5.9%; 0%), infusion reactions (3.5%; 1.2%), pneumonitis (2.4%; 4.7%), and severe skin reactions (2.4%; 7.1%). In arm 2, the most common immune-mediated AEs experienced by 1 or more patients included colitis (1.2%; 0%), hyperthyroidism (3.6%; 0%), hypothyroidism (3.6%; 1.2%), infusion reactions (2.4%; 0%), pneumonitis (7.2%; 0%), severe skin reactions (1.2%; 1.2%), and vasculitis (1.2%; 0%).

References

1. Peled N, Mazieres J, Kowalski D, et al. MK-7684A (vibostolimab [vibo] plus pembrolizumab [pembro] coformulation) with/without docetaxel in metastatic NSCLC after platinum-chemotherapy (chemo) and immunotherapy. Presented at: 2023 ESMO Immuno-Oncology Annual Congress; December 6-8, 2023; Geneva, Switzerland. Abstract 121P.
2. Merck announces findings from phase 2 KeyVibe-002 trial evaluating an investigational coformulation of vibostolimab and pembrolizumab in previously treated patients with metastatic non-small cell lung cancer (NSCLC). News release. Merck. December 7, 2023. Accessed January 3, 2024. https://www.merck.com/news/merck-announces-findings-from-phase-2-keyvibe-002-trial-evaluating-an-investigational-coformulation-of-vibostolimab-and-pembrolizumab-in-previously-treated-patients-with-metastatic-non-small-cell-lung/