Frontline Vibostolimab/Pembrolizumab Plus Chemo Meets Futility Threshold in ES-SCLC

Co-formulated therapy with the anti-TIGIT antibody vibostolimab and pembrolizumab (Keytruda) plus etoposide and platinum (EP) met the prespecified futility criterion for the primary end point of overall survival (OS) vs atezolizumab (Tecentriq) plus EP in patients with extensive-stage small cell lung cancer (ES-SCLC), according to data from a prespecified interim analysis of the phase 3 KEYVIBE-008 trial (NCT05224141) presented at the 2024 SITC Annual Meeting.¹

As frontline therapy the investigational regimen led to a median OS of 11.5 months (95% CI, 9.8-12.6) vs 12.9 months (95% CI, 11.6-14.8) with the control regimen (HR, 1.26; 95% CI, 1.00-1.59; P =.9762). Median progression-free survival (PFS), a secondary end point, was 5.3 months (95% CI, 4.4-5.4) vs 4.5 months (95% CI, 4.4-5.3), respectively (HR, 1.01; 95% CI, 0.82-1.23).

“Based on the benefit/risk profile observed, treatment with vibostolimab/pembrolizumab was discontinued in the KEYVIBE-008 trial,” Jacob Sands, MD, lead study author, assistant professor at Harvard Medical School, and Oncology Medical Director of the International Patient Center at Dana-Farber Cancer Institute in Boston, Massachusetts, said in a presentation of the data. “Investigation of vibostolimab/pembrolizumab is ongoing in non–small cell lung cancer [NSCLC].”

The announcement of the trial’s discontinuation was first made in August 2024 in accordance with the recommendation from an independent data monitoring committee.²

Despite the trial’s results there had been substantial evidence in support of the regimen’s potential efficacy, including findings from the phase 3 KEYNOTE-604 trial (NCT03066778) which showed improved PFS, though not OS, with the frontline combination of pembrolizumab and EP in ES-SCLC, preclinical data showing increased expression of TIGIT when PD-(L)1 signaling was inhibited and synergistic antitumor activity when TIGIT antibodies were combined with a PD-(L)1 inhibitor, and antitumor activity when vibostolimab was combined with pembrolizumab in NSCLC.¹

KEYVIBE-008 was a double-blind trial that enrolled patients at least 18 years of age with newly diagnosed previously untreated ES-SCLC and measurable disease per RECIST v1.1 criteria by local investigator. An ECOG performance status of 0 or 1, no active central nervous system metastases requiring treatment, and no pneumonitis or interstitial lung disease were also required.

Patients were randomly assigned 1:1 to 200 mg of vibostolimab and 200 mg of pembrolizumab, plus 100 mg/m² of etoposide and 75 mg/m² of cisplatin or 5 mg/mL/min of carboplatin at area under the curve (AUC) 5 for 4 cycles every 3 weeks (n = 230); or 1200 mg of atezolizumab, plus 100 mg/m² of etoposide and 75 mg/m² of cisplatin or 5 mg/mL/min of carboplatin AUC 5 every 3 weeks for 4 cycles (n = 230). Frontline therapy in the investigational and control arms was followed by vibostolimab/pembrolizumab and atezolizumab, respectively, until disease progression, unacceptable toxicity, or physician/patient decision.

The primary end point was OS. Secondary end points included PFS, ORR, and duration of response (DOR) all per RECIST v1.1 by blinded independent central review (BICR), and safety.

In the investigational arm the median patient age was 64 years (range, 25-85) and 67.0% of patients were male. Most patients resided in North America/Western Europe/Australia (50.4%), had an ECOG performance status of 1 (66.5%), and were current or former smokers (91.7%). The majority of patients also had stage IVB disease (60.0%), lactate dehydrogenase above the upper limit of normal (60.0%), and at least 3 metastatic sites (78.3%). Median tumor size was 142.0 mm (range, 17.0-518.0).

The median time from random assignment to data cutoff was 16.6 months (range, 11.3-26.1). Of the 230 patients who had been randomly assigned 229 started treatment in each arm. At data cutoff 16 patients in the investigational arm and 29 in the control arm were in ongoing treatment.

Additional efficacy results revealed that the 6- and 12-month OS rates with the investigational regimen were 78.7% and 49.1%, respectively, and 87.4% and 55.0%, respectively, with the control regimen. The 6- and 12-month PFS rates in the investigational arm were 30.0% and 12.4%, respectively, and 26.5% and 13.3%, respectively, in the control arm.

The ORR was 71.7% (95% CI, 65.4%-77.5%) in the investigational arm vs 74.8% (95% CI, 68.7%-80.3%) in the control arm. The median DOR was 4.2 months (range, 2.3-22.1+) with vibstolimab/pembrolizumab vs 3.9 months (range, 1.4+ to 20.1+) with atezolizumab. In the investigational arm best responses included complete response (CR; 6.1%), partial response (PR; 65.7%), stable disease (SD; 15.7%), and progressive disease (PD; 4.8%). A total of 7.8% of patients in this arm were not evaluable (NE) or had no response assessment. In the control arm best responses included CR (6.1%), PR (68.7%), SD (13.5%), and PD (5.2%); 6.5% of patients were NE or had no response assessment.

The median duration of therapy was 4.9 months (range, 0.1-24.2) in the investigational arm vs 4.9 months (range, 0.1-22.8) in the control arm. Most treatment-related adverse effects (TRAEs) were between grade 3 and 5 in the investigational (66.8%) and control (57.2%) arms. TRAEs leading to discontinuation of any treatment or death occurred in 11.8% and 1.7% of patients, respectively, in the investigational arm, and 6.6% and 0.9%, respectively, of patients in the control arm. Grade 3 to 5 immune-mediated AEs and infusion reactions occurred in 14.8% of patients in the investigational arm vs 3.5% in the control arm; 0.9% of events led to death in the investigational arm.

“Grade 3 or greater TRAEs and immune-mediated AEs were more frequent with vibostolimab/pembrolizumab vs atezolizumab, consistent with dual immune checkpoint inhibitor therapy,” Sands said. He added that no new safety signals were identified.

Common TRAEs in the investigational arm were anemia (all grade, 61.6%; grade ≥3, 16.6%), neutropenia (all grade, 56.8%; grade ≥3, 39.7%), leukopenia (all grade, 41.0%; grade ≥3, 19.2%), alopecia (all grade, 36.7%; grade ≥3, 0.4%), thrombocytopenia (all grade, 34.9%; grade ≥3, 17.5%), nausea (all grade, 31.9%; grade ≥3, 0.9%), decreased appetite (all grade, 31.9%; grade ≥3, 1.3%), constipation (all grade, 23.1%; grade ≥3, 1.3%), fatigue (all grade, 17.9%; grade ≥3, 1.7%), asthenia (all grade, 17.5%; grade ≥3, 1.3%), rash (all grade, 18.3%; grade ≥3, 0.9%), and pruritus (all grade, 15.7%; grade ≥3, 0%).

Immune-mediated AEs and infusion reactions included hypothyroidism (all grade, 16.6%; grade ≥3, 0%), hyperthyroidism (all grade, 10.5%; grade ≥3, 0.4%), infusion reactions (all grade, 5.7%; grade ≥3, 0.4%), pneumonitis (all grade, 3.9%; grade ≥3, 0.9%), pancreatitis (all grade, 3.1%; grade ≥3, 3.1%), adrenal insufficiency (all grade, 2.6%; grade ≥3, 0.9%), colitis (all grade, 2.2%; grade ≥3, 1.3%), severe skin reactions (all grade, 2.2%; grade ≥3, 2.2%), type 1 diabetes mellitus (all grade, 2.2%; grade ≥3, 2.2%), hypophysitis (all grade, 1.7%; grade ≥3, 1.7%), encephalitis (all grade, 1.7%; grade ≥3, 1.3%), hepatitis (all grade, 1.3%; grade ≥3, 0.4%), and gastritis (all grade, 0.4%; grade ≥3, 0%).

References

1. Sands J, Lu S, Aerts JG, et al. Coformulated vibostolimab/pembrolizumab plus chemotherapy as first-line therapy vs atezolizumab plus chemotherapy for extensive-stage small-cell lung cancer (ES-SCLC): randomized, phase 3 KEYVIBE-008 trial. Presented at: 2024 SITC Annual Meeting; November 6-10, 2024; Houston, TX. Abstract 1463.
2. Merck provides update on phase 3 KeyVibe-008 trial evaluating an investigational fixed-dose combination of vibostolimab and pembrolizumab in patients with extensive-stage small cell lung cancer. News release. Merck. August 8, 2024. Accessed November 8, 2024. https://www.merck.com/news/merck-provides-update-on-phase-3-keyvibe-008-trial-evaluating-an-investigational-fixed-dose-combination-of-vibostolimab-and-pembrolizumab-in-patients-with-extensive-stage-small-cell-lung-cancer/