Tomivosertib Development in Frontline NSCLC Ending After Findings from KICKSTART Trial

Topline findings from the primary analysis of the phase 2 KICKSTART trial (NCT04622007) evaluating tomivosertib (eFT508) vs placebo in combination with pembrolizumab (Keytruda) showed modest activity with the doublet but do not support the agent’s continued frontline development in patients with non–small cell lung cancer (NSCLC) and a PD-L1 expression level of 50%, according to an announcement from eFFECTOR Therapeutics.¹

An analysis of 36 progression-free survival (PFS) events revealed that PFS favored tomivosertib plus pembrolizumab vs placebo plus pembrolizumab (HR, 0.62; 95% CI, 0.3-1.3; P = .21); however, the two-sided P value did not meet the prespecified threshold (P ≤ .2). The investigational combination produced a median PFS of 13.0 weeks vs 11.7 weeks for placebo plus pembrolizumab. Although overall survival (OS) data remained immature, no trend favoring the tomivosertib regimen was observed. Regarding safety, grade 3 or higher treatment-emergent adverse effects (AEs) were observed in 67% of patients in the tomivosertib arm vs 37% in the placebo arm.

“While there was evidence of modest tomivosertib activity in the trial, based on the totality of the data currently available we do not see an obvious path forward to continue developing tomivosertib in frontline NSCLC,” Steve Worland, PhD, president and chief executive officer of eFFECTOR, stated in a news release. “We sincerely appreciate the contributions of all the patients, their families, and trial site professionals who contributed to the execution of the trial. We will continue to analyze trial data and hope to present our findings at a future medical conference.”

Tomivosertib is a highly selective MNK inhibitor engineered to bolster antitumor immune activity by stimulating T cells—thereby slowing their exhaustion—and enlarging the reservoir of central memory T cells.²

The randomized, double-blind, placebo-controlled KICKSTART trial evaluated the efficacy and safety of tomivosertib plus pembrolizumab as frontline therapy for patients with advanced NSCLC, or as an extension of frontline therapy for patients with NSCLC at the time of first radiographic disease progression on pembrolizumab alone.

All patients enrolled were required to be at least 18 years of age; have histologically confirmed inoperable, locally advanced or metastatic NSCLC; and have a PD-L1 expression level of 50% or greater, as assessed by an FDA-approved diagnostic test. Additional inclusion criteria were the availability of a representative tumor specimen allowing for NSCLC diagnosis accompanied by an associated pathology report and an ECOG performance status of 0 or 1. Patients were not eligible for enrollment if they harbored EGFR or ALK aberrations; had gastrointestinal disease that could hinder drug absorption or the interpretation of gastrointestinal AEs; and had known symptomatic brain metastases requiring at least 10 mg of prednisone per day.³

The study consisted of 3 patient cohorts. In cohort A, patients who received pembrolizumab as their initial therapy for metastatic disease were treated with tomivosertib or placebo in addition to pembrolizumab as an extension of frontline therapy. In cohort B, patients initiated pembrolizumab as first-line therapy alongside tomivosertib or placebo. In cohort C, patients with non-squamous disease who completed 4 to 6 cycles of a platinum-based chemotherapy doublet went on to receive tomivosertib or placebo plus pembrolizumab and pemetrexed, and those with squamous disease received tomivosertib or placebo plus pembrolizumab. In all experimental arms, tomivosertib was administered at 100 mg twice per day. In all arms, pembrolizumab was administered intravenously at either 200 mg once every 3 weeks or 400 mg once every 6 weeks.

The study’s primary end point was PFS in the frontline-extension and frontline settings. Key secondary end points included PFS in the combined population from both cohorts, OS, and overall response rate.^2,3

“While we’re disappointed that tomivosertib won’t be moving forward in frontline NSCLC, our strategy to maximize the value of all assets in our pipeline remains unchanged,” Worland continued. “Zotatifin [eFT226], with its novel mechanism distinct from that of tomivosertib’s, is a drug candidate that is poised to enter a randomized, potentially registrational trial in estrogen receptor–positive breast cancer later this year. Our focus is now further sharpened towards advancing zotatifin through development as efficiently as possible.”

References

1. eFFECTOR Therapeutics announces topline results of phase 2 KICKSTART trial of tomivosertib combined with pembrolizumab in non-small cell lung cancer. News release. eFFECTOR Therapeutics. April 4, 2024. Accessed April 4, 2024. https://investors.effector.com/news-releases/news-release-details/effector-therapeutics-announces-topline-results-phase-2
2. eFFECTOR Therapeutics doses first patient in phase 2b KICKSTART clinical trial. News release. eFFECTOR Therapeutics. June 9, 2021. Accessed April 4, 2024. https://investors.effector.com/news-releases/news-release-details/effector-therapeutics-doses-first-patient-phase-2b-kickstart
3. Tomivosertib combined with pembrolizumab in subjects with PD-L1 positive NSCLC (KICKSTART). ClinicalTrials.gov. Updated March 4, 2024. Accessed April 4, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT04622007