Tomivosertib Development in Frontline NSCLC Is Terminated

Holographic concept of lung cancer display, lung disease, treatment of lung cancer: © catalin - stock.adobe.com

Tomivosertib showed only modest activity in non–small cell lung cancer (NSCLC), according to the findings from the phase 2 KICKSTART trial (NCT04622007), leading the manufacturer to halt further development. Topline findings evaluating the agent vs placebo in combination with pembrolizumab (Keytruda) did not merit further development, according to a news release 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, 0.31.3; P = .21); however, the 2-sided P value did not meet the prespecified threshold (P ≤ .2). The investigational combination produced a median PFS of 13 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.¹

“Although 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 CEO of eFFECTOR, said in the news release.¹ “We sincerely appreciate the contributions of all the patients, their families, and trial site professionals who contributed to the trial. We will continue to analyze 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.²

Participants were required to be 18 years or older; 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, or 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 were given pembrolizumab as first-line therapy plus tomivosertib or placebo. In cohort C, patients with nonsquamous disease who completed 4 to 6 cycles of a platinum-based chemotherapy doublet went on to receive tomivosertib or placebo plus pembrolizumab and pemetrexed (Alimta), 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.³

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

“Although 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 said. “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 [in 2024]. Our focus is now further sharpened toward advancing zotatifin through development as efficiently as possible.”¹

REFERENCES:

1. Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell. 2021;39(3):346-360.e7. doi:10.1016/j.ccell.2020.12.014

2. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064

3. Mathieu L, Shah S, Pai-Scherf L, et al. FDA approval summary: atezolizumab and durvalumab in combination with platinum-based chemotherapy in extensive stage small cell lung cancer. Oncologist. 2021;26(5):433–438. doi:10.1002/onco.13752

4. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055

5. Karim NFA, Miao J, Reckamp KL, et al. SWOG S1929: Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer (ES-SCLC). J Clin Oncol. 2023;41(suppl 16):8504. doi:10.1200/JCO.2023.41.16_suppl.8504

6. FDA approves tepotinib for metastatic non-small cell lung cancer. FDA. February 16, 2024. Accessed April 24, 2024. https://tinyurl.com/3pceyyxj

7. FDA approves osimertinib with chemotherapy for EGFR-mutated non-small cell lung cancer. FDA. Updated February 20, 2024. Accessed April 24, 2024. https://tinyurl.com/mr2tvt3a

8. FDA approves amivantamab-vmjw for EGFR exon 20 insertion-mutated non-small cell lung cancer indications. FDA. March 1, 2024. Accessed April 24, 2024. https://tinyurl.com/zxpp5wmt

9. FDA approves alectinib as adjuvant treatment for ALK-positive non-small cell lung cancer. FDA. April 18, 2024. Accessed April 24, 2024. https://tinyurl.com/nnaja47c