NEW YORK – San Francisco-based Calithera Biosciences on Thursday said that it had dosed the first patient in a Phase II clinical trial of its investigational agent telaglenastat plus chemotherapy and the immune checkpoint inhibitor pembrolizumab (Merck's Keytruda) in first-line advanced, KEAP1- or NRF2-mutated non-small cell lung cancer.
The Phase II trial, dubbed KEAPSAKE, will randomize patients to either telaglenastat, a glutaminase inhibitor, plus the standard-of-care chemo-immunotherapy combination, or just the chemo-immunotherapy combo in patients with non-squamous, stage IV NSCLC. Patients must have KEAP1 or NRF2 mutations in their tumors as assessed by Guardant Health's Guardant360 liquid biopsy next-generation sequencing test. It is estimated that roughly 20 percent of NSCLC patients harbor such mutations.
The primary aims of the study, which will enroll approximately 120 patients, will be progression-free survival along with safety and tolerability. The investigators will also assess objective response rates, duration of response, and overall survival as secondary endpoints.
Though the trial is technically evaluating the combination in the first-line metastatic setting, patients who previously received adjuvant or neoadjuvant therapy, including immunotherapy, for localized NSCLC are still eligible to enroll in KEAPSAKE if the therapy was completed at least six months before they developed metastatic disease.
Recent preclinical studies have shown that the activation of the KEAP1/NRF2 pathway through loss of KEAP1 function or NRF2 activation can lead to poor clinical outcomes in this patient population. These tumors may be particularly sensitive to glutaminase inhibition, because the activation of the KEAP1/NRF2 pathway makes the tumor dependent on glutaminase activity for growth and survival.
"Therapies that inhibit glutaminase in tumors with KEAP1/NRF2 pathway activation could have a meaningful clinical impact for a substantial percentage of people with NSCLC," Calithera CEO Susan Molineaux said in a statement. "We're proud that KEAPSAKE is among the first clinical trials investigating a potential new therapy for these patients who have a poor prognosis."