IDE937 Generates Responses in NSCLC and Urothelial Cancer Harboring MTAP Deletions

Darrin Beaupre, MD, PhD

Treatment with the potent, selective, potential first-in-class MAT2A inhibitor IDE397 induced responses in patients with locally advanced or metastatic urothelial cancer or non–small cell lung cancer (NSCLC) harboring MTAP deletions, according to results from a phase 2 dose-expansion trial (NCT04794699).¹

Findings showed that efficacy-evaluable patients (n = 18) achieved an overall response rate of 38.9%, which included 1 complete response (CR) and 6 partial responses (PRs). The CR and 2 PRs were observed in patients with urothelial cancer, and 3 PRs were reported in patients with NSCLC. Additionally, 2 PRs were awaiting confirmation in 1 patient with urothelial cancer who experienced a 100% tumor reduction in the target lesion and in 1 patient with NSCLC adenocarcinoma.

Furthermore, 10 patients achieved stable disease, and the disease control rate was 94%. Tumor shrinkage was reported in 78% of patients.

"We are highly encouraged by the preliminary clinical efficacy and favorable safety profile observed with IDE397 at the 30-mg, once-a-day expansion dose, including multiple PRs responses and 1 CR by RECIST 1.1 [criteria] in [patients with] MTAP-deletion urothelial and lung cancer,” Darrin Beaupre, MD, PhD, chief medical officer of IDEAYA Biosciences, stated in a news release. “In addition, at this expansion dose we observed a favorable adverse [effect (AE)] profile with no drug-related serious AEs and mid-single digit percent grade 3 or higher drug-related AEs, which we believe has the potential to enable longer duration dosing as well as combinations.”

The phase 2 dose-expansion study stemmed from a phase 1 dose-escalation study evaluating IDE397 in adult patients with locally advanced or metastatic solid tumors harboring MTAP deletions. The ongoing study is enrolling patients at least 18 years of age who experienced disease progression after at least 1 prior line of therapy or were intolerant to additional standard therapy. Homozygous loss of MTAP or MTAP deletion is required.²

Other key inclusion criteria consist of measurable disease; an ECOG performance status of 0 or 1; adequate organ function; and recovery from acute effects of prior therapy.

Key exclusion criteria include known symptomatic brain metastases; known primary central nervous system malignancies; current active liver or biliary disease; impaired gastrointestinal function; active, uncontrolled infection; clinically significant cardiac abnormalities; prior treatment with a MAT2A inhibitor, PRMT inhibitor, and/or sacituzumab govitecan-hziy (Trodelvy); systemic anti-cancer therapy or major surgery within 4 weeks of enrollment; radiation therapy within 2 weeks of enrollment; and prior irradiation to more than 25% of the bone marrow.

The study is evaluating escalating doses of IDE397 alone, in combination with docetaxel and paclitaxel, and in combination with sacituzumab govitecan.² In the monotherapy dose-expansion cohort, patients with urothelial cancer or NSCLC are receiving the agent at 30 mg once per day.¹

The primary end points of the study are the incidence of dose-limiting toxicities; establishing the maximum tolerated dose and/or recommended phase 2 dose; and preliminary antitumor activity.²

In patients with urothelial cancer or NSCLC enrolled in the phase 2 dose-expansion cohort, the median number of prior lines of therapy was 2 (range, 1-7). The efficacy-evaluable population included 7 patients with urothelial cancer, 4 patients with adenocarcinoma NSCLC, and 7 patients with squamous NSCLC.¹

Additional findings showed that at the data cutoff, 11 of 18 patients remained on treatment. Among the 7 responders, 5 were still responding to treatment per RECIST 1.1 criteria. The median duration of treatment, duration of response, and progression-free survival were not yet reached.

Furthermore, the circulating tumor DNA (ctDNA) molecular response rate was 81%, with 13 of 16 evaluable patients experiencing a reduction in ctDNA of at least 50%.

Regarding safety, drug-related grade 3 or higher AEs occurred in 5.6% of patients treated in the 30-mg expansion cohort, and no patients experienced serious drug-related AEs.

Enrollment has started in the phase 1 portion of the trial investigating IDE937 in combination with sacituzumab govitecan. Additionally, an ongoing phase 1/2 trial (NCT05975073) is also evaluating IDE397 in combination with AMG 193 for patients with NSCLC harboring MTAP deletions.

References

1. IDEAYA announces positive interim phase 2 monotherapy expansion data for IDE397 a potential first-in-class MAT2A inhibitor in MTAP-deletion urothelial and lung cancer. News release. IDEAYA Biosciences. July 8, 2024. Accessed July 15, 2024. https://ir.ideayabio.com/2024-07-08-IDEAYA-Announces-Positive-Interim-Phase-2-Monotherapy-Expansion-Data-for-IDE397-a-Potential-First-in-Class-MAT2A-Inhibitor-in-MTAP-Deletion-Urothelial-and-Lung-Cancer
2. Study of IDE397 in participants with solid tumors harboring MTAP deletion. ClinicalTrials.gov. Updated June 27, 2024. Accessed July 15, 2024. https://clinicaltrials.gov/study/NCT04794699