MRT-2359 Shows Favorable Tolerability in Heavily Pretreated MYC-Driven Solid Tumors

Author(s):

MRT-2359 had acceptable tolerability with a favorable pharmacokinetic and pharmacodynamic profile in heavily pretreated patients with MYC-driven solid tumors, including lung cancer and high-grade neuroendocrine cancer.

Markus Warmuth, MD

MRT-2359 had acceptable tolerability with a favorable pharmacokinetic and pharmacodynamic (PD) profile in heavily pretreated patients with MYC-driven solid tumors, including lung cancer and high-grade neuroendocrine cancer, according to interim data from the dose-escalation portion of an ongoing phase 1/2 trial (NCT05546268).¹

MRT-2359 showed clinical activity across all dose levels examined. Of the 6 biomarker-positive patients, 1 experienced a confirmed partial response (PR), 1 had an unconfirmed PR, and 1 had durable stable disease (SD). Moreover, 1 patient who had unevaluable biomarker status also achieved durable SD. These patients had N-MYC high non–small cell lung cancer (NSCLC) adenocarcinoma; L-MYC/N-MYC high small cell lung cancer (SCLC); L-MYC/N-MYC high-grade neuroendocrine tumors of the prostate, bladder, and others; and neuroendocrine tumors of the lung.

At all doses, optimal PD modulation of GSPT1 by the agent was observed. MRT-2359 treatment reduced GSPT1 protein expression by about 60% in peripheral blood mononuclear cells and tumor tissue. Similar levels of degradation were noted spanning all dose levels, potentially indicative of saturated PD responses from 0.5 mg to 2 mg; this supported that 0.5 mg of the agent is a fully active dose. The level of GSPT1 degradation was linked with antitumor activity.

“We’re highly encouraged by the safety profile, the depth of pharmacodynamic modulation of GSPT1 in tumors, and even more so by the early evidence of anti-tumor activity of MRT-2359 in patients with biomarker-positive cancers,” Markus Warmuth, MD, chief executive officer of Monte Rosa Therapeutics, stated in the press release. “We believe these results, the first ever to show clinical activity of a rationally designed molecular glue degrader in solid tumors, represent an important advance for the field and underscore the potential for MRT-2359 to benefit patients living with a variety of difficult-to-treat cancers.”

The open-label, multicenter study enrolled patients with previously treated selected solid tumors, including NSCLC, SCLC, high-grade neuroendocrine cancer of any primary site, diffuse large B-cell lymphoma, and solid tumors with L-MYC or N-MYC amplification. Patients needed to be at least 18 years of age, a life expectancy of at least 3 months, an ECOG performance status of 0 to 2, measurable disease by RECIST v1.1 criteria, and acceptable organ function.²

They could not have previously received chemotherapy, definitive radiation, biological cancer treatment, or an investigational drug within 21 days prior to the first dose of study treatment. Other exclusion criteria included prior bisphosphonates or denosumab in 2 weeks before study treatment, prior exposure to a GSPT1 degrader that discontinued because of toxicity and having undergone previous hematopoietic cell transplantation and not experiencing recovery from effects related to the procedure, among others.

In the phase 1 portion of the research, participants were administered escalating doses of MRT-2359 to identify the maximum tolerated dose and recommended phase 2 dose (RP2D).¹ Once the RP2D is determined, the agent’s antitumor activity will be assessed in the phase 2 portion.

At the data cutoff date of September 7, 2023, 21 patients had received MRT-2359 and 15 were determined to be efficacy evaluable. The 15 evaluable patients received the agent at 0.5 mg, 1 mg, or 2 mg on a 5-days-on/9-days-off schedule.

Regarding safety, no signs of hypotension, cytokine release syndrome, or significant hypocalcemia were observed at any dose level evaluated. Those who received the agent at 0.5 mg or 1 mg experienced treatment-related adverse effects that were only grade 1 or 2 in severity. Those who received the agent at 2 mg experienced grade 4 thrombocytopenia (n = 2) and neutropenia (n = 1); the former was determined to be a dose-limiting toxicity. The grade 4 toxicities were noted to be transient and found to resolve with dose reductions. Notably, no participants discontinued treatment with MRT-2359 because of toxicity.

“We are excited to learn more about the clinical profile of MRT-2359 in our ongoing phase 1/2 clinical study, and early next year we plan to provide further clarity on the expected timing for the full phase 1 data disclosure in 2024,” Warmuth added in the press release.

References

Monte Rosa Therapeutics announces interim PK/PD and clinical data for MRT-2359 in phase 1/2 trial for MYC-driven solid tumors. News release. Monte Rosa Therapeutics. October 17, 2023. Accessed November 16, 2023. https://ir.monterosatx.com/news-releases/news-release-details/monte-rosa-therapeutics-announces-interim-pkpd-and-clinical-data
Study of oral MRT-2359 in selected cancer patients. ClinicalTrials.gov. Updated November 13, 2023. Accessed November 16, 2023. https://clinicaltrials.gov/study/NCT05546268