First-in-Class Drug AMG 193 Exploits Tumor Weakness for Targeted Therapy

Tumor microenvironment concept: © catalin - stock.adobe.com

AMG 193, an MTA-cooperative PRMT5 inhibitor, led to responses in patients with MTAP-deleted solid tumors with a favorable safety profile, according to first-in-human results of a dose-exploration/dose-expansion phase 1 trial (NCT05094336) that were presented at the 2024 ESMO Congress.^1,2

At a median follow-up of 4.5 months (95% CI, 4.0-5.5) in patients who received AMG 193 at active doses (800 mg daily, 1200 mg daily, and 600-mg twice daily; n = 76) the best overall response in both the dose-exploration and dose-expansion cohorts were reported and broken down by tumor type:

• Non–small cell lung cancer (NSCLC; n = 17): 2 confirmed partial responses (PRs), 3 unconfirmed PRs, 6 with stable disease (SD), 3 with progressive disease (PD), and 3 who were not evaluable (NE);
• Pancreatic ductal adenocarcinoma (n = 23): 2 confirmed PRs, 3 unconfirmed PRs, 4 with SD, 8 with PD, and 6 who were NE;
• Biliary tract cancer (n = 19): 2 confirmed PRs, 8 with SD, 3 with PD, and 6 who were NE;
• Esophageal/gastric cancer (n = 6): 1 confirmed PR, 1 unconfirmed PR, 2 with SD, and 2 with PD.

“There are 6 patients with PRs that are ongoing treatment beyond 6 months, despite the short duration of follow-up, a further 13 patients with PRs continue on treatment at the time of data cut, and there are 6 patients with SD that have been treated for 6 months or longer, implying that there may be clinical benefit even amongst those who do not achieve a partial response,” lead study author Adrian Sacher, MD, a thoracic oncologist and affiliate scientist of Princess Margaret Cancer-Centre of the University of Toronto in Toronto, Ontario, Canada, said in an oral presentation during the meeting. “AMG 193 … represents a novel class of targeted therapeutics designed to induce synthetic lethality in MTAP-deleted solid tumors while sparing normal tissue.”

Approximately 10% to 15% of cancers harbor homozygous MTAP deletions, including glioblastoma, mesothelioma, bladder cancer, pancreas cancer, esophageal cancer, squamous NSCLC, and melanoma, among others.

AMG 193 exploits a tumor-specific vulnerability via MTA-cooperative inhibition of PRMT5 in MTAP-deleted tumors; MTAP deletion causes MTA accumulation as well as partial loss of PRMT5 activity.³ Sacher noted that PRMT5 inhibition affects RNA splicing, gene expression and DNA repair, all of which lead to cell cycle arrest, senescence, and cell death. In prior data with first-generation PRMT5 inhibitors, he noted there was limited benefit due to dose-limiting hematologic adverse effects (AEs).

AMG 193 is a first-in-class, MTA-cooperative PRMT5 inhibitor that selectively targets MTAP-deleted tumors and spares normal cells, Sacher explained; because it preferentially binds the MTA-bound state of PRTM5, it completely inhibits it.

To be eligible for enrollment for the first-in-human, phase 1 trial, patients needed to be at least 18 years old, have histologically confirmed metastatic/locally advanced solid tumors with MTAP or CDKN2A deletion (only exploration), and measurable disease as assessed via RECIST v1.1 criteria.

In the dose-exploration phase (n = 80), patients were treated with daily doses of AMG 193 ranging from 40 mg, 120 mg, 240 mg, 480 mg, 800 mg, 1200 mg, or 1600 mg. The 1600-mg dose was not tolerated. The 1200-mg dose was also explored as a twice-daily 600-mg dose.

In the ongoing dose-expansion phase (n = 87), patients with pancreatic ductal adenocarcinoma, NSCLC, biliary tract cancer, esophageal/gastric cancer, glioma, and tumor-agnostic disease are being treated with the 1200-mg daily dose of AMG 193.

The coprimary end points are safety, tolerability, and maximum-tolerated dose/recommended phase 2 dose; secondary outcome measures are pharmacokinetics and antitumor activity. Pharmacodynamics and correlative biomarkers serve as exploratory end points.

The data cutoff date was May 23, 2024. Regarding baseline characteristics in all cohorts (n = 167), the median age was 62.0 years (range, 28-83), and half of patients were male (50.3%). A total 62.9% of patients had an ECOG performance status of 1, the median number of prior lines of therapy was 2 (range, 1-9), and 24.0% of patients had 4 or more lines of therapy.

Most patients had stage IV disease (85.0%). The tumor type breakdown was as follows: pancreatic ductal adenocarcinoma (28.7%), NSCLC (17.4%), biliary tract cancer (14.4%), gastric/esophageal (4.2%), glioblastoma (3.0%), and other solid tumors (32.3%). MTAP deletions were detected at baseline via local next-generation sequencing (NGS) in 60.5% of patients vs 28.7% of those detected through central immunohistochemistry (IHC). Additionally, 10.8% of patients were enrolled on the basis of CDKN2A deletions; 6.6% of those were found to have MTAP deletions detected by central IHC, MTAP intact by central IHC in 3.6%, and 0.6% were not evaluable by central IHC.

Regarding safety, any-grade and grade 3 treatment-related AEs in the dose-expansion phase occurred in 83.9% and 18.4% of patients, respectively, the most common of which were nausea (57.5%; 4.6%), vomiting (34.5%; 3.4%), and fatigue (25.3%; 1.1%).

Sacher noted that majority of toxicities in the dose-exploration phase were low grade, adding that “consistent with a tumor-selective mechanism of action, there was no clinically significant myelosuppression and no myelosuppressive events that led to treatment discontinuation.”

The rates of nausea and vomiting were analyzed further. In the fasted state, nausea and vomiting was found to be manageable and generally reversible with standard anti-emetic management; these were mostly low-grade events that typically resolved with continued dosing of AMG 193 and within 2 to 4 weeks.

“Preliminary results suggest that food does not alert exposure to AMG 193 and, thus, the fasting requirements for this study has been lifted, which may further improve the nausea and vomiting profile of this drug,” Sacher said.

Furthermore, pharmacokinetics and exposure-response data showed that the dose-proportional exposure went up to 1200 mg, and the 13-hour half-life was amenable to once-daily dosing. High exposure was also linked with a greater decrease in tumor size as well as a greater likelihood of achieving PR, based on exposure-response modeling.

Additional data in the dose-exploration phase showed that the median duration of response was 8.3 months (95% CI, 2.7-NE), and the median duration of disease control was 9.2 months (95% CI, 4.9-11.8). Responses reportedly occurred at 8 or 16 weeks, “underscoring the potential for delayed responses,” and 12 of the 80 patients on the dose-exploration phase remain on treatment.

Target engagement with AMG 193 was also confirmed via symmetric dimethylarginine (SDMA) reduction. Specifically, complete inhibition of tumor SDMA, or PRMT5 activity, was observed at doses 480 mg or higher, while doses 800 mg or higher achieved the strongest serum SDMA reduction, which confirms greater pharmacodynamic activity at high doses. There was also greater SDMA reduction seen with patients who achieved a PR or SD vs those who experienced disease progression.

Antitumor activity was also linked with reductions in circulating tumor (ct)DNA, a degree which Sacher said correlates with RECIST response. Complete ctDNA clearance was seen at doses 480 mg or higher, and 33 of the 40 patients with SD (83%) had greater than 50% reduction in their ctDNA. All 9 patients who achieved PRs had greater than 90% reduction in their ctDNA.

“These data suggest disease stabilization in most patients was a result of AMG 193 antitumor activity rather than just indolent disease,” he added.

In a transcriptomic analysis of paired pre- and on-treatment biopsies with AMG 193’s mechanism of action, a significant pathway analysis revealed a significant effect on cell cycle arrest as well as attenuation of DNA damage response. Furthermore, the splicing infidelity was seen through an increase in the number of alternative splicing events that was mostly driven by increased levels of intron retention.

AMG 193 is also being explored alone and in combination with chemoimmunotherapy regimens in NSCLC (NCT06333951),⁴ chemotherapy in pancreatic cancer (NCT06360354),⁵ and in combination with the MAT2A inhibitor IDE397 in patients with MTAP-null solid tumors (NCT05975073).⁶

Disclosures: Dr Sacher cited financial disclosures with Amgen, Genentech, Merck, Lilly, Pfizer, Bristol-Myers Squibb, Spectrum, GlaxoSmithKline, Lovance, CRISPR Therapeutics, BridgeBio Pharma, HotSpot Therapeutics, and AdaptImmune, and as serving as the institutional research and clinical trial principal investigator at AstraZeneca.

REFERENCES:

1. Sacher A, Villalona-Calero M, O’Neil B, et al. Phase I dose escalation and initial dose expansion results of AMG 193: an MTA-cooperative PRMT5 inhibitor, in patients (pts) with MTAP-deleted solid tumors. Presented at: 2024 ESMO Congress; September 13-17, 2024; Barcelona, Spain. Abstract 604O.

2. Rodon J, Prenen H, Sacher A, et al. First-in-human study of AMG 193, an MTA-cooperative PRMT5 inhibitor, in patients with MTAP-deleted solid tumors: results from phase 1 dose exploration. Ann Oncol. Published September 16, 2024. doi:10.1016/j.annonc.2024.08.2339

3. Belmontes B, Slemmons KK, Su C, et al. AMG 193, a clinical stage MTA-cooperative PRMT5 inhibitor, drives antitumor activity preclinically and in patients with MTAP-deleted cancers. Cancer Discov. Published September 16, 2024. doi:10.1158/2159-8290.CD-24-0887

4. AMG 193 alone or in combination with other therapies in subjects with advanced thoracic tumors with homozygous MTAP-deletion (master protocol). ClinicalTrials.gov. Updated September 5, 2024. Accessed September 16, 2024. https://clinicaltrials.gov/study/NCT06333951

5. A study evaluating AMG 193 in combination with other therapies in participants with advanced gastrointestinal, biliary tract, or pancreatic cancers with homozygous methylthioadenosine phosphorylase (MTAP)-deletion. ClinicalTrials.gov. Updated July 8, 2024. Accessed September 16, 2024. https://clinicaltrials.gov/study/NCT06360354

6. A phase 1/​2 study of AMG 193 in combination with IDE397 in participants with advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors. ClinicalTrials.gov. Updated September 5, 2024. Accessed September 16, 2024. https://clinicaltrials.gov/study/NCT05975073