SM-88 May Fill Unmet Need in Pancreatic Cancer

Article

Marcus Smith Noel, MD, discusses the early promise of SM-88 in the metastatic pancreatic cancer treatment landscape.

Marcus Smith Noel, MD

Marcus Smith Noel, MD

SM-88, a novel oral compound that is making headway in various solid tumors, has shown early efficacy in patients with metastatic pancreatic cancer. If the regimen continues to be well tolerated, according to Marcus Smith Noel, MD, it may have a place in the third-line setting, which is currently an area of significant unmet need.

The drug, which works by attacking oncogenic metabolism, is comprised of 4 oral agents: a tyrosine derivative (D,L-alpha-metyrosine), an mTOR inhibitor (sirolimus), a CYP3a4 inducer (phenytoin), and an oxidative stress catalyst (methoxsalen). The regimen is currently being tested in patients with metastatic pancreatic cancer who have progressed on at least 1 line of chemotherapy, as part of the multicenter phase II Tyme-88-Panc trial.

In part 1 of the study, results of which were presented at the 2019 Gastrointestinal Cancers Symposium, patients either received D,L-alpha-metyrosine at a twice-daily dose of 230 mg or at 460 mg. In both arms, patients were also given methoxsalen at 10 mg/day, phenytoin at 50 mg/day, and sirolimus at 0.5 mg/day. Fifty percent of patients had received 2 prior lines of treatment, 14.3% had received 3 prior lines, and 21.4% had received at least 4 prior lines of therapy.

At a median follow-up of 4.3 months, 67.8% of 28 evaluable patients were still alive as of December 31, 2018. Moreover, imaging data pertaining to 17 patients revealed that 1 patient experienced a partial response, while 7 patients achieved stable disease, translating to a clinical benefit rate of 47.1%.

In terms of tolerability, 84.2% of patients experienced a treatment-emergent adverse event (AE), with 16.2% of AEs deemed to be related to the investigational regimen. Of note, 1 patient who received D,L-metyrosine at 460 mg twice daily experienced 2 AEs, which were determined to be dose-limiting toxicities. However, these events were managed successfully, and as such, these patients resumed treatment. There was only 1 serious AE observed in the trial, in which the patient had hypotension; however, it is unclear if the event was directly related to SM-88.

The current standard of care for patients with pancreatic cancer is chemotherapy consisting of either gemcitabine plus nab-paclitaxel (Abraxane), or FOLFIRINOX, and more than half of patients who undergo this treatment experience grade >3 toxicity. There are no FDA-approved agents available in the third-line setting for these patients, leaving a significant unmet need in the space.

SM-88 is based on a novel derivative of the amino acid tyrosine, said Noel, who is an assistant professor at the University of Rochester Medicine’s Wilmot Cancer Institute. Because it is designed to target cancer metabolism, the hope is that the drug will kill cancer cells while sparing normal tissue. If the regimen continues to move through the pipeline to ultimately receive regulatory approval, Noel said that drug could serve as an effective third-line treatment option.

In an interview with OncLive, Noel discussed the early promise of SM-88 in the metastatic pancreatic cancer treatment landscape.

OncLive: What is the mechanism of action of SM-88?

Noel: SM-88 is a novel compound that is comprised of 4 oral agents. The basic premise of this drug is that it is designed to interfere with cancer metabolism. It is done so in a way where the toxicity is minimized. This drug is 4 oral agents that are taken twice daily, and it has been well tolerated thus far.

Could you speak to the ongoing research with the agent?

Early results from our phase I study do show some signals of clinical activity, so this is promising. We want to continue to follow this out throughout the remainder of the study, but so far, we are encouraged by what we see.

Where do you see SM-88 fitting into the treatment landscape of metastatic pancreatic cancer?

We have established first- and second-line agents for pancreatic cancer, but the third-line setting is pretty wide open. SM-88, being a drug that is well tolerated, may fit into the third-line space to hopefully improve survival.

Noel MS, Wang-Gillam A, Ocean AJ, et al. Phase II trial of SM-88 in patients with metastatic pancreatic cancer: preliminary results of the first stage. J Clin Oncol. 2019;37(suppl 4, abstr 200). doi: 10.1200/JCO.2019.37.4_suppl.200.

Related Videos
Katrina S. Pedersen, MD, MS, associate professor, John T. Milliken Department of Medicine, Division of Oncology, Medical Oncology program leader, cofounder, Young Onset Colorectal Cancer Program, Washington University School of Medicine in St. Louis, Siteman Cancer Center
Riccardo Lencioni, MD, FSIR, EBIR
Manish A. Shah, MD
Dae Won Kim, MD, Gastrointestinal Oncology Program, Moffitt Cancer Center
Michael J. Overman, MD, The University of Texas MD Anderson Cancer Center,
John Michael Bryant, MD,
Jacob Shreve, MD, MS, hematology/oncology fellow, Mayo Clinic
Efrat Dotan, MD, Fox Chase Cancer Center
A panel of 4 experts on gastrointestinal cancers
A panel of 4 experts on gastrointestinal cancers