Ocean Outlines Promise of SM-88 in Advanced Pancreatic Cancer

The oral modified dysfunctional tyrosine SM-88 has a novel mechanism of action that allows for it to provide encouraging survival benefit in patients with advanced pancreatic cancer without increased toxicity, according to Allyson Ocean, MD.

Results from the phase 2 TYME-88-Panc trial showed that SM-88 resulted in a median overall survival (OS) of 6.4 months in patients with advanced pancreatic cancer.1,2 Moreover, the RECIST clinical benefit rate (CBR) of stable disease (SD) or better was 44% with available imaging, and a 92% reduction in the risk of death among those who at least achieved SD was observed (HR, 0.08; P = .02). The CBR proved to be durable, with most of the patients who received the investigational agent maintaining disease stability for longer than 7 months.

With regard to safety, serious adverse effects (SAEs) that were potentially related to the study treatment were observed in 4% of those in the intent-to-treat (ITT) population; these toxicities included abdominal pain, arthralgia, and hypotension. One patient who reported an SAE continued to receive treatment. Ninety-four percent of participants in the ITT population experienced all-grade AEs; 17% were potentially associated with study treatment and 12% were grade 3/4 in severity.

“We really don't have a non-toxic treatment for this disease and getting a drug that improves OS in the third-line setting to more than 2.5 months, is a win. Also, the fact that this potential therapy would not have many adverse effects (AEs) is also a win,” said Ocean. “We just need more therapies in this disease. It really is a disease where most patients, unfortunately, do not live longer than 1 year when they have advanced disease. We definitely need more therapeutics, especially options that are well tolerated, easy for our patients to take, but also provide benefit in terms of disease control.”

In an interview with OncLive, Ocean,an associate professor of clinical medicine at Weill Cornell Medicine and NewYork-Presbyterian, who is also a consultant for Tyme Technologies Inc., discussed the encouraging results from the phase 2 TYME-88-Panc study of SM-88 in patients with advanced pancreatic cancer.

OncLive: What is the mechanism of action of SM-88? What makes it a novel agent in pancreatic cancer?

Ocean: SM-88 is a novel compound that's in the group of cancer metabolism–based therapies. The exact mechanism of action involves many different factors and is currently being elucidated. Preclinical work examining the agent’s mechanism of action have been published.

Basically, this is a tyrosine analogue, an amino acid, that gets into the cell and disrupts protein synthesis. The agent also has functions that act as a way to increase oxidative stress within the cell, meaning there is more formation of reactive oxygen species, which then kill the cancer cell. We’ve also seen data demonstrating that SM-88 can reduce endoplasmic reticulum stress; cancer cells increase this stress reaction and if we reduce it with medicines, then we can more effectively kill the cancer cell.

We've also seen SM-88 work by inhibiting autophagy, the process whereby cancer cells recycle their own components to help themselves maintain their growth. Inhibiting that process would also be helpful in terms of killing the cancer cells.

As you can see, there are many different ways that the agent exhibits action in the pancreatic cancer cell. Also, what we found out at the [2019] AACR Annual Meeting, is that [SM-88] does have an immunomodulatory component to it in that it doesn't directly bring more effector T cells into the cell, but it regulates the cross talk between the immune cells. [The agent] also works with macrophages to help bring the immune system into [the mix] to help kill the cells.

Could you shed light on the phase 2 data that have been reported with the agent?

A phase 2 study [with SM-88] was conducted in heavily pretreated patients with pancreatic cancer. [Results] showed that the [median] OS in the patients who took SM-88 was 6.4 months. In this setting, that is significantly better than the 2.5-month survival that is usually seen. The response rate is low, but this is not a drug that actually causes a huge response in cancer cells; it’s more beneficial in terms of maintaining stable disease. [The hope is that] if disease stability is maintained, that will translate into improved OS.

What's important to note is that, the survival advantage that is being seen in the clinical trials that have been conducted so far, comes at very little cost for patients. The toxicity profile [of SM-88] is very favorable; the agent really doesn't cause the same AEs as chemotherapy such as nausea, vomiting, hair loss, fatigue, etc. Hyperpigmentation of the skin can occur. However, for the most part, this agent is very well tolerated.

This is important for patients with pancreatic cancer who are facing third-line therapy, where their disease is progressing and they have already received 2 prior lines of chemotherapy. These patients are already beaten down from [prior treatment] and the thought of taking another chemotherapy in that setting is frightening, even for the doctors. It’s really a breath of fresh air to be able to offer these patients a clinical trial with a therapeutic agent that has a [favorable] toxicity profile.

What are the next steps for SM-88? What research efforts are underway?

We are now looking at SM-88 in the second-line setting through the Precision Promise clinical trials framework that's being done with the Pancreatic Cancer Action Network. Those trials have not opened yet, but they hopefully will soon. We will essentially be looking at SM-88 in [patients with] earlier-stage disease.

Going back to the preclinical analyses that were previously presented, have those data shed any additional light on the potential for SM-88 to be combined with other agents?

Because we now know that immunomodulatory factors are within the cell, 1 of the hallmarks of pancreatic cancer is that the stroma exists in the cell. The stroma has actually been an impediment to any therapies getting in there; that has been a very devoid environment of immune cells.

I can see, perhaps, combining SM-88 with a regimen that would effectively break down the stroma more, so they could get into the cells and therefore activate the immune cells around the cancer cells in the stroma to try to increase the presence of immune cells in that way. SM-88 certainly could be combined with immunotherapy; we're combining everything with immunotherapy.

However, what I like about SM-88 more than anything, is that it’s a metabolism-based therapy. These cancer cells are driven by their energy source. If we can get to their energy source, the reason for their growth, then we can start decreasing that growth.

Using these metabolism-based therapies, SM-88 being 1 of them, we can starve the cancer cell of its energy supply; this is a much more efficient way to kill the cell. That's what we really need to focus on; it’s a novel mechanism of action in the field. We’re dealing with the pancreas; insulin factors are high and insulin is a growth factor here. We need to be able to put the cell into a state that doesn't consume as much energy, sugar etc. This is why this agent is so novel, important, and potentially very helpful for combining with other therapies, as well; it's so nontoxic.

Is there anything else that you wanted to emphasize?

When I saw some scans of patients who had been on the study, even prior to the study when patients took the agent compassionately, on PET scans we saw tumor necrosis occur after SM-88 was received. That supported the notion that these cells are dying because they're losing their energy supply. We can see necrosis, which is cell death, on the scan and that is what made us realize that the mechanism of action was what we thought it was; it was trying to induce necrosis into the cell and it was doing that. That provided us with an early indication that the medicine was actually reaching its target and that the cells were dying. This was very important.

We observed good early signals [with the agent] in the earlier studies. Hopefully as these studies examining the agent continue, we'll continue to see more [favorable data]. It’s definitely too early to say, but trial[s are] enrolling again, now that the COVID-19 pandemic is [more under control]. Many sites are now open; we need to emphasize that patients now have access to these trials again.

References

1. TYME presents updated data at ESMO GI 2019 from TYME-88-Panc phase II study demonstrating encouraging overall survival trends in patients with advanced pancreatic cancer. News release. Tyme Technologies, Inc. July 5, 2019. Accessed August 26, 2020. https://bit.ly/2xNYEjr.
2. Noel MS, Wang-Gillam A, Ocean AJ, et al. SM-88 therapy in high-risk poor prognosis pancreatic cancer (PDAC). Ann Oncol. 2019;30(suppl_4). doi:10.1093/annonc/mdz155.058