RLY-2608 Induces Antitumor Activity in Patients With PIK3CA Mutations

Andreas Varkaris, MD, PhD

In the first-in-human phase 1 ReDiscover trial (NCT05216432), treatment with the PI3Kα inhibitor RLY-2608 resulted in sustained target inhibition with minimal impact on glucose homeostasis and a favorable safety profile in patients with PIK3CA-mutant solid tumors.¹

Interim data from the study also showed that RLY-2608 led to antitumor activity in patients with hormone receptor-positive/HER2-negative breast cancer across PIK3CA genotypes. Among the 16 patients with breast cancer and measurable disease, 9 (56%) experienced radiographic tumor reduction, and 13 (81%) reached either stable disease or partial response.

Regarding safety, RLY-2608 showed a differentiated and favorable toxicity profile, and most toxicities were low grade and manageable. Moreover, there were no dose-limiting toxicities observed, and the maximum-tolerated dose has yet to be reached.

“So far, we have been able to determine the pharmacokinetic characteristics, pharmacodynamic characteristics, and toxicity profile of this medication in a number of patients. We have treated 42 patients. However, 1 of the major goals of a phase 1 study is to determine the phase 2 recommended dose,” Andreas Varkaris, MD, PhD, told Targeted OncologyTM, in an interview. “We aim to optimize our strategy to determine the phase 2 recommended dose and move rapidly to expansion in a new group of patients that will benefit from therapy.”

RLY-2608 is the first allosteric, mutant-selective PI3Kα inhibitor which selectively inhibits PI3Kα mutations over wild-type PI3Kα, with a high degree of selectivity across the kinome and within the PI3K family. Preclinical breast cancer models have shown that treatment with RLY-2608 was comparable with the efficacy of alpelisib (Piqray) and inavolisib (GDC-0077).

Alpelisib was granted FDA approval in 2019 in combination with fulvestrant (Faslodex) for patients with hormone receptor-positive, HER2-negative, PIK3CA-mutant advanced or metastatic breast cancer who have progressed on or after endocrine therapy. Unlike alpelisib and inavolisib, RLY-2608 displayed minimal effects on glucose homeostasis. This led to its evaluation in the ReDiscover study.

In an interview with Targeted Oncology^TM, Varkaris, Massachusetts General Hospital in Boston, discussed findings from the ReDiscover trial and treating patients with PIK3CA mutations.

Targeted Oncology: Can you discuss PIK3CA mutations in patients with solid tumors and what this means regarding your ability to treat patients?

Varkaris: PIK3CA mutations are relatively common. They're seen in 14% of all solid tumors. But there are some subtypes of solid tumors that we find PIK3CA more commonly, for example, breast cancer tumors, especially hormone receptor-positive/ HER2-negative, advanced breast cancer tumors, express PIK3CA mutations in up to 40% of the cases. In the past, we have been able to treat these patients with altered generations of PI3Kinhibitors. We have an FDA approved drug called alpelisib, which is equally potent against the mutant, the wild-type enzyme, and has prolonged the life of patients with metastatic breast cancer with these mutations.

We look forward to a new generation of inhibitors that will allow us to inhibit the enzyme more potently, without affecting the normal cells, and increase the number of patients that we will be able to treat. Also, by having more targeted therapies, we'll be able to combine these new drugs with other targeted therapies, something that wasn't feasible in the past because of the toxicity profile.

Can you discuss the background and rationale for your first-in-human study?

At MGH, we led the development of all previous P13K inhibitors, and we were fortunate to see our patients responding from these therapies, especially [patients with] breast cancer. However, many times the toxicity profile is devastated. Also, we are not able to treat patients based on their high hemoglobin for example, diabetic patients or even some overweight patients. Many groups around the world have been trying to develop novel therapies that will be more specific for cancer cells compared with the normal cells. The major difference between the cancer cells and normal cells is the presence of these P1K3CA mutations.

A company, among others, managed to develop a PIK3CA-mutant specific inhibitor and we have tested it in the clinic. The background in studies done by the company showed that this inhibitor selectively inhibits the mutant forms of the PI3K compared with the wild-type, and they showed it in animal models. But today, what we presented was that this is also preserved in humans. We are able to hit the target, inhibit tumor growth with reasonable toxicity and without effect on the enzyme, which is a new era for all neutral specific inhibitors.

What were recent results from the ReDiscover trial that you can highlight?

More than 50% of our patients had tumor volume reduction, shown by images. We have 1 patient that was heavily treated with chemotherapy, HER2-directed therapy, and hormonal therapies that had a dramatic response, both in the clinical setting, laboratory, and radiograph. But we don't only stand in that 1 response. Most of our patients experience benefits. The toxicity profile that we have seen was the expected one by a drug that hits the tumor cells and does not hit the normal PI3K alpha enzyme. We have not observed any severe hyperglycemia, diarrhea, or skin rash. These 3 complications were associated with the earlier generation PI3K inhibitors and limited their efficacy. The data suggests that what we promised to deliver a drug that will hit the tumor cells with limited effect on the PI3K alpha wild-type has been delivered.

Based on your findings, what are your next steps with this research?

So far, we have been able to determine the pharmacokinetic characteristics, pharmacodynamic characteristics, and toxicity profile of this medication in a number of patients. We have treated 42 patients. However, 1 of the major goals of a phase 1 study is to determine the phase 2 recommended dose. So far, we have not reached any dose limiting toxicity and the maximum tolerated dose has not been determined. We aim to optimize our strategy to determine the phase 2 recommended dose and move rapidly to expansion in a new group of patients that will benefit from therapy.

What other research involving these inhibitors has struck your interest recently?

There is strong interest in combination therapies with pediatric inhibitors. Unfortunately, in the past, we have not been able to achieve that. And the primary reason was the toxicity profile of PI3K inhibitors. I have been in several discussions including the KRAS meeting and the prostate meeting, and the senior investigators have been asking whether at some point we will be able to combine targeted therapies with the PI3K inhibition pathway that has been implicated in the past with resistance to other targeted therapies. I think this is a good time to enter that era. We have novel therapies that hit the target sufficiently and cause shrinkage on their own. They have a wonderful toxicity profile that we can combine with other medications.

If researchers can figure out how to mitigate these toxicities, what role do you think these inhibitors can play in a treatment landscape?

I think we have proven that the toxicity profile of these targeted agents, at least the 1 that we [discussed] is favorable. We have not seen toxicities that make us suspicious that these inhibitors won't be able to be combined with other targeted therapies. I think we will live in a new era of precision oncology in which combination targeted therapies will be given to patients with more than 1 driver mutation or with tumors that are driven by a specific oncogene. But we know that resistance may be mediated by PI3K activation.

REFERENCE:

1. Varkaris A, Jhaveri K, Perez CA, et al. Pan-mutant and isoform selective PI3Kα inhibitor, RLY-2608, demonstrates selective targeting in a first-in-human study of PI3Kα-mutant solid tumor patients, ReDiscover trial. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT017.