In part due to its unique mechanism of action, the investigational pan-mutant and isoform selective PI3Kα inhibitor RLY-2608has the potential to decrease adverse effects (AEs) seen with other PI3K inhibitors without sacrificing efficacy, according to Komal Jhaveri, MD, FACP.

, investigators presented the trial schema of the ongoing phase 1 ReDiscover study (NCT05216432), which is the first-in-human trial of RLY-2608. The study is evaluating RLY-2608 monotherapy in previously treated patients with 

-mutated advanced solid tumors, RLY-2608 plus fulvestrant (Faslodex) in 

-mutated hormone receptor–positive/HER2-negative advanced or metastatic breast cancer, and RLY-2608 plus fulvestrant and a CDK4/6 inhibitor in 

-mutated hormone receptor–positive/HER2-negative advanced or metastatic breast cancer. Patients must be a least 18 years old, have an ECOG performance status of 1 or less, evaluable disease per RECIST v1.1, and no prior exposure to a PI3K inhibitor in order to be eligible for the trial.

, Komal Jhaveri, MD, FACP, section head, Endocrine Therapy Research Program, clinical director, Early Drug Development Service, Patricia and James Cayne Chair for Junior Faculty, at Memorial Sloan Kettering Cancer Center, in New York, New York, discussed RLY-2608 and the details of the ReDiscover trial.

What is the mechanism of action of RLY-2608 in the context of solid tumors, including breast cancer?

: RLY-2608is a mutant selective PI3K inhibitor.When we think about targeting PI3K, we can think about targeting PI3Kα, which is the oncogenic driver, but we can target both the mutant and the wild type [forms] with the currently approved drugs. It is the wild-type inhibition which really leads to the on-target hyperglycemia, which is the major challenge that we face for patients in clinic with these currently approved drugs.

The next wave of inhibitors, such as RLY-2608,are being developed to only inhibit the mutant PI3Kα and spare the wild-type inhibition. Hopefully, sparing the wild-type inhibition will overcome the issue of hyperglycemia, which we see with this class of drugs. That’s what is exciting about these newer generation mutant selective PI3K inhibitors.

What are the key data that have been reported with RLY-2608 to date?

We’ve already seen some data that were presented at the 

 this past year from the ongoing phase 1 trial. The [investigators] reported a patient who achieved partial response [PR] and this was a patient who was heavily pretreated, and had also received antibody-drug conjugates. At the 400-mg twice daily dosing [level they] achieved a PR. 

It was early days for efficacy; as a phase 1 study this was designed to look at the safety and the tolerability [profile of the agent]. The good news from the safety and tolerability piece that was presented was that there were no [instances of] grade 3 hyperglycemia, no grade 3 diarrhea, and no grade 3 rashes. What we’re seeing was manageable, low-grade, and low-incidence hyperglycemia and diarrhea with the agent so far. We look forward to additional results and more follow-up data with combination therapy with an endocrine backbone in combination with RLY-2608 and a larger data set to see the efficacy now that we’re at least getting excited about the safety.

What is the rationale for combining RLY-2608 with fulvestrant in breast cancer?

While we have seen activity with single-agent PI3K inhibitors, we know that the durability of benefit, at least in estrogen receptor (ER)–positive breast cancer, is seen when we combine them with endocrine therapy. This is because of the crosstalk between the PI3K/AKT/mTOR pathway and the ER pathway.

If you were to inhibit only the PI3K pathway, there’s upregulation of the ER pathway. If you combine both together, then hopefully you can have better efficacy and derive benefit, which was the basis for the [phase 3] SOLAR-1 trial [NCT02437318] that got approval for alpelisib [Piqray] plus fulvestrant. In ER-positive breast cancer, the strategy for any newer class of drug remains, at the very minimum, looking at an endocrine backbone in combination with a PI3K inhibitor, which is the same rationale that we’re looking for with RLY-2608 in combination with endocrine therapy.

Do you anticipate any challenges or barriers to enrollment in the first-in-human study?

We are obviously challenged [by the fact that] we have approvals of an mTOR inhibitor for ER-positive breast cancer and we have an approval for alpelisib. We also have approval for capivasertib [Truqap] as of November 2023.

Sometimes the challenge is [deciding whether] we just offer them those standard-of-care therapies or [other] trials that are available to patients. Will these trials allow prior toxicity or progression-related discontinuation of these prior therapies? These could be potential barriers, but the excitement around not having toxicity with this newer class of drugs is certainly the motivation for both physicians and patients alike. I’m hoping that would not be perceived as a barrier and that it would be a motivating factor for both physicians and patients to seek out these trials and see if we can get benefit from these drugs and not have the toxicities that we’re seeing with the currently approved agents.

Saura C, Sanz L, Kim J, et al. First-in-human study of RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, as a single agent in patients (pts) with advanced solid tumors and in combination with fulvestrant in pts with advanced breast cancer. 

. 2024;42(suppl 16):TPS1128. doi:10.1200/JCO.2024.42.16_suppl.TPS1128

Articles

RLY-2608, a pan-mutant and isoform selective PI3Kα inhibitor, shows promise in reducing adverse effects commonly associated with other PI3K inhibitors while maintaining efficacy. The ongoing phase 1 ReDiscover study is evaluating RLY-2608 in various combinations for PIK3CA-mutated advanced solid tumors and breast cancer. Early data indicate manageable safety profiles with no severe hyperglycemia, diarrhea, or rashes. Combining RLY-2608 with fulvestrant aims to enhance efficacy by targeting both the PI3K and ER pathways, addressing the crosstalk between them.

Komal Jhaveri, MD, FACP, highlights the novel PI3Kα inhibitor RLY-2608 and discusses the details of the first-in-human trial of the agent.

Jhaveri Discusses the First-in-Human Study of RLY-2608 in Advanced Solid Tumors

Dr Jhaveri on the Implications of Treatment With RLY-2608 in Advanced ER+ Breast Cancer

Komal Jhaveri, MD, FACP, section head, Endocrine Therapy Research Program, clinical director, Early Drug Development Service, Patricia and James Cayne Chair for Junior Faculty, Memorial Sloan Kettering Cancer Center, discusses the implications of investigating treatment with the PI3Kα inhibitor RLY-2608 in a first-in-human phase 1 trial (NCT05216432) for patients with 

-mutant advanced estrogen receptor (ER)–positive breast cancer.

Investigators shared background on this open-label study at the 

. Although single-agent PI3K inhibitors have shown activity in breast cancer, the durability of their benefit in ER-positive breast cancer is significantly enhanced when combined with endocrine therapy, Jhaveri begins. This is due to the crosstalk between the PI3K/AKT/mTOR pathway and the ER pathway. Inhibiting only the PI3K pathway can lead to upregulation of the ER pathway, she explains. However, inhibiting both pathways can potentially improve the efficacy of these agents and provide greater benefit, Jhaveri explains.

In ER-positive breast cancer, the treatment strategy for any new class of drugs typically involves using an endocrine therapy backbone in combination with a PI3K inhibitor, she continues. Therefore, in the phase 1 trial, RLY-2608 is being combined with endocrine therapy, Jhaveri states. Preliminary phase 1 clinical trial data, presented at the 

, showed early signals of clinical efficacy with this combination. One patient, who was heavily pretreated and had received antibody-drug conjugates such as fam-trastuzumab deruxtecan-nxki (Enhertu), achieved a partial response to RLY-2608 at a 400-mg twice-daily dose, she elucidates. However, because this analysis was conducted too early to assess efficacy, the phase 1 study primarily focuses on safety and tolerability, according to Jhaveri.

The safety and tolerability results that have been presented so far are encouraging, with no grade 3 hyperglycemia, diarrhea, or rashes reported, Jhaveri emphasizes. Instead, the observed adverse effects included manageable low-grade hypoglycemia and diarrhea, Jhaveri says. These early findings indicate that the combination is safe and well tolerated, Jhaveri notes. As investigators await additional results and more follow-up data with combination therapies involving an endocrine backbone and other drugs, a larger dataset will assist in building a better understanding of the efficacy of such treatments, Jhaveri concludes.

Videos

Komal Jhaveri, MD, FACP, discusses the implications of investigating treatment with RLY-2608 in patients with PIK3CA-mutant advanced ER+ breast cancer.

Clinical Updates in PIK3CA+ Metastatic Breast Cancer | Supplements and Featured Publications

Jhaveri Discusses the First-in-Human Study of RLY-2608 in Advanced Solid Tumors

Dr Jhaveri on the Implications of Treatment With RLY-2608 in Advanced ER+ Breast Cancer