Dr Ma on Interim Efficacy and Safety Data With RLY-2608 in PI3Kα-Mutant HR+/HER2– Breast Cancer

Cynthia X. Ma, MD, PhD, professor, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine in St. Louis, discusses positive interim data from the first-in-human, phase 1 ReDiscover trial (NCT05216432) evaluating RLY-2608 in combination with fulvestrant (Faslodex) in heavily pretreated patients with 

-mutated, hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer.

As of the August 12, 2024, interim data cutoff, 118 patients were enrolled in the dose-escalation and -expansion portions of the trial, with 64 receiving the recommended phase 2 dose (RP2D) of RLY-2608 at 600 mg twice daily plus fulvestrant, Ma begins. The patient population was heavily pretreated, with all patients having received at least 1prior CDK4/6 inhibitor and at least 1 prior line of endocrine therapy, she details. Among those treated at the RP2D, 45% had undergone at least 2 prior lines of therapy, 52% had received a prior selective estrogen receptor degrader, and 25% had been previously treated with chemotherapy or an antibody-drug conjugate.

On September 9, 2024, a press release announced that 

clinically meaningful progression-free survival

 (PFS) outcomes and a favorable safety profile in this patient population, Ma reports. At a median follow-up of 7.5 months, patients without 

 co-mutations who received the RP2D (n = 52) achieved a median PFS of 9.2 months, and the clinical benefit rate was 57% among 35 evaluable patients in the overall population. In patients with measurable disease at the RP2D (n = 30), the overall response rate (ORR) was 33% regardless of kinase mutation status, and tumor reductions were observed in 73% of patients. In those with measurable disease and kinase mutations (n = 15), the ORR reached 53%.

RLY-2608 plus fulvestrant was generally well tolerated, with most adverse effects being low grade, treatment-related, and manageable, Ma continues. Hyperglycemia, a common concern with PI3K inhibitors, was rare and primarily low grade, she notes. Rates of diarrhea and rash were also much lower compared with historical data from other PI3K inhibitors, such as alpelisib (Piqray) and capivasertib (Truqap), Ma adds. These safety and efficacy data indicate that RLY-2608 could be a meaningful new treatment option for this patient population pending further validation in randomized trials, she concludes.

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Cynthia X. Ma, MD, PhD, discusses positive interim data from the phase 1 ReDiscover trial in PI3Kα-mutated HR-positive, HER2-negative breast cancer.

In the phase 1 ReDiscover trial (NCT05216432), the first-in-human study of the mutant-selective PI3Kα inhibitor RLY-2608, investigators are aiming to leverage the agent’s mechanism of action to decrease the frequency of adverse effects (AEs) observed with PI3K inhibitors and offer an additional treatment option for patients with advanced solid tumors including breast cancer.

“RLY-2608 is a mutant-selective PI3K inhibitor,” Komal Jhaveri, MD, FACP, explained in an interview with 

. “When we think about targeting PI3K, we can think about targeting PI3Kα, which is the oncogenic driver, but we target both the mutant and the wild-type [forms] with the currently approved drugs. It is the wild-type inhibition [that] 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, [is] being developed to only inhibit the mutant PI3Kα and spare the wild-type inhibition. Hopefully [this] will overcome the issue of hyperglycemia, which we see with this class of drugs.”

Jhaveri is section head of the Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

In past preclinical work, RLY-2608 displayed tumor growth inhibition with maintained glucose homeostasis in hormone receptor (HR)–positive mouse xenograft models harboring 

 kinase and helical mutations. Additionally, the agent displayed minimal disruption of insulin levels in preclinical study.

“The preclinical work with this compound in cell line models and mouse models [has displayed] activity as monotherapy,” Cristina Saura Manich, PhD, head of the Breast Cancer Unit of the Service of Medical Oncology and principal investigator of the research group on breast cancer and melanoma at Vall d’Hebron University Hospital in Barcelona, Spain, said in an interview with 

. “This activity has been shown in mouse models with [kinase and helical domain] mutations. It’s interesting to see that with this compound, there is minimal perturbation of insulin levels that may be translated into less hyperglycemia in patients in the clinic.”

ReDiscover is a global, open-label, dose-escalation and expansion study that is evaluating RLY-2608 as monotherapy in patients with advanced solid tumors and in combination with fulvestrant (Faslodex) with or without a CDK4/6 inhibitor in patients with HR-positive/HER2-negative metastatic breast cancer. The triplet arms will evaluate RLY-2608 and fulvestrant with either ribociclib (Kisqali) or palbociclib (Ibrance; 

To be eligible for the study, patients must have at least 1 documented 

 mutation and an ECOG performance status of 1 or less. In the monotherapy arm, patients are required to have measurable disease per RECIST 1.1 criteria and be refractory, intolerant to, or decline standard therapy. The monotherapy arm includes patients with clear cell ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, other solid tumors, and unresectable or metastatic solid tumors with 

In the combination arms, patients must have HR-positive/HER2-negative unresectable or metastatic breast cancer that is not amenable to curative therapy and is measurable per RECIST 1.1 criteria. Patients must have received a maximum of 1 prior line of chemotherapy in the metastatic setting, at least 1 CDK4/6 inhibitor in the adjuvant or metastatic setting, at least 1 antiestrogen therapy in the adjuvant or metastatic setting, and at least 1 PARP inhibitor if a germline 

In part 1 of the monotherapy arm, patients received multiple ascending doses of RLY-2608; in part 2, they were treated with the recommended phase 2 dose (RP2D). In the doublet arm, patients received multiple ascending doses of RLY-2608 in part 1 and the RP2D in part 2 in combination with intramuscular fulvestrant 500 mg on day 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle. In the triplet arms, patients received RLY-2608 and fulvestrant in the same manner as the other arms in combination with either palbociclib 125 mg once daily for 21 days on and 7 days off or ribociclib at a dose of 400 mg or 600 mg daily for 21 days on and 7 days off.

The primary end points are the RP2D and the maximum-tolerated dose (MTD) of RLY-2608 as monotherapy and as a combination component as well as safety. Secondary end points include objective response rate, duration of response, disease control rate, quality of life, and pharmacokinetics.

“We are recruiting very well. Patients with HR-positive metastatic breast cancer have 

 mutations,” Saura Manich said. “In Europe and the United States, it’s a good opportunity [for patients]. The safety and toxicity profile and efficacy results we have already seen have encouraged investigators to offer this trial to patients.”

RLY-2608 Displays Preliminary Activity in Breast Cancer

Early findings from ReDiscover have been encouraging, with investigators being particularly excited about the safety profile of RLY-2608, Jhaveri said. In June 2024, Relay Therapeutics, Inc, the developer of the agent, announced new data from the study that updated preliminary efficacy and safety findings presented during the 2023 American Association for Cancer Research Annual Meeting.

At a data cutoff of July 24, 2023, the dose-escalation portion had been completed in the RLY-2608 plus fulvestrant arm, with 43 patients with HR-positive/HER2-negative locally advanced or metastatic breast cancer having received the combination at any dose level, including 17 at 600 mg twice daily and 5 at 400 mg twice daily. Additionally, 4 patients had been treated in the RLY-2608 monotherapy arm.

The median age of patients who received RLY-2608 plus fulvestrant at any dose and at the 600-mg dose was 59 years (range, 40-82) and 60 years (range, 49-80), respectively, and all patients in both groups were female. Most patents in both groups were White (67% and 59%, respectively) and had a median body mass index of less than 30 kg/m2 (74% and 82%). The median number of prior treatment regimens in the metastatic setting was 1 (range, 1-6) and 2 (range, 1-6), respectively.

Among patients with breast cancer with measurable disease per RECIST (n = 24), 4 patients experienced a partial response, including 1 who received RLY-2608 monotherapy, across dose levels and PI3Kα genotypes. Sixty-three percent (n = 15/24) of patients exhibited radiographic tumor reductions, 13 of which are ongoing. Most patients (80%) treated with the combination of RLY-2608 600 mg plus fulvestrant achieved radiographic tumor regression, including 1 with a partial response who remains on treatment.

Across all dose levels, 28 of 43 treated patients remain on treatment, with a median treatment duration of 15 weeks (range, 1-64). In patients with at least 6 months of follow-up who received RLY-2608 600 mg plus fulvestrant (n = 7), the interim clinical benefit rate was 86%, and the median treatment duration among all patients in this arm was 12 weeks (range, 1-41). Fifteen of 17 patients in this arm were still on treatment at the data cutoff.

“It’s early days for efficacy; as a phase 1 study, this is designed to look at the safety and the tolerability [profile of the agent],” Jhaveri noted. “We’re seeing 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.”

In terms of safety, patients with breast cancer across arms experienced any-grade treatment-emergent AEs (TEAEs) including nausea (44%), hyperglycemia (37%), increased blood creatine (33%), fatigue (28%), diarrhea (23%), hypokalemia (23%), headache (21%), decreased appetite (16%), and vomiting (16%). Grade 3 TEAEs consisted of fatigue (7%), hypokalemia (9%) and headache (2%).

In the 600-mg combination group, patients experienced any-grade nausea (41%), hyperglycemia (35%), increased blood creatine (35%), fatigue (12%), diarrhea (24%), hypokalemia (24%), headache (29%), decreased appetite (29%), and vomiting (18%). Grade 3 fatigue and hypokalemia were both reported at a rate of 6%.

Relay Therapeutics noted that there were no dose-limiting toxicities and that the MTD had not been defined. By the end of 2024, the company expects to disclose updated data from more than 100 safety-evaluable patients who received the doublet at all doses, more than 60 safety-evaluable patients treated at the 600-mg dose level, and findings from the landmark progression-free survival analysis of more than 40 patients with at least 6 months of follow-up. Early safety and tolerability data from the triplet arms are also expected by this time. ReDiscover is continuing to enroll patients at approximately 25 sites across 4 countries.

First-in-human study of mutant-selective PI3Kα inhibitor, RLY-2608, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer. ClinicalTrials.gov. Updated June 6, 2024. Accessed July 8, 2024. https://clinicaltrials.gov/study/NCT05216432

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

Corporate presentation. Relay Therapeutics Inc. June 2024. Accessed July 8, 2024. bit.ly/4bIpmuk

Articles

Experts provide insights on the first-in-human phase 1 ReDiscovertrial trial, evaluating the mutant-selective PI3Kα inhibitor RLY-2608, which is currently enrolling patients.

RLY-2608 Uses PI3Kα Mutant–Specific Inhibition to More Safely Treat Breast Cancer and Other Solid Tumors

Sara M. Tolaney, MD, MPH, discusses the ongoing development of mutation-selective PI3K inhibitors in PI3K-mutant metastatic breast cancer.

Dr Tolaney on the Development of Mutation-Selective PI3K Inhibitors in Breast Cancer

Sara M. Tolaney, MD, MPH, chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, associate director, Susan F. Smith Center for Women’s Cancers, senior physician, Dana-Farber Cancer Institute, associate professor, medicine, Harvard Medical School, discusses the ongoing development of mutation-selective PI3K inhibitors for patients with 

These agents have the potential to target 

 mutations with high specificity and spare wild-type 

, thus minimizing toxicities associated with PI3K inhibitors, Tolaney begins. Traditional PI3K inhibitors, such as alpelisib (Piqray), have demonstrated efficacy in breast cancer but are often accompanied by significant adverse effects, such as hyperglycemia and rash, which poses a challenge for patients, Tolaney explains.

Agents such as RLY-2608 and STX-478 show promise due to their mutation-selective nature, Tolaney states. Early phase 1 data indicate that these inhibitors may offer robust efficacy with a markedly reduced toxicity profile, she reports. Although the data are still immature and based on small patient cohorts, the initial findings are encouraging, according to Tolaney. RLY-2608, in particular, has demonstrated significant efficacy with minimal toxicity in patients with advanced solid tumors, which is an indication that it might become a well-tolerated standard treatment option in the future, Tolaney notes.

The introduction of these mutation-selective inhibitors also paves the way for novel combination strategies, Tolaney continues. Historically, combining PI3K inhibitors with other therapeutic agents has been challenging due to overlapping toxicities, she says. However, the improved safety profiles of these new inhibitors could allow for more innovative and effective treatment regimens, Tolaney emphasizes. For example, inavolisib (GDC-0077) has been successfully combined with palbociclib (Ibrance) and fulvestrant (Faslodex) in patients with hormone receptor–positive, HER2-negative, locally advanced or metastatic breast cancer with well-controlled blood sugar levels, indicating the potential for broader applications, Tolaney says.

RLY-2608 is currently under investigation in combination with fulvestrant and in triplet combinations that include CDK4/6 inhibitors in patients with advanced breast cancer, Tolaney details, adding that these studies are assessing the efficacy and safety of these combinations in larger, more diverse patient populations. If the toxicity profiles of these combinations remain favorable, these novel agents could significantly enhance the treatment paradigm for patients with 

-mutant cancers, Tolaney says. Ongoing research and forthcoming data will be crucial in determining the role of these PI3K inhibitors in clinical practice and in devising optimal combination strategies for various patient populations, Tolaney concludes.

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. 

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 Manich on the ReDiscover Study of RLY-2608 in PIK3CA-Mutant Advanced Solid Tumors

Cristina Saura Manich, MD, PhD, head, Breast Cancer Unit, the Service of Medical Oncology, Vall d’Hebron University Hospital; principal investigator, Breast Cancer and Melanoma Research Group, Vall d’Hebron Institute of Oncology, discusses the ongoing phase 1 ReDiscover study (NCT05216432) which investigated the PI3Kα inhibitor RLY-2608 in patients with advanced breast cancer and other solid tumors. 

The first-in-human, global, multi-center, dose escalation/expansion study is evaluating RLY-2608 as a single agent for adults with previously treated, 

-mutated advanced solid tumors who are refractory, intolerant, or have declined standard therapy. The study is also assessing RLY-2608 in combination with fulvestrant (Faslodex) for previously treated patients with 

-mutated, hormone receptor (HR)–positive, HER2-negative metastatic breast cancer. The monotherapy arm began treating patients in December 2021, and the RLY-2608 plus fulvestrant combination arm started in April 2022.

Initially, the trial tested RLY-2608 monotherapy in a dose escalation format, which yielded a favorable safety and efficacy profile. Prior data reported at the 2023 

 demonstrated clinical proof of mechanism, showing that RLY-2608 achieved selective target engagement at multiple predicted efficacious doses with a good safety and tolerability profile. Notably, 1 heavily pretreated patient with breast cancer achieved a partial response (PR) at the 400-mg twice daily dosing level, and initial anti-tumor activity was observed with the agent across a range of doses.

Overall, early data indicate that RLY-2608 may have broad therapeutic potential in 

-driven tumors. Based on these promising initial efficacy and safety results, the trial has expanded to evaluate RLY-2608 in combination with fulvestrant and either ribociclib (Kisqali) or palbociclib (Ibrance) in patients with 

-mutated HR-positive, HER2-negative advanced or metastatic breast cancer. The trial has been amended to reflect the good results achieved, highlighting both the efficacy and favorable toxicity profile. Currently, the trial is enrolling patients onto the doublet and triplet combination arms.

Cristina Saura Manich, MD, PhD, discusses the phase 1 ReDiscover study evaluating RLY-2608 in patients with PIK3CA-mutated advanced breast cancer and other 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.