Komal Jhaveri, MD, FACP, section head, Endocrine Therapy Research Program, clinical director, Early Drug Development Service, Memorial Sloan Kettering Cancer Center, discusses findings from the dose-escalation portion of the first-in-human phase 1 ReDiscover trial (NCT05216432) of the PI3Kα inhibitor RLY-2608 in patients with 

In arm 1 of the dose-escalation portion of ReDiscover, patients with 

-mutant advanced solid tumors received RLY-2608 monotherapy to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D). In arm 2 of the dose-escalation portion, patients with 

-mutant, hormone receptor–positive, HER2-negative advanced or metastatic breast cancer received RLY-2608 plus fulvestrant (Faslodex) to determine the MTD/RP2D.

Of the 42 total patients enrolled to the dose-escalation portion, arm 1 enrolled 19 patients to receive twice daily doses of RLY-2608 at 400 mg, 300 mg, 200 mg, 100 mg, or 50 mg or daily doses of 400 mg or 200 mg. Arm 2 enrolled 23 patients to receive twice-daily doses of RLY-2608 at 800 mg, 600 mg, 400 mg, 200 mg, or 100 mg in combination with fulvestrant.

Of the 16 patients with breast cancer and measurable disease, 9 experienced radiographic tumor regression with RLY-2608 and 81% achieved stable disease regardless of genotype. Eleven of the 16 patients are still receiving treatment. Despite these findings, longer follow-up is necessary to see whether additional patients experience tumor regression, Jhaveri says.

Notably, 1 heavily pretreated patient who received RLY-2608 monotherapy at 400-mg twice daily achieved a partial response (PR). This patient had received 12 prior lines of therapy, including fam-trastuzumab deruxtecan-nxki (Enhertu), and their tumor harbored 2 

 mutations. This finding was encouraging, as few patients in this trial had achieved PRs at the data cutoff date, according to Jhaveri. This trial has a small dataset, with few patients treated with the RLY-2608/fulvestrant combination at varying dose levels, and the MTD has yet to be determined, Jhaveri concludes.

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Komal Jhaveri, MD, FACP, discusses findings from the dose-escalation portion of the first-in-human phase 1 ReDiscover trial (NCT05216432) of the PI3Kα inhibitor RLY-2608 in patients with PIK3CA-mutant advanced breast cancer.

Dr Jhaveri on RLY-2608 in PIK3CA-Mutant Advanced Breast Cancer

Julia E. McGuinness, MD, assistant professor, medicine, Division of Hematology/Oncology, Columbia University, Herbert Irving Comprehensive Cancer Center, discusses combating gastrointestinal (GI) toxicities in 

Many therapies tend to cause GI toxicities among the first- and later-line treatment landscape for patients with 

-mutated breast cancer, McGuinness says. For example, the PI3K inhibitor, alpelisib (Piqray), can cause toxicities leading to dose interruptions or discontinuation, McGuinness explains.

Because of the toxicities that arise during treatment, there has been an increase in supportive management, McGuinness continues. It is important to use more selective agents to target mutations of interest in order for patients to avoid these severe toxicities, McGuinness concludes.

RLY-2608 is a highly selective PI3Kα inhibitor that is being evaluated for 

-mutated solid tumors, including breast cancer, in a phase 1 trial (NCT05216432).

Julia E. McGuinness, MD, discusses combating gastrointestinal toxicities in PI3K-mutated breast cancer.

Dr. McGuinness on Mitigating GI Toxicities With PI3K Inhibitors in PI3K-Mutated Breast Cancer

Erika P. Hamilton, MD, director, Breast and Gynecologic Cancer Research, Sarah Cannon Research Institute, discusses the potential of the PI3K inhibitor RLY-2608 in 

Although the FDA approved the PI3K inhibitor alpelisib (Piqray) in combination with fulvestrant (Faslodex) for patients with estrogen receptor–positive disease in May 2019, the adverse effects (AEs) associated with the combination can make it difficult to administer to some patients, Hamilton explains. Since PI3K is expressed in some normal tissue, treatment with PI3K inhibitors translates to AEs, Hamilton adds.

However, RLY-2608 is designed to be selective for 

 wild-type or PI3K expressed in normal tissue with more frequency, Hamilton adds. It is hoped that this selectivity will translate to improved efficacy and tolerability for patients with breast cancer harboring 

Erika P. Hamilton, MD, director, Breast and Gynecologic Cancer Research, Sarah Cannon Research Institute, discusses the potential of the PI3K inhibitor RLY-2608 in PI3K-mutated breast cancer.

Dr Hamilton on the Potential of RLY-2608 in PI3K-Mutated Breast Cancer

RLY-2608 led to sustained target inhibition with minimal effect on glucose homeostasis, acceptable safety, and antitumor activity in patients with 

-mutant solid tumors, according to interim data from the dose-escalation portion of the first-in-human phase 1 ReDiscover trial (NCT05216432).

Data presented at the 2023 AACR Annual Meeting showed that the PI3Kα inhibitor had antitumor activity in patients with hormone receptor (HR)–positive/HER2-negative breast cancer across PIK3CA genotypes. Of 16 patients with breast cancer and measurable disease, 56% (n = 9) experienced radiographic tumor reduction, and 81% (n = 13) achieved stable disease (SD) or partial response (PR). Moreover, RLY-2608 had a differentiated and favorable toxicity profile, with most toxicities being low grade and manageable.

As of March 2023, dose escalation was ongoing in both arms. No dose-limiting toxicities were observed, and the maximum tolerated dose (MTD) had not been reached.

“We have shown proof of mechanism for RLY-2608 as the first allosteric, pan-mutant selective, PI3Kα inhibitor,” lead study author Andreas Varkaris, MD, PhD, of Massachusetts General Hospital in Boston, said in a presentation of the data.

PI3Kα is the most frequently mutated kinase in solid tumors. Fourteen percent of all solid tumors harbor 

 mutations, and approximately 100,000 patients with breast cancer are found to harbor this mutation annually in the United States. 

 is crucial for cellular processes such as regulating glucose homeostasis.

was approved by the FDA in 2019 in combination with fulvestrant

 (Faslodex) for patients with HR-positive, HER2-negative, 

-mutant advanced or metastatic breast cancer who have progressed on or after endocrine therapy. However, alpelisib is not mutant-selective and is known to disrupt glucose metabolism resulting in hyperglycemia. Notably, wild-type 

 and off-isoform toxicity limit the clinical benefit derived with the agent, according to Varkaris. The adverse effects (AEs) that frequently result in discontinuation of the agent are hyperglycemia (all-grade, 65%; grade ≥3, 37%), diarrhea (60%; 7%), and rash (36%; 10%).

RLY-2608, the first allosteric, mutant-selective PI3Kα inhibitor, selectively inhibits 

, with a high degree of selectivity across the kinome and within the PI3K family. In preclinical breast cancer models, RLY-2608 demonstrated robust efficacy in both helical and kinase domain models comparable with the efficacy of alpelisib and inavolisib (GDC-0077). However, unlike alpelisib and inavolisib, RLY-2608 had minimal effects on glucose homeostasis, supporting its evaluation in ReDiscover.

ReDiscover is comprised of 2 parts: the dose-escalation and dose-expansion phases.

-mutant advanced solid tumors received RLY-2608 monotherapy as part of the dose-escalation portion of the research to determine the MTD/recommended phase 2 dose (RP2D). In the dose-expansion part, patients with diseases such as 

-mutant clear-cell ovarian cancer, cervical cancer, head and neck squamous cell carcinoma, and 

 double-mutant cancers will receive the agent at the RP2D.

-mutant, HR-positive/HER2-negative advanced or metastatic breast cancer received RLY-2608 in combination with fulvestrant in the dose-escalation part. After the MTD/RP2D for the combination is determined, the dose-expansion part will further evaluate the regimen in 2 groups of patients with 

-mutant, HR-positive/HER2-negative advanced breast cancer: those who have not received a prior PI3Kα inhibitor and those who are intolerant to a PI3Kα inhibitor.

The key end points of this trial include determining the MTD, RP2D, safety, pharmacokinetics, and antitumor activity of RLY-2608.

ReDiscover has enrolled 42 total patients. For the dose-escalation part, arm 1 enrolled 19 patients beginning in December 2021. RLY-2608 was examined at twice daily doses of 400 mg (n = 4), 300 mg (n = 3), 200 mg (n = 3), 100 mg (n = 1), or 50 mg (n = 2) and daily doses of 400 mg (n = 3) and 200 mg (n = 3). Arm 2 enrolled 23 patients beginning in April 2022. In this group, RLY-2608 was evaluated at twice daily doses of 800 mg (n = 6), 600 mg (n = 7), 400 mg (n = 4), 200 mg (n = 3), and 100 mg (n = 3) in combination with fulvestrant.

In the overall patient population, the median age was 60 years (range, 40-85). Most patients were female (81%) and White (86%). Regarding ECOG performance status, 50% had a status of 0 and 48% had a status of 1. Regarding PIK3CA, 52% had a helical genotype, 33% had kinase, and 14% had other. Thirty-eight percent of patients received 1 median number of prior treatment regimen in the metastatic setting, 12% received 2 prior lines, and 48% had 3 or more prior lines. Just under half of patients (43%) received prior chemotherapy/antibody-drug conjugates and 10% received an mTOR/AKT inhibitor.

Pharmacokinetic data showed a dose-dependent increase in exposure and low peak-to-trough fluctuations across dose levels in both arms. All tested doses of RLY-2608 in both arms reached plasma concentrations predicted to achieve 50% of AKT pathway inhibition. In preclinical models, continuous RLY-2608 exposure reaching 80% AKT pathway inhibition was correlated with efficacy. In ReDiscover, plasma concentration levels required for 80% AKT pathway inhibition were seen across dosing intervals at 400 mg twice daily in arm 1 and at 600 mg and 800 mg twice daily in arm 2.

An ex vivo pharmacodynamic assessment of RLY-2608 showed that 80% AKT pathway inhibition was reached at RLY-2608 doses of 400 mg twice daily in arm 1 and at 600 mg and 800 mg twice daily in arm 2.

An analysis of RLY-2608 on glucose homeostasis demonstrated that patients in both arms had average pre–RLY-2608 glucose concentrations. No grade 3 hyperglycemia per CTCAE v5.0 criteria were observed at any dose levels. Moreover, no patients required dose interruptions or reductions because of hyperglycemia. “Modest glucose changes were observed in a minority of patients, [which were] manageable with oral anti-hyperglycemic agents,” Varkaris noted.

Varkaris shared a case study of a 58-year-old female with HR-positive/HER2-negative breast cancer whose tumors harbored 

 H1047R and E453K mutations enrolled on the trial. The patient had received 12 prior lines of therapy, which included chemotherapy, endocrine therapy, and several HER2-targeted agents, including fam-trastuzumab deruxtecan-nxki (Enhertu). On the trial, the patient received RLY-2608 monotherapy at 400 mg twice daily in arm 1. The patient experienced an improvement in severe abdominal pain and palpable hepatomegaly, as well as decreased diffuse liver metastases, Varkaris explained. At their first radiographic assessment at 8 weeks, they achieved a partial response (PR) per RECIST criteria with an approximate 36% tumor reduction and no AEs. As of the data cutoff date, this patient’s response was ongoing.

The investigators assessed circulating tumor DNA (ctDNA) dynamics in 31 evaluable patients with paired ctDNA samples from cycle 1 day 1 to cycle 2 day 1, who received less than 400 mg of RLY-2608 in arm 1 (n = 9), 400 mg of the study treatment in arm 2 (n = 10), 400 mg of the study treatment in arm 1 (n = 2), and 600 mg or 800 mg of the study treatment in arm 2 (n = 10). In this analysis, 6 patients had at least 2 

In an analysis of 27 patients with breast cancer treated in both arms, 19 patients (n = 70%) were still receiving treatment at the data cutoff. The median treatment duration was 16 weeks (range, 4-44). Of the 24 RECIST-evaluable patients, 88% (n = 21) had persistent target lesions, SD, or PR. Of the 8 patients who discontinued the study treatment, 7 did so because of progressive disease (PD). No AEs resulted in treatment discontinuation in these patients.

In an analysis of 15 patients with solid tumors other than breast cancer treated in arm 1, the median treatment duration was 8 weeks (range, 1-52). A total of 14 patients discontinued the study treatment, all of whom discontinued because of PD. No AEs led to treatment discontinuation in these patients.

In the overall population, most AEs were low-grade, manageable, and reversible. Grade 3 treatment-emergent AEs (TEAEs) occurred in 24% of patients (n = 10), and no grade 4 or 5 AEs were reported.

The most common TEAEs observed across all doses and arms were nausea (all-grade, 31%; grade 3, 0%), increased blood creatinine (24%; 0%), fatigue (24%; 2%), headache (24%; 2%), hypokalemia (21%; 7%), decreased appetite (17%; 0%), diarrhea (17%; 2%), and hyperglycemia (17%; 0%). The most common TEAEs in arm 2 were nausea (44%; 0%), increased blood creatinine (30%; 0%), fatigue (22%; 0%), headache (30%; 4%), hypokalemia (17%; 4%), decreased appetite (9%; 0%), diarrhea (9%; 0%), and hyperglycemia (17%; 0%).

AE-related dose interruptions and dose reductions occurred in 31% and 2% of all patients, respectively. No patients discontinued the study treatment because of AEs. The median relative dose intensity was 98%.

“The differentiated and favorable safety profile confirms mutant and isoform selectivity,” Varkaris concluded.

The dose-escalation and cohort-enrichment parts of ReDiscover continue, and the dose-expansion part is expected to begin in the second half of 2023.

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 

-mutant solid tumor patients, ReDiscover trial. Presented at: 2023 AACR Annual Meeting; April 14-19, 2023; Orlando, FL. Abstract CT017.

Articles

RLY-2608 led to sustained target inhibition with minimal effect on glucose homeostasis, acceptable safety, and antitumor activity in patients with PIK3CA-mutant solid tumors, according to interim data from the dose-escalation portion of the first-in-human phase 1 ReDiscover trial.

RLY-2608 Shows Broad Therapeutic Potential in PIK3CA-Mutant Solid Tumors

Increasingly mutant-targeted PI3K inhibitors, such as the investigational agent RLY-2608, may provide more potent efficacy in hormone receptor (HR)–positive, HER2-negative breast cancer, while decreasing the adverse effects (AEs) that are often associated with this class of agents, according to Julia E. McGuinness, MD.

RLY-2608 is the first known allosteric PI3Kα pan-mutant and isoform-selective inhibitor.

 The safety and preliminary activity of this agent are being evaluated in a phase 1 first-in-human study (NCT05216432), which is investigating RLY-2608 as a single agent in adult patients with advanced solid tumors and in combination with fulvestrant (Faslodex) in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer.

Eligible patients include those with at least 1 documented primary 

 mutation per local assessment and no prior PI3K inhibitors. Patients in the breast cancer cohort must have received previous treatment with no more than 1 chemotherapy, at least 1 CDK4/6 inhibitor, and at least 1 anti-estrogen therapy. Recruitment for this trial is ongoing across 14 centers in the US and Spain.

“It’s getting increasingly complicated to figure out what the next therapy is for patients after they’ve progressed on CDK4/6 inhibitors. [Biomarker testing is] still crucial,” McGuinness said in an interview with 

In the interview, McGuinness discussed the rationale for combining this novel PI3K inhibitor with fulvestrant and emphasized the importance of developing increasingly mutant-specific PI3K inhibitors in HR-positive disease, including the need for therapies that don’t cause gastrointestinal (GI) AEs such as diarrhea.

McGuinness is an assistant professor of medicine in the Division of Hematology/Oncology at the Columbia University Herbert Irving Comprehensive Cancer Center in New York, New York.

: What is the rationale for this phase 1 trial of RLY-2608?

: Patients with HR-positive, HER2-negative metastatic breast cancer standardly receive first-line CDK4/6 inhibitors plus endocrine therapy. After they’ve progressed, we start talking about second-line therapies that are often guided by the mutational status of their tumors. About 40% of these patients have a 

 mutation, [for which] the standard treatment option is alpelisib [Piqray], a PI3K inhibitor.

The problem with alpelisib is it can have dose-limiting toxicities, including hyperglycemia. That’s because the drug is not specific to the mutated PI3K, so it can also affect wild-type [PI3K], and that’s where the AEs come from.

This novel agent, developed by Relay Therapeutics, is a mutant-specific PI3K inhibitor. The rationale behind it is that its [properties may] potentially be more effective [at targeting mutant-specific PI3K, resulting in less toxicity]. This has been supported by [Relay’s previous] work in animal models.

What information from this study was shared at the 2022 San Antonio Breast Cancer Symposium?

[We shared] a trial-in-progress update. We don’t yet have published data on toxicity or preliminary efficacy from this study. That being said, we started enrolling to the combination arm about 8 months ago in the US, [and enrollment] is open at Columbia. Hopefully we’ll have updated results at a future meeting.

How does the impetus for this study speak to the importance of biomarker testing in breast cancer?

These potential targeted therapies that will hopefully show improved clinical benefit and improved toxicity highlight the importance of continuing to identify these patients through molecular testing, either at progression or initial diagnosis.

What is the importance of developing more selective inhibitors in breast cancer that don’t cause GI AEs?

Many current therapies cause GI toxicity, even among our first-line therapies like abemaciclib [Verzenio], and PI3K inhibitors like alpelisib. These can often limit doses and cause dose interruptions or even, in severe cases, lead patients to discontinue the drugs. Because of these severe toxicities, although our supportive management of them is improving, it’s increasingly important, since we want patients to benefit from these drugs, to find more selective agents to target the mutations of interest so they can potentially be on these drugs longer and have a better quality of life on these medications.

Varkaris A, Hamilton E, Henry J, et al. First-in human global multi-center study of RLY-2608, a pan mutant and isoform selective PI3Kα inhibitor, as a single agent in advanced solid tumor patients and in combination with fulvestrant in patients with advanced breast cancer. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract OT3-22-01.

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 November 21, 2022. Accessed December 13, 2022. 

https://clinicaltrials.gov/ct2/show/NCT05216432

Julia E. McGuinness, MD, discusses the rationale for combining this novel PI3K inhibitor with fulvestrant and emphasized the importance of developing increasingly mutant-specific PI3K inhibitors in hormone receptor–positive breast cancer. 

Novel Therapeutic Approaches to Target PI3K Mutations in HR+/HER2– Breast Cancer | Supplements and Featured Publications

Dr Jhaveri on RLY-2608 in PIK3CA-Mutant Advanced Breast Cancer

Dr. McGuinness on Mitigating GI Toxicities With PI3K Inhibitors in PI3K-Mutated Breast Cancer

Dr Hamilton on the Potential of RLY-2608 in PI3K-Mutated Breast Cancer

RLY-2608 Shows Broad Therapeutic Potential in PIK3CA-Mutant Solid Tumors

RLY-2608 Shows Preclinical Potential for Selective PI3K Inhibition, Decreased AEs in HR+, HER2– Breast Cancer