ORLANDO – Relay Therapeutics' investigational PI3Kα inhibitor RLY-2608 generated encouraging responses among patients with PIK3Cα-mutated solid tumors, according to preliminary results presented by researchers at the American Association for Cancer Research's annual meeting on Tuesday.
In the ongoing first-in-human Phase I trial, dubbed ReDiscover, Relay enrolled heavily pretreated patients with solid tumors harboring PIK3Cα mutations. In one arm of the trial, patients with locally advanced or metastatic PIK3Cα-mutant hormone-positive, HER2-negative breast cancer received RLY-2608 with the hormone therapy fulvestrant. All 23 breast cancer patients in this arm had at least one prior endocrine therapy and a CDK4/6 inhibitor, and about one-fifth had also received prior mTOR or AKT inhibitor therapy.
In the trial's other arm, which included patients with all other cancer types, including breast cancer patients who weren't eligible for combination treatment, researchers tested the efficacy of RLY-2608 as a monotherapy. In this arm, 63 percent of patients had received more than three prior lines of treatment.
Andreas Varkaris, an oncologist at Massachusetts General Hospital, reported at the meeting that investigators had enrolled 42 patients as of early last month: 19 into the monotherapy arm and 23 into the breast cancer-specific RLY-2608-hormone therapy arm. Although dose escalation is still ongoing in both arms and the maximum tolerated dose of the drug remains unknown, Varkaris noted that none of the patients had experienced dose-limiting toxicities at the time of the data cutoff. This could change as patients receive higher doses, but Varkaris was still encouraged by the fact none of the patients had yet experienced grade 3 hyperglycemia, a serious side effect associated with other PI3K inhibitors. Only a few patients had modest changes in their blood glucose levels.
Across both the monotherapy and combination arms, nine of 16 breast cancer patients with RECIST-measurable disease had radiographic tumor reductions; 13 out of 16 had either stable disease or an unconfirmed partial response; and 11 out of the 16 patients were still responding to the treatment at the time of the data cutoff.
Varkaris highlighted the experience of one of his breast cancer patients who had received RLY-2608 monotherapy. After four weeks on the treatment, a circulating tumor DNA analysis revealed more than 90 percent reduction in variant allele frequency of both PIK3Cα and ESR1, and after eight weeks, the patient had experienced a 36 percent tumor reduction. This patient did not experience any treatment-associated adverse events, which Varkaris said confirmed the drug's mutant-selective inhibition.
In the RLY-2608 monotherapy arm on the whole, treatment responses were a bit more modest than they were among patients with breast cancer. In a conference call to discuss the data from ReDiscover, Don Bergstrom, Relay's R&D president, pointed out that the patient population evaluated on the monotherapy arm included only four patients — two with head and neck cancer and two with breast cancers harboring more than one PIK3Cα mutation. Additionally, of these four patients, only one was treated at a dose that met the target exposure threshold, and this patient achieved a confirmed partial response.
The company will begin enrolling more patients into a planned dose-expansion cohort during the second half of this year, including those with PIK3Cα-mutant clear-cell ovarian cancers, head and neck squamous cell carcinomas, cervical cancers, and other cancer types including those with PIK3Cα double mutations.
Although the ReDiscover trial is an early, first-in-human study, and the AACR results are preliminary, Relay believes the data already show that its drug has a better safety profile than competing agents, namely Novartis' Piqray (alpelisib). Since 2019, Piqray in combination with fulvestrant has been an option in the US for postmenopausal women with hormone receptor-positive, HER2-negative, PIK3Cα-mutated advanced or metastatic breast cancer.
"The data we share today validate potential advantages of highly selective inhibition of validated breast cancer targets," Peter Rahmer, Relay's chief corporate development officer, said during the call. "As we transition to enrolling the expansion cohorts of patients later this year, the goal is to demonstrate that this clinical profile translates to clinical efficacy and a differentiated long-term safety profile relative to non-selected PI3Kα inhibitors."
During the AACR presentation and conference call, Relay drilled down on the point that RLY-2608, with its more selective design, could do a better job of targeting just mutant cancer-associated PIK3Cα rather than wild-type PIK3Cα, and avoid the side effects of less selective, earlier drugs like Piqray.
During a discussion of the ReDiscover data at AACR, Fabrice Andre, head of research at the Gustave Roussy Institute in France, also highlighted the potential safety advantages of RLY-2608, which specifically targets three activating hotspot mutations. Piqray targets PIK3Cα, but it is not mutant-selective, Andre said.
"When you give an alpha-selective inhibitor that is not mutant-selective, there are substantial side effects," he said, estimating that more than a third of patients on non-mutant selective PI3K inhibitors experience grade 3 or higher hyperglycemia, more than 10 percent experience grade 3 rash, and around 6 percent experience grade 3 diarrhea. "That leads to permanent discontinuation of the drug in around 25 percent of patients and dose reductions in 63 percent of patients," he said.
"Fragile" patient populations, particularly elderly patients and individuals with diabetes or high body mass index, usually aren't offered Piqray at all, and he suggested that a mutant-specific PI3K inhibitor with a more favorable safety profile could be an option for these patients.
But the jury is still out on RLY-2608's efficacy, Andre said.
To warrant a head-to-head comparison with Piqray, RLY-2608 would need to demonstrate a seven-month median progression-free survival among breast cancer patients resistant to CDK4/6 inhibitors, and in Andre's view, the data on Relay's drug are simply too preliminary to draw any conclusions as to whether that seems likely. The "preliminary data are interesting, but we are still lacking more follow-up for progression-free survival," he said.