NEW YORK – Relay Therapeutics is shifting to a tumor-agnostic development strategy for its FGFR2 inhibitor lirafugratinib (RLY-4008) after the drug showed efficacy in multiple tumor types in the ongoing ReFocus trial.
The change in strategy for lirafugratinib, which Relay was expecting to launch first as a treatment for FGFR2 fusion-positive cholangiocarcinoma, is part of a pipeline reorganization.
In August, Relay reported that its total revenue in Q2 2023 had declined 67 percent to $119 million, compared to $365 million in Q2 2022. As of June 30, the firm had approximately $872 million in cash, cash equivalents, and investments, which it expected would fund operations until the second half of 2025. By focusing on launching lirafugratinib in a tissue-agnostic indication first, with a bigger market opportunity, the Cambridge, Massachusetts-based firm now expects to extend its cash runway into the first half of 2026.
In a conference call Thursday evening, Relay CEO Sanjiv Patel said the decision to move away from the smaller cholangiocarcinoma indication and pursue a broader tumor-agnostic indication was influenced by shifting market incentives imposed by the Inflation Reduction Act. Relay estimates there are about 85,000 cases of FGFR2-altered cancers that are not cholangiocarcinoma globally, compared to only about 6,000 cholangiocarcinoma cases.
The IRA gives the US Centers for Medicare & Medicaid Services power to negotiate drug prices for the most expensive medicines on the market nine years after they garner approval from the US Food and Drug Administration. Although negotiations have just begun for the 10 drugs CMS initially has identified for price controls, the pharmaceutical industry is reacting to the potential for lower revenues by deprioritizing early-stage programs in smaller or orphan indications, including in precision oncology.
"The IRA favors accessing larger opportunities initially versus the conventional approach of speed to market with smaller indications," said Patel. Accordingly, the company is also pausing development of its CDK2 inhibitor RLY-2139, which had been on track to enter clinical studies in breast cancer in early 2024, and an early-stage estrogen receptor-α degrader program. Meanwhile, it is doubling down on its mutant-selective PI3Kα inhibitor program in breast cancer.
In the Phase I/II ReFocus trial, Relay is assessing the safety and objective response rate of about 490 patients with advanced cholangiocarcinoma and other solid tumors harboring FGFR2 gene fusions, mutations, or amplifications. The first dose-escalation part of the trial is complete and the second dose-expansion portion is ongoing at the recommended Phase II dose.
In the expansion portion of the trial, initiated in Dec. 2021, there are seven cohorts of patients with various tumor types characterized by different FGFR2 alterations. As of Aug. 23, 84 patients were evaluable in these arms of the study.
In interim results presented this week at the 2023 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, the overall response rate among patients across FGFR2 alteration types was 28 percent and the disease control rate was 65 percent.
Nine out of 26 patients with FGFR2 fusions, or 35 percent, had a partial response. This included patients with pancreatic, ovarian, gastric, non-small cell lung, and breast cancer.
Don Bergstrom, Relay's president of R&D, said in the call most patients with FGFR2 fusions had tumor regression and a majority had disease control per RECIST criteria. He also highlighted that the durability of response was more than six months for patients with FGFR2 fusions and those with focal amplifications.
Among 14 heavily pretreated patients with hormone receptor (HR)-positive, HER2-negative breast cancer harboring FGFR2 alterations, four had a partial response. The researchers also saw activity in patients with solid tumors bearing FGFR2 amplifications. In that group, which included patients with gastric, breast, colorectal, and esophageal cancer, eight out of 34 patients, or 24 percent, had a partial response.
The safety profile of the drug in this trial was consistent with previously reported data. Most treatment-related adverse events were low-grade, and researchers observed no grade four or five adverse events.
Regarding the tumor indications in which lirafugratinib has shown the most promising activity, including HR-positive breast, gastric, pancreatic, non-small cell lung, ovarian, and head and neck cancer, Bergstrom said, "For these patients, late-line standard of care is typically chemotherapy, with response rates typically well less than 15 percent, highlighting the need for more effective targeted therapies for patients with FGFR2 alterations across a broad range of solid tumor types."
While a tumor-agnostic indication would provide Relay a bigger market opportunity, thus far the FDA has only approved such indications a handful of times, making the path to approval less certain than it would be for a histology-specific indication. Bergstrom said Relay will gather more data in ReFocus. "Then, we need to have an FDA interaction to clarify with them what the anticipated path forward would be for a tumor-agnostic population," including what type of data the agency wants in which tumor types, he said.
Peter Rahmer, Relay's chief corporate development officer, said that according to the FDA's 2022 draft guidance on tumor-agnostic drug approvals, "they want to see a good diversity of tumor types represented and consistency of signal across tumor types."
Relay will also be seeking lirafugratinib's approval in tumors with different types of FGFR alterations, and Rahmer speculated that the agency's guidance on tumor types "will hold even when you think about trying to pool alterations."
Relay's other major focus will be its PI3Kα program, which Patel said has a market opportunity "significantly larger than the several multibillion-dollar franchises" for drugs targeting EGFR alterations. Relay is conducting a Phase I trial of its PI3Kα inhibitor RLY-2608 in patients with advanced solid tumors as a monotherapy and in patients with hormone receptor-positive, HER2-negative advanced breast cancers in combination with fulvestrant.
All patients in the trial must harbor a PI3Kα mutation. Initial data Relay reported earlier this year showed anti-tumor activity at a range of doses in the breast cancer arm including a partial response in a patient who had 12 prior lines of therapy. Relay is planning to add another arm to the trial to assess the activity of RLY-2608 with fulvestrant and a CDK4/6 inhibitor by year end. "We have a lot going on with our PI3Kα franchise and look forward to a very data-rich next year, which should allow us to determine next steps," Patel said.