NEW YORK – After the majority of cholangiocarcinoma patients with FGFR2 fusions saw their tumors shrink with Relay Therapeutics' next-generation FGFR2 inhibitor in the ReFocus trial, oncologists at the European Society for Medical Oncology Congress urged the sponsor to expand enrollment in the study and take the data to regulators.
Antoine Hollebecque, senior medical physician at the Gustave Roussy Cancer Center in Paris, presented data on Sunday from a cohort in the Phase I/II ReFocus trial on 17 patients with unresectable or metastatic bile duct cancer who had received prior chemotherapy but no other FGFR inhibitors and harbored an FGFR2 fusion or rearrangement in their tumors. As of Aug. 1, 15 patients, or 88 percent, had an objective response to Relay's FGFR2 inhibitor, though all patients had some reduction in tumor size in radiographic scans. The objective response rate was confirmed in 14 patients, or 82 percent.
"These results suggest that RLY-4008 has the potential to transform the cholangiocarcinoma treatment paradigm and strongly support seamless expansion of ReFocus with registrational intent," said Hollebecque.
All the objective responses were partial responses, though one patient had a near complete response that allowed for surgery with curative intent. Two patients had stable disease.
Hollebecque described the experience with RLY-4008 of one of his patients, a 56-year-old woman whose cholangiocarcinoma had spread to the liver and bone and who had stopped responding to gemcitabine/cisplatin. She had an FGFR2 rearrangement, and with RLY-4008 saw a marked reduction in intrahepatic lesions and bone metastasis. "After more than six months, she remains on treatment, with 68 percent tumor regression," he said.
In Phase I of the ReFocus trial, researchers had established a 70 mg daily dose for RLY-4008 to take into Phase II expansion cohorts of patients with advanced cholangiocarcinoma and other advanced solid tumors. The 88 percent objective response rate seen in FGFR inhibitor-naïve bile duct cancer patients was with the 70 mg daily dose of RLY-4008. In 38 patients with bile duct cancer who received all doses of RLY-4008 in the study, the objective response rate was 63 percent with 92 percent experiencing tumor reduction to some extent. The patients who responded to RLY-4008 did so quickly, Hollebecque said, with a median time to response of 1.8 months.
RLY-4008 is designed to selectively target FGFR2 fusions and rearrangements, but also resistance mutations. The ability of the drug to home in on the FGFR2 receptor while sparing the other FGFR receptors is reflected in its safety profile. Based on 195 patients' experiences with the drug at various doses, Hollebecque said adverse events were mostly low grade and largely reversible. The most common adverse events at the recommended Phase II dose were stomatitis, nail toxicities, palmar plantar erythrodysesthesia, and dry mouth.
Based on this data, Hollebecque urged Relay to expedite development of RLY-4008 for cholangiocarcinoma patients. The company plans to enroll 100 FGFR inhibitor-naïve patients with FGFR2 fusions and rearrangements in an expansion cohort in ReFocus. During a call with investors, Relay CEO and President Sanjiv Patel said the firm is shooting to fully enroll this pivotal cohort in the second half of 2023 and release the full dose escalation data in ReFocus in the first half of next year.
"We are definitely eager to see if these data are going to be confirmed in the rest of the population," Chiara Braconi, associate professor at University of Glasgow's Institute of Cancer Sciences, said while reviewing the data at ESMO.
If Relay is successful in taking RLY-4008 through the US Food and Drug Administration, it will be the fourth FGFR inhibitor to enter the market for advanced cholangiocarcinoma patients with FGFR2 fusions or rearrangements who have progressed on chemotherapy. There are two FDA-approved FGFR inhibitors, Incyte's Pemazyre (pemigatinib) and BridgeBio/Helsinn's Truseltiq (infigratinib), and the agency earlier this year granted priority review to Taiho Oncology's new drug application for futibatinib in the same setting.
RLY-4008's specificity for the FGFR2 receptor has given it a better risk/benefit profile than Pemazyre and Truseltiq, Patel told investors during the call. "We believe the dose of these [already marketed] agents is actually limited by the toxicity related to the off-target inhibition," he said. "Our therapeutic hypothesis was that a highly selective inhibitor of FGFR2 can be optimized for the inhibition of FGFR2, potentially leading to high response rates and better durability of response."
Even though cross-trial comparisons are imperfect, Braconi pointed out that the 82 percent confirmed objective response rate seen with RLY-4008 is significantly higher than the 37 percent, 23 percent, and 42 percent objective response rates reported for Pemazyre, Truseltiq, and futibatinib, respectively. "We see a very remarkable response rate, which compares very favorably with what we have so far," Braconi said, but cautioned that the data needs to mature to have a full understanding of the drug's efficacy and safety.
For example, since most of the patients responding to RLY-4008 are still receiving treatment, it's not possible to compare the FGFR inhibitors in terms of duration of response. Moreover, the responses seen with Pemazyre, Truseltiq, and futibatinib have translated to lengthy median overall survival times, ranging from over a year to up to 20 months. This represents a significant improvement over the six-month overall survival generally seen with standard of care chemotherapy, Braconi said. However, the overall survival data are not yet available for RLY-4008.
In terms of toxicity, RLY-4008 also looks better than the other FGFR inhibitors. These drugs tend to have a "peculiar toxicity profile," Braconi observed, causing hyperphosphatemia, diarrhea, and ocular adverse events, such as dry eye. Rarely, FGFR2 inhibitors can cause retinal detachment, "which is quite a limitation for the treatment of these patients," Braconi said.
Across all doses of RLY-4008 in ReFocus there was one trial discontinuation due to retinal detachment. Overall, RLY-4008 appears to have a very different toxicity profile than the FGFR inhibitors on the market, Braconi said, but added that she wants to see data on more patients to better understand the risk of retinal detachment with Relay's drug.
Despite her enthusiasm for the data to date on RLY-4008, she still wondered whether there is a biological reason for why the objective responses look so good with this drug. For example, she wondered if patients could have or lack co-occurring mutations that might bias the population toward good responses, citing for example that prior research suggests that when patients with FGFR2 alterations have KRAS mutations, they don't respond as well to Pemazyre.
And even though RLY-4008 is designed to inhibit FGFR2 resistance mutations that may emerge with treatment, it'll be important to track patients and see how tumors try to evade this pressure, she added. Braconi further wondered whether de novo resistance mutations may emerge in FGFR2 or other genes.
Relay is conducting serial ctDNA analysis to better understand the mechanisms of resistance with RLY-4008 and testing patients for co-occurring mutations at baseline to investigate their potential impact on response. "Although, with the level of clinical activity we're seeing, it would be unlikely that the 88 percent response rate would be solely due to having some sort of population imbalance," Pete Rahmer, Relay's chief corporate development officer, said during the call with investors. "In a future disclosure, we'll share a more complete molecular characterization of our patients at baseline and serial characterization."
Even though Relay is planning to further study its drug in an expanded cohort of 100 cholangiocarcinoma patients, Ian Chau, a consultant medical oncologist at the Royal Marsden National Health Service Trust, wondered during the ESMO presentation if this would be enough to bring the drug to patients, since RLY-4008 will likely be the fourth to market in its class. "Do you think another single-arm study of 100 patients is enough? Or do you think we need to now randomize against pemigatinib?" Chau wondered.
"I know there's discussion with the FDA because these results are impressive. Obviously, we'd like to register this drug," Hollebecque replied, noting that even though RLY-4008 is entering a crowded market, that market is small since cholangiocarcinoma is a rare cancer. Around 8,000 people are diagnosed with bile duct cancer each year in the US, and between 10 percent and 15 percent of patients harbor FGFR2 fusions.
Ultimately, Hollebecque said he believed "there's a place for this drug because the activity seems very, very high." The other FGFR inhibitors garnered accelerated approval in the US based on activity seen in single-arm trials, and Hollebecque and Braconi noted that given the benefit seen in those studies, randomized trials in the first-line setting have been difficult to enroll
Relay, meanwhile, is betting that RLY-4008 has potential not just as a cholangiocarcinoma treatment but as a pan-tumor precision oncology therapy. The firm is planning to share data next year on the activity of the drug from the other solid tumor cohorts in the ReFocus trial. Preliminary data Relay disclosed last year provided a glimpse of the drug's activity in other tumor types. For example, RLY-4008 resulted in a confirmed partial response in a breast cancer patient with an FGFR2 mutation, and some patients with FGFR2 amplifications had tumor shrinkage.
"We believe FGFR2 has all the hallmarks of a cancer driver oncogene, which makes it an attractive precision oncology target," Patel said, estimating that its selective FGFR2 inhibitor could potentially address between 8,000 and 20,000 advanced cancer patients with FGFR2 alterations each year in the US. Following the ESMO presentation on RLY-4008 in cholangiocarcinoma, Relay announced it is working with Foundation Medicine to develop a companion diagnostic for the drug using the FoundationOne CDx next-generation sequencing panel.
Rahmer highlighted that Relay has a total of 13 precision oncology drug candidates in its pipeline, including RLY-2608, a pan-mutant-selective PI3Kα inhibitor for breast cancer that the firm will share initial data on in the first half of 2023. At the end of Q2 2022, Relay had $838 million in cash, cash equivalents, and investments, with which it expects to fund operations into 2025. The company is also hoping to raise more than $300 million through an underwritten public offering of shares of its common stock.