Revolution Medicines’ stock slid 6.3% Thursday after newly released FDA review documents sparked investor unease around Rasonque’s market position in a key KRAS subgroup.
The FDA granted early approval to Rasonque, a RAS inhibitor, in August for previously treated pancreatic cancer following strong overall survival data. Its phase 3 results made waves at this year’s American Society of Clinical Oncology annual meeting, lifting RevMed to top-tier valuation.
But FDA review documents released Thursday fueled investor anxiety over Rasonque’s performance in patients with KRAS G12D tumors, which represent the most common subtype of KRAS mutations in pancreatic cancer. In the landmark RASolute 302 trial that supported Rasonque’s approval, KRAS G12D mutations were found in 43% of patients.
While Rasonque achieved a 33% objective response rate (ORR) across all KRAS mutation subtypes, it posted a lower ORR, at 24%, in G12D patients. The G12V subgroup, which made up 36% of the trial population, saw the biggest ORR, at 50%; while those with G12R mutations only logged a 7% ORR, underperforming the chemotherapy control group’s 14%.
The FDA asked for the exploratory efficacy analyses by RAS subgroups during a May 1 pre-submission teleconference, and RevMed provided the data, along with responses to myriad other requests, on May 15.
According to analysts at Leerink Partners and Jefferies, the subgroup analysis drove RevMed’s share weakness Thursday. Investors were concerned that the data left competitive risk for Rasonque and opted to pull back given how the drug is fueling the company’s high market valuation, Jefferies’ Faisal Khurshid pointed out in an Oct. 8 note.
Both teams argued that investors overreacted; in Leerink analysts’ words, the subgroup analysis “doesn’t change anything for Rasonque.”
Khurshid questioned whether 24% and 33% marks that big of a difference. Perhaps more importantly, Rasonque appears to confer benefits despite lower ORR numbers in G12D and G12R patients.
According to exploratory analyses RevMed performed, overall survival favored Rasonque with a 51% improvement over chemo in G12D patients and 39% in G12R patients, even as the G12V group enjoyed a massive 68% improvement.
In a statement to Fierce, RevMed stressed that overall survival is “the gold standard endpoint in oncology and is what matters most to patients and physicians, particularly in pancreatic cancer,” pointing to Rasonque’s major 60% death risk reduction in the RASolute 302 trial.
“Consistent OS improvement over chemotherapy across key patient subgroups supported the FDA’s approval of Rasonque with an approved indication that is independent of tumor RAS genotype,” the company added.
Leerink analysts said the difference was not that surprising based on preclinical data indicating strong binding and inhibition of G12V. Besides, “G12R has always been a challenge for any molecule,” the team wrote in an Oct. 8 note.
As the FDA noted in its review, different KRAS mutations exhibit different equilibrium between the active and inactive states, which may affect the accessibility for a RAS(ON) inhibitor like Rasonque, which locks the RAS protein in its active state.
G12R also shows certain mechanisms that make cancer cells less dependent on RAS signaling and therefore more resistant to Rasonque, the FDA noted.
Jefferies’ Khurshid acknowledged the possibility that the G12D group “may be somewhat better-served by G12D-specific drugs,” but pointed out that this thesis “doesn’t play out until we have availability of G12D-specific agents,” which by his estimate likely won’t be approved until 2029 the earliest.
Even so, RevMed itself is a leader in the KRAS G12D-selective inhibitor space with its zoldonrasib, Khurshid noted. RevMed recently reported an ORR of 82% for zoldonrasib combined with a modified chemotherapy regimen of FOLFIRINOX in patients with previously untreated RAS G12D pancreatic cancer from a phase 1/2 trial. In a separate phase 1 study, zoldonrasib plus Rasonque delivered an ORR of 50% in second-line patients.
RevMed is running phase 3 pancreatic cancer trials for zoldonrasib in those regimens.
“[B]ased on data so-far it doesn’t look like any of the competitor G12Ds are any better than zoldonrasib,” Khurshid said.
The FDA reviewed and approved Rasonque in an expedited timeframe under the Commissioner’s National Priority Voucher (CNPV) pilot program. In a recent interview with Fierce, the FDA’s oncology chief, Angelo de Claro, M.D., noted that the agency’s review team “recognized the importance of this application and were dedicated to completing the work.”
“In general, when topline results are received during early clinical trials, the OCE may proactively start working with a company to ensure that their application meets our review needs,” de Claro said.
Documents now published by the FDA show heavy communication between the agency and RevMed in May after the company toplined the strong phase 3 results in April. Recognizing the compressed review window under CNPV, the FDA noted the challenge with scheduling formal milestone meetings during the review and instead resorted to impromptu interactions as needed.