Revolution Medicines’ recently approved drug showed a 24% overall response rate and a high rate of side effects in patients whose cancer has a G12D mutation, reinforcing Mizuho’s view that a more specific agent such as Verastem Oncology’s VS-7375 “should come first for G12D patients.”
Less than a week after detailed subgroup data from Revolution Medicines’ newly approved pancreatic cancer drug shook the biotech’s stock, Verastem Oncology has shown “robust clinical activity” in one of those very subgroups.
In the Phase 1/2 TARGET-D 101 trial, Verastem’s oral KRAS G12D–targeting inhibitor VS-7375 showed “robust clinical activity with a favorable safety and tolerability profile” across multiple dose levels and tumor types, the biotech reported Wednesday. The study, which has enrolled 295 patients, was designed to assess the safety and efficacy of VS-7375 alone and in combination for patients with advanced solid tumors harboring a KRAS G12D mutation, including pancreatic, colorectal and non-small cell lung cancers.
Half of patients, or four of eight with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received 900 mg of VS-7375 daily in the second-line setting, saw a confirmed objective response rate (ORR) after an average of 6.4 months, Verastem said. In 14 patients treated in third- and fourth-line settings, the confirmed ORR was 36%.
The pancreatic cancer data are particularly notable after the FDA released review documents last week showing that RevMed’s recently approved RAS inhibitor Rasonque was more effective in some mutation subgroups than others. While the drug reached a 33% ORR across all KRAS mutations in the Phase 3 RASolute 302 trial, the response was not equal in all patients. Half of those whose cancer possesses a G12V mutation saw a response. But the ORR in patients with a G12D mutation—who represented 43% of the trial—was 24%, and just 7% of participants with G12R mutations responded.
Verastem’s PDAC results met the expectations of Mizuho analysts, who had been looking for a confirmed ORR for VS-7375 of 35% or greater in these patients.
With Rasonque showing a confirmed ORR of just 24% in patients with KRAS G12D mutations--along with skin and gastrointestinal adverse events and required dose reductions, “this reinforces our view that an allele-specific agent should come first for G12D patients, with pan-RAS reserved for later lines or combinations,” the analysts wrote.
VS-7375 is a selective oral KRAS G12D dual ON/OFF inhibitor—meaning it is designed to bind both the active and inactive states of the mutated protein.
Across Verastem’s TARGET-D trial, 2% of patients discontinued treatment due to adverse events, with the most common treatment-related adverse events (TRAE) at a 900-mg dose being low-grade nausea, vomiting and diarrhea. Serious TRAEs occurred in 10% of patients, with 2% seeing serious GI TRAEs. There were two deaths in the modified intent-to-treat population, but both were unrelated to treatment with VS-7375, Verastem said.
With these results, Verastem will move VS-7375 into a Phase 3 trial in first-line mPDAC, the design of which the FDA has signed off on, the company said Wednesday. That trial is set to kick off by the end of this year.
Meanwhile, Verastem’s candidate also met or came close to meeting Mizuho’s expectations in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), where the analysts were hoping to see ORRs of at least 50% and 30%, respectively.
Patients with NSCLC treated in the second-line setting or later with 600 mg of VS-7375 experienced a 43% confirmed ORR. “Durable responses were observed and PFS is trending favorably,” Verastem reported. As for CRC—for which the drug was being tested in the third-line setting—900 mg of VS-7375 combined with anti-EGFR therapy led to 33% unconfirmed ORR.
KRAS G12D mutations account for just over a quarter of all KRAS mutations and are most prevalent in pancreatic and colorectal cancers at 40% and 15%, respectively, according to Verastem’s Wednesday release. There are currently no FDA-approved therapies specifically targeting this mutation in cancer.
“Patients with KRAS G12D-driven cancers deserve an effective, highly targeted therapy suitable for long-term treatment,” Michael Kauffman, president of development at Verastem, said in a prepared statement. “Today’s first multi-tumor clinical dataset for VS-7375 demonstrates compelling and robust responses across KRAS G12D-mutated cancers, marking an important development milestone and reinforcing our conviction that VS-7375 has the potential to become both a best-in-class therapy and the first therapy used for these patients.”
