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Pictured: Roche building in Pleasanton/iStock, JHVEPhoto Roche’s Genentech on Thursday released early-stage data on its KRAS inhibitor, divarasib, as it hopes to join Amgen and Mirati in the potential blockbuster cancer market. Phase I study results published in The New England Journal of Medicine showed divarasib as an oral monotherapy with durable response in patients with non-small cell lung cancer (NSCLC). Of the 60 NSCLC patients treated, over 53% had a confirmed response with a median progression-free survival (PFS) of 13.7 months. Response rate and PFS were slightly higher in the highest dose group, which is the dosing that will be used in future trials. In the 55 colorectal cancer patients treated, 29.1% achieved a confirmed response with a median PFS of 5.6 months. Partial response was also observed in 36% patients with other solid tumor types. Divarasib is a covalent KRAS G12C inhibitor. This class of drug is designed to bind to the P2 pocket of the cancer protein, trapping it in a state of inactivity. Amgen was the first to get a KRAS inhibitor approved by the FDA in late May 2021. Lumakras (sotorasib) was greenlighted under the FDA’s accelerated approval program as a second line treatment for patients with locally advanced or metastatic NSCLC. In a Phase II study, patients on Lumakras saw a confirmed objective response rate (ORR) of 36% with a median PFS of 6.8 months. About 18 months later, the FDA approved Mirati Therapeutics’ Krazati (adagrasib) for NSCLC with the G12C mutation in the KRAS gene. Krazati’s Phase II data was a little stronger than Lumakras with a 43% ORR and median PFS of 8.5 months. While Roche’s Phase I data appear to be potentially stronger than the competition, the trial size was smaller and racial diversity limited. In addition, responses were assessed by investigators as opposed to blinded independent review, so superiority conclusions are as of now premature. “[Divarasib] appears to show numerically more responses and longer progression-free survival among patients with either NSCLC or colorectal cancer than those observed with existing single-agent KRAS G12C inhibitors; however, conclusions drawn from cross-trial comparisons must be interpreted cautiously,” the study authors wrote. In the Genentech-funded study, 93% of patients experienced treatment-related adverse events. Four patients discontinued treatment and 19 patients had their dosage reduced. Common side effects included nausea, diarrhea and vomiting. The safety pro to be similar to that of Krazati and Lumakras. “It will be important to evaluate divarasib in larger randomized trials, as well as to evaluate it in combination with other promising agents,” Adrian Sacher, a principal author of the study told Healio News. “These studies are ongoing, and we look forward to their results.” Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.

Skepticism around Krazati and the long-term value of the KRAS inhibitor class has increased in the past few months. After overseeing the approval of KRAS inhibitor Krazati, Mirati Therapeutics CEO David Meek is stepping down from the company, effective immediately. Mirati unveiled the change in leadership Tuesday with its financial results for the second quarter, during which Krazati brought in $13.4 million in sales, coming in above Wall Street’s expectations. Meek’s departure has disrupted plans for Mirati’s founder and president, Charles Baum, M.D., Ph.D., who had planned to retire by the end of June. Now Baum, who handed the reins to Meek just two years ago, will reassume the top job on an interim basis while Mirati searches for a permanent replacement.  Meek was credited for bringing Krazati across the FDA finish line in a rivalry with Amgen’s first-to-market KRAS inhibitor Lumakras. But in a fresh setback for the Mirati drug, reviewers at the European Medicines Agency recently declined to back Krazati, arguing that its data don’t fulfill certain requirements for a conditional nod. Skepticism around Krazati and the long-term value of KRAS inhibitors has grown during the past few months. And Meek’s sudden exit won’t exactly restore confidence, especially as Mirati prepares to start a new phase 3 trial. Also Tuesday, Mirati said it plans to launch a phase 3 trial to test the combination of Krazati and Keytruda in newly diagnosed KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients whose tumors have high PD-L1 expression of at least 50% on the tumor proportion score (TPS). During an investor call Tuesday, Guggenheim analyst Michael Schmidt said the planned phase 3 “makes a lot of sense to us.” The decision is based on interim phase 2 results from the KRYSTAL-7 trial. Back in December, an early tumor shrinkage readout from the trial in an inclusive first-line KRAS-mutant NSCLC group disappointed investors. In an updated analysis of PD-L1-high patients unveiled Tuesday, Mirati said Krazati and Keytruda showed a confirmed overall response rate of 63%, which the company said is “meaningfully higher” than the 39% to 45% range historically observed with Keytruda as a monotherapy. The new number was slightly better than the 59% rate that Mirati shared from the subgroup in December, but this time it’s in a larger group of patients and over a longer time of follow-up.  The Krazati-Keytruda pairing has yet to reach its median progression-free survival mark in KRYSTAL-7. But the regimen’s performance there is also tracking above Keytruda monotherapy’s historical data, according to Mirati.  The new analysis cut the data by February, and Mirati will consider another data analysis—and a possible submission for a medical meeting—later this year, Mirati’s chief medical officer Alan Sandler, M.D., said on the call. Liver toxicity—a major problem for Amgen’s proposed Lumakras-Keytruda combo—remained relatively mild for the Mirati regimen. The updated KRYSTAL-7 trial recorded grade 3 ALT and AST liver enzyme elevations in 10% and 14% patients, respectively, with no grade 4 cases or above. Increased levels of these two liver enzymes may suggest liver damage. Armed with the new results, Mirati said it plans to launch the phase 3 trial by year-end. The study will focus on KRAS G12C-mutant NSCLC patients with high PD-L1 expressions, and it will use Keytruda monotherapy as the control arm. Mirati is still finalizing the detailed trial design, including size, with the FDA, but the company said it expects to use progression-free survival as the primary endpoint and enroll around 500 patients. The company was quick to point out that this is a blockbuster indication in the U.S. and Europe, with more than 30,000 first-line patients. Guggenheim’s Schmidt also raised the possibility of an accelerated approval through the FDA’s Project FrontRunner, which allows for early approvals based on surrogate endpoints from an ongoing, randomized phase 3 trial.  Sandler said Mirati will go for the traditional regulatory pathway. Project FrontRunner comes with a high bar, he said, and “there’s a certain time commitment that is involved in a study and increased complexity when conducting a study in that manner.” The new clinical trial also contradicts Mirati’s original plan, unveiled in December, to first study the Krazati-Keytruda combo in PD-L1-low patients. In KRYSTAL-7, Krazati and Keytruda showed some clinical activity in patients with TPS below 50%, the company said. But existing data suggest the doublet approach isn’t enough to beat the standard treatment of Keytruda and chemo, according to the company. Meanwhile, Mirati has launched another phase 2 trial coded KRYSTAL-17, which adds Krazati to both Keytruda and chemo. Pending the readout, the company plans to decide on what to do with the lower TPS indication in the first half of 2024. This subgroup represents about 60% of all KRAS G12C patients. Editor's Note: The story has been updated with additional information from Mirati's second-quarter earnings call Tuesday afternoon.