MADRID—A flurry of companies are mining the KRAS G12C pathway to try and find the best tunnel to success in a type of cancer that was once thought undruggable. But challenges abound—liver toxicity, dosing limitations and relapse.
A program from Merck & Co., known as MSD here, is early days, but initial pharmacokinetic data from the KRAS G12C inhibitor MK-1084 presented at the European Society for Medical Oncology suggest the company may be able to find a way around some of the hard places that have troubled earlier entrants to the space.
Those entrants, of course, are Mirati Therapeutics—recently acquired by Bristol Myers Squibb, upping the ante—and Amgen, which has run into trouble with a post-marketing study for Lumakras, the first KRAS inhibitor to hit the market.
“It used to be a target that was considered undruggable,” Jane Healy, M.D., Ph.D., Merck’s VP for early drug development, told Fierce Biotech on the sidelines of ESMO.
That’s no longer true, but as Lumakras and Mirati’s Krazati have hit the market, their utility has been more limited than expected.
Revealed at ESMO, MK-1084 alone posted an objective response rate (ORR) of 22% across all doses and tumor types during dose escalation after a median follow-up time of 8.1 months. These patients could have any previous type of therapy with a solid tumor and a confirmed G12C mutation. There were no deaths or grade 5 treatment-related adverse events reported.
In the combination arm with Merck’s own Keytruda, patients with previously untreated metastatic non-small cell lung cancer (NSCLC) saw what Healy described as a “quite dramatic” ORR of 71% with a median follow-up of 5.2 months. This was “pretty nice data,” according to Healy.
Initial data show the potential for a lower clinical dose and better schedule, she explained. That could mean less potential for drug-drug interactions in the real world and, most importantly, a lower likelihood of liver injury.
“It's very important, not only for allowing the patients to stay on treatment as long as they can to get the best efficacy benefit, but certainly, to prevent toxicity and side effects,” Healy said.
Another challenge with the KRAS pathway is that it’s one of many that are affected with this type of cancer, so the disease can build up resistance easily to small molecule inhibitors. Merck believes that the data so far tell them that the safety profile should allow for better use in combinations.
“Giving combinations either with things in the pathway or orthogonal mechanisms that work differently and hit something else in the cancer can really help address those forms of resistance and get more benefit to patients early on,” Healy said. “That's why we're super laser-focused on getting a good safety profile for this molecule.”
The next steps for Merck include getting more data on specific tumor types, but Healy is happy with the 71% ORR in the combo arm.
“If the drug particularly is well-tolerated and doesn't have a lot of toxicity [or] side effects that could overlap with those other agents, we will have more freedom to have those combinations and make sure that we're getting effective doses of both therapies in those combinations,” Healy said.
But Merck has fellow Big Pharmas also challenging in KRAS cancers. Many are much further along in the clinic with human data already out.
Roche, for example, published phase 1 data this summer linking divarasib to an improved response rate and durability over Amgen and Mirati’s rival therapies. Meanwhile, Lilly displayed data in the spring at the American Association for Cancer Research meeting matching LY3537982 with existing therapies but with a potentially improved safety profile. Behind them, smaller biotechs like Frontier Medicines and Quanta Therapeutics are also working on KRAS therapies.
To read more of Fierce Biotech's coverage of the ESMO Congress, click here. Fierce Pharma's coverage is available here.