As companies increasingly look to combinations to boost the efficacy of KRAS therapies, a Phase 2 study is offering some of the first clinical evidence for combining KRAS and EGFR in frontline lung cancer.
On Saturday, GenFleet Therapeutics shared data from an open-label study that paired its KRAS inhibitor fulzerasib with Erbitux, an EGFR-targeting antibody from Merck KGaA and Eli Lilly. Among 33 patients evaluated at data cut-off, the investigator-assessed overall response rate was 81.8% and disease control rate reached 100% — meaning all patients experienced tumor shrinkage. In a subgroup of patients with brain metastases, the overall response rate was 70%.
Vanesa Gregorc“This is in line with what we usually see for targeted agents when they work really well,” Vanesa Gregorc, principal investigator, told Endpoints News ahead of her presentation at the American Society of Clinical Oncology conference in Chicago.
Fulzerasib is on track to become the first KRAS inhibitor to win approval in China, GenFleet Chief Business Officer John Chen said in an interview, and the company hopes the new results can open the door to Phase 3 development in the US and Europe.
Whereas non-small cell lung cancer patients who test positive for mutations in EGFR or ALK could receive targeted therapies as their first option, patients with KRAS-mutated tumors don’t yet have that choice. Amgen’s Lumakras and Bristol Myers Squibb’s Krazati are only approved to treat patients who have already received at least one prior treatment, although both are seeking to move to earlier settings.
By leaving immunotherapy and chemotherapy — mainstays in current frontline treatment — out of the picture, GenFleet emphasized that fulzerasib and Erbitux could be a more tolerable regimen. In the study, 17.5% of patients experienced grade 3 or above treatment-related adverse events, and three discontinued permanently due to reactions to Erbitux.
Over the past few years, clinical trials in colorectal cancer have shown that combining Lumakras and Krazati with EGFR drugs such as Erbitux or Vectibix improved efficacy. Testing the same approach in lung cancer is the next step in rethinking the relationship between those types of treatments, Gregorc said.
“The historical paradigm was, if you have a KRAS-mutant patient, you don’t use EGFR drugs,” said Gregorc, an oncologist at the San Raffaele Research Hospital in Milan, who’s also worked on Lumakras and Krazati trials.
Durability will be a key question for future drugs, she said. In GenFleet’s trial, which was based in Europe, 88% of patients were still on treatment with a median follow-up of 5.1 months. As other companies also explore the KRAS/EGFR combo in lung cancer, the side effect profile could become the key metric to watch, she added.
GenFleet is partnered with Innovent in China, where fulzerasib is under regulatory review for second-line NSCLC and could become the first KRAS G12C inhibitor on the market. Instead of trying to compete directly with Amgen and Mirati globally, it’s looking to go straight to first-line with its global Phase 3 lung cancer study in 2025. It’s also aiming to start a registrational trial with the KRAS/EGFR combo in colorectal cancer.