KRAS analysis vaults Merck's flagship Keytruda back into the spotlight
The jewel in Merck’s crown — Keytruda — just got more precious.
On Thursday, the US drugmaker broke out an exploratory analysis showing the checkpoint inhibitor helped patients live longer as the first line of defense in patients with a form of non-small cell lung cancer (NSCLC) whose tumors expressed PD-L1, regardless of KRAS status.
KRAS mutations occur in roughly a fifth of patients diagnosed with non-small cell lung cancer, and data suggest that these mutations are associated with poor response to treatment, noted Jonathan Cheng, vice president of oncology clinical research at Merck Research Laboratories, in a statement.
The exploratory analysis was conducted on the KEYNOTE-042 trial, which pitted the blockbuster therapy Keytruda against chemotherapy in metastatic nonsquamous NSCLC whose tumors expressed PD-L1. Of the 1,274 patients in the trial — 301 patients had KRAS evaluable data (n=232 without any KRAS mutation; n=69 with any KRAS mutation, including n=29 with the KRAS G12C mutation).
Keytruda reduced the risk of death by 58% in patients with any KRAS mutation, and by 72% in patients with the KRAS G12C mutation, versus chemotherapy, the company said.
For decades, scientists have scratched their heads about KRAS, the notorious cancer-causing protein. “Some have described KRAS as the beating heart of cancer,” Darryl McConnell, Boehringer’s head of discovery research noted in an interview with Endpoints News earlier this year.
KRAS’ smooth terrain long eluded manipulation, largely due to the absence of a distinct pocket for a drug to latch on to. However, the process of trial and error finally yielded progress — triggering a flock of companies, including Merck, Amgen, J&J, and AstraZeneca, to engineer compounds designed to annex the oft’ mutated oncogene. Recently, Germany’s Boehringer Ingelheim entered the fold. Analysts have been intoxicated with the potential of KRAS drugs for use in cancer patients with few options at their disposal — forecasting approved drugs will reap billions in peak sales.
The first KRAS pocket established by Amgen for attack is G12C, although smaller rival Mirati is at the large drugmaker’s heels. The KRAS G12C mutation is found in roughly 14% of NSCLC patients and 5% of colorectal cancer patients. Unlike Amgen and Mirati — Boehringer’s early-stage drug is a pan-KRAS inhibitor hits SOS1 as well as G12C. SOS1 is a protein that turns KRAS from an “off” to “on” state.
Amgen’s keenly watched AMGN510 made a splash at the ASCO conference this year after a small, early study showed five out of 10 patients suffering from advanced, drug-resistant NSCLC saw a partial response to the experimental treatment, including one who went on to achieve a complete response after the data cutoff point. In September, those data were updated at the World Conference on Lung Cancer. Researchers tracked a 54% partial tumor response, and observed tumors shrinking in seven of 13 NSCLC patients.
Meanwhile, encouraging Phase I/II data emanating from Mirati’s experimental drug, MRTX849, for advanced solid tumors that harbor KRAS G12C mutations were unveiled in late October. The little biotech has tied up with Novartis — and the two are looking at combining the G12C drug with a therapy that targets SHP2, which functions as a key regulator of cell cycle control.
Revolution Medicines has the same potential combo in-house. Other KRAS contenders include Moderna and Merck’s mRNA-5671; J&J’s collaboration with Wellspring on ARS-3248, a G12C targeted small molecule; and AZD4785, licensed by AstraZeneca from Ionis — although the compound has been discontinued after a poor showing in clinical trials.
As an oncogene, KRAS has the potential to render normal cells cancerous. Akin to HRAS and NRAS, it belongs to the RAS family of oncogenes and plays a key role in cell division, cell differentiation, and apoptosis.