Amgen’s KRAS G12C Inhibitor Impresses in Phase 2 NSCLC Trial
By Ruchi Jhonsa, Ph.D.
After successfully clearing the Phase 1 trial, Amgen had evaluated its KRAS G12C inhibitor, Sotorasib (AMG510) in Phase 2, NSCLC trial, CodeBreak100. On 5th October, the company announced topline data from the study, which is claimed to be more or less consistent with Phase 1 data. However, the actual data values are yet to be revealed.
KRAS-Mutant Lung Cancers
Lung cancer is the most common form of cancer and the leading cause of cancer-related deaths worldwide. Through years of research, mutations driving lung cancer have been identified. While these mutations lie in several genetic loci, the most commonly found is in the KRAS gene- a locus that produces protein primarily involved in controlling cell division. Approximately 13% of Americans with NSCLC have the KRAS G12C mutation with an amino acid change in the 12th position.
While considerable progress has been made in the lung cancer treatments mainly for targeted therapies against oncogenic drivers, such as EGFR, HER2, EML4-ALK, MET, ROS1, and BRAF mutations, the treatment options are limited for KRAS-mutant lung cancer, and chemotherapy remains the first-line recommendation. This is mostly due to the difficulties faced in finding surface targets on the protein where drugs could bind or find an inhibitor that could specifically target mutant KRAS protein.
The quest for finding a suitable therapy for KRAS mutant cancers has been going on for over three decades. However, with new advances in drug development and novel mechanistic and structural insights about KRAS protein, new therapies are coming into the scene. One of the important structural insights was discovering a hidden groove on the mutant KRAS protein where inhibitors could bind and lock the protein in the inactive state, blocking oncogenic signaling without affecting the normal function of unmutated KRAS protein. Using this knowledge, Amgen developed sotorasib, a KRAS protein inhibitor that traps the mutated KRAS protein in its inactive form and prevents cell multiplication and cancer growth.
In the Phase 2 trial, the drug showed an objective response rate consistent with Phase 1. The company also reported that the time for which the tumor continued to respond to treatment, also called Duration of response, is promising, and more than half of the responders continued treatment until the data cutoff date. The drug remained safe and tolerable throughout the trial. Details from the trials will be discussed at the IASLC 2020 World Congress on Lung Cancer in January next year.
“Targeting KRAS has been a 40-year quest that has left patients with limited options. These topline data underscore our belief in the potential for sotorasib to become the standard of care for non-small cell lung cancer patients with the KRAS G12C mutation who remain in need of new treatment options,” said David M. Reese, M.D., Executive Vice President of R&D.
Competitor Next Door
While Amgen is ready to evaluate Sotorasib’s superiority over chemotherapy in Phase 3, it faces competition from AstraZeneca, Mirati Therapeutics, and Gilead Sciences. While Astra’s drug flopped in the Phase 1 trial mostly owing to its non-specific targeting towards all KRAS proteins (mutant and non-mutant), Gilead has no data so far, leaving Mirati’s drug as the only real competitor against Amgen.
Mirati’s KRAS targeted drug, MRTX1257, works using the same mechanism as Amgen’s and has shown a similar response to sotorasib in the initial Phase 1 data. Of the six NSCLC patients, three had partial responses, resulting in a response rate in line with that achieved by Amgen in the indication. However, with data from only a small patient population, it is too early to jump to conclusions.
While it remains to be seen whether KRAS’s direct inhibition with these new compounds is effective, concurrent inhibition of genes essential for cancer survival may be required to potentiate effectiveness. In that vein, Mirati entered a collaboration with Novartis in July 2019 to determine whether the addition of the SHP2 inhibitor TNO155 can lead to prolonged responses. The idea being that the SHP2 inhibitor would prevent the conversion of KRAS protein in the active state, and the KRAS G12C inhibitor would trap the KRAS in an inactive state. The exploitation of this collateral dependency could enhance the effect of KRAS directed therapies.
So far, Amgen is the only one leading the race in the KRAS arena, and if found potent in the Phase 3 trial, it could expect a big profit out of it considering the number of people who have KRAS-mutant cancers. The company also holds a lot of faith in the drug and hopes to see some good news in the coming years.
“We now have more than 500 patients who have been enrolled across clinical studies, and we are rapidly moving forward with a broad-based development program, which includes monotherapy studies in non-small cell lung cancer, colorectal cancer, and other solid tumors harboring the KRAS G12C mutation, as well as a suite of combination studies,” said David M. Reese.
Editor: Rajaneesh K. Gopinath, Ph.D.
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