Evidence Supports the Potential Use of KRAS(G12C) Inhibitor, Maybe Even in Combination

Preclinical and emerging clinical evidence support AMG 510 as a single-agent KRAS(G12C) inhibitor for patients with solid tumors that harbor a KRAS^G12C mutation, but additional preclinical evidence may also support the agent in combination, according to data described in a Nature article.

AMG 510 is reportedly the first KRAS(G12C) inhibitor to enter clinical trials; currently the investigational agent is being evaluated in a phase 1/2 clinical trial (ClinicalTrials.gov Identifier: NCT03600883) for adult patients with advanced solid tumors harboring a KRAS^G12Cmutation. KRAS^G12C is believed to be carried by approximately 13% of patient with lung adenocarcinoma, 3% with colorectal cancer, and 2% with other solid tumors.

An early readout of the phase 1 portion of the study was presented at the IASLC 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer in Barcelona, Spain, and included 23 evaluable lung cancer patients, Cancer Therapy Advisor reported. Patients who received the highest dose (960 mg) had a disease control rate of 100% and overall response rate of 54%, which included only partial responses.

As described in Nature, several preclinical experiments suggest that AMG 510 may have greater antitumor activity in combination with other therapies than used alone. For instance, when AMG 510 was combined with chemotherapeutic carboplatin, “significant inhibition” of tumor growth was seen in mouse models.

In addition, AMG 510 combined with a MEK inhibitor appeared to have a “synergistic” effect on tumor cells in vitro and to have “significantly enhanced” antitumor activity in vivo.

AMG 510 was also seen to “synergize” with anti-programmed cell death 1 (anti–PD-1) medications. Complete responses occurred in 9 of 10 mice treated with the combination. Further analysis revealed a marked increase of T-cell infiltration into the tumor when AMG 510 alone was used.

In addition, mice that were cured with the combination were rechallenged with CT-26 (KRAS^G12D) and CT-26 KRAS^G12C tumors, and none of the tumors became established, suggesting that the combination therapy may instill long-term tumor-specific T-cell responses.

Disclosure: Some of the authors disclosed financial relationships with pharmaceutical companies. For a full list of disclosures, please refer to the original study.

Reference

Canon J, Rex K, Saiki AY, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity [published online October 30, 2019]. Nature. doi: 10.1038/s41586-019-1694-1