KRAS G12C Inhibitor Shows Promising Effects in NSCLC, Other Solid Tumors

A pair of abstracts based on a phase 1/2 trial of adagrasib (MRTX849) a KRAS G12C inhibitor, showed promising results for patients with lung, bowel, and other solid tumors, researchers reported at the 2020 European Organisation for Research and Treatment of Cancer (EORTC), the National Cancer Institute (NCI) and the American Association for Cancer Research (AACR) Symposium on Molecular Targets and Cancer Therapeutics.¹

The phase 1/2 KRYSTAL-1 trial (NCT03785249) is determining adagrasib’s safety, tolerability, drug levels, molecular effects, and clinical activity in patients with advanced solid tumors that have a KRAS G12C mutation and have previously been treated with standard measures, including chemotherapy and immunotherapy. Adagrasib works by selectively binding to KRAS p.G12C in its inactive state, which stops it from sending cell-growth signals and leads to cancer cell death. In the KRYSTAL-1 trial, patients received 600 mg of adagrasib twice daily.

Although KRAS is the most commonly altered oncogene in human cancers, no KRAS inhibitors were given FDA approval for clinical trials until 2018. Adagrasib was one of a group of KRAS inhibitors green lit for clinical trials starting in January 2019.

One abstract presented at the symposium focused on the drug’s impact on patients with non-small cell lung cancer (NSCLC). Of the 51 evaluable NSCLC patients in the trial (14 from phase 1/1b and 37 from phase 2), 45% had an objective response, defined as tumors shrinking by 30% or more and not growing or spreading.² The trial also saw partial or complete response or stable disease in 96% of NSCLC patients.

“KRAS p.G12C patients are a population where there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, the treatment options are limited,” lead author and presenter Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, and professor of medicine at Harvard Medical School, said during the symposium. “The fact we are seeing responses in 45% of patients, which indicates that adagrasib may be an effective therapy, is incredibly meaningful as it opens up the possibility of a new treatment option for this subset of lung cancer patients.”

There were 14 patients in phase 1/1b of the trial who were followed for longer, with a median time frame of 9.6 months. Six, or 43%, of those patients saw an objective response and 5 of the 6 were still being treated as of the August 30 cutoff date for inclusion in the dataset analyzed for the abstract. Treatment has lasted longer than 11 months in 4 of those patients.

Another abstract examined results in 31 patients who had colorectal cancer (CRC) or other solid tumors.³ Melissa Johnson, MD, associate director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology, was lead author and presented the findings.

The CRC cohort included 18 evaluable patients, 3 (17%) of which had objective responses to the treatment, and 2 of which were still receiving adagrasib as of August 30. CRC patients had a 94% disease control rate, and 12 of those 17 patients were still being treated. Of the 18 in the CRC cohort, 10 had been on treatment for more than 4 months at the time of the analysis.

In a group of 6 patients with other solid tumors, 4 of them—one patient each with endometrial cancer, pancreatic cancer, ovarian cancer, and bile duct cancer—had partial responses. Two patients with appendiceal cancer achieved stable disease, and all 6 were still being treated at the time of the analysis.

Researchers concluded that adagrasib showed durable clinical activity in patients with previously treated NSCLC and KRAS p.G12C mutation. In pretreated patients with CRC and other solid tumors, they determined that the clinical activity was promising. The trial found that the safety profile is acceptable, with the most common adverse effects being nausea, diarrhea, vomiting, fatigue, and increased levels of an enzyme that indicates minor liver irritation.

References

1. Targeted inhibitor of mutated KRAS gene shows promise in early trial for lung, bowel, and other solid tumors. News Release. Dana-Farber Cancer Institute; October 24, 2020. Accessed October 29, 2020. https://www.newswise.com/articles/targeted-inhibitor-of-mutated-kras-gene-shows-promise-in-early-trial-for-lung-bowel-and-other-solid-tumors​

2. Jänne PA, Rybkin II, Spira AI, et al. KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Advanced/Metastatic Non–Small-Cell Lung Cancer (NSCLC) Harboring KRAS G12C Mutation. Abstract presented at: 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 24-25, 2020. Abstract 3LBA.

3. Johnson ML, Ou SH, Barve M, et al. KRYSTAL-1: Activity and Safety of Adagrasib (MRTX849) in Patients with Colorectal Cancer (CRC) and Other Solid Tumors Harboring a KRAS G12C Mutation. Abstract presented at: 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics; October 24-25, 2020. Abstract 4LBA.

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