1. Froelich, Warren

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An investigational drug that targets a mutant form of the KRAS gene, the most commonly mutated gene in cancer and previously considered "undruggable," shrank a variety of lung, colorectal, and other solid tumors with manageable side effects, according to findings from a new patient study.

Mutated KRAS Gene. M... - Click to enlarge in new windowMutated KRAS Gene. Mutated KRAS Gene

The drug known as adagrasib (MRTX849) was designed to zero in on the activity of the KRAS G12C mutation, generally associated with a poor prognosis and lack of response to standard treatments.


"KRAS G12C patients are a population for which there are no proven targeted therapies," said Pasi A. Janne, MD, PhD, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, who presented some of the results at the 2020 EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Symposium, held online October 24-25, 2020.


"Once chemotherapy or immune therapy fails in a patient, treatment options are limited."


KRAS mutations drive some of the most common and deadly carcinomas, including lung, colorectal, and pancreatic tumors, with KRAS G12C mutations accounting for some 44 percent of all KRAS mutations.


This mutation is particularly prevalent in non-small cell lung cancer (NSCLC), occurring in about 14 percent of lung adenocarcinomas-the most common subtype of NSCLC. Aside from lung cancer, the mutation occurs in 3-4 percent of colorectal and 2 percent of pancreatic cancer patients.


Study Details

In the KRYSTAL-1 Phase I/II multi-institutional trial that tested adagrasib, Janne and colleagues reported that, of 51 patients with NSCLC, some 45 percent had an objective response to the agent, meaning their tumors shrank by more than 30 percent or more and did not grow or spread to other parts of the body. The disease control rate was 96 percent, meaning that 49 of the patients had a partial or complete response or stable disease.


Among 14 patients in a Phase I/Ib cohort who had been followed for a longer time period (median time of 9.6 months), an objective response was seen in six (43%). Five of these six patients were still ongoing therapy as of the cutoff date, with four of these six patients receiving the agent for more than 11 months.


"The fact that we are seeing responses in 45 percent of patients with adagrasib is incredibly meaningful as it opens up the possibility of a new treatment option for this subset of lung cancer patients," noted Janne, who is also Professor of Medicine at Harvard Medical School and the Scientific Director of the Belfer Center for Applied Cancer Science at the Dana-Farber Cancer Center.


For decades, scientists have recognized the role that KRAS mutations play in cancer, though many have struggled to find surface targets on the protein that would disrupt its promotion of unchecked cell growth. Indeed, a long history of unsuccessful efforts to target KRAS mutations led many to believe they were simply "undruggable."


But recent computational and molecular studies have revealed a narrow pocket in KRAS G12C that might be vulnerable to attack, resulting in the design of small molecules potentially able to intercept its cancer-causing activity. Adagrasib, one of these agents, irreversibly and selectively binds to, and locks onto, the KRAS G12C pocket in its inactive state, stopping it from sending cell growth signals, leading to cancer cell death.


Until recently, no KRAS inhibitor had moved beyond preclinical testing. But in 2018, adagrasib was among several KRAS inhibitors approved by the FDA for study in clinical trials. Beginning in January 2019, the KRYSTAL-1 Phase I/II clinical trial was launched to study safety, pharmacokinetics, as well as clinical activity and efficacy of the agent in patients with advanced or metastatic solid tumors harboring a KRAS G12C mutation.


Abstract Findings

As outlined in an abstract presented at the symposium, all patients enrolled in the KRYSTAL-1 trial were previously treated with chemotherapy and immunotherapy. Each was given 600 mg twice daily of adagrasib, with a median treatment time of 8.2 months (range 1.4-13.1).


Treatment-related adverse side effects in 79 patients who participated in the Phase I/Ib (18) and II (61) parts of the trial were analyzed. Women comprised 57 percent of the trial with a median age of 65 years. The most commonly reported side effects (greater than 20%) included nausea (54%), diarrhea (51%), vomiting (35%), fatigue (32%), and increased levels of an enzyme alanine aminotransferase, an indicator of minor liver irritation (20%).


Another team of researchers revealed findings of adagrasib's activity against colorectal and other solid tumors from the clinical trial. Melissa Johnson, MD, Associate Director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute in Nashville, Tenn., and partner with Tennessee Oncology in Chattanooga, presented the results.


In brief, the cohort included 18 out of 31 participants with colorectal cancer who could be evaluated. Three (17%) experienced confirmed objective responses to the treatment, with two still receiving treatment as of August 30, 2020. Disease control was seen in 17 of the 18 colorectal cancer patients (94%), with 12 of those 17 patients still being treated at time of analysis, including 10 for more than 4 months.


In a group of six patients with other solid tumors, four 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; all six were still being treated at the time of analysis.


The most common treatment-related adverse events included diarrhea (58%), nausea (52%), fatigue (42%), and vomiting (36%).


According to a press release, researchers are considering future trials that would combine adagrasib with other targeted therapies, such as pembrolizumab for NSCLC; cetuximab for colon cancer; investigational SHP-2 inhibitor, TNO-155, in either NSCLC or colon cancer; and afatinib for NSCLC.


Warren Froelich is a contributing writer.