Adagrasib Shows Promise in Phase 1/2 Trial for KRAS G12C Mutated NSCLC, CRC, and Other Solid Tumors

Adagrasib (MRTX849) demonstrated an acceptable safety profile and promising clinical activity in pretreated patients with non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors with a KRAS G12C mutation, according to results from the multi-cohort phase 1/2 KRYSTAL-1 study presented at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics.¹

Adagrasib works by irreversibly and selectively binding to the KRAS G12C mutation in its inactive state, blocking its ability to send cell-growth signals and leading to cancer cell death. The mutation occurs in approximately 14% of lung adenocarcinomas, the most common subtype of NSCLC, 3% to 4% of colorectal cancers, and 2% of pancreatic cancers, which translates into more than 100,000 people each year worldwide.

In this study, adagrasib was evaluated in patients with advanced or metastatic solid tumors harboring a KRAS G12C mutation previously treated with chemotherapy and anti-PD-1/PD-L1 therapy. In dose expansion, a dose of 600 mg twice daily was assessed and established as the recommended phase 2 dose.

The primary end points of the study include safety, pharmacokinetics, clinical activity, and efficacy. Exploratory objectives include evaluation of pharmacodynamic biomarkers and correlation of molecular markers with antitumor activity.

Regarding patients with NSCLC, as of August 30, 2020, 79 patients (57% female; median age, 65 years [range, 25-85]; 22%/78% ECOG PS 0/1) with pretreated NSCLC were treated with 600 mg of adagrasib twice daily in phase 1/1b (n = 18) or a phase 2 (n = 61) cohort.² Among 51 patients evaluable for clinical activity (14 from phase 1/1b and 37 from phase 2), 45% of patients had an objective response; this included 5 patients who had an unconfirmed partial response (PR) and remain on treatment. The disease control rate was 96%.

Among the 14 patients evaluable for clinical activity from phase 1/1b with longer follow-up, the confirmed objective response rate (ORR) was 43% and the majority of patients with responses (4/6) have had treatment ongoing for over 11 months. The median time on treatment was 8.2 months (range, 1.4-13.1+).

The most commonly reported (>20%) treatment-related adverse events (TRAEs) in patients with NSCLC included nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased alanine aminotransferase (ALT; 23%). Moreover, the only commonly reported (>2%) grade 3 or 4 serious TRAE was hyponatremia (3%).

“KRAS G12C patients are a population for which there are no proven targeted therapies. Once chemotherapy or immune therapy fails in a patient, treatment options are limited,” Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana Farber Cancer Institute, said in a press release. “The fact that we are seeing responses in 45% 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.”

As of the same data cutoff date, preliminary safety data are available for 31 patients treated with 600 mg of adagrasib twice weekly in phase 1/1b (CRC, n = 2) and select phase 2 cohorts (CRC, n = 22; other solid tumors, n = 7).³ For all 31 patients, baseline characteristics included median age of 63 years (range, 25-80), 45% female, and 29%/71% with ECOG PS of 0/1, respectively.

Of the evaluable patients with CRC, 17% (3/18) had a confirmed objective response and 2 of the 3 patients remain on treatment. Disease control was also observed in 94% (17/18) of patients and 12 of the 18 patients remain on treatment.

Moreover, 6 patients in the other solid tumor cohort were evaluable for clinical activity. Confirmed PRs were observed in 1 patient with endometrial cancer and 1 patient with pancreatic cancer; unconfirmed PRs were also observed in 1 patient with ovarian cancer and 1 with cholangiocarcinoma. Further, 2 patients with appendiceal cancer who were treated achieved stable disease. All 6 of these patients remain on treatment.

Regarding safety, the most commonly reported (>20%) TRAEs in patients with CRC or other solid tumors included diarrhea (58%), nausea (52%), fatigue (42%), and vomiting (36%).

Of note, researchers are also looking at combining adagrasib with other targeted therapies moving forward, such as pembrolizumab (Keytruda) for NSCLC, cetuximab (Erbitux) for CRC, the investigational SHP-2 inhibitor TNO-155 in either NCSLC or CRC, and afatinib for NSCLC.

References:

1. Targeted inhibitor of mutated KRAS gene shows promise in early trial for lung, bowel, and other solid tumors [news release]. Published October 24, 2020. Accessed November 19, 2020. https://www.newswise.com/articles/targeted-inhibitor-of-mutated-kras-gene-shows-promise-in-early-trial-for-lung-bowel-and-other-solid-tumors?sc=sphr&xy=10021790

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

3. Johnson ML, Ou SHI, 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. Presented at the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics. Abstract #: 4LBA.