Adagrasib Shows Early Activity in KRAS G12C+ NSCLC, CRC, and Other Solid Tumors

Pasi A. Jänne, MD, PhD

Adagrasib (MRTX849), a potent and selective inhibitor of KRAS G12C, showcased encouraging clinical activity with an acceptable safety profile in patients with KRAS G12C–positive non–small cell lung cancer (NSCLC), colorectal cancer (CRC), and other solid tumors, according to results from the phase 1/2 KRYSTAL-1 trial (NCT03785249) presented during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics.^1,2

Results showed that adagrasib elicited an objective response rate of 45% in 51 patients with pretreated NSCLC. Five patients who reported an unconfirmed partial response (PR) are still receiving treatment. Moreover, the disease control rate reported with the agent was 96%.¹

Additionally, among 14 evaluable patients in the phase 1/2b cohort who had longer-term follow-up of a median of 9.6 months, the objective response rate (ORR) reported with adagrasib was 43% (n = 6/14), with most patients (n = 5/6) still receiving treatment at the time of data cutoff. Four of the 6 patients reported a duration of treatment of longer than 11 months although the median time on treatment was 8.2 months.

“[Patients with] KRAS G12C [mutations] are a population for which there are no proven targeted therapies,” Pasi A. Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute, stated in a press release.³ “Once chemotherapy or immune therapy fails in a patient, treatment options are limited. 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 [patients with] lung cancer.”

Another abstract from the trial presented during the meeting showed that among 18 patients with KRAS G12C–positive CRC, 17% (n = 3/18) experienced a confirmed objective response; 2 of the 3 patients remained on treatment at the time of data cutoff.² Additionally, among 6 patients with other solid tumors, confirmed PRs were reported in 1 patient with endometrial cancer, 1 with pancreatic cancer, 1 with ovarian cancer, and 1 with cholangiocarcinoma.

In the study, investigators set out to examine the safety, tolerability, drug levels, molecular effects, and clinical activity of adagrasib in patients with advanced solid tumors that harbored a KRAS G12C mutation who received prior treatment with chemotherapy and anti–PD-1/PD-L1 therapy.⁴

To be eligible for participation, patients had to have a histologically confirmed diagnosis of a solid tumor malignancy and a KRAS G12C mutation, unresectable or metastatic disease, and adequate organ function. If they had a history of intestinal disease, underwent major gastric surgery, was unable to swallow oral therapies, or had another active cancer, they were not permitted for inclusion.⁴

Patients enrolled to the trial received adagrasib at a dose of 600 mg twice daily. The primary end points of the trial included safety, pharmacokinetics, and clinical activity of the agent. Moreover, exploratory objectives comprised examination of pharmacodynamic biomarkers and correlation of molecular markers with antitumor activity.

The median age of participants in the NSCLC subgroup (n = 79) was 65 years and 57% were female. Twenty-two percent of participants had an ECOG performance status of 0, while 78% had a status of 1.

The median age was 63 years for the 31 patients included in the preliminary safety data analysis who had CRC in the phase 1/1b cohort (n = 2) and the phase 2 cohort (n = 22), or other solid tumors in the phase 2 cohort (n = 7). Forty-five percent of these patients were female. Additionally, 29% and 71% had an ECOG performance status of 0 or 1, respectively.

The treatment-related adverse effects in 110 patients who participated in the phase 1/1b and 2 portions of the trial, including those with CRC and other solid tumors, as well as those with NSCLC. Toxicities included nausea (54%), diarrhea (51%), vomiting (35%), fatigue (32%), and increased levels of an enzyme indicative of minor liver irritation (20%). The only serious AE to be observed in more than 1 patient was low sodium in the blood; this was reported in 2 patients.

Adagrasib will also be examined in combination with other novel agents, including pembrolizumab (Keytruda) in NSCLC, cetuximab (Erbitux) in colon cancer, the investigational SHP-2 inhibitor TNO-155 in NSCLC or colon cancer, and afatinib (Gilotrif) in NSCLC.

References

1. 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. Presented at: 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics; October 24-25, 2020; Virtual. Abstract LBA-03. https://bit.ly/37FGYJT.
2. Johnson ML, Ou SHI, Rybkin II, 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: 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Therapeutics; October 24-25, 2020; Virtual. Abstract LBA-04. https://bit.ly/3mmx8kb.
3. 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 25, 2020. Accessed October 26, 2020. https://bit.ly/2TFqut7.
4. Phase 1/2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. ClinicalTrials.gov. Updated October 8, 2020. Accessed October 25, 2020. https://clinicaltrials.gov/ct2/show/NCT03785249.