Adagrasib Demonstrates Significant Disease Control in KRAS G12C+ Non-Small Cell Lung Cancer

Pasi A. Jänne, MD, PhD

Adagrasib (MRTX849) demonstrated promising antitumor activity as monotherapy in patients with previously treated KRAS G12C–mutant non–small cell lung cancer (NSCLC), according to findings from the phase 1/2 KRYSTAL-1 trial.

“Adagrasib provides durable benefit to patients with non–small cell lung carcinoma harboring KRAS G12C mutations, including durable response and broad disease control that was observed,” said Pasi A. Jänne, MD, PhD, when presenting the updated data during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.

Adagrasib is a potent, covalent inhibitor of KRAS G12C, which is mutated in approximately 14% of NSCLC adenocarcinomas; the agent selectively binds to KRAS G12C in its inactive GDP-bound state in comparison with wild-type KRAS.

KRYSTAL-1 is an ongoing phase 1/2 trial exploring adagrasib in multiple cohorts of patients with KRAS G12C–mutant advanced solid tumors (NCT03785249). The study planned to enroll up to 391 patients with unresectable or metastatic disease, progression on or after treatment with a PD-1/PD-L1 inhibitor following treatment with chemotherapy—or in combination with chemotherapy for patients with NSCLC. Patients with treated and/or stable brain metastases were also eligible for enrollment.

The phase 1 dose-escalation portion of the study assessed increasing doses of adagrasib from 150 mg daily up to 600 mg twice a day, which was the dose selected for expansion. Phase 1b was a dose-expansion phase and evaluated adagrasib in several potential combination regimens in patients with NSCLC. Then the phase 2 portion of the study evaluated single-agent adagrasib in cohorts of patients with NSCLC, colorectal cancer (CRC), and other solid tumors.

Primary end points of the phase 1 portion were safety, maximum tolerated dose, pharmacokinetics (PK), and the recommended phase 2 dose; secondary outcome measures included objective response rate (ORR) by RECIST 1.1, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). In the phase 2 portion, the primary end point was ORR and the secondary was safety.

Jänne, director of the Lowe Center for Thoracic Oncology, the Belfer Center for Applied Cancer Science, and the Chen-Huang Center for EGFR Mutant Lung Cancers at Dana-Farber Cancer Institute, and professor of medicine at Harvard Medical School, presented during the meeting on results from the patients with KRAS G12C–mutant NSCLC who were treated with adagrasib monotherapy in the phase 1/1b (n = 18) and 2 (n = 61) parts of the trial.

Of all 79 patients, the median age was 65 years (range, 25-85), and 57% were female. The majority of patients were White (85%), had an ECOG performance status of 1 (78%), were current or former smokers (95%), and had nonsquamous histology (96%). The median number of prior lines of therapy was 2 (range, 1-9) and 92% had received prior anti–PD-1/PD-L1 inhibitor.

“Adagrasib exhibits favorable PK properties,” Jänne said, with average concentrations seen about 2 to 5 times above the target threshold for full dose interval, based on animal models. The agent’s half-life was about 24 hours.

Among 51 patients from the pooled dataset, the ORR was 45%, consisting of all partial responses (PRs). Another 26 patients (51%) achieved stable disease for a disease control rate of 96%. In 14 of the patients from the phase 1/1b group, the ORR was 43%, and 57% had stable disease for a disease control rate of 100%.

Jänne noted that 5 patients had had unconfirmed responses at the time of the data cutoff which have all since been confirmed.

At a median follow-up of 9.6 months, the median duration of treatment in the patients from the phase 1/1b portion was 8.2 months (range, 1.4-13.1+) with 5 of 6 responders remaining on treatment, with treatment ongoing for more than 11 months in two-thirds. The median time to response was 1.5 months.

From the pooled group of patients, the median time to response was again 1.5 months. Eighty-three percent of responders remain on the study without progression, and 65% of all 51 patients are still on treatment.

Among 110 patients with KRAS G12C–mutant NSCLC and CRC treated with adagrasib at 600 mg twice daily, treatment-related adverse events (TRAEs) were reported in 85% of the group, grade 3/4 events were seen in 30%, and 2% of events were grade 5. The most common TRAEs of any grade were nausea in 54%, diarrhea in 51%, vomiting in 35%, fatigue in 32%, and increased alanine aminotransferase (ALT) in 20%. Frequent grade 3/4 TRAEs included fatigue in 6%, increased ALT in 5%, increased aspartate aminotransferase in 5%, and QT prolongation in 3%.

The fatal TRAEs included pneumonitis in 1 patient with recurrent pneumonitis and cardiac failure. A total of 7.3% of TRAEs led to treatment discontinuation.

Exploratory Analyses and Next Steps

The study investigators considered whether adagrasib could be effective against central nervous system disease. In preclinical data, a single dose of 100 mg/kg in mice resulted in brain concentrations that exceeded the cellular IC₅₀ of adagrasib. Jänne said that this suggested that there was a high degree of brain penetration.

When tested in patients, one patient with KRAS G12C–mutant NSCLC and brain metastasis who received 600 mg twice daily of adagrasib demonstrated a PR and 67% tumor shrinkage, as well as response in a brain lesion that had not undergone radiation.

A PR observed in a patient who had a coexisting STK11 N41 mutation encouraged the investigators to explore the potential impact of common co-mutations. Patients with KRAS G12C and STK11 mutations (n = 14) had an ORR of 64% compared with 33% in those with STK11 wild-type tumors (n = 30). Four other patients with STK11 mutations achieved stable disease and only 1 had progressive disease.

In patients with KEAP1 co-mutations (n = 14), the ORR was 36% versus 48% in patients with KEAP1 wild-type tumors (n = 29). And in patients with TP53 co-mutations (n = 23), the ORR was 48% versus 38% in those with TP53 wild-type tumors (n = 24).

A combination arm of the study of adagrasib plus pembrolizumab (Keytruda) in patients with NSCLC has cleared the dose-limiting toxicities observation period and enrollment in the arm is ongoing at full dose. Additional combination arms of adagrasib with afatinib (Gilotrif), TNO155, and palbociclib (Ibrance) are also planned or enrolling.

_Reference

_{Janne PA, Rybkin II, Spira A, 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 Cancer Therapeutics; October 24-25, 2020; Virtual. Abstract 3LBA.}