Adagrasib Demonstrates Favorable Efficacy, Pharmacokinetic Profile in Advanced KRAS G12C+ NSCLC

Gregory J. Riely, MD, PhD

Adagrasib (MRTX849) yielded durable responses and broad disease control, in addition to providing extensive predicted coverage throughout the dosing interval, in patients with KRAS G12C–mutant advanced non–small cell lung cancer, according to updated findings of the phase 1/1b/2 KRYSTAL-1 study that were presented during the 2021 European Lung Cancer Conference.

Data showed that the 600-mg twice-daily dose of adagrasib, a selective inhibitor of KRAS G12C, yielded an overall response rate (ORR) of 43% and 45% in the phase 1/1b (n = 14) and phase 1/1b and 2 cohorts (n = 51) of the trial, respectively. These were comprised of all partial responses.

The disease control rate was 100% in the phase 1/1b population and 96% in the phase 1/1b and 2 cohort. In total, 57% and 51% of patients, respectively, had stable disease. Disease progression did not occur in the phase 1/1b cohort and occurred in 2% of those in the phase 1/1b and 2 pooled cohort.

Pharmacokinetic (PK) data indicated that adagrasib yielded a Cave of 2.63 µg/mL, which is 2- to 5-fold above the target threshold for the full dosing interval. Moreover, investigators found that the Cave PK parameter was best matched to nonclinical antitumor activity. Additionally, the extensive volume of distribution was predicted based on nonclinical studies.

“The observed steady-state concentration was above the target threshold for the full dosing interval,” lead study author Gregory J. Riely, MD, PhD, vice chair of Clinical Research, Department of Medicine at Memorial Sloan Kettering Cancer Center, said in a virtual presentation during the meeting. “We also observed low peak to trough ratio at 1.27 and a half-life of 24 hours.”

Adagrasib is a covalent inhibitor of KRAS G12C that irreversibly and selectively binds KRAS G12C in its inactive GDP-bound state, according to Riely. The agent has been optimized for desired properties, demonstrating high selectivity for KRAS G12C mutations over wild-type and favorable PK properties, including oral bioavailability, a half-life of approximately 24 hours, and extensive tissue distribution.

By maintaining a continuous exposure to adagrasib above the target threshold, investigators theorized that inhibition of KRAS-dependent signaling will be enabled for the complete dosing interval, which could maximize depth and duration of the agent’s antitumor activity.

“KRAS G12C mutations act as an oncogenic driver and occur in approximately 14% of patients with NSCLC,” according to Riely. “The KRAS protein cycles between GTP-on and GDP-off states and has a protein resynthesis of approximately 24 hours.”

To be eligible for enrollment, patients had to have KRAS G12C–mutant unresectable or metastatic NSCLC following progression on or after treatment with a PD-1/PD-L1 inhibitor in combination with or following chemotherapy. Those with treated and/or stable brain metastases were permitted.

In the phase 1, dose-escalation portion of the trial, investigators examined various once-daily doses of adagrasib: 150 mg, 300 mg, 600 mg, 1200 mg, as well as 600 mg given twice daily. The 600-mg, twice-daily dose moved to the expansion phase and became the recommended phase 2 dose.

The phase 1b section looked at adagrasib alone, as well as in combination with pembrolizumab (Keytruda), afatinib (Gilotrif), and cetuximab (Erbitux). The phase 2 portion looked at adagrasib alone in patients with NSCLC (n = 61), colorectal cancer, and other solid tumors.

The primary end points of the phase 1b study consisted of safety, maximum-tolerated dose, PK, and the recommended phase 2 dose, as well as ORR in the phase 2 portion.

Secondary end points in the phase 1b portion included ORR, duration of response, progression-free survival, and overall survival. Secondary outcome measures in the phase 2 portion included safety. The data cutoff date was August 30, 2020.

The majority of patients enrolled were women (61% in phase 1/1b (n = 18) and 57% in phase 1/1b and 2 (n = 79). Patients in the phase 1/1b portion were mostly White (83%) as well as in the phase 1/1b and phase 2 portion (85%). The majority of patients across all phases were current or former smokers (89% and 95%, respectively) and had nonsquamous histology (100% and 96%). Patients had an average of 3 (range, 1-9) and 2 (range, 1-9) prior lines of therapy, respectively, and the majority of patients had previously received a PD-1/PD-L1 inhibitor (89% and 92%).

Additionally, investigators launched a mechanistic biomarker analysis on 3 patients who had biopsies taken on day 8 of cycle 1, which were compared with pretreatment biopsies.

Additional clinical findings indicated the 600-mg, twice-daily dose of adagrasib in the phase 1/1b portion had a clinical benefit rate of 96%. After a median follow-up of 9.6 months, 5 of 6 responders remain on treatment, which has been ongoing for more than 11 months in most patients who responded to treatment (n = 4/6). The median time to response was 1.5 months, and the median duration of treatment was 8.2 months (range, 1.4 to 13.1+).

“We see some clear evidence that we’re inhibiting KRAS signaling. The gene set enrichment analysis [identified] downregulation of KRAS signaling and downregulation of MYC, E2F, G2M, and MTORC1,” Riely explained. “This is a relatively small number of patients, so there is some variability. We’re seeing a trend, but it’s hard to determine significance based on this small number of samples. [In the] KRAS signaling subset, you see that there is a relatively uniform reduction in DUSP6 and SPRY4, though not perfect in this small sample.”

Investigators also conducted a preliminary analysis examining co-mutations with KRAS G12C. Baseline next-generation sequencing reports were reviewed in order to conduct the analysis for all patients with NSCLC who had available mutation data. Notably, patients who had KRAS G12C mutations and an STK11 co-mutation experienced an ORR of 64%, although there were no apparent trends with KEAP1, TP53, or other common mutations and response rate.

“As many know, co-mutations in STK11 and KEAP1 are thought to predict lack of benefit from immunotherapy,” Riely said. “We decided to look at response rate in this cohort of patients.”

In order to understand why STK11 mutations were associated with response, investigators did an analysis and hypothesized that adagrasib recruits tumor infiltration, which may be able to reverse STK11 immune-mediated suppression.

ORR in patients with NSCLC Harboring KRAS G12C Co-Mutations

Regarding safety for all patients treated ar the 600-mg twice-daily dose (n = 110), the most common all-grade, treatment-related adverse effects (TRAEs) included nausea (54%), diarrhea (51%), vomiting (35%), and fatigue (32%). Grade 3/4 TRAEs included fatigue (6%), increased alanine aminotransferase (5%), aspartate aminotransferase (5%), and QT prolongation (3%). There were 2 grade 5 TRAEs: pneumonitis, which developed in a patient with recurrent pneumonitis; and cardiac failure. In total, TRAEs led to discontinuation in 4.5% of patients.

“Adagrasib is a KRAS G12C–selective covalent inhibitor with a long half-life and extensive predictive target coverage throughout the dosing interval,” Riely concluded. “[It] is well tolerated and provides durable response and broad disease control to [this patient population].”

Reference

Riely GJ, Ignatius Ou SH, Rybkin II, et al. KRYSTAL-1: Activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (pts) with advanced non-small- cell lung cancer (NSCLC) harboring KRASG12C mutation. Presented at: 2021 European Lung Cancer Conference; March 25-27, 2021; virtual. Abstract 99O_PR