Adagrasib With or Without Cetuximab Produces Encouraging Clinical Activity in KRAS G12C–Mutant CRC

Jared Weiss, MD

Adagrasib (MRTX849), both alone and in combination with cetuximab (Erbitux), demonstrated encouraging responses and disease control in heavily pretreated patients with KRAS G12C–mutated colorectal cancer (CRC), according to Jared Weiss, MD, who added that next steps will be to evaluate the combination in the second-line treatment of this population.

Results from the phase 1/2 KRYSTAL-1 trial (NCT03785249), which were presented during the 2021 ESMO Congress, showed that adagrasib monotherapy elicited an overall response rate (ORR) of 22% (n = 10/45), which included 1 unconfirmed partial response (PR).¹ Stable disease was observed in 64% of patients. The disease control rate (DCR) was 87% in these patients. The median duration of response (DOR) yielded with the agent was 4.2 months (95% CI, 2.3-6.9), a median time to response (TTR) of 1.4 months, and a median progression-free survival (PFS) of 5.6 months (95% CI, 4.1-8.3).

The combination of adagrasib and cetuximab induced an ORR of 43% (n = 12/28), and this was comprised of 2 unconfirmed PRs. Stable disease was observed in 57% of patients, and the DCR was 100%. The median TTR for the combination was 1.3 months.

“Adagrasib monotherapy demonstrated promising clinical activity with a response rate of 22% and DCR of 87%,” Weiss said. “Combined adagrasib and cetuximab therapy showed even more encouraging clinical activity, with a response rate of 39% and a DCR of 100%. Both monotherapy and combined therapy are tolerable, with a manageable safety profile. The combination approach is being evaluated in the second-line setting in the randomized, phase 3 KRYSTAL-10 study [NCT04793958].”

In an interview with OncLive®, Weiss, an associate professor of medicine in the Division of Oncology, Department of Medicine, at the University of North Carolina (UNC) School of Medicine, and associate director of finance, UNC Lineberger Clinical Protocol Office, UNC Lineberger Comprehensive Cancer Center, shed light on the exploration of adagrasib as a monotherapy and in combination with cetuximab in patients with KRAS G12C–mutated metastatic CRC, key findings from the KRYSTAL-1 study, and next steps for research.

OncLive®: Could you provide some background on adagrasib? What was the rationale to examine the agent’s use in combination with cetuximab in CRC?

Weiss: KRAS G12C mutations occur in about 3 or 4% of [patients with] CRC. They are oncogenic drivers, and they are strong negative predictors of cetuximab efficacy in [this disease]. The KRAS protein cycles between GTP on and GDP off states and has a protein resynthesis of about 24 hours. Adagrasib is a covalent inhibitor of KRAS G12C; it irreversibly and selectively binds [to] KRAS G12C in its inactive GDP-bound state, and was optimized for desirable properties, including a long half-life of about 1 day, dose-dependent pharmacokinetics, and brain penetration.

Maintaining continuous adagrasib exposure above a target threshold enables the inhibition of KRAS-dependent signaling for the complete dosing interval and maximizes antitumor activity. Preclinical data implicated EGFR signaling as the dominant resistance mechanism of CRC cells to KRAS G12C inhibition. [Additionally], preclinical data indicated that combined inhibition of EGFR and KRAS G12C resulted in greater phospho-ERK modulation, and in vivo, in both CDX and PDX models, resulted in deeper and more durable tumor regressions.

Therefore, we hypothesized that combining adagrasib with cetuximab, an EGFR inhibitor, may enhance inhibition of KRAS-dependent signaling, or overcome adaptive feedback, to improve outcomes.

What was the design of the KRYSTAL-1 trial and what were the methods used?

KRYSTAL-1 is a multicohort, phase 1/2 study [that enrolled] patients with solid tumors and a KRAS G12C mutation, unresectable or metastatic disease, and who had no treatment with curative intent or standard-of-care [treatment available to them]. [The] phase 1 [portion of the trial] employed a standard accelerated titration design and resulted in a recommended phase 2 dose of 600 mg twice daily; this was subsequently explored in multiple phase 1b and 2 cohorts.

The presentation [at the 2021 ESMO Congress] was in reference to patients with CRC who were treated with adagrasib monotherapy. In that case, we had 46 patients, with a median follow-up of 8.9 months. Perhaps even more importantly, for the first time, [we also had] combination data on cetuximab [plus] adagrasib; [this cohort was comprised of] 32 patients and had a median follow-up of 7.0 months.

What were the key findings from this study?

In 45 evaluable patients treated with adagrasib monotherapy, the ORR was 22%; this included 1 unconfirmed PR. The disease control rate [DCR] was 87%. There was no apparent association between co-mutational status and response rate. DOR was 4.2 months, the median TTR was 1.4 months, and the median progression-free survival [PFS] was 5.6 months.

With the combination of adagrasib and cetuximab, in 28 evaluable patients, the ORR was 43% at the time of data cutoff, including 2 unconfirmed partial responses. Following data cutoff, but before presentation, 1 of these unconfirmed PRs became confirmed, [but] the other did not and was quoted as stable disease for best response. Therefore, the final ORR was 39%, and the final DCR was 100%. Again, there was no apparent association between co-mutational status and response. Again, the median TTR was rapid; it was 1.3 months, otherwise known as first assessment. For the combination, I was unable to share DOR or PFS data for a very happy reason. The data are immature, with 71% of the patients remaining on treatment.

In terms of toxicity with both monotherapy and the combination, gastrointestinal adverse effects [AEs] were most common. With combination therapy, there was nausea in 63% of patients, diarrhea in 56%, vomiting in 50%, and fatigue in 47%. These [AEs] were similar to those reported with the monotherapy. [However, additional toxicities] seen with combination therapy included acneiform, rash, and dry skin. Less grade 3/4 toxicity [was observed] with combination therapy; [this was experienced by only] 16% of [these] patients. With the combination, 2 treatment-related AEs led to discontinuation: one grade 2 malaise and one grade 2 hypersensitivity reaction to cetuximab [infusion].

Are next steps planned for this research?

The next step for this regimen is the phase 3 KRYSTAL-10 study, which is a randomized, open-label study of second-line adagrasib plus cetuximab vs chemotherapy in patients with metastatic CRC and KRAS G12C mutations.

Patients with CRC and this mutation, who had progressed on frontline fluoropyrimidine-based doublet chemotherapy, are being randomized to receive either the combination of adagrasib and cetuximab, or to a fluoropyrimidine doublet of which they have not previously been exposed. Notably, anti-VEGF or VEGFR therapy is allowed in the comparator arm, per investigator discretion.

That study will accrue at about 300 sites in Europe, Asia, in the United States; it has already started accruing in the United States.

Reference

1. Weiss J, Yaegar RD, Johnson M.L, et al. KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or combined with cetuximab (cetux) in patients (pts) with colorectal cancer (CRC) harboring a KRASG12C mutation. Ann Oncol. 2021;32(5):1283-1346. doi:10.1016/annonc/annonc741