Expert Point of View: Federica Di Nicolantonio, MD, PhD

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“KRAS G12C inhibitors as monotherapy yield a relatively low overall response rate, but when you combine them with an EGFR [epidermal growth factor receptor] inhibitor, the response rate is nearly double,” said ­Federica Di Nicolantonio, MD, PhD, Professor of Oncology at the University of Turin in Italy, the invited discussant of the KRYSTAL-1 trial at the European Society for Medical Oncology (ESMO) Congress 2021.1

The hope is to improve upon outcomes with current treatments for KRAS-mutated metastatic colorectal cancer in the first-line setting, where progression-free survival on first-line therapy has been about 9 months, and median overall survival 21 months,2 she noted. 

Both adagrasib and sotorasib, a KRAS G12C inhibitor already approved in non–small cell lung cancer (NSCLC), produced higher response rates in NSCLC than in colorectal cancer. The story is “reminiscent” of what has been observed with BRAF inhibitors, to which about 50% of patients with metastatic melanoma respond, compared with about 5% with metastatic colorectal cancer.

Rationale for Combination Therapy

Dr. Di Nicolantonio explained a possible reason for the lack of efficacy of the single agent in colorectal cancer. Adagrasib is a KRAS G12C inhibitor that binds to and inactivates the mutated version of the KRAS protein, halting signaling that can promote tumor growth. When oncogenic signaling (in the RAS/BRAF/MEK pathway) is inhibited, feedback loops are triggered that re-phosphorylate the receptor tyrosine kinase on the membrane. Since EGFR is widely expressed in colorectal cancer, it can be an effective way to prevent feedback reactivation and resistance to KRAS inhibition.

“Based on this preclinical rationale, when you combine a KRAS inhibitor with an anti-EGFR agent—specifically a monoclonal antibody—you see a striking and profound synergy in mouse models,” Dr. Di Nicolantonio said.

The response rate for single-agent adagrasib in KRYSTAL-1 was 22%, “which is more or less in line with, if not slightly better than,” the 12% response rate for sotorasib monotherapy among 25 patients treated with the full dose of 960 mg in CodeBreaK100,3 she said. 

In KRYSTAL-1, with the combination, the response rate was 43% (39% for confirmed responses), with disease stabilization in the remaining patients. “This yielded an overall disease control rate of 100%, which is remarkable to those of us who contributed to the preclinical development [of adagrasib] and provided the biologic rationale for this combination,” she commented.

Additional Findings

The data are immature for progression-free survival, but Dr. Di Nicolantonio predicted the findings will mirror what is seen with BRAF inhibitors combined with anti-EGFR agents in the second-line setting, hitting “just over 4 months…. Time will tell.”

Dr. Di Nicolantonio noted that the findings for the combination are comparable to those of the phase Ib CodeBreaK101 trial, the “first glance” of which was also presented at the ESMO meeting.4 In 18 patients treated with sotorasib combined with panitumumab, the unconfirmed response rate was 33%, with 100% of patients achieving disease control. The population did not include patients with prior exposure to a KRAS G12C inhibitor.

The safety profile for adagrasib is also similar to that observed with sotorasib and aligns with what is known from the data in NSCLC. The main toxicity is gastrointestinal, and the addition of cetuximab did not worsen overall toxicity but did add some skin toxicity in KRYSTAL-1.

Not surprisingly, she said, no association was found between response and tumor mutations. She is hoping to see correlative studies that will explore features relevant to the biology of metastatic colorectal cancer—analyses including tumor sidedness, transcriptomics, methylome, Immunoscore, and microbiota—which could identify factors affecting the response to KRAS G12C inhibitors. Potential mechanisms of acquired resistance should also be explored, she said.

“We are eagerly awaiting the phase III KRYSTAL-10 trial of second-line adagrasib plus cetuximab vs conventional chemotherapy. We are also eager to see other combinations of KRAS G12C inhibitors, especially with SHP2 inhibitors, for which we have solid preclinical data,” she added.

DISCLOSURE: Dr. Di Nicolantonio reported no conflicts of interest.


1. Weiss J, Yaeger R, Johnson ML, et al: KRYSTAL-1: Adagrasib (MRTX849) as monotherapy or in combination with cetuximab in patients with colorectal cancer harboring a KRAS G12C mutation. ESMO Congress 2021. Abstract LBA6. Presented September 19, 2021.

2. Chida K, Kotani D, Masuishi T, et al: The prognostic impact of KRAS G12C mutation in patients with metastatic colorectal cancer: A multicenter retrospective observational study. Oncologist 26:845-853, 2021.

3. Hong DS, Fakih MG, Strickler JH, et al: KRAS G12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.

4. Fakih M, Falchook GS, Hong DS, et al: CodeBreaK 101 subprotocol H: Phase Ib study evaluating combination of sotorasib, a KRAS G12C inhibitor, and panitumumab, an EGFR inhibitor, in advanced KRAS p.G12C-mutated colorectal cancer. ESMO Congress 2021. Abstract 434P. Presented September 16, 2021.

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