KRAS G12C–mutated colorectal cancer represents 3% to 4% of metastatic colorectal cancers. Like other KRAS-mutated metastatic colorectal cancers, this group of patients represents a patient population with an unmet need, with limited options beyond two lines of therapy. In contrast to other KRAS mutations, KRAS G12C results in a cysteine substitution that is readily targetable by small-molecule inhibitors.
The First KRAS G12C Inhibitor
Sotorasib was the first KRAS G12C inhibitor to show clinical activity in non–small cell lung cancer (NSCLC) and colorectal cancer with KRAS G12C mutations in the CodeBreaK100 phase I clinical trial.1 The CodeBreaK100 phase II clinical trial of sotorasib monotherapy in chemotherapy-resistant KRAS G12C–mutated metastatic colorectal cancer reported an overall response rate of 9.7%, median progression-free survival of 4 months, and median overall survival of 10.6 months.2 These results failed to meet the primary overall response rate endpoint.
Marwan Fakih, MD
Investigators recognized the importance of concurrent EGFR inhibition with KRAS inhibition to optimize tumor response. So, the combination of sotorasib and panitumumab (CodeBreaK101) was investigated in 40 patients with chemotherapy-resistant colorectal cancer. A confirmed overall response rate of 30% and a median progression-free survival of 5.7 months were reported, although overall survival data were still immature.3
As recently reported in The New England Journal of Medicine, and summarized in this issue of The ASCO Post, Yaeger et al provided the results of the KRYSTAL-1 phase II adagrasib and phase Ib adagrasib plus cetuximab studies in KRAS G12C–mutated metastatic colorectal cancer.4 The objective response rate, median progression-free survival, and median overall survival were 19%, 5.6 months, and 19.8 months with the monotherapy arm and 46%, 6.9 months, and 13.4 months with the combination therapy. The duration of response was numerically longer with the combination (median = 7.6 months) than with the monotherapy (4.3 months).
Comparison of Studies: Sotorasib vs Adagrasib
Although adagrasib monotherapy had a higher overall response rate and longer progression-free and overall survival than previously reported with sotorasib monotherapy, it is important to note some differences in the populations investigated. In the CodeBreaK100 trial, 100% of patients treated with sotorasib monotherapy received oxaliplatin, irinotecan, and a fluoropyrimidine prior to study enrollment, whereas 77% of the adagrasib monotherapy population were exposed to all three drugs.
Similarly, the sotorasib phase II trial was enriched with patients who had prior exposure to trifluridine and/or regorafenib (44%) in comparison to the adagrasib monotherapy population in KRYSTAL-1 (23%). It is possible that a more refractory patient population with more aggressive tumor biology in CodeBreak100 was predisposed to lesser efficacy to KRAS G12C inhibition.
Furthermore, the overall survival of 19.8 months on adagrasib monotherapy cannot be explained solely by adagrasib clinical activity. Indeed, this figure is numerically higher than the overall survival of 13.4 months noted with the more effective adagrasib plus cetuximab combination. This cannot be explained by the crossover to adagrasib plus cetuximab on the monotherapy trial, since just six patients crossed over to the combination. A high rate of treatment after disease progression (66%) was reported by the investigators on the monotherapy arm, likely resulting in this outlier survival outcome.
Rationale for Combination Therapy
As confirmed by preclinical data, synergistic activity can be derived by blocking epidermal growth factor receptor (EGFR) phosphorylation concurrently with KRAS G12C inhibition.5 Mitogen-activated protein kinase (MAPK) inhibition downstream of EGFR has long been recognized to result in feedback activation of EGFR, therefore leading to tolerance to downstream MAPK inhibition. This phenomenon is well recognized preclinically and clinically with BRAF inhibition in BRAF V600E–mutated colorectal cancer.6 Clinical synergy, evidenced by improved overall response rate, progression-free survival, and duration of response with adagrasib/cetuximab and with sotorasib/panitumumab over their respective KRAS G12C inhibitor monotherapy highlights the need to move to combination therapy in KRAS G12C–mutated colorectal cancer.
Both KRYSTAL-1 and CodeBreaK101 reported impressive response rates and progression-free survival with adagrasib/cetuximab and sotorasib/panitumumab combinations in KRAS G12C–mutated colorectal cancer. The small number of patients in the two studies does not allow cross comparison. Although the overall response rate of 41% with adagrasib/cetuximab appears numerically superior to the 30% rate with sotorasib/panitumumab, it is important to note that the confidence intervals are overlapping.
There is a real potential for accentuating the clinical activity with the earlier integration of a KRAS G12C inhibitor plus cetuximab or panitumumab with FOLFIRI or FOLFOX chemotherapy backbones.— Marwan Fakih, MD
Tweet this quote
It is possible that the KRYSTAL-1 adagrasib regimen may have efficacy advantages based on the more favorable pharmacokinetics of twice daily administration. Such advantages remain theoretical, as the covalent binding of KRAS G12C inhibitors may not require sustainable steady-state concentrations for either sotorasib or adagrasib. Dosing frequency and dose escalations must take into consideration efficacy factors as well as toxicity risks. Adagrasib monotherapy dosing on KRYSTAL-1 was associated with a higher rate of gastrointestinal toxicity than sotorasib monotherapy, which led to a higher rate of treatment interruptions and dose reductions (45% for adagrasib and 18% for sotorasib). Such factors may become particularly important as combinations of KRAS G12C inhibitors, anti-EGFR antibodies, and systemic chemotherapy are considered in prospective trials.
Another KRAS G12C Inhibitor on the Horizon
Other KRAS G12C inhibitors have recently shown interesting monotherapy activity. GDC-6036, a small-molecule inhibitor, has shown single-agent activity (with a 20% overall response rate) in a phase I escalation study in KRAS G12C–mutated colorectal cancer.7 Further updates from the European Society for Medical Oncology (ESMO) Congress 2022 meeting reported a confirmed overall response rate of 31% at the recommended dose of 400 mg twice daily. This agent is also currently being investigated in combination with cetuximab in KRAS G12C–mutated metastatic colorectal cancer (ClinicalTrials.gov identifier NCT04449874).
Closing Thoughts
The results of KRYSTAL-1 and CodeBreaK101 clearly justify the development of adagrasib/cetuximab and sotorasib/panitumumab in phase III clinical trials in second- and third-line settings. KRYSTAL-10 (NCT04793958) is a second-line phase III trial comparing adagrasib/cetuximab with standard second-line chemotherapy. If this trial is positive, it would provide a chemotherapy-free second-line treatment for this target population, sparing patients from side effects of cytotoxic agents. CodeBreaK300 (NCT05198934) is a third-line phase III trial comparing low-dose sotorasib plus panitumumab vs standard-dose sotorasib (960 mg daily) plus panitumumab vs regorafenib or trifluridine. If this trial is positive, it will provide a registrational path for the combination in chemotherapy-resistant KRAS G12C–mutated colorectal cancer. The successful outcome of either of these studies will be a win for our patients and will provide a path forward to KRAS G12C targeting in colorectal cancer.
Additional investigations should no doubt include chemotherapy plus targeted therapy combinations. Building on the success of combination EGFR inhibitors and chemotherapy in RAS wild-type left-sided colorectal cancer,8 there is a real potential for accentuating the clinical activity with the earlier integration of a KRAS G12C inhibitor plus cetuximab or panitumumab with FOLFIRI (fluorouracil, leucovorin, irinotecan) or FOLFOX (fluorouracil, leucovorin, oxaliplatin) chemotherapy backbones. Similar strategies have been recently evaluated with encorafenib, cetuximab, and combination chemotherapy in BRAF V600E–mutated colorectal cancer, with encouraging early efficacy.9
DISCLOSURE: Dr. Fakih has served as a consultant or advisor to AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Incyte, Merck, Mirati Therapeutics, Nouscom, PsiOxus, Roche/Genentech, Taiho Oncology, and XinThera; and has received institutional research grants from Bristol Myers Squibb, Genentech, and Verastem.
REFERENCES
1. Hong DS, Fakih MG, Strickler JH, et al: KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.
2. Fakih MG, Kopetz S, Kuboki Y, et al: Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): A prespecified analysis of a single-arm, phase 2 trial. Lancet Oncol 23:115-124, 2022.
3. Kuboki Y, Yaeger R, Fakih M, et al: Sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: Safety and efficacy for phase Ib full expansion cohort. ESMO Congress 2022. Abstract 315O. Presented September 12, 2022.
4. Yaeger R, Weiss J, Pelster MS, et al: Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med 388:44-54, 2022.
5. Amodio V, Yaeger R, Arcella P, et al: EGFR blockade reverts resistance to KRASG12C inhibition in colorectal cancer. Cancer Discov 10:1129-1139, 2020.
6. Kopetz S, Grothey A, Yaeger R, et al: Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med 381:1632-1643, 2019.
7. Desai J, Han S, Forster MD, et al: Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer with KRAS G12C mutation. ESMO Congress 2022. Abstract 362P. Presented September 10, 2022.
8. Yoshino T, Watanabe J, Shitara K, et al: Panitumumab plus mFOLFOX6 versus bevacizumab plus mFOLFOX6 as first-line treatment in patients with RAS wild-type metastatic colorectal cancer: Results from the phase 3 PARADIGM trial. 2022 ASCO Annual Meeting. Abstract LBA1. Presented June 4, 2022.
9. Tabernero J, Yoshino T, Kim TW, et al: BREAKWATER safety lead-in: Encorafenib + cetuximab + chemotherapy for BRAFV600E metastatic colorectal cancer. ESMO Congress 2022. Abstract LBA26. Presented September 12, 2022.
