In a phase III CodeBreaK 300 study, treatment with sotorasib at a dose of either 960 mg or 240 mg plus panitumumab resulted in significantly longer progression-free survival (PFS), as assessed by blinded independent central review (BICR), than standard-of-care treatment with trifluridine-tipiracil or regorafenib in patients with chemorefractory metastatic colorectal cancer (mCRC) with KRAS G12C mutation. The objective response was higher with both sotorasib combinations than with standard-of-care treatment.
Adverse events associated with sotorasib-panitumumab (at both doses of sotorasib) were as expected, with no new safety concerns and the occurrence of few discontinuations related to adverse events. The findings were reported at ESMO 2023 Congress in Madrid by Dr. Filippo Pietrantonio of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy along with a simultaneous publication on 22 October in the NEJM by Prof. Marwan G. Fakih of the City of Hope Comprehensive Cancer Center in Duarte, CA, US, and study colleagues.
The authors explained in the background that KRAS G12C is a driver mutation that occurs in approximately 3-4% of patients with mCRC and may be associated with poor prognosis. In patients with disease that is refractory to initial treatment, the standard late-line treatments, trifluridine-tipiracil or regorafenib, have shown limited efficacy with objective response of 1-2%; median PFS ≤2.0 months, but are associated with side effects. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated mCRC.
KRAS G12C inhibition alone has shown limited activity in patients with mCRC. Treatment-induced resistance selective to KRAS G12C inhibition develops primarily through upstream reactivation of the EGFR pathway and is supported by the synergistic activity of concomitant KRAS G12C and EGFR inhibition in preclinical models.
In CodeBreaK 101, a recent single-group phase Ib study involving patients with chemorefractory mCRC with mutated KRAS G12C, the confirmed response rate was 30% with sotorasib-panitumumab as compared with 9.7% with sotorasib alone. The recommended phase 2 dose of sotorasib is 960 mg once daily. A lower dose, 240 mg once daily, is being tested because of the nonlinear pharmacokinetic properties of sotorasib.
In an international phase III, multicentre, open-label, randomised study, the Code-BreaK 300 investigators assigned patients with chemorefractory mCRC with mutated KRAS G12C to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator’s choice of trifluridine-tipiracil or regorafenib (standard-of-care treatment; 54 patients). The primary endpoint was PFS as assessed by BICR according to the RECIST version 1.1. Key secondary endpoints were overall survival (OS) and objective response.
After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median PFS was 5.6 months (95% confidence interval [CI] 4.2 to 6.3) and 3.9 months (95% CI 3.7 to 5.8) in the 960 mg sotorasib-panitumumab and 240 mg sotorasib-panitumumab groups, as compared with 2.2 months (95% CI 1.9 to 3.9) in the standard-of-care group. The hazard ratio (HR) for disease progression or death in the 960 mg sotorasib-panitumumab group as compared with the standard-of-care group was 0.49 (95% CI 0.30 to 0.80; p = 0.006), and the HR in the 240 mg sotorasib-panitumumab group was 0.58 (95% CI 0.36 to 0.93; p = 0.03).
The authors commented that one limitation of this study is that it was neither designed nor powered to detect a significant difference among the groups in OS. OS data are maturing, and longer follow-up is needed to determine the effects of treatment on this endpoint. The objective response was 26.4% (95% CI 15.3 to 40.3), 5.7% (95% CI 1.2 to 15.7), and 0% (95% CI 0.0 to 6.6) in the 960 mg sotorasib-panitumumab, 240 mg sotorasib-panitumumab, and standard-of-care groups.
Although this study was not powered to compare the two sotorasib-panitumumab groups with each other, the 960 mg sotorasib dose appeared to yield more clinically significant benefits than the 240 mg dose with respect to all the efficacy endpoints, without additional side effects. The percentage of patients in the 960 mg sotorasib-panitumumab group who had a response is particularly notable, considering the greater potential to relieve tumour-related symptoms associated with a high burden of metastatic disease in the context of late-line treatment. These observations support the 960 mg dose as the more favourable regimen of the two groups.
Whether a lower sotorasib dose may be associated with different mechanisms of primary and secondary resistance remains to be investigated by translational analyses of the study. Potential resistance mechanisms are the focus of future research, with KRAS G12C amplification and secondary KRAS mutations being already identified.
Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related side effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab. The study protocol strongly recommended the use of prophylactic treatment for skin-related side effects, and treatment with sotorasib-panitumumab did not appear to exacerbate the incidence of these effects beyond that expected for panitumumab alone.
The authors commented that these findings are important in the context of the poor survival outcomes associated with KRAS G12C mutation in patients with mCRC. Dual KRAS G12C and EGFR blockade is also currently being studied in an earlier line of treatment in a randomised KRYSTAL-10 study.
In an accompanied editorial article, Dr. Rona Yaeger of the Department of Medicine, Memorial Sloan Kettering Cancer Center in New York, NY, US wrote that this is the first randomised study that provides data supporting the use of KRAS-targeted therapy in patients with CRC. The CodeBreaK 300 is an exciting first step for targeting KRAS in CRC with PFS as the primary endpoint, and it will be important to see the final OS results in this population of patients with refractory mCRC. Mature data from this study and data from KRYSTAL-10 will provide much-needed insight. KRYSTAL-10 is a phase III randomised study in which second-line treatment with the KRAS G12C inhibitor adagrasib in combination with the EGFR antibody cetuximab is being compared with standard chemotherapy in the assessment of OS and PFS (primary endpoints) among patients with advanced solid tumours with KRAS G12C mutation.
The study was funded by Amgen.
- Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C. NEJM; Published online 22 October 2023. DOI: 10.1056/NEJMoa2308795
- LBA10 - F. Pietrantonio, L. Salvatore, T. Esaki, et al. Sotorasib plus panitumumab versus standard-of-care for chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC): CodeBreak 300 phase III study. Annals of Oncology 2023;34 (suppl_2):S1266. DOI: https://doi.org/10.1016/j.annonc.2023.10.016
- Yaeger R. Combination Therapy and Appropriate Dosing to Target KRAS in Colorectal Cancer. N Engl J Med 2023;389:2197-2199.