Early Trials Confirm KRAS G12C-Mutated Colorectal Cancer Is ‘Druggable’

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Patients with previously treated advanced colorectal cancer harbouring a KRAS G12C mutation may benefit from the combination of adagrasib plus cetuximab or sotorasib plus panitumumab, indicate findings from two trials reported at the ESMO Congress 2022 in Paris, France. 

Presenting the discussion at the session, Elena Elez, from Vall d’Hebron Institute of Oncology in Barcelona, Spain, said that the findings from the KRYSTAL-1 and CodeBreaK 101 trials demonstrate that the “KRAS G12C mutation is druggable in metastatic colorectal cancer” and that “optimal” inhibition might be achieved by targeting the EGFR–MAPK pathway dependency in the disease. 

Samuel Klempner, from Massachusetts General Cancer Center in Boston, USA, gave an update on the KRYSTAL-1 trial of the KRAS G12C inhibitor adagrasib with or without the EGFR inhibitor cetuximab in patients with unresectable or metastatic colorectal cancer with a confirmed KRAS G12C mutation. 

Phase II data were reported for adagrasib 600 mg monotherapy given twice daily to 44 patients who have been followed up for a median 20.1 months, as well as phase Ib results for 32 patients who received adagrasib plus cetuximab and were followed up for a median 17.5 months. 

Participants in both trial arms had received a median three lines of prior therapy, with almost all having received fluoropyrimidine, oxaliplatin and irinotecan chemotherapy and over 80% an anti-VEGF agent, the presenter said. 

Adagrasib monotherapy achieved a confirmed objective response in 19% of the 43 evaluable patients, while 86% achieved disease control and 79% tumour shrinkage.  

The median duration of response was 4.3 months, median progression-free survival (PFS) 5.6 months and median overall survival (OS) 19.8 months. The 6- and 12-month rates of PFS were 47% and 15%, respectively, with corresponding OS rates of 93% and 69%. 

Next the presenter reported the outcomes for 28 evaluable patients given adagrasib plus cetuximab, with objective responses, disease control and tumour shrinkage achieved by 46%, 100% and 93% of participants, respectively. 

In this group, the median duration of response was 7.6 months, median PFS 6.9 months and median OS 13.4 months. The PFS rates at 6 and 12 months were 60% and 24%, respectively, with corresponding OS rates of 84% and 61%. 

Samuel Klempner said that the combination of adagrasib plus cetuximab was tolerable and that there was no evidence of worsening toxicity with the combination versus adagrasib monotherapy. 

The most common treatment-related adverse events (TRAEs) with the combination were grade 1 and 2 nausea (41% and 22%), vomiting (41% and 13%) and diarrhoea (34% and 19%), with grade 3 diarrhoea, dermatitis acneiform and stomatitis occurring in one patient each. There were two grade 4 TRAEs – cetuximab infusion reaction and hyperkalemia – and no grade 5 events. 

While 16% of TRAEs resulted in cetuximab discontinuation, none of the patients discontinued adagrasib because of toxicity, the investigator said. 

Samuel Klempner concluded that adagrasib plus cetuximab is now being trialled as a second-line regimen in the phase III KRYSTAL-10 study, as well as the late-line setting in phase II of KRYSTAL-1. 

The safety and efficacy results for the fully enrolled dose-expansion cohort of the CodeBreaK 101 trial results were presented by Yasutoshi Kuboki, from the National Cancer Center Hospital East in Kashiwa-shi-Chiba, Japan. 

He explained that the phase Ib study included 40 patients with advanced colorectal cancer, a confirmed KRAS G12C mutation and disease progression during or after treatment with fluoropyrimidine, oxaliplatin, irinotecan or an angiogenesis inhibitor.  

Treatment with sotorasib 960 mg/day alongside panitumumab 6 mg/kg twice weekly was “well tolerated”, Yasutoshi Kuboki told delegates. Grade 3 TRAEs occurred in 23% of patients, there were no grade 4 or 5 toxicities, and no TRAEs leading to discontinuation. 

Turning to efficacy, the presenter said that confirmed objective response occurred in 30% of the patients – all of which were partial – and the disease control rate was 93%, with “no obvious differences in response” in patients with left- and right-sided tumours. 

The majority (88%) of patients experienced a reduction in a RECIST target lesion and, after a median treatment duration of 5.9 months, 25% of participants were continuing on treatment, with a median duration of response of 4.4 months at data cutoff. 

After a median 11.0 months of follow-up, PFS was a median of 5.7 months and the median durations were comparable in patients with left and right primary tumours (5.8 vs 5.5 months). The 6- and 9-month rates of PFS were 41.1% and 12.3%, respectively. 

Median OS was unreached in the full group and in the primary tumour subgroups after a median follow-up of 8.8 months, with 6- and 9-month rates of 91.5% and 82.5% respectively.  

Yasutoshi Kuboki summarised that sotorasib plus panitumumab had a safety profile “consistent” with the individual drugs and an objective response rate “3-fold higher than previously reported with sotorasib monotherapy”. 

He said that the median PFS with the combination “appears clinically meaningful and longer than that reported for sotorasib monotherapy” and that “the OS data appear promising”. 

The presenter concluded that the phase III global CodeBreaK 300 trial is now underway and comparing sotorasib plus panitumumab with an investigators’ choice of agent in KRAS G12C-mutated metastatic colorectal cancer. 

Session discussant Elena Elez said that the two combination regimens presented “have a favourable safety profile, [are] feasible in [a] heavily pretreated population and able to be explored with other treatment combinations and in earlier lines of treatments.” 

She emphasized that the “efficacy of these strategies may be optimized [by] fine-tuning patient selection” using biomarker assessment. 

References  

LBA24 - Klempner SJ, Weiss J, Pelster M et al. KRYSTAL-1: Updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer harbouring a KRASG12C mutation. Ann Oncol 2022; 33 (suppl_7): S808–S869. Doi: 10.1016/annonc/annonc1089

315O - Kuboki Y, Yaeger R, Fakih MG, et al. Sotorasib in combination with panitumumab in refractory KRAS G12C-mutated colorectal cancer: Safety and efficacy for phase Ib full expansion cohort. Ann Oncol 2022; 33 (suppl_7): S136–S196. Doi:10.1016/annonc/annonc1048