Divarasib Plus Cetuximab Demonstrates Promising Clinical Activity and Manageable Safety in KRAS G12C–Mutant CRC

Jayesh Desai, MBBS, FRACP

The selective, oral KRAS G12C inhibitor divarasib (formerly GDC-6036), demonstrated promising clinical activity in patients with colorectal cancer (CRC) treated with the agent plus cetuximab (Erbitux). The safety profile of the agent was consistent with previously reported data on cetuximab as a single agent, as well as divarasib as a single agent, according to data presented at the 2023 AACR Annual Meeting by Jayesh Desai, MBBS, FRACP.

Results from a phase 1b study (NCT04449874) demonstrated that patients (n = 29) experienced a confirmed overall response rate (ORR) of 62%. Among patients who 5 patients who had prior treatment with a KRAS G12C inhibitor, 3 responded to treatment with divarasib. The unconfirmed ORR was 66% at clinical data cutoff of November 21, 2022. No patients discontinued treatment because of treatment-related adverse effects (TRAEs); however, 38% of patients discontinued treatment with 10 patients stopping due to progressive disease and 1 because of physician decision.¹

“The addition of an anti-EGFR therapy to divarasib may lead to a robust clinical benefit in patients with KRAS G12C-positive CRC,” Desai, the associate director of clinical research and a medical oncologist at the Peter MacCallum Cancer Centre in Melbourne Australia, said in a presentation of the data.

“Responses were durable—14 of the 18 patients who had a response continue on active treatment and we don’t, at this point in time, have a median duration of response or median progression-free survival that we can report on.”

There were no dose-limiting toxicities reported and TRAEs resulted in a dose modification for 28% of patients, with 10% requiring a dose reduction. Additionally, 41.4% of patients experienced a grade 3/4 AE, the most common of which were diarrhea (10.3%), hypomagnesaemia (6.9%), rash (3.4%), paronychia (3.4%), and infusion-related reactions (3.4%). The most common any-grade events included rash (93.0%), diarrhea (72.4%), nausea (65.5%), vomiting (48.3%), and dry skin (27.6%).

Divarasib, which is approximately 5 to 20 times more potent and 10 to 50 times more selective in vitro than the currently approved KRAS G12C inhibitors sotorasib (Lumakras) and adagrasib (Krazati) in CRC, has a pharmacokinetic profile that is comparable with cetuximab when given at 400 mg and there were no drug-drug interaction issues on the trial, Desai noted.

Patients received divarasib with cetuximab in a 3 + 3, dose-escalation design. Divarasib was administered at 200 mg for 3 patients and then at 400 mg per day for 6 patients with 400 mg/m² of intravenous cetuximab given initially and then 250 mg/m² weekly until intolerable toxicity or disease progression. The maximum-tolerated dose was not reached. Those in the dose-expansion cohort (n = 20) received divarasib daily at 400 mg in 21-day cycles and the same cetuximab dosing as those in the dose-escalation group.

The selective oral KRAS G12C inhibitor, which irreversibly locks the protein in an inactive state to turn off its oncgenic signaling, has previously demonstrated antitumor activity in patients with KRAS G12C–positive advanced solid tumors.

In the phase 1b study, divarasib is under investigation in additional cohorts for patients with non–small cell lung cancer (NSCLC) in combination with atezolizumab (Tecentriq) and in combination with erlotinib (Tarceva). In solid tumors the agent is being evaluated as a doublet with bevacizumab (Avastin), the SHP2 inhibitor GDC-1971, and the PI3Kα inhibitor inavolisib (GDC-0077).

Previously, data presented at the European Society for Medical Oncology Annual Congress 2022 on single-agent divarasib showed that TRAEs were manageable with dose modifications and supportive medications.² Dose modifications due to TRAEs for patients with CRC (n = 55) vs all patients (n = 136) occurred at rates of 14.5% vs 24.0%, respectively, dose reductions at 5.5% vs 13.0%, and withdrawal of treatment at 0.0% vs 2.0%. Seven grade 5 events were reported on the trial and all were related to disease progression. Early efficacy data for patients treated at all dose levels demonstrated a confirmed ORR of 24%; patients treated with a 400-mg dose (n = 39) experienced an ORR of 31%, which Desai noted has now increased to 36%.^1,2

Notably, the confirmed ORR of 62% with the combination therapy in the phase 1b trial is higher than the confirmed ORR of 36% with divarasib as a single agent. As patients with CRC typically have lower response rates to KRAS G12C inhibitors than patients with other indications such as NSCLC, resistance mechanisms such as signaling through the EGFR pathway led investigators to combine GDC-6036 inhibition with EGFR inhibition in this trial, Desai explained.¹

Among enrolled patients in the phase 1b study, the median number of prior therapies received was 2 (range, 1-8) with 100% of patients having prior 5-fluorouracil/capecitabine (Xeloda) treatment, 93% oxaliplatin, 83% irinotecan, and 83% bevacizumab. The median age of patients was 59 years (range, 33-87), median time on treatment was 5.5 months (range, 1.6-11.2), 52% of patients were women, 55% had an ECOG score of 0 and 45% had a score of 1, and 17% of patients received prior treatment with a KRAS G12C inhibitor.¹

To be eligible for enrollment, patients with locally advanced or metastatic solid tumors with a KRAS G12C mutation must have received at least 1 prior treatment or were intolerable to standard therapy. Those with previously treated brain metastases were permitted. Safety, pharmacokinetics, and preliminary antitumor activity per RECIST 1.1 criteria served as key end points.

Desai also shared that the upcoming phase 1/1b INTRINSIC study (NCT04929223) is recruiting patients with CRC for treatment with divarasib plus cetuximab with or without FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) and the phase 2/3 BFAST study (NCT03178552) is recruiting patients with NSCLC for treatment with divarasib vs docetaxel.

“There are development plans for CRC as well as for NSCLC. It’s more evolved in NSCLC with the BFAST trial as can be seen,” Desai concluded. “I think the main strategy [with this agent] would be looking at this in combinations as far as CRC is concerned.”

Editor’s Note: Dr Desai is a consultant for BeiGene, Pierre Fabre, Bayer, GlaxoSmithKline, Merck KGaA, Boehringer Ingelheim, Roche/Genentech, Daiichi Sankyo Europe GmbH, Novartis, Pfizer, and Amgen. He receives grant/research support from Roche/Genentech, GlaxoSmithKline, Novartis, Bionomics, BeiGene, Lilly, Bristol Myers Squibb, and AstraZeneca/MedImmune.

References

1. Desai J, Han SW, Lee JS, et al. Phase Ib study of GDC-6036 in combination with cetuximab in patients with colorectal cancer (CRC) with KRAS G12C mutation. Cancer Res.2023;83(suppl 8):CT029. doi:10.1158/1538-7445.AM2023-CT029
2. Desai J, Han SW, Forster MD, et al. Phase Ia study to evaluate GDC-6036 monotherapy in patients with colorectal cancer (CRC) with KRAS G12C mutation.Ann Oncol. 2022;33 (suppl 7):S701-702. doi:10.1016/j.annonc.2022.07.500