Preliminary Data Show Improved Responses with Cetuximab Plus Divarasib in KRAS G12C–mutated CRC

Early antitumor activity seen with the anti-EGFR agent cetuximab (Erbitux) plus the oral KRAS G12C inhibitor divarasib (formerly GDC-6036) in patients with KRAS G12C–mutated colorectal cancer (CRC) validates attempts to overcome KRAS G12C–mediated resistance mechanisms through the addition of EGFR inhibition and appears to produce higher overall response rates (ORR) in this population than KRAS G12C inhibitors alone, according to Jayesh Desai, MBBS, FRACP.¹

Findings from the KRAS G12C–mutated CRC cohort in the phase 1b study (NCT04449874) of divarasib and cetuximab were presented at the 2023 AACR Annual Meeting. Of the 29 patients who received the regimen, 62% experienced a confirmed ORR. Responses were seen in 3 out of 5 patients previously treated with a KRAS G12C inhibitor. The regimen was well tolerated, and its toxicity profile was consistent with that of cetuximab and divarasib monotherapy alone. No treatment-related discontinuations or dose-limiting toxicities were reported.¹

Previously reported phase 1a data from this study demonstrated that single-agent divarasib had early clinical activity and a manageable safety profile. At a 400-mg dose, divarasib produced an ORR of 31% (n = 12); this has increased to 36%.^1,2

“Our early look at the efficacy data [with the combination] is very encouraging, with a 62% confirmed [ORR]. We’re looking forward to seeing further maturity of these data to [reveal] the durability of responses,” said Desai, who is a medical oncologist, head of the Phase I/Early Drug Development Program, and associate director of clinical research at the Peter MacCallum Cancer Centre. He is also an associate professor and chair of the Sir Peter MacCallum Department of Oncology at the University of Melbourne in Australia.

In an interview with OncLive^®, Desai reported prior phase 1 data on the use of divarasib monotherapy in KRAS G12C–mutated CRC, presented early efficacy, safety, and pharmacokinetic data from the use of divarasib plus cetuximab from this phase 1 trial, and discussed ongoing and future directions for the development of divarasib within CRC, non–small cell lung cancer (NSCLC), and other solid tumors.

OncLive: How does the KRASG12C inhibitor GDC-6036 differ from other targeted options for KRAS?

Desai: GDC-6036 is a KRASG12C inhibitor. It is particularly selective and potent, and targets KRAS G12C quite effectively as a [result]. I’ve been involved in the development of GDC-6036. [This] phase 1 study, which has now had an expansion cohort, [evaluated this agent] in combination with cetuximab [for] patients with CRC. [We are] looking at targeting both EGFR and KRAS G12C [with this combination]. These data were presented at AACR.

What safety and efficacy data on the use of single-agent GDC-6036 were previously reported from the phase 1a portion of this trial?

We previously presented data [on] single-agent GDC-6036 at the 2022 ESMO Congress. That showed a few things. Firstly, the safety profile with GDC-6036 is pretty good. [Toxicities are] well managed in most patients, and there is a low rate of patients requiring dose reductions or treatment discontinuation. In most instances, we can manage [adverse effects (AE)] that arise on trials with supportive care and the use of other medications.

We also presented efficacy data [from this trial] at both the IASLC WCLC 2022 Conference and the 2022 ESMO Congress. The efficacy of [single-agent GDC-6036] in CRC demonstrated a confirmed partial response [PR] rate of 31% in patients who received the full dose of 400 mg a day within that cohort. During my presentation, I shared that [these] data have matured further. As a single agent, we now see a confirmed PR rate of 36% in patients who are treated [with GDC-6036] at 400 mg per day.

Could you discuss the rationale for combining GDC-6036 with cetuximab in patients with KRAS-mutated CRC?

We have become more and more aware of the importance of EGFR in CRC as far as signaling is concerned. In the context of KRAS and KRAS G12C, there are a few key things to note. When targeting KRAS G12Cin CRC, EGFR remains activated. When using EGFR- and KRAS G12C–targeting drugs preclinically, there is strong synergy between both of those agents. Similar data have been generated with GDC-6036 [and] cetuximab, and that has informed the rationale for this combination cohort.

What were the key eligibility criteria for the combination cohort? What baseline characteristics should be noted in the enrolled population?

Key eligibility [criteria] for this combination [cohort] included patients with refractory CRC [who] have a KRAS G12C mutation. One thing I’d also like to note is that we allowed patients who had received prior KRAS G12C inhibitors to [receive] this combination.

We enrolled a total of 29 patients into the study, and 26 patients were treated with the full 400 mg dose of GDC-6036, along with cetuximab. The demographics were typical in terms of what you’d expect for a refractory CRC population.

What antitumor activity was observed with the combination regimen in this phase 1b trial?

At AACR, I reported the initial efficacy data that we’ve seen with this combination. I was pleased to share that we have seen a confirmed ORR of 62% with the combination of GDC-6036 and cetuximab. One other key point is that there were 5 patients [out] of the 29 patients enrolled, who had prior treatment with [KRAS] G12C inhibitors and developed resistant disease. Of those 5 patients, 3 had a confirmed PR with the combination. At this point in time, the data aren’t mature enough for us to have a median progression-free survival [PFS] or median duration of response [DOR] readout. Of the 19 patients who responded, 14 of those patients remain on active treatment. At a further time point, we’ll be able to get an accurate readout in terms of median PFS and DOR.

Was the safety profile of this combination consistent with previously reported safety data on single-agent GDC-6036 and single-agent cetuximab?

The safety profile [for the combination] was what we might expect to see with each agent individually. There wasn’t any additive or cumulative toxicity seen when combining both agents. From a general safety perspective, this combination was well tolerated and [its toxicity] was quite manageable. Of the 29 patients who were treated, only 3 patients required dose reductions to be able to continue treatment, and no patients had treatment discontinued because of GDC-6036 toxicity.

[Overall], this combination of GDC-6036 and cetuximab was well tolerated and very deliverable to patients, with only a small number of patients requiring any dose reduction, and no patients requiring discontinuation of treatment [due to treatment-related adverse effects].

Your team also looked at the pharmacokinetic profile of this combination. What was observed in this analysis?

We looked at [pharmacokinetics] at steady state. The combination’s pharmacokinetic profile was very similar to what we’d seen with [GDC-6036 as a] single agent. There were no drug-drug interactions or any concerns about combining these 2 agents.

Based on these findings, what next steps are planned for the investigation of GDC-6036 in CRC?

Given the encouraging activity we’ve seen with this combination, further development is occurring. There is a [phase 1/1b] clinical trial known as INTRINSIC [NCT04929223], which is currently enrolling patients and is looking at the GDC-6036 and cetuximab combination [with or without FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin)]. We also have additional arms [in this study] looking at other rational combinations in the context of CRC, including [GDC-6036] and chemotherapy.

What other avenues exist for evaluating GDC-6036 in combination with other therapies across different tumor types?

Broadly speaking, GDC-6036 is a potent KRAS G12C inhibitor. Strong opportunities exist [for the agent’s investigation] in the context of NSCLC, both as a single agent and in combination. [We should be] looking at other potential targeted approaches [with GDC-6036], including combining [it] with an EGFR inhibitor, SHP2 inhibitors, or immunotherapy. In the context of CRC, there is now a strong rationale for combining [GDC-6036] withEGFR [inhibitors]. There are also opportunities to look at [GDC-6036 in] combination with agents such as SHP2 [inhibitors], and potentially chemotherapy, which is a standard of care at this point in time in CRC.

Disclosures: 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-S702. doi:10.1016/j.annonc.2022.07.500