Garsorasib Plus Cetuximab Shows Early Efficacy in Heavily Pretreated KRAS G12C+ CRC

The combination of garsorasib (D-1553) and cetuximab (Erbitux) elicited responses and was found to be well tolerated in heavily pretreated patients with KRAS G12C–mutated colorectal cancer (CRC), according to findings from a phase 2 study (NCT04585035) presented at the 2023 ESMO Congress.¹

At a median follow-up of 9.1 months (range, 2.3-12.9), the doublet elicited an overall response rate (ORR) of 45.0% (95% CI, 29.3%-61.5%) in this population (n = 40), which consisted entirely of partial responses. Fifty percent of patients had stable disease as their best overall response, and 5.0% of patients experienced disease progression. The disease control rate (DCR) was 95.0% (95% CI, 83.1%-99.4%).

Moreover, the median time to response was 5.9 weeks (range, 5.0-24.1), and the median duration of response (DOR) was 8.6 months (95% CI, 4.9-not applicable). The median progression-free survival (PFS) was 7.6 months (95% CI, 5.5-10.0).

The 3-month PFS rate was 89.7% (95% CI, 74.7%-96.0%); these rates were 59.0% (95% CI, 40.5%-73.4%), 34.6% (95% CI, 18.5%-51.4%), and 23.1% (95% CI, 6.2%-46.2%) at 6, 9, and 12 months, respectively. Due to the limited follow-up period, the median overall survival (OS) had not yet been reached. The 9-month OS rate was 82.4% (95% CI, 62.0%-92.5%).

“[The] combination of garsorasib and cetuximab shows promising preliminary efficacy in heavily pretreated patients with KRAS G12C–mutated CRC and a robust improvement over garsorasib monotherapy and standard of care,” Rui-Hua Xu, MD, of the Department of Clinical Research at Sun Yat-sen University Cancer Center in Guangzhou, China, said in a presentation of the data. “[The] combination…[may provide a new treatment option for [this population.]”

Garsorasib is a potent, selective, and covalent inhibitor of KRAS G12C that irreversibly and selectively binds GDP-bound KRAS G12C.² The agent binds in the switch II pocket of KRAS G12C to keep in the active GDP-bound state via a mechanism that is comparable to that of other KRAS G12C inhibitors. Preclinical data revealed that the agent is able to strongly inhibit tumor growth and has high oral bioavailability and central nervous system penetration.

Arm F of the single-arm, global, phase 2 trial enrolled patients with advanced or metastatic CRC that had progressed following at least 1 previous regimen.¹ Patients needed to have tumors that harbored KRAS G12C mutations and measurable disease.

In the phase 1a dose-escalation portion of the research, garsorasib monotherapy was evaluated at daily doses ranging from 150 mg to 1600 mg. In phase 1b, the agent was paired with cetuximab. Once the recommended phase 2 dose (RP2D) was determined, patients entered phase 2. There, patients with solid tumors received garsorasib at a twice daily dose of 600 mg.

Data from patients with CRC who received garsorasib at 600 mg twice daily (n = 23) or 800 mg once daily (n = 1) were reported at the 2023 ASCO Annual Meeting.³ Data showed that in the total population, the ORR with single-agent garsorasib was 20.8% (95% CI, 7.1%-42.2%), and the DCR was 95.8% (95% CI, 78.9%-99.9%). The median DOR was 6.28 months (95% CI, 2.78-NA). The median PFS was 5.42 months (95% CI, 2.89-9.53) with a 6-month PFS rate of 44.4%. The OS data were not mature yet, but the 6-month OS rate was 95.8% (95% CI, 73.9%-99.4%).

The key end points for the phase 2 portion of the research are ORR; DCR, PFS, and DOR by RECIST v1.1 criteria; OS; safety and pharmacokinetics.1

At the 2023 ESMO Congress, Xu shared preliminary findings on the doublet in 40 evaluable patients with KRAS G12C–mutated CRC who were naïve to KRAS G12C inhibitors. At the time of the data cutoff date of August 10, 2023, 52.5% of patients were still receiving treatment. The most common reason for discontinuation was disease progression (42.5%) followed by withdrawn consent (5.0%).

The median patient age was 54.0 years (range, 32-76) and 37.5% of patients were female. Most patients were Asian (82.5%) and had an ECOG performance status of 1 (72.5%). All patients had stage IV disease at baseline. Primary disease locations included left colon (32.5%), right colon (30.0%), and rectum (37.5%).

The median number of prior lines of therapy received was 2, with a range of 1 to 6. Eighty percent of patients previously received at least 2 lines of therapy and 45.0% received at least 3 prior lines. All patients received prior oxaliplatin and 90% received prior irinotecan. Moreover, 97.5% of patients were previously exposed to fluoropyrimidine, 92.5% had anti­­-VEGF therapy, and 27.5% had regorafenib (Stivarga) and/or trifluridine/tipiracil (Lonsurf) and/or fruquintinib (Elunate).

Additional efficacy data showed that 92.5% of patients experienced a reduction in target lesions with garsorasib plus cetuximab.

Regarding safety, 85.0% of patients experienced an any-grade adverse effect (AE) that was related to garsorasib and 100% experienced an any-grade AE related to cetuximab; these effects were grade 3 in 2.5% and 12.5% of patients, respectively. No patients experienced a grade 4/5 treatment-related AE (TRAE).

TRAEs led to drug interruption of garsorasib for 10.0% of patients and cetuximab for 17.5% of patients. “Dose interruption was transient and most of the patients resumed treatment,” Xu noted. Drug reduction and discontinuation of cetuximab was required in 7.5% and 2.5% of patients, respectively. No deaths occurred.

All patients who experienced the combination experienced a TRAE, and for 12.5% of patients, these effects were grade 3. The most common TRAEs that occurred in at least 10% of patients were rash (any grade, 70.0%; grade 3, 5.0%), increased aspartate aminotransferase (32.5%; 0%), increased alanine aminotransferase (25.0%; 0%), paronychia (25.0%; 0%), increased blood bilirubin (17.5%; 0%), skin fissures (15.0%; 0%), constipation (12.5%; 0%), dermatitis acneiform (10.0%; 2.5%), diarrhea (10.0%; 0%), dry skin (10.0%; 0%), and nausea (10.0%; 0%).

“No significant difference in safety profile between combination treatment and the individual drugs [was observed,” Xu concluded.

Editor’s Note: Dr Xu disclosed serving as an invited speaker for Bristol Myers Squibb, MSD, BeiGene, Junshi, and Hengrui and having an advisory board position with Astellas, Merck, MSD, AstraZeneca, Junshi, Hengrui, BeiGene, Innovent, CPPC, and Keymed Bioscience.

References

1. Xu R-H, Xu Y, Yan D, et al. Safety and efficacy of D-1553 in combination with cetuximab in KRAS G12C mutated colorectal cancer (CRC): a phase II study. Ann Oncol. 2023;34(suppl 2):S410-S411. doi:10.1016/j.annonc.2023.09.1741
2. Li Z, Song Z, Zhao Y, et al. D-1553 (garsorasib), a potent and selective inhibitor of KRASG12C in patients with NSCLC: phase 1 study results. J Thorac Oncol. 2023;18(7):940-951. doi:10.1016/j.jtho.2023.03.015
3. Ruan D-Y, Lee MA, Deng Y, et al. Safety and efficacy of D-1553 in KRAS G12C-mutated colorectal cancer: results from a phase I/II study. J Clin Oncol. 2023;41(suppl 16):3563. doi:10.1200/JCO.2023.41.16_suppl.3563