In a Phase III trial involving patients with chemo-refractory metastatic colorectal cancer (mCRC) harboring KRASG12C mutations, the combined use of sotorasib and panitumumab surpassed the efficacy of the investigator's selected treatment. The study, which examined two distinct doses of sotorasib, revealed enhanced progression-free survival (PFS) at both dosage levels. Notably, superior outcomes were observed with the higher dose of sotorasib.

The CodeBreaK 300 trial included 160 participants diagnosed with metastatic colorectal cancer (CRC) carrying KRASG12C mutations. These individuals had undergone a minimum of one prior treatment, experiencing disease progression following fluoropyrimidine, irinotecan, and oxaliplatin therapies.

Participants were assigned randomly to one of three treatment groups in the CodeBreaK 300 trial: the first group received a daily dose of 960 mg of sotorasib along with panitumumab administered at 6 mg/kg every two weeks (n=53); the second group received a daily dose of 240 mg of sotorasib combined with panitumumab at 6 mg/kg every two weeks (n=53); and the third group had the investigator's choice, which involved either trifluridine/tipiracil or regorafenib (n=54).

In the group receiving a combination of 960 mg of sotorasib and panitumumab, the objective response rate stood at 26%, while the group with 240 mg of sotorasib combined with panitumumab exhibited a 6% response rate. Contrastingly, the arm with the investigator's choice recorded a 0% objective response rate. Regarding disease control rates, they were 72%, 68%, and 46%, respectively, for the mentioned treatment arms.

With a median follow-up of 7.8 months, the CodeBreaK 300 trial revealed distinct median progression-free survival (PFS) durations across the three arms. The investigator's choice arm exhibited a median PFS of 2.2 months, while the 240 mg sotorasib-panitumumab arm demonstrated a significantly extended PFS of 3.9 months. The most notable outcome was observed in the 960 mg sotorasib-panitumumab arm, where the median PFS reached 5.6 months. It is important to highlight that overall survival data had not reached maturity as of the data cutoff point.

The incidence of Grade 3 or higher treatment-related adverse events (TRAEs) differed among the treatment arms, with rates of 36% in the 960 mg sotorasib arm, 30% in the 240 mg sotorasib arm, and 43% in the investigator’s choice arm. Notably, there were no fatal TRAEs reported in any of the arms. The predominant grade 3 or higher TRAEs associated with sotorasib and panitumumab included dermatitis acneiform, hypomagnesemia, rash, and diarrhea. In the investigator’s choice arm, the most common grade 3 or higher TRAEs were neutropenia, nausea, and anemia.

KOL insights

“Sotorasib 960 mg plus panitumumab is a potential new standard-of-care therapy for patients with previously treated, KRASG12C-mutated metastatic colorectal cancer,” – MD, Italy.

“With these new data, sotorasib plus panitumumab showed consistent efficacy across key subgroups at both doses and supports the biologic rationale of combining these two biomarker-directed therapies.” – MD, Italy.

Conclusion

During ESMO 2023, company revealed that in a Phase III trial, LUMAKRAS-VECTIBIX exhibited superior outcomes compared to the investigator's choice of two standard-of-care treatments, namely Taiho Oncology's LONSURF (trifluridine and tipiracil) and Bayer's STIVARGA (regorafenib). The trial investigated the efficacy of LUMAKRAS at two different dosages, namely 960 mg and 240 mg.

While acknowledging the promise seen in the study results, the emphasis remains on overall survival as the paramount endpoint, particularly in this advanced treatment stage. The ultimate decision on whether LUMAKRAS-VECTIBIX becomes the established last-line therapy for KRAS G12C-mutated colorectal cancer patients hinges on forthcoming data concerning overall survival and quality of life. The latest findings indicate that sotorasib in conjunction with panitumumab maintained consistent effectiveness across significant subgroups at both dosage levels. This reinforces the biological rationale for combining these two therapies directed by biomarkers. Survival beyond 5 years is achieved by fewer than 20% of individuals diagnosed with metastatic colorectal cancer (mCRC), highlighting the imperative for additional treatment alternatives. This need is mainly for patients with KRAS mutations, as evidence-based targeted solutions for this subgroup are currently lacking.

Amgen's Senior Vice President expressed intentions to engage in discussions with regulators regarding the CodeBreaK 300 data. Additionally, the company plans to kick off a Phase III study for LUMAKRAS in the frontline setting for colorectal cancer with KRAS G12C mutations.

For more insight into colorectal cancer, their respective geographical patient burden, treatment, and changing market landscape-related advancements, refer to these reports:

• Colorectal Cancer Market Insight And Market Forecast
• Metastatic Colorectal Cancer Market Insight And Market Forecast
• KRAS Inhibitors Market Insights and Market Forecast