Sotorasib and Panitumumab for Treatment-Resistant Colorectal Cancer with KRAS G12C Mutations

KRAS G12C mutations occur in approximately 3-4% of patients with metastatic colorectal cancer. KRAS G12C inhibitor monotherapy has shown limited effectiveness in these patients. Combining the epidermal growth factor receptor (EGFR) inhibitor panitumumab with the KRAS G12C inhibitor sotorasib was shown to be a new, effective treatment strategy in results published on December 7, 2023, in NEJM from the CodeBreaK 300 study.

Targeting KRAS G12C Mutations in Colorectal Cancer

Targeted approaches are becoming increasingly important in colorectal cancer treatment. KRAS G12C mutations have become a focus of innovative treatment strategies in this field.

CodeBreaK 300 targets colorectal cancer with KRAS G12C mutations and is the first randomized study to do so.

RAS stands for "Rat Sarcoma" virus, a name derived from this gene family's original discovery in rat sarcoma viruses. In humans, the RAS gene family encodes proteins that regulate essential functions such as cell growth, differentiation and survival. It includes three particularly important oncogenes: HRAS, KRAS and NRAS.

The RAS signaling pathway, in carcinogenesis, is one of 10 key signaling pathways. RAS genes are essential for normal cell function, but mutations can give them oncogenic properties and trigger cancer development. Mutated RAS genes have been linked to many cancers, particularly colorectal, pancreatic and lung cancer, and melanoma.

• Related topic: Sotorasib Received FDA Approval in May 2021 for KRAS G12C-Mutant Lung Cancer

Details of CodeBreaK 300

The phase 3, multicenter, open-label randomized CodeBreaK 300 study enrolled patients with metastatic colorectal cancer resistant to previous chemotherapy.

Patients received:

• Sotorasib 960 mg + panitumumab (53 patients)
• Sotorasib 240 mg + panitumumab (53 patients)
• Standard care (trifluridine-tipiracil/regorafenib) (54 patients)

The primary endpoint was progression-free survival (PFS), assessed by blinded independent review. Secondary endpoints were overall survival and objective response rate.

Results

• Median follow-up: 7.8 months
• PFS:
  • Sotorasib 960 mg + panitumumab: 5.6 months
  • Sotorasib 240 mg + panitumumab: 3.9 months
  • Standard treatment: 2.2 months
• Risk reduction versus standard care: 51% for 960 mg (HR: 0.49, 95% CI 0.30-0.80) and 42% for 240 mg (HR 0.58, 95% CI 0.36-0.93).
• Overall survival data are not yet mature
• Objective response rates:
  • Sotorasib 960 mg + panitumumab: 26.4%
  • Sotorasib 240 mg + panitumumab: 5.7%
  • Standard treatment: 0%
• Grade 3/4 adverse events:
  • Sotorasib 960 mg + panitumumab: 35.8%
  • Sotorasib 240 mg + panitumumab: 30.2%
  • Standard treatment: 43.1%

In conclusion, both sotorasib doses combined with panitumumab significantly improved PFS over standard treatment in chemotherapy-resistant KRAS G12C-mutant metastatic colorectal cancer. Toxicity was manageable and consistent with the individual profiles of both agents.

Editorial Commentary on the Study

Fakih and colleagues report results from the phase 3 CodeBreaK 300 trial in patients with metastatic colorectal cancer carrying KRAS G12C mutations. It tested sotorasib, a selective inhibitor of a mutation in Kirsten rat sarcoma viral oncogene homolog (KRAS) involving a change from glycine to cystine, combined with the epidermal growth factor receptor (EGFR) inhibitor panitumumab. Two investigational groups, one receiving full-dose sotorasib (960 mg once daily) plus panitumumab and the other lower-dose sotorasib (240 mg once daily) plus panitumumab, were compared with a group receiving standard 3rd- and 4th-line treatment. PFS was significantly longer in both sotorasib–panitumumab groups than with standard care. This provides the first randomized trial evidence supporting KRAS targeting in colorectal cancer.

Why Combine Agents?

In CodeBreaK 300, the investigational groups received combination therapy with inhibitors of the activated oncogene KRAS G12C and EGFR . Support for this approach comes from preclinical and clinical studies of BRAF V600E or KRAS G12C inhibitors, which have shown that targeting the oncogene alone is insufficient in colorectal cancer. BRAF V600E-mutant tumors offer a useful model for understanding why combination treatment is needed. BRAF V600E-mutant cancers sometimes have simpler signaling networks in which BRAF V600E inhibition profoundly suppresses extracellular signal-regulated kinase (ERK) signaling. In the intestine, however, receptor tyrosine kinases (RTKs), particularly EGFR , are expressed at higher levels. These receptors make little contribution to signaling in colorectal cancers with mutated BRAF V600E, because high ERK activity activates negative feedback loops that suppress receptor signaling in these tumors with mutated BRAF V600E.

When treatment begins and ERK is inhibited, receptors are released from this negative feedback, activating the ERK pathway, allowing ERK signaling to rebound despite treatment and generating drug-resistant RAF dimers. The EGFR inhibitor in the combination is used to block this feedback reactivation. With KRAS G12C inhibitors, EGFR inhibitors similarly target the release of EGFR from negative feedback loops and prevent drug-resistant signaling downstream of EGFR (namely wild-type KRAS and neuroblastoma ras viral oncogene homolog [NRAS]).

It is unknown whether targeting RTKs in noncolorectal epithelial tumors will increase responses to KRAS G12C inhibitors; KRAS G12C inhibitors combined with EGFR antibodies are being evaluated in an ongoing trial in patients with lung and pancreatic cancer.

Why a Higher Dose?

The high RTK levels associated with colorectal cancer effectively raise the threshold for ERK pathway inhibition needed to shrink tumors. A higher drug dose is required to inhibit all ERK activation. CodeBreaK 300 suggests that clinical doses of current KRAS G12C inhibitors lie near a threshold where more potent medicines or higher doses change response rates. Despite the small sample, higher-dose sotorasib produced a higher response rate and longer PFS than the lower dose.

Cancers with a less prominent RTK network show less striking differences in response between different KRAS G12C inhibitors or different sotorasib doses. These findings are important for the FDA's Project Optimus, designed to identify dose levels of molecularly targeted agents that maximize effectiveness and safety. Deep target inhibition is needed for a response, but the dose required varies by tumor type. Reducing a dose to manage toxicity may limit effectiveness against some cancers.

KRYSTAL-10 Results Will Be Important

Progression-free survival was the primary endpoint in CodeBreaK 300. Final overall survival results will be important in this chemotherapy-resistant metastatic colorectal cancer population. Mature results from this trial and KRYSTAL-10 will provide much-needed insights. KRYSTAL-10 is a randomized trial in patients with advanced solid tumors carrying a KRAS G12C mutation, comparing second-line treatment with the KRAS G12C inhibitor adagrasib plus the EGFR antibody cetuximab against standard chemotherapy in phase 3.

In conclusion, CodeBreaK 300 marks an important and exciting beginning for targeting KRAS in colorectal cancer. The trial focused on cancers carrying a KRAS G12C mutation, testing the effectiveness of inhibitors developed specifically for these cancers and substantially advancing research in this field. KRAS G12C inhibitors, other new RAS inhibitors and a better understanding of treatment resistance increase the hope that patients with colorectal cancer carrying a KRAS mutation will benefit from the development of more effective therapeutic strategies.