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The FDA Approves Sotorasib With Panitumumab for Treatment of Patients with KRAS G12C-Mutated Metastatic Colorectal Cancer

Key Takeaways

  • Sotorasib and panitumumab received FDA approval for KRAS G12C-mutated mCRC, based on CodeBreaK 300 study results showing improved progression-free survival.
  • KRAS G12C mutations occur in 3-4% of mCRC cases and are associated with poor treatment responses and outcomes.
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Data from the CodeBreaK 300 trial supported the FDA's approval.

Sotorasib (Lumakras, Amgen Inc) with panitumumab (Vectibix, Amgen Inc) received FDA approval for adult patients with KRAS G12C-mutated metastatic colorectal cancer (mCRC) who were previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. Additionally, they approved the therascreen KRAS RGQ PCR Kit (QIAGEN GmbH) as a companion diagnostic device to aid in identifying patients who may be eligible for these therapies.1

AI depiction of colorectal cancer | Image Credit: © Ruby Stock - stock.adobe.com

AI depiction of colorectal cancer | Image Credit: © Ruby Stock - stock.adobe.com

CRC is the third leading cause of cancer-related mortality in the United States, accounting for approximately 11% of all diagnoses. Although survival outcomes in earlier stages of disease are favorable, those with metastatic disease or mutations have significantly worse outcomes. KRAS G12C mutations occurs in an estimated 3% to 4% of patients with mCRC and are among the most common genetic alterations in CRC. Presence of these mutations is associated worse treatment responses and overall outcomes.2

Sotorasib is a KRAS G12C inhibitor that blocks downstream proliferation and survival signaling of cancerous cells. It originally received accelerated approval from the FDA on May 28, 2021, for treatment of adult patients with KRAS G12C‑mutated locally advanced or metastatic non–small cell lung cancer. The decision was based on favorable data from the CodeBreaK 100 trial (NCT03600883).3-5

Panitumumab is the first and only FDA approved human monoclonal anti-EGFR antibody for treatment of patients with EGFR-expressing mCRC following disease progression after prior treatment with fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy. It was approved in 2006, which was followed by an additional approval in 2014 for use in combination with leucovorin calcium, fluorouracil, and oxaliplatin as first-line treatment in patients with wild-type KRAS (exon 2) mCRC.2

The FDA approval of sotorasib with panitumumab was based on data from the phase 3 multicenter, randomized, open-label, active-controlled CodeBreaK 300 (NCT05198934) study, which evaluated the safety and efficacy of sotorasib and panitumumab compared with standard of care (trifluridine/tipiracil or regorafenib) in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (mCRC).6

KRAS G12C mutations were identified from tissue samples using the QIAGEN GmbH kit. A total of 160 patients were randomized 1:1 to receive either 960 mg of sotorasib once daily plus panitumumab (n=53), 240 mg of sotorasib once daily plus panitumumab (n=53), or the investigator’s choice of trifluridine–tipiracil or regorafenib (standard care; n=54). The primary end point of the study was progression-free survival (PFS), with secondary end points of overall survival (OS) and objective response (OR).3

"In metastatic colorectal cancer, KRAS mutations are historically associated with worse mortality rates and inferior outcomes compared to non-mutated tumors, and standard treatment options have shown minimal benefit," Marwan G. Fakih, MD, primary study investigator and co-director of the Gastrointestinal Cancer Program at the City of Hope, said in a press release. "The CodeBreaK 300 study showed superior progression-free survival compared to the investigated standard of care and represents a clinically meaningful benefit for patients with KRAS G12C-mutated metastatic colorectal cancer."2

At a median follow-up of 7.8 months, patients receiving 960 mg of the combination therapy achieved a PFS of 5.6 months (95% confidence interval [CI], 4.2 to 6.3) compared with 3.9 months (95% CI, 3.6 to 5.7) in the 240 mg arm. For patients receiving the standard care, there was a PFS of 2.0 months (95% CI, 1.9 to 3.9). OS data are maturing; however, the OR was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960 mg, 240 mg, and standard care groups, respectively.3

Grade 3 or higher treatment related adverse events were reported in 35.8%, 30.2%, and 43.1% of patients in the 960 mg, 240 mg, and standard care arms, respectively. The most common were skin-related toxic effects and hypomagnesemia when treated with sotorasib and panitumumab.3

"There is an immense need for continued innovation and precision medicine to help address metastatic colorectal cancer," Michael Sapienza, chief executive officer of the Colorectal Cancer Alliance, said in a press release. "This new combination approach is an important breakthrough for patients with KRAS G12C-mutated metastatic colorectal cancer, offering a new beneficial treatment option for patients living with this devastating and challenging disease."2

REFERENCES
1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. FDA. January 16, 2025. Accessed January 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-sotorasib-panitumumab-kras-g12c-mutated-colorectal-cancer?utm_medium=email&utm_source=govdelivery
2. FDA approves Lumakras (sotorasib) in combination with Vectibix (panitumumab) for chemorefractory KRAS G12C metastatic colorectal cancer. News release. Amgen. January 17, 2025. Accessed January 17, 2025. https://www.amgen.com/newsroom/press-releases/2025/01/fda-approves-lumakras-sotorasib-in-combination-with-vectibix-panitumumab-for-chemorefractory-kras-g12cmutated-metastatic-colorectal-cancer?_gl=1*9iwnxm*_up*MQ..*_ga*MTU3NDgxOTUzOC4xNzM3MTI0MjI2*_ga_CBMSV0J9VL*MTczNzEyNDIyNS4xLjAuMTczNzEyNDIyNS4wLjAuMA..
3. Fakih M, Salvatore L, Esaki T, et al. Sotorasib plus Panitumumab in refractory colorectal cancer with mutated KRAS G12C. N J Engl Med. October 22, 2023. doi: 10.1056/NEJMoa2308795.
4. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC. FDA. May 28, 2021. Accessed January 17, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sotorasib-kras-g12c-mutated-nsclc
5. A Phase 1/​2, study evaluating the safety, tolerability, pk, and efficacy of sotorasib (amg 510) in subjects with solid tumors with a specific KRAS mutation (CodeBreaK 100). Updated October 4, 2024. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT03600883
6. Sotorasib and panitumumab versus investigator's choice for participants with kirsten rat sarcoma (KRAS) p.G12C mutation (CodeBreak300). Updated October 15, 2024. Accessed January 17, 2025. https://clinicaltrials.gov/study/NCT05198934
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