FDA Grants Adagrasib Accelerated Approval for Treatment of KRAS G12C-Mutated CRC

Adagrasib (Krazati; Bristol Meyers Squibb) in combination with cetuximab (Erbitux; Eli Lilly and Company) receives accelerated approval from the FDA for treatment of adult patients with previously treated KRAS G12C-mutated locally advanced or metastatic colorectal cancer (CRC) who have received fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The decision is based on results from the phase 1/2 KRYSTAL-1 trial (NCT03785249), which demonstrated successful objective response rates (ORR) and duration of response (DOR) results in pretreated patients with CRC.¹

Adagrasib is a potent, oral administered small-molecule covalent inhibitor that targets KRAS G12C and prevents the KRAS protein from shifting into its active state, inhibiting the proliferation of malignant cells. Image Credit: © Jo Panuwat D - stock.adobe.com

CRC is one of the most common malignancies and is the third leading cause of cancer-related deaths in men and the fourth leading cause in women. As of 2024, an estimated 106,590 cases of colon cancer (54,210 in men and 52,380 in women) and 46,220 rectal cancer cases (27,330 in men and 18,890 in women) will be diagnosed. While rates of CRC diagnoses have dropped over the years in older adults, due to increased access to early screening and lifestyle modifications, rates of CRC in individuals younger than age 55 have been increasing by 1% to 2% per year.¹

KRAS is a frequently mutated oncogene, a cell which can transform into a tumor cell, that drives growth of tumors in approximately 50% of patients with CRC, as well as other malignant diseases. The KRAS protein shifts between active and inactive cycles and is responsible for cell survival, proliferation, and migration through regulated pathways. When genetically altered, the KRAS protein remains in the active cycle, which drives oncogenic signaling, contributing to tumor growth. Until the FDA accelerated approval of adagrasib, there was no approved therapy that specifically targeted the KRAS mutation in CRC.²

Adagrasib is a potent, oral administered small-molecule covalent inhibitor that targets KRAS G12C and prevents the KRAS protein from shifting into its active state, inhibiting the proliferation of malignant cells. Adagrasib has a long half-life of 23 hours, an attribute crucial to treating KRAS G12C, which regenerates every 24 to 48 hours.^3,4

KRYSTAL-1 is an open-label, multicenter, multiple expansion cohort phase 1/2 trial designed to assess the safety and efficacy of adagrasib in combination with cetuximab in 94 patients with colorectal cancer containing KRAS G12C mutations. The primary end point for the phase 2 cohort of the was the objective response rate (ORR), while secondary end points included the duration of response (DOR).^3,4

The results demonstrated a confirmed ORR of 34% (n=94, 95% CI: 25-45), indicating the study met its primary end point. Additionally, the study authors observed a median DOR of 5.8 months (95% CI: 4.2-7.6). Serious adverse events (AEs) occurred in 30% of patients, as well as common AEs in approximately 20% of participants, including rash, nausea, fatigue, abdominal pain, decreased appetite, and musculoskeletal pain.^3,4

“Today’s approval of adagrasib in CRC is the second in the US for this therapy,” Wendy Short Bartie, senior vice president, US oncology and hematology at Bristol Myers Squibb, said in a press release. “We are proud to make adagrasib—the first KRAS G12C inhibitor to be FDA approved beyond non-small cell lung cancer—available to CRC patients, and look forward to further evaluating adagrasib [for other indications].”⁴

References

1. Key statistics for colorectal cancer. American Cancer Society. Accessed June 24, 2024. https://www.cancer.org/cancer/types/colon-rectal-cancer/about/key-statistics.html
2. Sun L, Chua C, Tian W, et al. MicroRNA signaling pathway network in pancreatic ductal adenocarcinoma. Journal of Genetics and Genomics. August 6, 2015. doi:10.1016/j.jgg.2015.07.003.
3. Yaeger R, Weiss J, Pelster M, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Enlg J Med. December 21, 2022. doi: 10.1056/NEJMoa2212419.
4. Bristol myers squibb announces u.s. fda accelerated approval of krazati® (adagrasib) in combination with cetuximab for adult patients with previously treated kras g12c-mutated locally advanced or metastatic colorectal cancer (crc). Business Wire. June 21, 2024. Accessed June 24, 2024. https://www.businesswire.com/news/home/20240621519236/en
5. Mirati Therapeutics Inc. Phase 1/2 study of MRTX849 in patients with cancer having a KRAS G12C mutation KRYSTAL-1. ClinicalTrials.gov. Updated June 21, 2024. Accessed June 24, 2024. https://clinicaltrials.gov/study/NCT03785249