SUMMARY: The FDA on June 21, 2024, granted accelerated approval to Adagrasib (KRAZATI®) plus Cetuximab (ERBITUX®) for adults with KRAS G12C-mutated locally advanced or metastatic Colorectal Cancer (CRC), as determined by an FDA-approved test, who have received prior treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy.
Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 152,810 new cases of colorectal cancer will be diagnosed in the United States in 2024 and about 53,010 patients will die of the disease. The lifetime risk of developing colorectal cancer is about 1 in 23.
Approximately 15-25% of the patients with colorectal cancer present with metastatic disease at the time of diagnosis (synchronous metastases) and 50-60% of the patients with colorectal cancer will develop metastatic disease during the course of their illness. First line treatment of metastatic colorectal cancer includes Oxaliplatin or Irinotecan, in combination with a Fluoropyrimidine and Leucovorin (FOLFOX or FOLFIRI respectively), along with a VEGF targeting agent such as Bevacizumab or EGFR targeting agents such as Cetuximab and Panitumumab (VECTIBIX®). Patients with Stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to EGFR targeted therapy. Patients who progress following these therapies are considered to have refractory disease. These patients sometimes are rechallenged with previously administered chemotherapeutic agents, but often receive STIVARGA® (Regorafenib), an oral multikinase inhibitor with antiangiogenic activity, or LONSURF® (a fixed dose combination of Trifluridine and Tipiracil). These therapies however have shown limited efficacy.
The KRAS (Kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. By relaying signals from outside the cell to the cell nucleus, the protein instructs the cell to grow, divide and differentiate. KRAS gene is in the Ras family of oncogenes, which also includes two other genes, HRAS and NRAS. When mutated, oncogenes have the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS G12C mutation occurs in approximately 12-15% of Non Small Cell Lung Cancers (NSCLC) and in 3-5% of colorectal cancers and other solid cancers. G12C is a single point mutation with a Glycine-to-Cysteine substitution at codon 12. This substitution favors the activated state of KRAS, amplifying signaling pathways that lead to oncogenesis. Currently, no targeted therapies driven by a positive-selection biomarker are approved specifically for the treatment of patients with KRAS-mutated colorectal cancer.
Adagrasib (KRAZATI®) is a potent, orally available, small molecule covalent inhibitor of KRAS G12C. This drug irreversibly and selectively binds KRAS G12C in its inactive, GDP-bound state. Unlike Sotorasib (LUMAKRAS®)), which is also a selective covalent inhibitor of KRAS G12C, Adagrasib has a longer drug half-life of 23 hours, as compared to 5 hours for Sotorasib, has dose-dependent extended exposure, and can penetrate the CNS. Unlike the efficacy of single-agent KRAS G12C inhibitors in Non Small Cell Lung Cancer with KRAS G12C mutation, KRAS G12C inhibition alone has limited activity in patients with colorectal cancer. This has been attributed to upstream reactivation of the Epidermal Growth Factor Receptor (EGFR) pathway resulting in treatment-induced resistance, following selective inhibition of KRAS G12C. However, dual KRAS G12C and EGFR blockade can overcome treatment resistance in patients with colorectal cancer with KRAS G12C mutation.
Cetuximab (ERBITUX®) is an anti-EGFR monoclonal antibody that is indicated for the treatment of RAS wild-type metastatic colorectal cancer, either as monotherapy or in combination with chemotherapy. Combining Cetuximab with Adagrasib may overcome treatment resistance and enhance the inhibition of KRAS-dependent signaling and improve outcomes.
The present FDA approval was based on the ongoing KRYSTAL-1, multicenter, expansion cohort Phase 1-2 trial, in which the use of Adagrasib as monotherapy or in combination with Cetuximab was evaluated in patients with previously treated metastatic colorectal cancer with mutant KRAS G12C. Eligible patients had locally advanced or metastatic KRAS G12C-mutated colorectal cancer, and had previous treatment with Fluoropyrimidine, Oxaliplatin, and Irinotecan-based chemotherapy, and a VEGF inhibitor, if eligible. These patients were heavily pretreated, having received a median of three prior lines of therapy, and their disease had shown resistance to previous treatments. Patients received Adagrasib 600 mg orally twice daily along with Cetuximab 500 mg/m2 IV every two weeks, or 400 mg/m2 IV as initial dose followed by 250 mg/m2 IV weekly. Tumor assessments were performed every 6 weeks. Treatment was continued until disease progression or unacceptable toxicity, Adagrasib discontinuation required Cetuximab discontinuation, however patients could continue Adagrasib if Cetuximab was discontinued. The median patient age was 59 years old, and 51% were women and both treatment groups were well balanced. The Primary efficacy endpoint of the study was the confirmed Overall Response Rate (ORR), assessed by Blinded Independent Central Review (BICR). Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS), and Safety. Efficacy was assessed in 94 (N=94) enrolled patients.
The study met its Primary endpoint and the ORR was 34%. All responses were Partial Responses (PR), indicating a reduction in tumor burden in responding patients. The median Duration of Response was 5.8 months, with 31% of responders experiencing a Duration of Response of at least 6 months. The most common adverse reactions were rash, nausea, vomiting, diarrhea, fatigue, musculoskeletal pain, hepatotoxicity, anemia, headache, dry skin, decreased appetite, abdominal pain, constipation, edema, cough, and peripheral neuropathy.
In conclusion, the KRYSTAL-1 trial has demonstrated that Adagrasib in combination with Cetuximab shows promising clinical activity and a manageable safety profile in heavily pretreated patients with metastatic CRC harboring the KRAS G12C mutation. These findings highlight a potential new treatment option for patients who have limited therapeutic alternatives and underscore the evolving landscape of precision medicine in oncology, particularly in targeting specific mutations that drive tumor growth and survival.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-cetuximab-kras-g12c-mutated-colorectal-cancer.
