Trial Data Show Potential Benefit of Krazati Plus Cetuximab in KRAS-Mutated Locally Advanced or Metastatic Colorectal Cancer

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The combination of Krazati (adagrasib) plus cetuximab showed promise in patients with previously treated KRAS^G12C-mutated locally advanced or metastatic colorectal cancer (CRC) in recently released trial findings. Data from the Phase I/II KRYSTAL-1 trial, presented at the 2024 American Association for Cancer Research annual meeting on April 8 and published in Cancer Discovery, show the potential of the therapy in a difficult to treat form of CRC that has limited treatment options.¹

“Patients with KRAS^G12C-mutated colorectal cancer have historically faced poor prognoses and remain in need of additional treatment options,” Scott Kopetz, MD, PhD, FACP, associate vice president for translational research, and professor, Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, said in a press release. “Although KRAS had previously been considered ‘undruggable,’ these data from KRYSTAL-1 reinforce the potential benefit of [Krazati] for these specific patients.”¹

In prior clinical trials, Krazati, an oral, highly selective KRAS^G12C inhibitor, has demonstrated a long half-life, extensive tissue distribution, and has been well tolerated.2

In February 2024, the FDA granted Priority Review status to the combination of Krazati with cetuximab for patients who received prior treatment for KRAS^G12C-mutated locally advanced or metastatic CRC based on findings from the open-label, multicenter, multiple expansion cohort of the Phase I/II KRYSTAL-1 trial.³ The application was assigned a Prescription Drug User Fee Act (PDUFA) goal date of June 21, 2024.

The KRYSTAL-1 trial enrolled patients with previously treated KRAS^G12C-mutated unresectable or metastatic CRC. The trial’s primary endpoint was objective response rate (ORR) as determined by blinded independent central review, with secondary endpoints that included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Among 94 patients administered Krazati plus cetuximab, at a median follow up of 11.9 months, the combination produced an ORR of 34%. For the secondary endpoints, median PFS was 6.9 months (95% CI, 5.7-7.4), median OS was 15.9 months (95% CI, 11.8-18.8), and median DOR was 5.8 months.

“[Krazati] plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRAS^G12C-mutated colorectal cancer,” wrote the authors of the study published in Cancer Discovery. “These data support a potential new standard of care and highlight the significance of testing and identification of KRAS^G12C mutations in patients with colorectal cancer.”⁴

In terms of safety, the profile for the Krazati/cetuximab combination was found to be manageable and consistent with the known safety profile of each individual medication.

In prior trials, the most common adverse events reported with Krazati were reduced appetite, diarrhea, dyspnea, edema, fatigue, hepatotoxicity, musculoskeletal pain, nausea, renal impairment, and vomiting. The most common grade three or four laboratory abnormalities reported with Krazati were reduced hemoglobin, reduced leukocytes, reduced lymphocytes, reduced neutrophils, hypokalemia, hyponatremia, elevated alanine aminotransferase, elevated alkaline phosphatase, elevated aspartate aminotransferase, and elevated lipase.⁵

“While there has been progress in the treatment of colorectal cancer, there remain groups of patients, such as those with KRAS-mutated cancers, who continue to need new, targeted treatment options,” Anne Kerber, senior vice president, head of late clinical development, Hematology, Oncology, Cell Therapy at Bristol Myers Squibb, said in the release. “These data highlight the significance of testing and identification of KRAS^G12C mutations in patients with CRC.”¹

References

1. KRAZATI (adagrasib) in Combination with Cetuximab Demonstrates Clinically Meaningful Activity as a Targeted Treatment Option for Patients with Previously Treated KRAS G12C-Mutated Locally Advanced or Metastatic Colorectal Cancer (CRC). Bristol Myers Squibb. News release. April 8, 2024. Accessed April 10, 2024. https://news.bms.com/news/corporate-financial/2024/KRAZATI-adagrasib-in-Combination-with-Cetuximab-Demonstrates-Clinically-Meaningful-Activity-as-a-Targeted-Treatment-Option-for-Patients-with-Previously-Treated-KRAS-G12C-Mutated-Locally-Advanced-or-Metastatic-Colorectal-Cancer-CRC/default.aspx

2. Mirati Therapeutics Announces U.S. FDA Accelerated Approval of KRAZATI™ (adagrasib) as a Targeted Treatment Option for Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) with a KRASG12C Mutation. Mirati Therapeutics. News release. December 12, 2022. Accessed April 10, 2024. https://www.multivu.com/players/English/8999051-mirati-therapeutics-fda-accelerated-approval-of-krazati-adagrasib/

3. U.S. Food and Drug Administration (FDA) Accepts Supplemental New Drug Application for KRAZATI® (adagrasib) in Combination with Cetuximab as a Targeted Treatment Option for Patients with Previously Treated KRAS G12C-Mutated Locally Advanced or... Bristol Myers Squibb. News release. February 20, 2024. Accessed April 10, 2024. https://news.bms.com/news/details/2024/U.S.-Food-and-Drug-Administration-FDA-Accepts-Supplemental-New-Drug-Application-for-KRAZATI-adagrasib-in-Combination-with-Cetuximab-as-a-Targeted-Treatment-Option-for-Patients-with-Previously-Treated-KRAS-G12C-Mutated-Locally-Advanced-or/default.aspx

4. Rona Yaeger, Nataliya V. Uboha, Meredith S. Pelster, Tanios S. Bekaii-Saab, Minal Barve, Joel Saltzman, Joshua K. Sabari, Julio A. Peguero, Andrew Scott Paulson, Pasi A. Jänne, Marcia Cruz-Correa, Kenna Anderes, Karen Velastegui, Xiaohong Yan, Hirak Der-Torossian, Samuel J. Klempner, Scott E. Kopetz; Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer. Cancer Discov 2024; https://doi.org/10.1158/2159-8290.CD-24-0217

5. Krazati. Prescribing information. Mirati Therapeutics Inc; 2022. Accessed April 10, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/216340s000lbl.pdf