EAY191-E5 (A ComboMATCH Treatment Trial) – Testing the Use of AMG 510 (Sotorasib) and Panitumumab as a Targeted Treatment for KRAS G12C Mutant Solid Tumor Cancers 

The study chair for this treatment trial is Kristen R. Spencer, DO, MPH (New York University/NYU Langone Perlmutter Cancer Center), and the translational co-chair is Dustin A. Deming, MD (University of Wisconsin/UW Carbone Cancer Center).*

Sotorasib is an oral medication that is approved by the US Food and Drug Administration (brand name Lumakras™) as a single therapy for the treatment of adults with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC) who have received at least one prior systemic cancer treatment. It is in a class of medications called KRAS inhibitors.

The KRAS gene plays an important role in controlling how cells grow and their ability to survive. It usually cycles between ‘off’ and ‘on’ states as needed, but the G12C mutation keeps KRAS in the ‘on’ state, triggering uncontrolled cell growth. Sotorasib works by attaching itself to the KRAS G12C protein and disabling it.

However, not all tumors with a KRAS G12C mutation respond to KRAS inhibitor drugs. And even those that do tend to quickly develop resistance to them.

The phase 2 trial EAY191-E5 (ComboMATCH-E5), part of the ComboMATCH precision medicine initiative, is based on preclinical research indicating that adding an epidermal growth factor receptor (EGFR) inhibitor to KRAS G12C inhibition can be synergistic. This trial will compare sotorasib with or without the EGFR antagonist panitumumab across advanced solid tumor types. Researchers seek to confirm evidence of synergistic clinical activity with these two targeted drugs in combination (Yasutoshi K. Nat Med. January 2024).

Panitumumab is a monoclonal antibody that binds to the EGFR protein and slows or stops the growth of cancer cells. Panitumumab is FDA-approved (brand name Vectibix®) as a single therapy for adults with confirmed wild-type RAS metastatic cancers of the colon and rectum. Wild-type RAS is cancer without mutations in the KRAS and NRAS genes.

The ComboMATCH-E5 trial includes two patient cohorts:

• Cohort One aims to enroll 66 patients with KRAS G12C-mutated advanced cancer who have not received prior KRAS G12C inhibitor therapy. Participants will be randomized 1:1 to receive sotorasib and panitumumab or sotorasib alone. Patients may have any solid tumor cancer except NSCLC or colorectal cancer (CRC); those patients are excluded because FDA-approved treatments already exist for those cancer types, as described above.
• Cohort Two aims to enroll 39 patients with KRAS G12C-mutated advanced cancer who have received prior KRAS G12C inhibitor therapy. All participants will be assigned to receive sotorasib and panitumumab in combination. Patients with NSCLC or CRC are included if the disease has progressed despite receiving the FDA-approved treatment. Patients cannot have been previously treated with a KRAS G12C inhibitor in combination with an EGFR inhibitor.

Very little information is available on resistance mechanisms to KRAS G12C inhibitors across all cancer types or the potential ability of this combination therapy to overcome this resistance. Therefore, patients in Cohort One who receive sotorasib alone will be eligible to enroll in Cohort Two if they experience progression.

Enrollment to ComboMATCH-E5 will be limited to 15 patients in any cancer type. This is to ensure that the trial includes multiple types of cancer. 

Both sotorasib and panitumumab will be given at FDA-approved doses. Treatment will continue until disease progression or intolerable toxicity. Tumor imaging reassessment will occur every 8 weeks. The trial's primary endpoints are progression-free survival (Cohort One) and the overall response rate (Cohort Two).

To take part in this treatment trial, patients must first enroll in the ComboMATCH registration trial (EAY191) to help determine eligibility. 

Learn more about EAY191-E5 at ecog-acrin.org.

EAY191-E5 is part of ComboMATCH, a large precision medicine initiative with a coordinated set of clinical trials evaluating novel drug combinations. The ComboMATCH patient registration trial is being led by the ECOG-ACRIN Cancer Research Group and National Cancer Institute; treatment trials are being led by the Alliance for Clinical Trials in Oncology, Children’s Oncology Group, ECOG-ACRIN, NRG Oncology, and SWOG Cancer Research Network.

*Dr. Spencer chairs the ECOG-ACRIN Genomics Subcommittee and Clonal Hematopoiesis Working Group, both part of the Developmental Therapeutics Committee, which Dr. Deming chairs.