KRAS G12C Sotorasib: [2022] An Updated Overview in CRC
Update On The CodeBreaK 100 Trial/KRAS G12C Sotorasib
The CodeBreaK 100 is a very large clinical trial that started with a safety study, phase 1, to define the recommended dose of Sotorasib (AMG 510) in patients with KRAS G12C-Mutations.
This study was open for patients with non-small cell lung cancer (NSCLC), patients with colorectal cancer and all solid tumors with KRAS G12C-Mutation. The study initially defined that the 9/60 milligram dose of Sotorasib (AMG 510) once daily is the recommended dose to go further. It was quite well tolerated with minimal side effects, and it showed significant activity in patients with non-small cell lung cancer (NSCLC) as well as patients with colorectal cancer and showed activity in patients with all solid tumors.
The activity was more robust in patients with non-small cell lung cancer (NSCLC) and led to further expansion in the phase 2 trial in non-small cell lung cancer (NSCLC). That led to the approval of Sotorasib as monotherapy in patients with non-small cell lung cancer (NSCLC) that had failed on prior standard therapies (prior systemic therapy).
Now I personally focus more on colorectal cancer, and what I would like to do is to focus more on the data and efficacy in colorectal cancer. The initial phase of the study on CodeBreaK 100 evaluated patients with colorectal cancer at different dose levels of Sotorasib (AMG 510) and showed that approximately three-quarters of those patients had disease control major shrinkages.
However, what we call a “partial response” occurred in only about 7% of patients. The initial assessment of the duration of disease control, or what we call median progression-free survival, was approximately four. This caused the study to be expanded to include a larger group of people with colorectal cancer and a KRAS G12C-Mutation. 62 of these people were given Sotorasib monotherapy at a fixed dose of 9/60 milligrams per day.
The data is once again from that study, which is part of the umbrella of the CodeBreaK 100, and shows an overall response rate of 10%, but the majority of patients had disease control with a median progression-free survival of 4 months. The overall survival in that study was a median of 10.6 months.
Now, note that the patients who enrolled in CodeBreaK 100 were patients who were resistant to standard-of-care therapy (prior systemic therapy), a patient population that has a poor outcome and is associated with a response rate of approximately 1 to 3% on approved salvage therapies such as Regorafenib or Trifluridine.
So that’s what we learned on the CodeBreaK 100 as far as colorectal cancer. What I would like to note, however, is that CodeBreaK 100 looks beyond monotherapy. Treatments with Sotorasib (AMG 510) in patients with non-small cell lung cancer (NSCLC) and colorectal cancer: It’s really an umbrella study that looks at different combinations to try to enhance the activity of Sotorasib (AMG 510) in both non-small cell lung cancer (NSCLC) and colorectal cancer.
Therefore, there are multiple studies within the CodeBreaK 100. It’s almost what we often call an “octopus study” because it has so many. Now, specifically in colorectal cancer, one combination that is of significant interest is the combination of Sotorasib with Panitumumab, again, in patients with KRAS G12C-Mutations, and patients with refractory disease who have failed standard of care and who have received Sotorasib plus Panitumumab were investigated in a cohort of 40 patients.
In those patients, the overall response rate was 30%. That’s the objective response rate for partial responses, and the medium progression-free survival was 5.7 months(complete or partial response). Now, what this particular study or cohort of patients teaches us or tells us is that if you add EGFR inhibition to KRAS inhibition in patients with KRAS G12C, you augment the activity of Sotorasib.
And you improve the outcome of patients with this robust efficacy data in an otherwise refractory patient population. were actually the background and rationale for the randomized clinical trial. That is a registrational trial that is ongoing today looking at Sotorasib plus Panitumumab plus Panitumumab versus the control arm of standard of care, either Regorafenib or Trifluridine, in the third-line treatment or beyond for patients with KRAS G12C-Mutated colorectal cancer.
4 Key Takeaways about KRAS G12C Sotorasib
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The CodeBreaK clinical development program for the drug sotorasib by Amgen is designed to study patients with advanced solid tumors containing the KRAS G12C mutation and address the unmet medical need for these cancers.
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The Phase 1 and 2, first-in-human, open-label multicenter CodeBreaK 100 research enrolled KRAS G12C-mutant solid tumor patients. Patients must have had systemic anticancer therapy appropriate for their tumor type and stage. Phase 2’s primary outcome was centrally determined objective response rate. 124 of the 126 NSCLC patients in the Phase 2 study had RECIST-evaluable lesions at baseline. The Phase 2 colorectal cancer (CRC) experiment has completed enrollment and published findings.
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CodeBreaK 200, a global Phase 3 randomized active-controlled study comparing sotorasib to docetaxel in KRAS G12C-mutated NSCLC, enrolled 345 patients. Previously treated, locally advanced and unresectable or metastatic KRAS G12C-mutated NSCLC was eligible. Overall survival, objective response rate, and patient-reported outcomes are secondary endpoints to progression-free survival.
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Amgen is enrolling patients in several Phase 1b studies of sotorasib monotherapy and combination therapy for advanced solid tumors (CodeBreaK 101). 12 A Phase 2 randomized study will test sotorasib in stage IV KRAS G12C-mutated NSCLC patients requiring first-line treatment.
What Is The Standard Of Care For Colorectal Cancer Patients?
KRAS mutations are present in about 50% of patients with colorectal cancer. KRAS mutations are associated with a worse outcome in patients with metastatic disease. However, there are different KRAS mutations and activating mutations that are associated with resistance to anti-EGFR therapy, particularly KRAS G12C, which is present in approximately 3–4% of patients with metastatic colorectal cancer.
This particular mutation is amenable to inhibition by a small molecule called Sotorasib. Sotorasib binds particularly to the Sistine Moty of KRAS G12C and locks it in the KRAS G12C GDP format, which is inactive and therefore blocks the signaling of KRAS G12C. Because Sotorasib is specific only to KRAS G12C mutation, and does not work in other KRAS mutations and therefore the design of the study of so Sotorasib was limited to patients with KRAS G12C.
Link to the Original Interview: https://oncologytube.com/v/40539
Read and Share the Article Here: https://oncologytube.com/v/41399
What Is The CodeBreaK 100 Trial Design?
The CodeBreaK 100 design is an umbrella study that began with a safety and dose determination. Component. Patients with KRAS G12C-Mutation were eligible, regardless of whether they had lung cancer, colorectal cancer, or any solid tumor with KRAS G12C-Mutation. The initial part of the study defined the 9/60 milligrams per day dose as the recommended dose, and subsequently, this study was turned into multiple phase 2 trials.
One, focusing on non-small cell lung cancer (NSCLC), led to the approval of Sotorasib (AMG 510) for non-small cell lung cancer (NSCLC) with an overall response rate of approximately 30% and a phase 2 clinical trial in colorectal cancer with the KRAS G12C mutation in patients who have progressed on prior chemotherapy. This showed activity but was not robust enough to lead to the approval of monotherapy.
So for thoracic and colorectal cancer, only 10% of patients, or 7%, actually responded in that initial cohort of patients. Since. A phase 2 trial with Sotorasib monotherapy was also performed, again confirming the activity of Sotorasib monotherapy but not enough to lead to the approval of monotherapy in colorectal cancer as the overall response rate was 10% and the medium progression-free survival was 4 months.
So we do know that we hit the target in colorectal cancer. We know that the monotherapy has activity, but it’s not substantial. As far as further design and further arms on CodeBreaK 100, and given the limited activity of Sotorasib (AMG 510) alone, there have been many additional arms to look at combinations of Sotorasib (AMG 510) plus additional agents.
I want to say that the most promising among those is the combination of Sotorasib (AMG 510) plus Panitumumab. And that is a very rational design because we know that when you hit KRAS and you block KRAS, you have feedback through the EGFR receptor. So blocking the EGFR receptor and KRAS G12C at the same time may result in better activity.
And indeed the CodeBreaK 100 had an arm of Sotorasib plus Panitumumab that investigated that combination in patients who have progressed on prior standard chemotherapy and who have KRAS G12C-Mutation and showed that the overall response rate in that setting was augmented to 30% and the medium progression-free survival improved to 5.7.
Because these exciting data have led to the activation of a recent phase 3 clinical trial that evaluates Sotorasib plus Panitumumab in comparison to standard of care in the third line setting treatment of patients with KRAS G12C with metastatic colorectal cancer.
How Do Physicians Address Patients With KRAS G12C?
I think, as a provider, it is important to know what the genomic profile of your patient has. You do not want to miss a KRAS G12C patient. Yes, those are only 4% of patients, but they may have durable clinical benefit from KRAS G12C targeting. I would advise everybody to be on the lookout for KRAS G12C, and if those patients have progressed on first- and second-line (treatment) therapy, please be on the lookout for clinical trials that allow patients to participate and receive KRAS G12C inhibitors.
There are many agents today that are being evaluated in patients with KRAS G12C. Adagrasib plus Rituximab is being evaluated in the second-line setting in patients with KRAS G12C-Mutated colorectal cancer. In addition, so-called thoracic (oncology), as we mentioned earlier, with significant efficacy data in refractory disease, are now being evaluated in a phase 3 clinical trial against Regorafenib or Trifluridine for patients with refractory colorectal cancer.
Marwan G. Fakih, MD – About The Author, Credentials, and Affiliations
Marwan G. Fakih, M.D., is a professor in the Department of Medical Oncology & Therapeutics Research, co-directs the Gastrointestinal Cancer Program, and is the Judy & Bernard Briskin Distinguished Director of Clinical Research. He has been named multiple times by Castle Connolly as one of “America’s Top Doctors.”
After doing well at the Roswell Park Cancer Institute in Buffalo, New York, and the University of Michigan in Ann Arbor, Dr. Fakih joined City of Hope in 2012. Dr. Fakih is from Lebanon, and he went to the American University of Beirut to get his medical degree.
Dr. Fakih is committed to educating his patients at every stage. As a prolific writer, he has written more than 200 papers and run many clinical trials in medical oncology in cancer research, most of which have been about finding new ways to treat advanced colorectal cancer.