Sotorasib Combo Approval May Improve PFS, Other Outcomes in KRAS G12C+ CRC

Marwan G. Fakih, MD

City of Hope Comprehensive Cancer Center

Duarte, California

The availability of sotorasib (Lumakras) plus panitumumab (Vectibix) is a “welcome step” in the treatment of patients with metastatic colorectal cancer (CRC) harboring KRAS G12C mutations, according to Marwan G. Fakih, MD.

In a discussion with CancerNetwork® on the FDA approval of sotorasib/panitumumab in KRAS G12C-mutant metastatic CRC, Fakih highlighted how this regulatory decision may positively impact progression-free survival (PFS), patient longevity, and other outcomes in this population. He described how this newly approved combination may offer advantages over prior standards of care in the field such as trifluridine/tipiracil (Lonsurf) and regorafenib (Stivarga) based on data from the phase 3 CodeBreaK 300 trial (NCT05198934), in which he served as the lead investigator.

According to Fakih, data from CodeBreaK 300 cement sotorasib/panitumumab as a third-line therapy option in KRAS G12C-mutated CRC. However, these findings, along with other ongoing clinical trials in the space, may warrant consideration for the use of the sotorasib-based regimen in earlier treatment settings. Additionally, he detailed other initiatives associated with novel RAS inhibitors and immunotherapy combinations that may yield further improvements in the CRC field.

“The FDA approval [of sotorasib/panitumumab] provides easier access, more visibility to the combination, an ability to discuss it more with providers, and, most importantly, improvements in the outcomes and survival of our patients with KRAS G12C mutations,” Fakih stated.

Fakih is a professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program at City of Hope Comprehensive Cancer Center in Duarte, California.

CancerNetwork®: What does the FDA approval of sotorasib plus panitumumab mean for patients with chemorefractory KRAS G12C-mutated metastatic CRC?

Fakih: The approval of sotorasib in combination with panitumumab is a welcome step for this patient population. KRAS G12C-mutated colorectal cancer affects [approximately] 4% of patients with metastatic colorectal cancer. Those individuals unfortunately have limited options beyond the first 2 lines of treatment. Typically, they receive a fluoropyrimidine such as 5-fluorouracil [5-FU], capecitabine [Xeloda], oxaliplatin, irinotecan, and bevacizumab [Avastin] within their first 2 lines of treatment, or even in their first line altogether. Following that, our options of care were limited to trifluridine as well as regorafenib at the time of the conduct of the CodeBreaK 300 trial. Both agents have limited effectiveness; response rates are less than 5%. Approximately half the patients progress by the 2-month mark, and the impact on survival, while positive, is quite limited.

Since the [CodeBreaK 300] study has been performed, another 2 options have become available, and those include fruquintinib [Fruzaqla] as well as trifluridine/bevacizumab as FDA-approved treatments for patients with metastatic colorectal cancer including KRAS G12C [mutations].2,3 But we recognize that even with those treatments, the overall response rate is still 6% or less. There is still a need for novel treatments.

The sotorasib/panitumumab [combination] reflects a targeted therapy for KRAS G12C, and the CodeBreaK 300 trial shows, conclusively, the positive impact on PFS. The updated data showed a median PFS of [5.6] months, which was superior to trifluridine or regorafenib on the standard-of-care arm, which was 2 months from this study. That was the primary end point of this study, clearly more than doubling the time to progression in patients with metastatic colorectal cancer. There was a strong trend towards improvement in overall survival. The study was a small phase 3 trial, so it was not powered to statistically confirm superiority from the overall survival.

But that’s important; it means that you are more likely to see responses. [Approximately] 30% of patients will have an objective response with this combination, which is higher than what you would expect with second-line treatment. This combination is approved in more of a third-line setting, but 30% is not a response rate we see with second-line chemotherapy in metastatic KRAS-mutated colorectal cancer, which means that this may palliate the symptoms related to metastatic disease as well. [It will not] just prolong the time to progression [or] the PFS, but also reduce the burden of disease in patients, which ultimately has a positive impact on their longevity.

How do other efficacy and safety findings from the CodeBreaK 300 trial support the clinical utility of sotorasib/panitumumab?

The good thing is that the CodeBreaK 300 study replicates prior phase 2 data that we had in this particular setting. The importance of the CodeBreaK 300 study is that it also looked at 2 different doses of sotorasib. It puts the issue to rest that the 960 mg dose should be used in favor of the 240 mg dose. The response rates were [approximately] 30% with the 960 mg daily sotorasib dose vs 7.5% for the 240 mg daily dose. The CodeBreaK 300 study confirms the dosage, not just the combination’s [efficacy]. Hopefully, that puts minds at ease as to what is the starting dose in this setting.

As far as safety, the combination was quite safe, and most of the adverse effects were related to the anti-EGFR therapy, panitumumab, with skin toxicity and electrolyte disturbances. Sotorasib itself has very minimal adverse effects, usually mild fatigue, mild elevations in liver function tests, and mild anemia.

How would this treatment be implemented into clinical practice?

The data [from CodeBreaK 300] may even have implications on second-line therapy. Frankly, in this setting, we now have a combination therapy that has a very favorable overall response rate, which appears to be even higher than one would expect, historically, with FOLFIRI/bevacizumab in the second-line setting after progressing on FOLFOX/bevacizumab in the first line, and vice versa. This is a discussion that I would have with patients. This is an easier regimen than systemic chemotherapy; it has a more favorable [adverse] effect profile. Perhaps it’s more appropriate to even think about it in the second-line treatment if our patients with KRAS G12C mutations avoid chemotherapy-related toxicity and leave the FOLFIRI and bevacizumab or FOLFOX/bevacizumab in the second line, which depends on what first-line [treatment] they receive.

The third-line treatment is an area of consideration. The CodeBreaK 300 study clearly cements this regimen as a third-line treatment, but opens the door for consideration for second-line treatment as well based on the efficacy data.

Are there any plans to further assess sotorasib/panitumumab in this patient population or in other diseases?

KRAS G12C is a rare alteration.If we look at other gastrointestinal malignancies, the frequency is even less than what we see in colorectal cancer. It’s in the order of 1%, and it makes it harder to proceed with combination therapy in a conclusive manner and to compare that to monotherapy and others. I think the field is now moving to consolidate in CRC with this combination and to look at sotorasib/panitumumab in earlier lines of treatment. A phase 1b clinical trial [NCT04185883] has evaluated the combination of FOLFIRI plus sotorasib and panitumumab in the first-line treatment of patients with KRAS G12C mutations, and those data were presented several months ago at the 2024 European Society for Medical Oncology Congress.4 The response rate was very favorable, exceeding 70%, suggesting that there’s potential synergy with chemotherapy with this combination. Similar data have also shown favorable efficacy in pretreated patients with the combination of chemotherapy with FOLFIRI, sotorasib, and panitumumab.

The next step is the ongoing randomized phase 3 clinical trial [NCT06252649] in the first-line setting, which is looking at FOLFIRI/bevacizumab vs FOLFIRI plus sotorasib and panitumumab to see if moving this combination earlier on in the management of metastatic CRC would provide an even bigger impact on the outcome.5

Beyond this approval, what other developments in the gastrointestinal cancer space may impact the treatment field in the future?

There are a lot of novel agents under development; specifically, [there is] a plethora of antibody drug conjugates that lead to a more concentrated administration of chemotherapy within tumors in a targeted fashion. Many of those studies are in phase 1 to phase 3 development. There are novel RAS inhibitors that are under investigation, some of them targeting KRAS G12B, and some of them targeting KRAS in general. The KRAS G12C space itself is crowded as well, with multiple agents being evaluated in that area.

We are all excited about the RAS inhibitors. There has also been development with immunotherapy, particularly with novel CTLA-4 inhibitors in combination with PD-1 or PD-L1 inhibitors in microsatellite stable colorectal cancer. The future is bright, and we are hoping that we will see more and more improvements for our patients.

References

1. FDA approves sotorasib with panitumumab for KRAS G12C-mutated colorectal cancer. News release. FDA. January 16, 2025. Accessed February 4, 2025. https://shorturl.at/1WviB
2. Takeda receives U.S FDA approval of Fruzaqla (fruquintinib) for previously treated metastatic colorectal cancer. News release. Takeda. November 8, 2023. Accessed February 4, 2025. https://bit.ly/3SwkD8U
3. FDA approves trifluridine and tipiracil with bevacizumab for previously treated metastatic colorectal cancer. News release. FDA. August 2, 2023. Accessed February 4, 2025. https://bit.ly/3DEWtjV
4. Siena S, Yamaguchi K, Rodriguez JCR, et al. 505O Sotorasib (soto), panitumumab (pani) and FOLFIRI in the first-line (1L) setting for KRAS G12C–mutated metastatic colorectal cancer (mCRC): safety and efficacy analysis from the phase Ib CodeBreaK 101 study. Ann Oncol. 2024;35(suppl 2):S429-S430. doi:10.1016/j.annonc.2024.08.574
5. Kim TW, Price T, Grasselli J, et al. A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with KRAS G12C–mutated metastatic colorectal cancer (CodeBreaK 301). J Clin Oncol. 2025;43(suppl 4):TPS326. doi:10.1200/JCO.2025.43.4_suppl.TPS326