Sotorasib Plus Panitumumab in Refractory KRAS G12C-Mutated Colorectal Cancer

Marwan G. Fakih, MD, City of Hope Comprehensive Cancer Center, highlights his recent publication in NEJM on sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. He provides background on the current treatment pathways for patients with KRAS G12C-mutated disease who are refractory to chemotherapy, details the design and intended outcomes of the study, and what the results show generally about the effectiveness of sotorasib plus panitumumab as well as specifically about the varying dosages administered.

Can you provide background on the current treatment pathways for patients with KRAS G12C-mutated CRC who are refractory to chemotherapy? Are new treatment options a growing need?

Dr. Fakih: I believe we understand that patients with KRAS mutations, whether it is KRAS G12C or other variants, generally experience a more restricted overall survival (OS) compared with patients with BRAF wild-type in colorectal cancer. Typically, these patients are limited to 2 effective chemotherapy options: FOLFOX with bevacizumab and FOLFIRI-bevacizumab. More recently, trifluridine-bevacizumab has become an option. However, despite these treatments, the median OS remains around the 2-year mark, and beyond 2 lines of therapy, responses become exceedingly rare in the third-line setting.

Recognizing this unmet need, KRAS G12C represents a subset of KRAS mutations found in about 4% of metastatic colorectal cancer patients. What distinguishes this mutation is its amenability to drug targeting; it can be inhibited by small molecules designed to target the cysteine moiety on KRAS G12C, thereby preventing its activation from the GDP to the GTP state, essentially “turning off” this molecular switch.

Sotorasib is among the small molecules developed to inhibit KRAS G12C. It is the first covalent small molecule inhibitor of KRAS G12C that entered clinical trials and exhibited clinical activity in patients with KRAS G12C mutations, both in colorectal cancer and non-small cell lung cancer. Addressing the unmet needs of this 4% patient subset after 2 lines of therapy, the goal has been to explore monotherapy inhibition with KRAS G12C inhibitors further in colorectal cancers bearing this mutation.

Previously, a phase 2 clinical trial published in Lancet Oncology demonstrated that using sotorasib as a single agent in patients with metastatic colorectal cancer carrying the KRAS G12C mutation showed some clinical activity. However, this activity was modest, with an objective response rate of nearly 10% and a median progression-free survival (PFS) of approximately 4 months. There is a clear imperative to improve upon these results.

Prior findings have suggested that solely targeting the MAP kinase pathway in colorectal cancer may not suffice. Preclinical data has consistently supported the idea that inhibiting the EGFR, along with its downstream elements like BRAF or KRAS, could result in synergistic activity. Furthermore, insights from the CodeBreaK 101 trial indicate potential additional benefits from combining panitumumab with sotorasib.

Can you detail the design and intended outcomes of your phase 3 study?

Dr. Fakih: Armed with this preclinical data and drawing from the safety data in CodeBreaK 101, the recently published study in the New England Journal of Medicine sought to evaluate the advantages of combining panitumumab and sotorasib as a combination therapy compared to the existing standard of care in settings beyond the third line. The control arm in this study comprised either trifluridine-tipiracil or regorafenib monotherapy—both Food and Drug Administration-approved agents for the third-line setting in colorectal cancer. This sets the context for the study.

Two doses of sotorasib were under scrutiny in this research: the 960 milligram dose, which is the recommended phase 2 dose based on previous phase 1 studies and is the approved monotherapy dose for KRAS G12C-mutated non-small cell lung cancer, and the 240 milligram dose level. The primary reason for assessing these 2 dosage levels was the inadequate evaluation of the lower-dose levels in earlier studies. There had been lingering concerns that the 960 milligram dose might not be essential, especially considering the nonlinear pharmacokinetics between the 240 and 960 milligram doses. Hence, this study aimed to conclusively address the dosing question and confirm whether 960 milligrams might be superior to 240 milligrams.

Consequently, the study was designed as a randomized phase 3 clinical trial to establish, with statistical significance, that the combination of sotorasib and panitumumab surpasses the available options in terms of PFS for patients with KRAS G12C mutations in a third-line setting. This design aimed to definitively prove the superiority of this combination therapy.

What did your results show generally about the effectiveness of sotorasib plus panitumumab as well as specifically about the varying dosages?

Dr. Fakih: The study successfully achieved its primary endpoint, focusing on PFS for both dosage levels of sotorasib—240 milligrams and 960 milligrams—meeting the predefined criteria for superiority against the standard of care. In comparison to the observed median PFS of 2.2 months for patients receiving the standard of care, the results were notable. At the 240 milligram dose level, the median PFS extended to 3.9 months. However, at the higher dose of 960 milligrams, the median PFS significantly increased to 5.6 months, indicating a more clinically substantial improvement.

Furthermore, the differences in response rates were apparent. The control arm exhibited a 0% overall response rate, aligning with prior trials that saw response rates of only 1% in initial registrational trials for regorafenib or trifluridine. In contrast, the higher dose level of sotorasib demonstrated a substantial objective response rate of 26.4%. Meanwhile, the lower sotorasib dose of 240 milligrams showed diminished response rates at 5.7%. Though the study was not explicitly designed for a statistical comparison between the 960 milligram and 240 milligram dose response rates, the clinical significance of these differences is evident.

While both dosage levels of sotorasib surpassed the control arm with a median PFS of only 2.2 months, the 5.6 months median PFS associated with the 960 milligram dose stands out as more clinically meaningful than the 3.9 months seen with the 240 milligram dose. Hence, considering the better response rate and more substantial PFS, the preference for treating patients leans towards the 960 milligram dose.

It is important to note that these findings align well with a phase 2 trial of sotorasib and panitumumab, showing similar response rates and median PFS at the 960 milligram level. This consistency across studies adds a reassuring layer of validity to the data obtained in this trial.

What are there toxicity findings for patients in the investigative arms? How do they dosages compare?

Dr. Fakih: It is reassuring that both the 960 and 240 milligram arms in this study exhibited excellent tolerability. Sotorasib, whether used alone or in combination with panitumumab, presents a notably favorable toxicity profile. The observed adverse effects were generally manageable, such as mild anemia, occasional mild elevations in aspartate aminotransferase and alanine aminotransferase levels, and minimal fatigue. This agent is highly tolerable overall.

It is worth noting that most of the adverse events observed in both the 240 and 960 milligram arms were related to panitumumab and aligned with the typical side effects associated with panitumumab monotherapy. These primarily involved skin-related issues and electrolyte imbalances, including hypomagnesemia or acneiform rash and other skin toxicities. However, these were manageable using supportive care strategies established for panitumumab monotherapy.

Consequently, the study provides substantial confidence regarding the safety of the 960 milligram dose level. This consistency in safety aligns well with earlier data derived from trials involving sotorasib at the 960 milligram dose level, whether used alone or in combination with panitumumab. Therefore, I see no hesitation in advocating for the use of the 960 milligram dose level, especially considering that these combinations are now endorsed by the National Comprehensive Cancer Network and are incorporated into the guidelines.

For patients with KRAS G12C mutations in third-line therapy for colorectal cancer, the 960 milligram dose level in conjunction with panitumumab appears to be the appropriate choice based on the safety and efficacy profile observed in this study.