Possible New Standard for Treated Advanced CRC With KRAS Mutations

SAN DIEGO — A third of patients with previously treated unresectable/metastatic KRAS^G12C-mutated colorectal cancer (CRC) responded to a combination of targeted drugs, a preliminary prospective study showed.

The results showed objective responses in 32 of 94 patients treated with the KRAS inhibitor adagrasib (Krazati) and the EGFR inhibitor cetuximab (Erbitux). An additional 48 patients had stable disease, resulting in a disease control rate of 85.1%. After a median follow-up of 11.9 months, median overall survival (OS) was 15.9 months.

In a subgroup of 83 patients with paired tissue and blood samples, 27 of 29 responses occurred in patients with KRAS^G12C in circulating tumor (ct)DNA, reported Scott Kopetz, MD, PhD, of the University of Texas MD Anderson Cancer Center in Houston, at the American Association for Cancer Research meeting.

“We can acknowledge that current late-line standard-of-care therapies consistent with the population enrolled in this study produce response rates of 1-6% and median progression-free survival [PFS] of 1.9-5.7 months and overall survival [of 6.4-10.8 months], reiterating the need for more effective options,” said Kopetz. “Adagrasib and cetuximab demonstrated a clinically meaningful response rate of 34%, median progression-free survival of 6.9 months, and median overall survival of 15.9 months in these heavily pretreated patients.

“The safety profile is consistent with our prior known safety profiles. It was tolerable and consistent,” he added. “So this data really supports adagrasib plus cetuximab as a potential new standard of care for patients, and this dataset has been submitted to the FDA for consideration of accelerated approval.”

The results were published simultaneously in Cancer Discovery.

The study population was diverse, including 53.2% female, 13.8% Black/African American, and 17% Hispanic, providing reassurance that the results are applicable to clinical practice, said invited discussant Alex Adjei, MD, PhD, of the Cleveland Clinic. Acknowledging the caveats associated with cross-trial comparisons, he said the results compare favorably with those of the CodeBreaK 300 trial that evaluated sotorasib (Lumakras) plus panitumumab (Vectibix) in a similar patient population.

“Based on this, both agents in combination with EGFR inhibition are included in the NCCN [National Comprehensive Cancer Network] guidelines for refractory CRC that has KRAS^G12C mutations,” said Adjei.

Adagrasib currently has approval for previously treated KRAS^G12C-mutated non-small cell lung cancer. About 3-4% of CRC tumors harbor KRAS^G12C mutations, which are associated with poor prognosis.

Kopetz reported updated results from the phase I/II KRYSTAL-1 trial involving patients with unresectable/metastatic CRC. As previously reported, preliminary data showed a response rate of 19% with single-agent adagrasib, increasing to 46% with the addition of cetuximab in 28 patients. At that time, median PFS was 5.6 months with adagrasib alone and 6.9 months with the combination.

The 94 patients included in the updated report had a median treatment history of three prior lines of systemic therapy and as many as nine prior regimens. The lung (71.3%) and liver (63.8%) were the predominant sites of metastasis. Three-fourths of the patients had concurrent TP53 mutation.

The 32 responding patients all had partial responses. The median duration of tumor response was 5.8 months. About 90% of the patients had some degree of tumor shrinkage. Median PFS was 6.9 months, and the median OS included a 6-month OS of 87.8%. A subgroup analysis generally showed a consistent response across key subgroups, including number of prior systemic therapies, sites of metastatic disease, and concurrent mutations.

The most frequent any-grade treatment-related adverse events (TRAEs) were nausea (60.6%), vomiting (51.1%), diarrhea (48.9%), dermatitis acneiform (47.9%), fatigue (42.6%), dry skin (34.0%), hypomagnesemia (28.7%), headache (26.6%), and rash (22.3%). Grade ≥3 TRAEs were uncommon and included headache (3.2%), hypomagnesemia, nausea, dermatitis acneiform, and rash (2.1% each).

Kopetz said the global phase III, randomized KRYSTAL-10 trial has completed enrollment and will compare the combination of adagrasib and cetuximab versus FOLFIRI or mFOLFOX6 chemotherapy as second-line therapy in unresectable/metastatic CRC harboring KRAS^G12C mutations. The primary endpoints are PFS and OS.

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