Targeted Combination Wins in KRAS-Positive Metastatic Colorectal Cancer

— Standard dose of sotorasib plus panitumumab reduced risk of progression by 51% vs standard care


MADRID -- The combination of a KRAS G12C inhibitor and an EGFR inhibitor significantly improved progression-free survival (PFS) compared with standard treatment in patients with chemorefractory metastatic colorectal cancer (mCRC), the randomized phase III CodeBreaK 300 trial showed.

At a median follow-up of 7.8 months, patients treated with the standard dose of sotorasib (Lumakras) 960 mg plus panitumumab (Vectibix) had a median PFS of 5.6 months versus 2.2 months for those treated with an investigator's choice of regorafenib (Stivarga) or trifluridine-tipiracil (Lonsurf), with a hazard ratio of 0.49 (95% CI 0.30-0.80, P=0.006), reported Filippo Pietrantonio, MD, of the Istituto Nazionale dei Tumori in Milan, during the European Society for Medical Oncology (ESMO) annual congress.

The median PFS at a lower sotorasib dose of 240 mg plus panitumumab was 3.9 months (HR 0.58, 95% CI 0.36-0.93, P=0.03), according to the study, which was also published in the .

Pietrantonio noted that the combination "is a potential new standard-of-care therapy for patients with previously treated KRAS G12C-mutated metastatic colorectal cancer."

Overall survival results were immature at the time of the analysis, Pietrantonio said. The objective response was 26.4% with 960-mg sotorasib/panitumumab, 5.7% with 240-mg sotorasib/panitumumab, and 0% with standard care.

Discussant Miriam Koopman, MD, PhD, of the University Medical Center in Utrecht, the Netherlands, noted that while the trial showed promising results with a high percentage of tumor shrinkage, and a significant PFS benefit in heavily pretreated patients with mCRC, "improvement in PFS alone is not enough in a late-line metastatic setting. We really need overall survival data."

In describing the rationale for the study, Pietrantonio noted that KRAS G12C is a driver mutation that occurs in approximately 3% to 4% of patients with mCRC and may be associated with poor prognosis. Moreover, in patients with disease refractory to initial therapies, the standard late-line treatments of trifluridine-tipiracil or regorafenib have shown limited efficacy, and at a cost of toxic effects.

In the , the combination of sotorasib and panitumumab led to an overall response of 30% in patients with KRAS G12C-mutated mCRC, suggesting that the combination is an effective strategy.

Koopman said the number of patients in CodeBreaK 300 -- slightly more than 50 patients in each arm -- suggested that "the phase III nature of the study can be questioned."

However, she noted that the median PFS 0f 2.2 months in CodeBreaK 300's control arm was comparable to treatment arms containing trifluridine-tipiracil or regorafenib in other phase III trials in heavily pretreated mCRC, "supporting the validity of the outcome of sotorasib and panitumumab in CodeBreaK."

Koopman also pointed out that results from the phase III SUNLIGHT trial -- which tested bevacizumab (Avastin) plus trifluridine-tipiracil -- provided a new standard for last-line treatment of patients with mCRC, although this study did not provide a subgroup analysis of patients with a KRAS G12C mutation.

Thus, "we need a comparison of sotorasib plus panitumumab versus bevacizumab plus trifluridine-tipiracil in patients with a KRAS G12C-mutated tumor," she said.

In , a total of 160 patients were randomized 1:1:1 to either 960-mg sotorasib plus panitumumab, 240-mg sotorasib plus panitumumab, or standard treatment. Overall, the median age of the study participants was 62, and 49.4% were men.

Of these patients, 15% had received one previous line of therapy, and 85% had received two or more previous lines. More patients in the 960-mg sotorasib group (45.3%) had a right-sided tumor compare with the 240-mg sotorasib and standard-care groups (32.1% and 29.6%, respectively) .

Median duration of response was 4.4 months in the 960-mg sotorasib group, but not estimated in other groups due to an insufficient number of responses.

Treatment-related grade ≥3 adverse events occurred in 35.8%, 30.2%, and 43.1% of patients in the sotorasib 960 mg, sotorasib 240 mg, and standard-care groups, respectively. Skin-related toxic effects (rash and dermatitis acneiform) and hypomagnesemia were the most common adverse events seen with sotorasib/panitumumab, while neutropenia and nausea were the most common in the standard-care group.

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.


The study was funded by Amgen.

Pietrantonio reported financial relationships with Amgen, Astellas Pharma, Bayer, Bristol Myers Squibb, GSK, Merck KGaA, Merck Sharp & Dohme, Pierre Fabre, and Servier; co-authors also reported multiple relationships with industry.

Koopman reported financial relationships with Amgen, Bayer, Bristol Myers Squibb, GSK, Merck-Serono, Nordic Pharma, Personal Genome Diagnostics, Pierre Fabre, Roche, Servier, Sirtex, and Sanofi-Aventis.

Primary Source

New England Journal of Medicine

Source Reference: Fakih MG, et al "Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C" N Engl J Med 2023; DOI: 10.1056/NEJMoa2308795.