Targeted combination therapy triumphs in KRAS-positive metastatic colorectal cancer

MADRID — The combination of a KRAS G12C inhibitor and an EGFR inhibitor significantly improved progression-free survival (PFS) compared to standard of care in patients with chemotherapy-resistant metastatic colorectal cancer (mCRC). was shown in the randomized phase III CodeBreaK 300 trial.

With a median follow-up of 7.8 months, median PFS was 5.6 months for patients treated with standard-dose sotorasib (Lumaclas) 960 mg and panitumumab (Vectibix) compared with investigator-selected regorafenib (Stivarga). The median PFS for patients treated with was 2.2 months. or trifluridine-tipiracil (Lonsurf), hazard ratio 0.49 (95% CI 0.30-0.80; P=0.006), as reported by Filippo Pietrantonio, MD, National Institute of Oncology, Milan, during the European Society of Medical Oncology (ESMO) annual meeting.

Median PFS for low-dose sotorasib 240 mg combined with panitumumab was 3.9 months (HR 0.58, 95% CI 0.36-0.93; P=0.03), according to the study. New England Medical Journal.

Dr. Pietrantonio said the combination “could become a new standard of care for previously treated patients.” KRAS G12C– Mutated metastatic colorectal cancer. ”

Pietrantonio said the overall survival results were immature at the time of analysis. Objective response was 26.4% with 960 mg sotorasib/panitumumab, 5.7% with 240 mg sotorasib/panitumumab, and 0% with standard therapy.

Discussant Miriam Koopman, MD, from the University Medical Center in Utrecht, the Netherlands, said the trial showed promising results with high tumor regression rates and a significant PFS benefit in heavily pretreated mCRC patients. However, “the patient’s symptoms have improved.” PFS alone is not sufficient in late metastatic settings. We really need overall survival data. ”

In explaining the rationale for the study, Pietrantonio said: KRAS G12C is a driver mutation that occurs in approximately 3% to 4% of mCRC patients and may be associated with poor prognosis. Furthermore, in patients with disease refractory to initial therapy, standard late-stage treatments with trifluridine tipiracil or regorafenib have limited efficacy and come at the cost of toxicity.

inside Phase Ib CodeBreaK 101 studythe combination of sotorasib and panitumumab achieved an overall response rate of 30% in patients with: KRAS G12Cmutated mCRC suggests that this combination is an effective strategy.

Koopman said the number of patients in CodeBreaK 300 (slightly more than 50 in each arm) suggests that “the nature of the Phase III study is questionable.”

However, she noted that the median PFS of 0f 2.2 months in the control arm of CodeBreaK 300 was comparable to treatment arms containing trifluridine tipiracil or regorafenib in other phase III trials in heavily pretreated mCRC. “This study supports the validity of the results for sotorasib and panitumumab in CodeBreaK.” . ”

Professor Koopman also noted that the results of the phase III SUNLIGHT trial testing bevacizumab (Avastin) and trifluridine tipiracil set a new standard for last-line treatment for patients with mCRC, although the study did not provide a subgroup analysis. He pointed out that he had not done so.patient KRAS G12C mutation.

Therefore, “there is a need to compare the combination of sotorasib and panitumumab with the combination of bevacizumab and trifluridine-tipiracil in patients with the disease.” KRAS G12C-It’s a mutated tumor,” she said.

in code break 300, a total of 160 patients were randomized 1:1:1 to either 960 mg sotorasib and panitumumab, 240 mg sotorasib and panitumumab, or standard treatment. Overall, the median age of study participants was 62 years, and 49.4% were male.

Of these patients, 15% had received 1 prior line of therapy and 85% had received 2 or more prior lines of therapy. More patients had right-sided tumors in the 960 mg sotorasib group (45.3%) compared with the sotorasib 240 mg group and the standard-of-care group (32.1% and 29.6%, respectively).

Median duration of response was 4.4 months in the sotorasib 960 mg arm, but could not be estimated due to insufficient number of responses in other arms.

Treatment-related grade 3 or higher adverse events occurred in 35.8%, 30.2%, and 43.1% of patients in the sotorasib 960 mg, sotorasib 240 mg, and standard treatment groups, respectively. The most common adverse events seen with sotorasib/panitumumab were skin-related toxic effects (rash and acneiform dermatitis) and hypomagnesemia, with neutropenia and nausea being the most common in the standard treatment arm. It was common.