CodeBreaK 300: Sotorasib + panitumumab prolongs PFS in metastatic CRC

The addition of sotorasib to panitumumab significantly improves progression-free survival (PFS) in patients with chemorefractory KRAS G12C-mutated metastatic colorectal cancer (CRC) compared with the investigator’s choice of standard-of-care (SoC) treatment, according to the CodeBreaK 300 trial presented at ESMO Asia 2023.

“Combining the KRAS G12C inhibitor sotorasib with the epidermal growth factor receptor inhibitor panitumumab showed promise in an early trial involving patients with chemorefractory CRC with mutated KRAS G12C, but additional data are needed,” said the researchers. [N Engl J Med 2023;doi:10.1056/NEJMoa2308795]

Hence, the researchers conducted a global, active-controlled, phase III trial involving 160 patients with KRAS G12C-mutated metastatic CRC. Participants were randomized in a 1:1:1 ratio to receive sotorasib 960 or 240 mg once daily in addition to panitumumab 6 mg/kg every 2 weeks or the investigator’s choice of SoC therapy (trifluridine/tipiracil or regorafenib). Patients continued treatment until disease progression, initiation of another anticancer treatment, withdrawal of consent, intolerance of treatment, or death.

At a median follow-up of 7.8 months, patients who have been treated with the 960-mg dose of sotorasib + panitumumab had a significantly longer median PFS, as assessed by blinded independent central review, compared with those receiving the investigator’s choice of therapy (5.6 vs 2.2 months; hazard ratio [HR], 0.49; two-sided p=0.006). [ESMO Asia 2023, abstract 91MO]

Similarly, participants treated with sotorasib 240 mg + panitumumab also demonstrated a significantly longer median PFS vs those receiving SoC therapy (3.9 vs 2.2 months; HR, 0.58; two-sided p=0.030).

Regarding key secondary endpoints, high objective response rates were observed with either dose of sotorasib + panitumumab, particularly those treated with the 960-mg sotorasib dose (26 percent), while none was reported in the SoC group.

The disease control rate was also higher among patients on sotorasib + panitumumab compared with those receiving the investigator’s choice of SoC therapy (72 percent [960 mg] and 68 percent [240 mg] vs 46 percent).

Overall survival data were still immature at data cut-off.

Safety profile

The most common grade ≥3 treatment-related adverse events (TRAEs) observed were dermatitis acneiform, hypomagnesemia, rash, and diarrhoea in the sotorasib + panitumumab groups and neutropenia, anaemia, and nausea in the SoC therapy group.

Both doses of sotorasib, as well as panitumumab, were tolerable, with no new safety signals identified and no fatal TRAEs reported.

A potential new SoC for CRC?

“The CodeBreaK 300 trial met its primary endpoint for superior PFS vs investigator’s choice of therapy in metastatic CRC,” said lead author Dr Yasutoshi Kuboki from the Experimental Therapeutics and GI Oncology Department at National Cancer Center Hospital East, Kashiwa, Japan.

“[Overall, combining] sotorasib with panitumumab led to a statistically significant improvement in PFS, with the 960-mg dose demonstrating a more clinically meaningful benefit,” Kuboki highlighted.

“These results, along with previous data from non-small cell lung cancer [trials], support sotorasib 960 mg as the sotorasib dose for metastatic CRC,” Kuboki noted. “Sotorasib 960 mg + panitumumab is a potential new SoC therapy for patients with chemorefractory KRAS G12C-mutated mCRC.”