ESMO 2023: Sotorasib + panitumumab prolongs PFS in chemorefractory KRASG12C-mutated mCRC

Clinical trial results showed limited efficacy of monotherapy with a KRAS^G12C inhibitor in patients with KRAS^G12C-mutated mCRC. Preclinical studies suggested upstream reactivation of EGFR signalling in the mitogen-activated protein kinase (MAPK) pathway as a dominant mechanism of CRC resistance to KRAS^G12C inhibition. Dual blockade of KRAS^G12C and EGFR has demonstrated suppression of MAPK signalling and cancer cell growth in vitro. [Lancet Oncol 2022;23:115-124; Cancer Discov 2020;10:1129-1139; Cell Rep 2022;39:110993]

“Combining KRAS^G12C inhibition with anti-EGFR therapy may be useful for treating patients with KRAS^G12C-mutated CRC,” Pietrantonio said.

In the single-arm, phase Ib CodeBreaK 101 trial involving 40 patients with chemorefractory KRAS^G12C-mutated mCRC, combined treatment with oral sotorasib 960 mg QD and intravenous panitumumab 6 mg/kg Q2W was associated with a confirmed overall response rate (ORR) of 30 percent – a rate 3-fold greater than that demonstrated with sotorasib monotherapy (9.7 percent) in the phase II CodeBreaK 100 trial (n=62). These results warranted further evaluation of sotorasib plus panitumumab in KRAS^G12C-mutated mCRC. [Ann Oncol 2022;33(Suppl 9):S1445-S1446; Lancet Oncol 2022;23:115-124]

CodeBreaK 300 study
The phase III, open-label, randomized, active-controlled CodeBreaK 300 trial compared the efficacy and safety of sotorasib plus panitumumab vs investigator’s choice of standard care in 160 patients with chemorefractory KRAS^G12C-mutated mCRC who had not received a KRAS^G12C inhibitor before. The patients were randomized to receive sotorasib 960 mg QD plus panitumumab 6 mg/kg Q2W (n=53), sotorasib 240 mg QD plus panitumumab 6 mg/kg Q2W (n=53), or standard care with T/T or regorafenib (n=54) until disease progression, unacceptable toxicity, initiation of another anticancer therapy, withdrawal of consent, or death. [Pietrantonio, et al, ESMO 2023, abstract LBA10; N Engl J Med 2023;doi:10.1056/NEJMoa2308795]

The primary endpoint was PFS as assessed by blinded independent central review (BICR), whereas key secondary endpoints were ORR and overall survival (OS).

“In the intention-to-treat population [median age, 62.0 years; male, 49.4 percent; ≥2 prior lines of treatment, 85.0 percent], most patients had received oxaliplatin, irinotecan and fluoropyrimidine [93.8 percent] and/or anti-angiogenic therapy [87.5 percent],” Pietrantonio noted. “Baseline patient characteristics were generally balanced across the three groups, except that right-sided primary tumours were more prevalent in the sotorasib 960 mg plus panitumumab group [45.3 percent] than the sotorasib 240 mg plus panitumumab [32.1 percent] and investigator’s choice groups [29.6 percent].”

Efficacy results
“Over a median follow-up of 7.8 months, BICR-assessed PFS was significantly prolonged with both sotorasib doses in combination with panitumumab. Median PFS was 5.6 months with sotorasib 960 mg plus panitumumab and 3.9 months with sotorasib 240 mg plus panitumumab, vs 2.2 months with standard care by investigator’s choice [960 mg dose vs standard care: hazard ratio (HR), 0.49; 95 percent confidence interval (CI), 0.30–0.80; p=0.006] [240 mg dose vs standard care: HR, 0.58; 95 percent CI, 0.36–0.93; p=0.030],” Pietrantonio reported. (Figure 1) [Pietrantonio, et al, ESMO 2023, abstract LBA10; N Engl J Med 2023;doi:10.1056/NEJMoa2308795]

“CodeBreaK 300 met its primary endpoint of PFS [with sotorasib plus panitumumab] vs standard care in patients with pretreated KRAS^G12C-mutated CRC. These results further suggest more clinically meaningful benefit with the 960 mg dose of sotorasib [than the 240 mg dose, although this trial was not powered to compare the two combination groups],” Pietrantonio said. (Figure 1)

BICR-assessed ORR was 26.4 percent in the sotorasib 960 mg group, 5.7 percent in the sotorasib 240 mg group, and 0 percent in the standard care group. Corresponding disease control rates were 71.7 percent, 67.9 percent and 46.3 percent. (Table 1)

According to Pietrantonio, tumour shrinkage of any extent occurred in 81 percent of patients in the sotorasib 960 mg group, 57 percent of patients in the sotorasib 240 mg group, and 20 percent of patients in the standard care group.

OS data were immature in the primary analysis. At the time of data cut-off, 34.4 percent of patients (n=55) had died.

Safety results

In CodeBreaK 300, the safety profile of the sotorasib-panitumumab combination was generally similar with both doses of sotorasib. No new safety issues or treatment-related fatal events were reported. [Pietrantonio, et al, ESMO 2023, abstract LBA10; N Engl J Med 2023;doi:10.1056/NEJMoa2308795]

Rates of grade ≥3 treatment-related adverse events (TRAEs) were 35.8 percent (n=19) with sotorasib 960 mg plus panitumumab and 30.2 percent (n=16) with sotorasib 240 mg plus panitumumab vs 43.1 percent (n=22) with standard care by investigator’s choice. In the sotorasib plus panitumumab groups, the most common grade ≥3 TRAEs were dermatitis acneiform (11.3 percent with 960 mg dose and 3.8 percent with 240 mg dose), hypomagnesaemia (5.7 percent and 7.5 percent), rash (5.7 percent and 1.9 percent) and diarrhoea (3.8 percent and 5.7 percent); none of these TRAEs were reported in the standard care group. Neutropenia (23.5 percent), anaemia (5.9 percent) and nausea (2.0 percent) were the most common grade ≥3 TRAEs in the standard care group. In the sotorasib plus panitumumab groups, neutropenia occurred in none of the patients, anaemia occurred in 1.9 percent of patients, while nausea occurred in 1.9 percent and 3.8 percent of patients on the 960 mg and 240 mg dose of sotorasib, respectively. (Table 2)

Rates of serious TRAEs were 5.7 percent in the sotorasib 960 mg group, 0 percent in the sotorasib 240 mg group and 7.8 percent in the standard care group. Rates of TRAEs leading to treatment discontinuation were 3.8 percent, 1.9 percent, and 2.0 percent, respectively.

AEs of interest in CodeBreaK 300 included hepatotoxicity. Rates of any-grade hepatotoxic AEs, consisted primarily of laboratory abnormalities, were 11.3 percent, 5.7 percent and 7.8 percent in the sotorasib 960 mg, sotorasib 240 mg and standard care groups, respectively.

Clinical significance of CodeBreaK 300
“CodeBreaK 300 is the first phase III trial investigating the effects of combining KRAS^G12C inhibition with anti-EGFR therapy [vs standard care by investigator’s choice] in heavily pretreated patients with KRAS^G12C-mutated mCRC,” pointed out Koopman. [Pietrantonio, et al, ESMO 2023, abstract LBA10; N Engl J Med 2015;372:1909-1919; Lancet 2013;381:303-312; N Engl J Med 2023;388:1657-1667]

“Despite the limited number of patients in CodeBreaK 300, the median PFS with investigator’s choice standard therapy closely aligns with [that of] T/T or regorafenib in other phase III trials, supporting the validity of CodeBreaK 300’s results,” she commented. “We are awaiting data on OS and quality of life, which will determine the role of sotorasib plus panitumumab in late-line treatment of KRAS^G12C-mutated mCRC.”