Panitumumab + mFOLFOX6 ups OS in 1L left-sided RAS wild-type mCRC in Japanese trial

Panitumumab plus modified FOLFOX6 (mFOLFOX6; fluorouracil, leucovorin, and oxaliplatin) as first-line therapy significantly improves overall survival (OS) vs bevacizumab plus mFOLFOX6 in patients with left-sided RAS wild-type (wt) metastatic colorectal cancer (mCRC), results of the Japanese PARADIGM trial have shown.

The phase III, open-label, multicentre trial included 823 patients with RASwt mCRC, an Eastern Cooperative Oncology Group performance status of 0 or 1, and a life expectancy of ≥3 months. The patients were randomized 1:1 to receive mFOLFOX6 in combination with panitumumab or bevacizumab. The primary endpoint of OS was hierarchically tested, first in patients with left-sided primary tumours (panitumumab group, n=312; bevacizumab group, n=292), followed by the overall population (panitumumab group, n=400; bevacizumab group, n=402) only if statistical significance was shown in the left-sided population. [Yoshino T, et al, ASCO 2022, abstract LBA1]

“Baseline patient characteristics were well balanced between the panitumumab and bevacizumab groups in both the left-sided and overall populations,” said investigator Dr Takayuki Yoshino of the National Cancer Center Hospital East in Kashiwa, Japan.

After a median follow-up of 61 months, median OS in the left-sided population was 37.9 months vs 34.3 months in the panitumumab vs bevacizumab group (stratified hazard ratio [HR], 0.82; 95 percent confidence interval [CI], 0.68–0.99; p=0.031). “The OS curves began to separate from around 28 months after randomization,” reported Yoshino.

In the overall population, median OS was 36.2 months vs 31.3 months for panitumumab vs bevacizumab (stratified HR, 0.84; 95 percent CI, 0.72–0.93; p=0.030). However, this difference appeared to be driven by the left-sided population, as no significant OS improvement was seen in patients with right-sided primary tumours in an exploratory analysis (median, 20.2 months vs 23.2 months; stratified HR, 1.99; 95 percent CI, 0.79–1.51).

Progression-free survival (PFS) did not differ significantly between the two treatment groups in the left-sided (stratified HR, 0.98; 95 percent CI, 0.82–1.17) and overall (stratified HR, 1.01; 95 percent CI, 0.87–1.18) populations.

However, response rates were higher with panitumumab vs bevacizumab in both the left-sided (80.2 percent vs 68.6 percent) and overall (74.9 percent vs 67.3 percent) populations. Median tumour shrinkage was 59.4 percent vs 43.6 percent in the left-sided population, and 57.3 percent vs 43.6 percent in the overall population. Median duration of response was longer with panitumumab vs bevacizumab in the left-sided population (13.1 months vs 11.2 months).

The improved tumour responses with panitumumab vs bevacizumab translated into higher R0 resection rates in patients treated with the anti-EGFR antibody in both the left-sided (18.3 percent vs 11.6 percent) and overall (16.5 percent vs 10.9 percent) populations.

“Grade ≥3 adverse events [AEs] occurred in 71.8 percent vs 64.9 percent of patients in the panitumumab vs bevacizumab group, with AEs leading to treatment discontinuation in 23.8 percent vs 18.4 percent of patients. Both treatments had manageable safety profiles, with no new safety signals identified,” said Yoshino.

As expected, panitumumab was associated with higher rates of skin, nail and mucosal AEs (such as acne-like dermatitis, stomatitis, paronychia, and dry skin) than bevacizumab.

“These results support panitumumab plus mFOLFOX6 as a first-line therapy for patients with RASwt left-sided mCRC,” Yoshino concluded.

Results of PARADIGM are similar to those of the European FIRE-3 trial, which showed significantly improved OS with the anti-EGFR agent cetixumab in combination with FOLFIRI (fluorouracil, leucovorin, and irinotecan) vs bevacizumab plus FOLFIRI in first-line treatment of patients with RASwt left-sided mCRC (median, 38 months vs 28 months; HR, 0.71; 95 percent CI, 0.55–0.92; p=0.01), but not in those with right-sided primary tumours (median, 19 months vs 23 months; HR, 1.14; 95 percent CI, 0.71–1.84; p=0.60). [Br J Cancer 2021;124:587-594]