Maintenance Panitumumab Monotherapy Tested Against Combination with Fluorouracil-Leucovorin for Colorectal Cancer

Maintenance therapy with single-agent anti-EGFR panitumumab resulted in inferior outcomes compared with panitumumab combined with fluorouracil-leucovorin in patients with RAS wild-type metastatic colorectal cancer, according to the results of the phase II VALENTINO study.

Based on these results, a “subsequent phase III trial would have an extremely low probability of meeting a primary end point of noninferiority,” Filippo Pietrantonio, MD, of Fondazione IRCCS Instituto Nazionale dei Tumori, Milan, Italy, and colleagues wrote in JAMA Oncology.

According to the study, anti-EGFR therapy added to doublet chemotherapy is the recommended first-line treatment for patients with RAS wild-type metastatic colorectal cancer. However, data are lacking on the role of maintenance or intermittent strategies after anti-EGFR induction.

In this study, Pietrantonio and colleagues randomly assigned 229 patients to first-line panitumumab plus FOLFOX-4 for eight cycles, followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (Arm A) or maintenance with panitumumab alone (Arm B). The primary endpoint was 10-month progression-free survival.

With a median follow-up of 18.0 months, the 10-month progression-free survival for Arm A was 59.9% compared with 49.0% for Arm B. Median progression-free survival for panitumumab plus fluorouracil-leucovorin was 12.0 months compared with 9.9 months for panitumumab alone. Arm B was inferior to Arm A (upper limit of 1-sided 90% CR of the hazard ratio=1.857).

The researchers pointed out that the benefit of adding fluorouracil-leucovorin to panitumumab in the maintenance setting did not differ by subgroups, including patients with poor prognosis and primary resistance to anti-EGFR agents.

Overall survival at a median follow-up of 18 months was not significantly different between the two arms. 

Patients assigned to combination maintenance did experience a higher rate of grade 3 or greater treatment-related adverse events (42.4% vs 20.3%) and panitumumab-related adverse events (31.8% vs 16.4%) compared with Arm B, but the researchers noted that the safety profile was manageable in both arms.

In an accompanying editorial, Gayathri Anandappa, MBBS, MPhil, MRCP, and David Cunningham, MD, FRCP, FMedSci, of Royal Marsden Hospital, London, wrote that this study failed to address the question of additional benefit seen with adding panitumumab to fluorouracil/leucovorin because there was no fluorouracil/leucovorin alone arm.

“Patients were randomized upfront before induction chemotherapy, but even so, the results in both the intention-to-treat population and the per-protocol population favored continuing panitumumab with fluorouracil/leucovorin,” they wrote. “Randomizing patients who had disease response (stable disease or better response) after induction chemotherapy might have further amplified a beneficial effect from continuing combined panitumumab with fluorouracil/leucovorin.” 

In addition, Anandappa and Cunningham pointed out that this trial was designed prior to the recognition that sidedness is a predictive biomarker of response to anti-EGFR antibodies, and that these agents are now used in combination with FOLFOX in the first-line in patients with left-sided RAS/RAF wild-type tumors.

“The VALENTINO study adds to the growing evidence of de-escalation of oxaliplatin chemotherapy but continuing anti-EGFR agent with the fluorouracil/leucovorin backbone in the first-line setting,” they concluded. “Patient selection using sidedness, presence of RAS mutations in pretreatment circulating tumor DNA, and miR31-3p levels in baseline tissue may allow physicians to streamline use of panitumumab with fluorouracil/leucovorin in the first-line setting in the future.”