Maintenance Therapy With Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients With RAS Wild-Type Metastatic Colorectal Cancer

Abstract

IMPORTANCE Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. OBJECTIVETo determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. DESIGN, SETTING, AND PARTICIPANTSThis open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m 2 at day 1, leucovorin calcium, 200 mg/m 2 , and fluorouracil, 400-mg/m 2 bolus, followed by 600-mg/m 2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. INTERVENTIONSPatients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. MAIN OUTCOMES AND MEASURESThe prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. RESULTSOverall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07;P = .01).Duringmaintenance,armAhadahigherincidenceofgrade3orgreatertreatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. CONCLUSIONS AND RELEVANCEIn patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT02476045

Negative Hyperselection of Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer Who Received Panitumumab-Based Maintenance Therapy

“…Consistent with the literature, 13 , 19 MSI-high status was associated with poor PFS outcome at the univariable analysis, although the number of MSI-high occurrences in this data set was quite small (only five patients) and did not allow us to properly assess its independent prognostic role. The type of maintenance treatment retained its value in terms of PFS but not OS; this result has been already reported 11 and may be due to the low number of OS events at the time of data cutoff and to the underpowered sample size.…”

“…The Valentino study was a multicenter, randomized, open-label, phase II trial that investigated the progression-free survival (PFS) noninferiority of maintenance with single-agent panitumumab (arm B) versus panitumumab plus FU plus LV (arm A) after an induction treatment with panitumumab plus FOLFOX-4 in patients with RAS wild-type mCRC. 11 The trial enrolled 229 patients (arm A, n = 117; arm B, n =112) and showed that maintenance with single-agent panitumumab is inferior to panitumumab plus FU/LV in terms of PFS.…”

The Landscape of Actionable Gene Fusions in Colorectal Cancer

“…To date, the therapeutic algorithm for the choice of the best treatment for mCRC patients has been characterized by a negative selection, restricting the treatment with anti-EGFR agents to patients with wild-type RAS and BRAF mCRC [109,110]. Moving forward the era of positive selection in mCRC, results from the phase III BEACON trial, which randomized 665 pretreated patients with BRAF V600E mutant mCRC to receive triplet therapy (encorafenib, binimetinib and cetuximab), doublet therapy (encorafenib and cetuximab), or the investigator’s choice of irinotecan or FOLFIRI and cetuximab, showed an impressive median overall survival of 9 months (95% confidence interval (CI): 8, 11.4) for the triplet targeted therapy compared to 5.4 months (95% CI: 4.8, 6.6) for standard therapy (hazard ratio (HR) 0.52; 95% CI: 0.39, 0.7, p < 0.0001) and an ORR of 26% (95% CI: 18, 35) for the triplet targeted therapy compared to 2% (95% CI: 0,7, p < 0.0001) for standard therapy [111,112].…”

Implementing anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer: challenges and future perspectives

“…These results have been confirmed in subsequent studies of firstline treatment of molecularly selected mCRC with chemotherapy plus anti-EGFR MoAbs, such as the VALENTINO trial that investigated the combination of FOLFOX plus panitumumab. 24 We conducted a post hoc analysis for assessing the feasibility and the efficacy of FOLFIRI plus cetuximab in elderly patients who were enrolled in the CAPRI-GOIM clinical trial, considering that the majority of mCRC cases are diagnosed in the elderly. 25 Phase II and III studies have shown the safety and clinical activity of bevacizumab in combination with fluoropyrimidine-based regimens in elderly patients with mCRC who are unfit for chemotherapy doublets.…”