Panitumumab Plus Fluorouracil and Folinic Acid Versus Fluorouracil and Folinic Acid Alone as Maintenance Therapy in RAS Wild-Type Metastatic Colorectal Cancer: The Randomized PANAMA Trial (AIO KRK 0212)

Abstract

Purpose: The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer.

Methods: Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873).

Results: Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%).

Conclusion: In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.

Conflict of interest statement

Dominik Paul ModestHonoraria: Merck Serono, Amgen, Roche, Servier, Bristol Myers Squibb, Taiho Pharmaceutical, Merck Sharp & Dohme, Pierre Fabre, Onkowissen, Sanofi, LillyConsulting or Advisory Role: Merck Serono, Amgen, Merck Sharp & Dohme, Roche, Servier, Incyte, Bristol Myers Squibb, Pierre Fabre, Lilly, Cor2Ed, IQvia, OnkowissenResearch Funding: Amgen, ServierTravel, Accommodations, Expenses: Amgen, Merck Serono, Servier Meinolf KarthausConsulting or Advisory Role: AmgenTravel, Accommodations, Expenses: Amgen Stefan FruehaufStock and Other Ownership Interests: AbbVie, Bristol Myers Squibb/Pfizer, Johnson & Johnson/Janssen, Merck Ullrich GraevenHonoraria: Daiichi Sankyo, Boehringer Ingelheim, Amgen, Servier, AstraZeneca, Bristol Myers Squibb, MSD OncologyConsulting or Advisory Role: Merck KGaA, Bristol Myers Squibb, Hexal, Amgen, Celgene, Johnson & Johnson, MSD OncologyTravel, Accommodations, Expenses: Merck KGaA, Amgen, Boehringer Ingelheim, GlaxoSmithKline Lothar MüllerHonoraria: Roche Alexander Otto KönigHonoraria: Ipsen, Pierre FabreConsulting or Advisory Role: Roche Pharma AG Ludwig Fischer von WeikersthalHonoraria: Novartis, Roche Pharma AG, AstraZeneca, Pierre Fabre, Lilly GmbH Albrecht KretzschmarHonoraria: Roche Pharma AG, Merck Serono, Shire, Amgen, Medac, Servier, Sanofi, MSD, Bristol Myers Squibb, Bayer Schering Pharma, Aspen Pharma, Roche PharmaConsulting or Advisory Role: Roche Pharma AG, Shire, AmgenTravel, Accommodations, Expenses: PharmaMar, Merck Serono, Ipsen, Medac Eray GoekkurtConsulting or Advisory Role: MSD, Bristol Myers Squibb, Roche, Sanofi Annika KurreckHonoraria: ServierTravel, Accommodations, Expenses: Roche, Medac Arndt StahlerHonoraria: Roche, Servier, Taiho PharmaceuticalTravel, Accommodations, Expenses: Amgen, Roche, Lilly, Pfizer Anke Reinacher-SchickHonoraria: Amgen, Roche, Pfizer, Sanofi/Aventis, Merck Serono, Celgene, Lilly, Bristol Myers Squibb, Servier, MSD, Aurikamed, IOMEDICO, Promedicis, MCI Group, AstraZenecaConsulting or Advisory Role: Amgen, Roche, Pfizer, Merck Serono, Celgene, Bristol Myers Squibb, Servier, Baxalta, MSD, AstraZeneca, Pierre FabreResearch Funding: Roche, Celgene, Ipsen, Amgen, Alexion Pharmaceuticals, AstraZeneca, Lilly, Servier, AIO-Studien, Georgius Agricola Stiftung Ruhr, Rafael Pharmaceuticals, ERYTECH Pharma, BioNTechTravel, Accommodations, Expenses: Ipsen, Amgen, Roche, Servier, MCI Group, Pierre Fabre, AstraZeneca, Merck Serono, MSD Stefan KasperHonoraria: Bristol Myers Squibb, MSD Oncology, AstraZeneca, Merck Serono, Amgen, Roche, Servier, Lilly, Sanofi/AventisConsulting or Advisory Role: Roche, Merck Serono, Amgen, MSD Oncology, Sanofi, Bristol Myers Squibb, Lilly, AstraZeneca, Servier, Janssen-CilagResearch Funding: Merck Serono, Bristol Myers Squibb, Celgene, Lilly, Servier, Roche/GenentechTravel, Accommodations, Expenses: Merck Serono, Lilly, Amgen, Sanofi, RocheOther Relationship: Sanofi, Amgen, Merck Serono, Bristol Myers Squibb, Roche, Lilly Volker HeinemannHonoraria: Roche, Celgene, Amgen, Sanofi, Merck, Sirtex Medical, Baxalta, Lilly, Boehringer Ingelheim, Taiho Pharmaceutical, ServierConsulting or Advisory Role: Merck, Amgen, Roche, Sanofi, Boehringer Ingelheim, Celgene, Sirtex Medical, Baxalta, Servier, Halozyme, MSD, Bristol-Myers Squibb, MSD OncologyResearch Funding: Merck, Amgen, Roche, Celgene, Boehringer Ingelheim, Sirtex Medical, Shire, ServierTravel, Accommodations, Expenses: Merck, Roche, Sirtex Medical, Amgen, Servier, Shire, MSD, Bristol Myers Squibb Sebastian StintzingHonoraria: Merck KGaA, Roche, Amgen, Bayer, Sanofi, Lilly, Pierre Fabre, Takeda, Taiho Pharmaceutical, Servier, MSDConsulting or Advisory Role: Merck KGaA, Roche, Sanofi, Bayer, Amgen, Boehringer Ingelheim, Lilly, Takeda, MSD, Servier, Pierre FabreResearch Funding: Pierre Fabre, Roche Molecular Diagnostics, Merck SeronoTravel, Accommodations, Expenses: Merck KGaA, Roche, Sanofi, Bayer, Sirtex Medical, Amgen, Lilly, Takeda, Pierre Fabre Tanja TrarbachResearch Funding: AmgenTravel, Accommodations, Expenses: Ipsen, Takeda, OMT, AbbVie, Novartis, MSD, Sanofi/Aventis, Amgen, Johnson & Johnson/JanssenNo other potential conflicts of interest were reported.

Figures

FIG 1.

Study design. aDropouts include death, progression, adverse events, and investigator's decision. CR, complete remission; ECOG, Eastern Cooperative Oncology Group; FOLFOX, fluorouracil, folinic acid, and oxaliplatin; FU/FA, fluorouracil and folinic acid; mCRC, metastatic colorectal cancer; PD, progressive disease; PFS, progression-free survival; Pmab, panitumumab; PR, partial remission; R, random assignment; SD, stable disease; WT, wild type.

FIG 2.

CONSORT diagram. FOLFOX, fluorouracil, folinic acid, and oxaliplatin; FU/FA, fluorouracil and folinic acid; PFS, progression-free survival; Pmab, panitumumab; secondary resections, resection of metastases.

FIG 3.

Kaplan-Meier estimates of the full analysis set for PFS and OS. Indicated HRs derived from Cox regression testing. P values derived from log-rank tests. (A) Kaplan-Meier estimate of PFS of the full analysis set (primary end point) and (B) Kaplan-Meier estimate of OS of the full analysis set (secondary end point). FU/FA, fluorouracil and folinic acid; FU/FA/Pmab, panitumumab plus FU/FA; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; Pmab, panitumumab.

FIG 4.

Subgroup analysis of progression-free survival. Forest plot with indicated analyses. Hazard ratios for progression or death with 95% CI. ECOG, Eastern Cooperative Oncology Group; FU/FA, fluorouracil and folinic acid; left-sided primary tumor, splenic flexure to rectum; Pmab, panitumumab; right-sided primary tumor, caecum to transverse colon.

FIG A1.

Dose intensity per treatment cycle and substance during maintenance therapy (full analysis set). Relative doses are expressed as means. Patients evaluated = patients evaluated in respective cycle; reference doses were fluorouracil 2,400 mg/m2 and Pmab 6 mg/kg. FU/FA, fluorouracil and folinic acid; Pmab, panitumumab.

FIG A2.

Kaplan-Meier estimates of the safety set for OS since from start of induction therapy. P values derived from log-rank tests. No maintenance = patients with induction therapy who did not receive maintenance therapy. The no maintenance therapy group includes 112 patients who were not randomly assigned and 17 patients who were randomly assigned but did not receive maintenance therapy (refer to CONSORT diagram). FU/FA, fluorouracil and folinic acid; FU/FA/Pmab, panitumumab plus FU/FA; OS, overall survival; Pmab, panitumumab.