GOLFIG Chemo-Immunotherapy in Metastatic Colorectal Cancer Patients. A Critical Review on a Long-Lasting Follow-Up

Michele Caraglia; Pierpaolo Correale; Rocco Giannicola; Nicoletta Staropoli; Cirino Botta; Pierpaolo Pastina; Antonello Nesci; Nadia Caporlingua; Edoardo Francini; Laura Ridolfi; Enrico Mini; Giandomenico Roviello; Domenico Ciliberto; Rita Maria Agostino; Alessandra Strangio; Domenico Azzarello; Valerio Nardone; Antonella Falzea; Salvatore Cappabianca; Marco Bocchetti; Graziella D'Arrigo; Giovanni Tripepi; Pierfrancesco Tassone; Raffaele Addeo; Antonio Giordano; Luigi Pirtoli; Guido Francini; Pierosandro Tagliaferri

doi:10.3389/fonc.2019.01102

GOLFIG Chemo-Immunotherapy in Metastatic Colorectal Cancer Patients. A Critical Review on a Long-Lasting Follow-Up

Front Oncol. 2019 Nov 8:9:1102. doi: 10.3389/fonc.2019.01102. eCollection 2019.

Authors

Michele Caraglia^{1

2}, Pierpaolo Correale³, Rocco Giannicola³, Nicoletta Staropoli⁴, Cirino Botta⁴, Pierpaolo Pastina⁵, Antonello Nesci⁶, Nadia Caporlingua⁶, Edoardo Francini⁷, Laura Ridolfi⁸, Enrico Mini⁹, Giandomenico Roviello⁹, Domenico Ciliberto⁴, Rita Maria Agostino³, Alessandra Strangio³, Domenico Azzarello³, Valerio Nardone⁵, Antonella Falzea³, Salvatore Cappabianca^{1

2}, Marco Bocchetti^{1

2}, Graziella D'Arrigo¹⁰, Giovanni Tripepi¹⁰, Pierfrancesco Tassone⁴, Raffaele Addeo¹¹, Antonio Giordano^{12

13}, Luigi Pirtoli¹², Guido Francini⁷, Pierosandro Tagliaferri⁴

Affiliations

¹ Department of Precision Medicine, University of Campania "L. Vanvitelli", Naples, Italy.
² Biogem Scarl, Institute of Genetic Research, Laboratory of Precision and Molecular Oncology, Ariano Irpino, Italy.
³ Medical Oncology Unit, "Bianchi-Melacrino-Morelli" Grand Metropolitan Hospital, Reggio Calabria, Italy.
⁴ Medical Oncology Unit, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
⁵ Radiation Oncology Unit, Siena University Hospital, Siena, Italy.
⁶ Unit of Pharmacy, Section of Anti-blastic Drugs, "Bianchi-Melacrino-Morelli" Grand Metropolitan Hospital, Reggio Calabria, Italy.
⁷ Medical Oncology Unit, Siena University Hospital, Siena, Italy.
⁸ Immunotherapy, Cell Therapy and Biobank, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori IRCCS, Meldola, Italy.
⁹ Section of Clinical Pharmacology and Oncology, Department of Health Sciences, School of Medicine/Translational Oncology Unit, Careggi University Hospital, University of Florence, Florence, Italy.
¹⁰ Statistical Unit, IFC-CNR (CNR), Grand Metropolitan Hospital-IFC, Reggio Calabria, Italy.
¹¹ Oncology Unit, Day Hospital, San Giovanni di Dio Hospital, ASL Napoles 2 Nord, Frattamaggiore, Italy.
¹² Sbarro Institute for Cancer Research and Molecular Medicine and Center of Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, United States.
¹³ Department of Medical Biotechnology, University of Siena, Siena, Italy.

Abstract

Background: GOLFIG is a chemo-immunotherapy regimen established in preclinical models that combines gemcitabine + FOLFOX (fluoropyrimidine backbone coupled to oxaliplatin) poly-chemotherapy with low-dose s. c. recombinant interleukin-2 (rIL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). Promising antitumor effects in metastatic colorectal cancer (mCRC) patients were obtained in previous phase II and III trials. Here we report the results of 15 years of follow-up. Methods: This is a multi-institutional retrospective analysis including 179 mCRC patients receiving GOLFIG regimen between June 2002 and June 2018. Sixty-two of them received the treatment as frontline (enrolled in the GOLFIG-2 phase III trial) and 117 as second/third line (49 enrolled in the GOLFIG-1 phase II trial and 68 as compassionate use). One hundred twelve patients showed a primary left side and 67 a primary right side; K/N-ras mutational status was available in 74 cases, and an activating mutation was detected in 33. Kaplan-Meier and Cox regression analyses were carried out to relate PFS and OS with different parameters. Results: Overall, we recorded a mean PFS and OS of 15.28 (95% CI: 10.36-20.20) and 24.6 (95% CI: 19.07-30.14) months, respectively, with 14 patients surviving free of progression for 10 years. This regimen, in our updated survey of the GOLFIG-2 trial, confirmed superiority over FOLFOX in terms of PFS (hazard ratio (HR) = 0.58, p = 0.006) with a trend to a longer OS (HR = 0.69, P = 0.06) in the first line. Our analysis also confirmed significant antitumor activity in pre-treated patients, reporting a mean PFS and OS of 12.55 (95% CI: 7.19-17.9) and 20.28 (95% CI: 14.4-26.13) months, respectively. Immune-related adverse events (irAEs) were recorded in 24% of the cases and were related to a longer survival (HR = 0.36; P = 0.0001). Finally, patients' outcome was not correlated to sex, sidedness, and MT-K/N-ras. Conclusions: The GOLFIG regimen is a reliable underestimated therapeutic option in pre-treated mCRC patients and offers a strong rationale to design further trials.

Keywords: GOLFIG; chemotherapy; colorectal cancer; immunotherapy; metastatic; phase III clinical trial; real-world medicine.

Copyright © 2019 Caraglia, Correale, Giannicola, Staropoli, Botta, Pastina, Nesci, Caporlingua, Francini, Ridolfi, Mini, Roviello, Ciliberto, Agostino, Strangio, Azzarello, Nardone, Falzea, Cappabianca, Bocchetti, D'Arrigo, Tripepi, Tassone, Addeo, Giordano, Pirtoli, Francini and Tagliaferri.