Phase II randomized study of maintenance therapy with regorafenib (REGO) versus placebo after first-line platinum and fluoropyrimidines-based chemotherapy in HER2 negative locally advanced/metastatic gastric (GC) or gastroesophageal junction (GEJ) cancer: Results of a-MANTRA study (GOIRC-05-2016).

person Angela Damato Medical Oncology Unit, Comprehensive Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy info_outline Angela Damato, Domenico Bilancia, Francesco Iachetta, Antonia Strippoli, Francesca Filiali, Rossana Casaretti, Ilaria Bernardini, Giovanna Bellotti, Giovanni Luca Frassineti, Francesca Di Fabio, Michele Aieta, Michele Ghidini, Chiara Trentin, Giovanni Gerardo Cardellino, Erika Gervasi, Alessandra Romagnani, Saverio Cinieri, Nicola Normanno, Carmine Pinto

Authors person Angela Damato Medical Oncology Unit, Comprehensive Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy info_outline Angela Damato, Domenico Bilancia, Francesco Iachetta, Antonia Strippoli, Francesca Filiali, Rossana Casaretti, Ilaria Bernardini, Giovanna Bellotti, Giovanni Luca Frassineti, Francesca Di Fabio, Michele Aieta, Michele Ghidini, Chiara Trentin, Giovanni Gerardo Cardellino, Erika Gervasi, Alessandra Romagnani, Saverio Cinieri, Nicola Normanno, Carmine Pinto Organizations Medical Oncology Unit, Comprehensive Cancer Centre, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy, Azienda Ospedaliera S. Carlo, Potenza, Italy, Medical Oncology, Comprehensive Cancer Centre, AUSL-IRCCS di Reggio Emilia, Italy - Reggio Emilia, Reggio Emilia, Italy, Comprehensive Cancer Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Catholic University of the Sacred Heart, Rome, Italy, Department of Medical Oncology, ASST Brianza-Ospedale di Vimercate, Vimercate, Italy, Experimental Clinical Abdominal Oncology Unit, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Napoli, Italy, Medical Oncology Unit, Ramazzini Hospital, Carpi, Italy, Oncology Unit, Azienda Ospedaliera "SS Antonio e Biagio e Cesare Arrigo”, Alessandria, Italy, Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori "Dino Amadori" (IRST), Meldola, Italy, Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy, Medical Oncology, IRCCS-CROB, Rionero in Vulture, Italy, Operative Unit of Medical Oncology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, Department of Medical Oncology, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), Trento, Italy, Medical Oncology Unit, Azienda Ospedaliero Universitaria Santa Maria della Misericordia, Udine, Italy, Medical Oncology Unit. Comprehensive Cancer Center, AUSL-IRCCS di Reggio Emilia, Reggio Emilia, Italy, Perrino Hospital, Brindisi, Italy, Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori – IRCCS Fondazione G. Pascale, Napoli, Italy, Medical Oncology Unit, Comprehensive Cancer Centre, AUSL-IRCCS Reggio Emilia, Reggio Emilia, Italy Abstract Disclosures Research Funding No funding sources reported Background: REGO is an oral multi-targeted TKI that showed promising activity in advanced HER2-neg gastric cancer pts. The a-MANTRA study aimed to evaluate the efficacy and safety of REGO as maintenance after first-line (1L) therapy in advanced GC/GEJ tumors. Methods: This is a randomized, double-blind, placebo-controlled, multicenter Phase-II study in which HER2 neg advanced GC/GEJ pts with disease control after 1L platinum and fluoropyrimidines-based therapy, were randomized (1:1 ratio) to receive maintenance placebo (ARM A) or REGO (ARM B) starting at 80 mg with an escalation up to 160 mg (once daily on d1-21 q28 days), until intolerance or PD. The primary endpoint was Progression Free Survival 1 (PFS1). Two-sided 80% CIs were calculated to detect HR of 0.57, using a one-sided α=0.10 to have 90% power, translating to 3 months of improvement in mPFS. 118 subjects were required to observe 88 events. The interim analysis (IA) was planned after 44 events. Results: 67 pts were randomized in 18 Italian Cancer Centers; 64 pts (33 in ARM A and 31 in ARM B) received treatment. Most of the pts were male (64.1%), Caucasian (96.8%), ECOG PS 0 (81.2%), and median age 66 (40-80) yrs; the main primary tumor side was proximal (64.1%) with intestinal subtype (54.7%). Peritoneum metastases were present in 42.2%. IA showed a 98% probability of achieving a positive and statistically significant result for mPFS1. The study was stopped early due to the introduction of ICIs as 1L in PD-L1-positive pts. The objective responses to 1L chemotherapy were RP (50.0%), SD (42.2%), and CR (7.8%). At a median follow-up of 31 months (IQR 19.1-33-8), 28 (84.8%) and 26 (83.8%) events for each arm were reported. The main reason for discontinuation was PD (66.7% and 35.5%). The mPFS was 3.91 (80% CI, 2.27-5.98) and 5.19 months (80% CI, 4.0-7.26) with HR= 0.736 (80%CI, 0.51-1.04; p=0.1318). The mOS was 11.25 and 16.97 months (80%CI, HR=0.596 [0.318-1.103], p=0.1003). The most common G3-4 toxicities in ARM A and B were fatigue (3.0 vs 6.4%), thrombocytopenia (3.0 vs 3.2%), hand-foot syndrome (0 vs 12.9%), diarrhea and skin rash (0 vs 3,2%, respectively). Conclusions: Despite the promising trend, considering the sample was not sized for the statistical study hypothesis, REGO maintenance therapy after 1L chemotherapy did not reach statistically significant results in mPFS1. No significant safety concerns were raised. New study designs following the REGO with ICIs are currently underway. Clinical trial information: NCT03627728.

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