Background: Rolapitant (VARUBI) is a selective, long-acting neurokinin-1 receptor antagonist (RA) for the prevention of CINV. Rolapitant effectively prevented CINV in phase 3 trials of patients (pts) receiving highly or moderately emetogenic chemotherapy (HEC, MEC). While MEC and HEC regimens are commonly used to treat pts with gastrointestinal and colorectal cancers (GI/CRC), very few studies have evaluated the effectiveness of a neurokinin-1 RA regimen in these pts. We assessed the incidence of CINV and efficacy of rolapitant in a subset of pts with GI/CRC. Methods: This is a post hoc analysis of 3 similarly-designed, randomized, placebo-controlled trials. Pts with cancer of the esophagus, stomach, colon/rectum, or anus received a single oral dose of 180 mg oral rolapitant or placebo prior to HEC or MEC. All pts received a 5-hydroxytryptamine type 3 (5-HT3) RA and dexamethasone (active control). The HEC studies included cisplatin, and the MEC study carboplatin, oxaliplatin, irinotecan, epirubicin, and doxorubicin. Endpoints included complete response (CR; no emesis and no use of rescue medication), no emesis, no nausea (maximum visual analogue scale [VAS] < 5 mm), no significant nausea (maximum VAS < 25mm) and complete protection (CP; no emesis, no use of rescue medication, and no significant nausea) in the overall (0-120 h), acute (≤ 24 h), and delayed (> 24-120 h) phases. Results: Out of 188 GI/CRC pts, 101 pts received rolapitant and 87 received active control. Pts treated with rolapitant had significantly higher rates of CR, no nausea, no emesis, and CP in the overall phase (P < 0.05). Rolapitant was well-tolerated and overall incidence of treatment-emergent adverse events comparable in both groups. Conclusions: Addition of rolapitant to 5-HT₃RA and dexamethasone therapy significantly improved CR, no nausea, no emesis, and CP in pts with GI/CRC receiving emetogenic chemotherapy. Clinical trial information: NCT01500226, NCT01499849, NCT01500213