Regorafenib Extends PFS in Locally Advanced Biliary Tract Cancer

The oral multi-kinase inhibitor regorafenib extended progression-free survival (PFS) in patients with metastatic or unresectable biliary tract cancer (BTC) who were previously treated with gemcitabine (Gemzar) and a platinum-based chemotherapy, according to results from the phase II REACHIN study presented at the 2019 Gastrointestinal Cancers Symposium.

In the randomized, double-blind study, regorafenib doubled median PFS compared with placebo (3.0 months vs. 1.5 months; HR, 0.49; 95% CI, 0.29-0.81; P = .005); however, the researchers have seen no significant difference in overall survival (OS) thus far.¹

“Two other phase II nonrandomized trials have also shown improvement in PFS, and this is the third trial proving this,” Anne Demols, MD, PhD, Department of. Gastroenterology, Erasme University Hospital, Brussels, Belgium, adding the trial’s importance as there is currently no standard of care in the second-line setting, “representing a high clinical unmet need.”

In previous studies, regorafenib—–a potent inhibitor of multiple kinases that binds to and inhibits kinases involved in tumor angiogenesis, oncogenesis, and tumor microenvironment––appeared safe and effective in patients with certain gastrointestinal tumors who have progressed on standard therapies, as well as in lung and colorectal cancer.

Demols and colleagues evaluated the safety and efficacy of regorafenib compared with placebo, both in combination with best supportive care, in 66 patients with locally advanced unresectable or metastatic BTC following progression with gemcitabine and a platinum-based chemotherapy. Increased PFS from 6 to 12 weeks served as the primary endpoint, while secondary endpoints included OS, overall response rate (ORR), and safety.

Patients randomized to the regorafenib arm (n = 33) received 160 mg once daily for 3 weeks of every 4-week cycle (3 weeks on and 1 week off).

Primary tumor locations in both the treatment and placebo arms were intrahepatic (70% vs. 58%, respectively), extrahepatic (18% vs. 9%), gallbladder (15% vs. 12%), and peri-hilar (9% in each arm).

The estimated PFS rate at 6 months was 21% (95% CI, 7%-35%) in the regorafenib arm compared with 3% (95% CI, 0%-12%) in the placebo arm, and all but 1 patient progressed.

At a median follow-up of 20 months, 9 patients were still alive at the time of analysis (4 in the regorafenib arm and 5 in the placebo arm), for which the median OS was 5.3 months and 5.0 months, respectively (HR, 0.76; 95% CI, 0.44-1.30; P = .31). Estimated survival rates at 3, 6, 12, 18, and 24 months in the regorafenib group were 67% (95% CI, 51-83), 48% (95% CI, 31-65), 27% (95% CI, 11-43), 16% (95% CI, 2-30), and 16% (95% CI, 2-30), respectively, compared with 69% (95% CI, 53-85), 40% (95% CI, 22-58), 15% (95% CI, 2-29), 5% (95% CI, 0-15), and 5% (95% CI, 0-15) among those who received placebo.

There were no complete or partial responses in either treatment arm. In the regorafenib arm, 23 patients had stable disease and 8 had progressive disease for a disease control rate (DCR) of 70% (95% CI, 51%-84%) compared with 11 and 21 patients, respectively, for a DCR of 33% (95% CI, 18%-52%) in the placebo arm (P = .002).

Seventeen patients (53%) in the regorafenib arm and 10 patients (32%) in the placebo arm went on to receive at least 1 additional line of therapy, while 9% and 3%, respectively, received 2 more (P = .13). The most common subsequent anticancer treatments were oxaliplatin—5-fluorouracil/leucovorin (Folfox) or irinotecan–5-fluorouracil/leucovorin (Folfiri).

The median treatment duration of regorafenib was 11.0 weeks and 6.3 weeks for placebo. Dose reductions were necessary in 14 regorafenib-treated patients and 5 placebo recipients. The most common reason for stopping treatment was progressive disease (regorafenib arm, n = 24; placebo arm, n = 30). Two patients in each arm discontinued due to adverse events (AEs).

Drug-related grade ≥3 AEs occurred in 12 patients in the regorafenib group (36%) and 8 patients who received placebo (24%). The most common grade ≥3 AEs in the regorafenib arm included fatigue (n = 6), nausea (n = 2), cutaneous toxicity (n = 2), vomiting, diarrhea, hypophosphatemia, mucositis, and hypothyroidism (n = 1 each). The researchers noted that no unexpected or new safety signals were encountered in the study.

1. Demols A, Borbath I, Van Den Eynde M, et al. Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced (nonresectable) and metastatic biliary tumors: A randomized double-blinded placebo-controlled phase II trial. Presented at: 2019 Gastrointestinal Cancers Symposium; January 17-19, 2019; San Francisco. Abstract 345.

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