The Phase III PRABITAS trial evaluated whether a simplified 14-day schedule of trifluridine/tipiracil (FTD/TPI) plus bevacizumab could maintain overall survival (OS) while reducing treatment-related toxicity compared with the conventional 28-day schedule in patients with refractory metastatic colorectal cancer (mCRC). This investigator-initiated, pragmatic randomized trial focused on optimizing the administration of an established treatment combination, with study procedures designed to reflect routine clinical practice.
The results were presented by Hiroya Taniguchi at the ESMO Congress 2026 (LBA31) and published in The Lancet on October 24, 2026, under the title “14-day versus 28-day trifluridine–tipiracil plus bevacizumab for refractory metastatic colorectal cancer (PRABITAS): a pragmatic, multicentre, open-label, randomised, phase 3, non-inferiority trial in Japan.”
The study was authored by Tomoki Sakakida, Hiroya Taniguchi, Masako Asayama, Yusuke Suwa, Takaya Shimura, Seiichiro Mitani, Akitaka Makiyama, Hiroyuki Arai, Hiroshi Matsuoka, Mitsuru Yokota, Yoshinao Takano, Kyoko Kato, Hisanobu Oda, Takeshi Kajiwara, Kohei Ogawa, Nobuhiro Shibata, Kentaro Sawada, Takato Yomoda, Toshihiro Kudo, Hiroyuki Okuda, Yuta Okumura, Chihiro Tanaka, Masato Nakamura, Takashi Tsuda, Takahito Kitajima, Hiroshi Tsukuda, Eiji Shinozaki, Mitsuhiro Furuta, Tomomi Kashiwada, Koichi Okuya, Hiroyuki Mushiake, Junichi Hasegawa, Koei Nihei, Takashi Mizushima, Takashi Mine, Takuro Mizukami, Chiho Kudo, Ayako Mishima, Kenta Murotani, and Toshiki Masuishi, on behalf of the PRABITAS investigators.
Why the Dosing Schedule Matters
FTD/TPI plus bevacizumab is an established treatment option for refractory mCRC, supported by the Phase III SUNLIGHT trial, which demonstrated an OS benefit with the combination compared with FTD/TPI alone. However, the conventional 28-day regimen is associated with hematological and gastrointestinal toxicities that may require dose reductions, treatment delays, or interruptions.
Previous retrospective and early-phase prospective studies suggested that administering FTD/TPI plus bevacizumab on a biweekly schedule could reduce toxicity while maintaining antitumor activity. However, whether this modified schedule preserved survival compared with the conventional combination regimen had not been established in a randomized trial. PRABITAS was therefore designed to assess the noninferiority of the 14-day schedule for OS, while also evaluating treatment tolerability and other efficacy outcomes.
Inside the PRABITAS Study
PRABITAS (jRCTs041230120) was a pragmatic, multicenter, open-label, randomized Phase III noninferiority trial conducted across 178 hospitals in Japan. Between December 26, 2023, and May 20, 2025, 972 patients with refractory mCRC were randomized 1:1 to receive either the simplified 14-day schedule or the conventional 28-day schedule.
In the 14-day group, patients received FTD/TPI 35 mg/m² orally twice daily on days 1–5, combined with bevacizumab 5 mg/kg intravenously on day 1 of each 14-day cycle. In the 28-day group, FTD/TPI was administered at the same dose on days 1–5 and 8–12, with bevacizumab on days 1 and 15 of each 28-day cycle.
Eligible patients had previously received fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF therapy, as well as anti-EGFR therapy when clinically indicated. An Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 was permitted. The trial used broader eligibility criteria than conventional explanatory trials, allowing participation by selected patients with organ dysfunction or significant comorbidities. Overall, 145 patients (15%) were classified as explanatory trial-ineligible according to prespecified criteria.
The primary endpoint was OS, with a prespecified noninferiority margin of 1.25 for the hazard ratio (HR). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), time to treatment failure, and safety. The intention-to-treat population included 970 patients, with 484 assigned to the 14-day group and 486 to the conventional group. The median age was 68 years, and 59% of patients had RAS-mutated disease.
Noninferior Survival With the 14-Day Schedule
At the May 20, 2026, data cutoff, the median follow-up was 17.9 months (IQR 14.3–22.6). Median OS was 11.3 months (95% CI 10.2–12.5) with the 14-day schedule compared with 10.3 months (95% CI 9.5–11.6) with the conventional 28-day schedule. The stratified HR was 0.93 (95% CI 0.80–1.08), meeting the prespecified noninferiority criterion because the upper confidence limit remained below 1.25.
The 12-month OS rates were 47.5% (95% CI 42.9–52.0) and 44.0% (95% CI 39.5–48.5), respectively. Although median OS was numerically longer with the simplified schedule, the prespecified superiority analysis did not demonstrate a statistically significant difference (p=0.35).
Secondary efficacy outcomes were broadly comparable between groups. Median PFS was 3.9 months in both treatment groups (HR 0.93; 95% CI 0.81–1.06). Among patients with measurable disease, the ORR was 1.6% with the 14-day schedule versus 2.4% with the conventional schedule, while the DCR was 52.1% versus 46.6%, respectively. Median time to treatment failure was 3.8 months in the 14-day group compared with 3.6 months in the 28-day group (HR 0.90; 95% CI 0.79–1.03).
The OS findings were generally consistent across prespecified subgroup and sensitivity analyses. Among patients eligible for conventional explanatory trials, the OS HR was 0.90 (95% CI 0.76–1.05). In the smaller explanatory trial-ineligible population, the corresponding HR was 1.02 (95% CI 0.70–1.50), with no significant interaction according to eligibility status.
Reduced Toxicity and Treatment Modifications
The simplified 14-day schedule was associated with lower rates of several hematological and gastrointestinal adverse events compared with the conventional regimen. The most notable difference involved neutropenia. Grade ≥3 neutropenia occurred in 13% of patients receiving the 14-day schedule versus 39% receiving the conventional schedule, corresponding to an absolute difference of 25 percentage points (95% CI 20–31).
Grade ≥3 leukopenia occurred in 7% versus 18%, while febrile neutropenia was reported in 1% versus 5%, respectively. Granulocyte colony-stimulating factor (G-CSF) use was also lower in the 14-day group (3% vs 13%). Gastrointestinal adverse events were generally less frequent with the simplified schedule. Grade ≥2 anorexia occurred in 15% of patients in the 14-day group compared with 26% in the conventional group. Grade ≥2 nausea was reported in 12% versus 18%, and grade ≥2 diarrhea in 4% versus 10%, respectively.
Overall, grade ≥3 treatment-related adverse events among the ten prespecified adverse-event terms occurred in 24% of patients receiving the 14-day regimen versus 49% receiving the conventional schedule. Treatment-related serious adverse events were reported in 4% versus 8%, respectively.
Differences were also observed in treatment delivery. Among evaluable patients receiving at least two cycles, dose reductions were required in 31% of patients in the 14-day group compared with 48% in the 28-day group. Treatment cycle delays occurred in 58% versus 68%, respectively.
Median relative dose intensity was higher with the 14-day schedule (82.7% vs 77.0%), while the median treatment exposure period was similar between groups. However, two treatment-related deaths occurred in the 14-day group, including one gastrointestinal hemorrhage and one gastrointestinal perforation, both attributed to bevacizumab. No treatment-related deaths were reported in the conventional group.
What PRABITAS Means for Clinical Practice
The Phase III PRABITAS trial demonstrated that a simplified 14-day schedule of FTD/TPI plus bevacizumab was noninferior to the conventional 28-day schedule in terms of OS in patients with refractory mCRC. The modified schedule was associated with lower rates of several clinically relevant hematological and gastrointestinal toxicities, as well as fewer dose reductions and treatment delays.
These findings provide randomized evidence supporting the 14-day schedule as an alternative administration strategy for FTD/TPI plus bevacizumab, with OS meeting the prespecified noninferiority criterion.
However, several limitations should be considered. The trial was conducted exclusively in Japan, adverse-event collection was restricted to ten prespecified toxicities, and imaging assessments were not mandated at fixed intervals. Moreover, health-related quality of life was not formally evaluated, limiting conclusions about the patient-perceived benefits of reduced toxicity.
Overall, PRABITAS provides evidence that modifying the dosing schedule of an established combination can improve aspects of tolerability while maintaining OS outcomes. Further evaluation of patient-reported outcomes and applicability across different clinical settings may help inform the broader implementation of this approach.
The full article is available in The Lancet.
