Lin, Bruce

PURPOSE Cholangiocarcinoma is a rare cancer associated with poor prognosis. Pemigatinib was the first FGFR1-3 inhibitor approved for second-line therapy and beyond, on the basis of the phase II FIGHT-202 trial. Here, we assess efficacy and safety of first-line pemigatinib. METHODS FIGHT-302 is a phase III, randomized, global trial evaluating pemigatinib as first-line therapy (ClinicalTrials.gov identifier: NCT03656536 ). Adults with advanced cholangiocarcinoma with FGFR2 rearrangement were randomized 1:1 to receive pemigatinib (13.5 mg once daily) or chemotherapy (1,000 mg/m 2 gemcitabine plus 25 mg/m 2 cisplatin once per day on days 1 and 8 of every 3-week cycle for ≤8 cycles) and were stratified by prior receipt of chemotherapy, geographic region, and tumor burden. Pemigatinib crossover was allowed for patients progressing on chemotherapy. The primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. RESULTS Overall, 4,563 patients were prescreened, 196 were screened, and 167 randomly assigned to receive pemigatinib (n = 83) or chemotherapy (n = 84) before early closure of the study because of a change in standard of care. The median PFS was 8.3 months in the pemigatinib group versus 6.8 months in the chemotherapy group (hazard ratio, 0.58 [95% CI, 0.39 to 0.87]; nominal P = .0078); objective response rate was 47% versus 15%, and the median duration of response was 14.2 versus 6.3 months. Median overall survival was similar (24.4 v 25.0 months, respectively). In the crossover group (n = 42, second-line pemigatinib), the median PFS was 8.1 months. Safety was consistent with the known profile of pemigatinib. CONCLUSION To our knowledge, this was the largest, first-line, randomized, phase III trial of a targeted therapy for advanced FGFR2- rearranged cholangiocarcinoma. Pemigatinib demonstrated prolonged median PFS compared with chemotherapy, with no new safety findings.

4017 Background: First-line mCCA treatment is chemotherapy and immunotherapy. Based on the phase 2 FIGHT-202 trial, pemigatinib was the first FGFR1-3 inhibitor approved in second line and beyond for mCCA with FGFR2 rearrangement. Results from the phase 3, randomized, global FIGHT-302 trial evaluating pemigatinib as first-line therapy are reported here (NCT03656536). Methods: Patients (pts) aged ≥18 y with previously untreated mCCA with FGFR2 rearrangement were randomized 1:1 to receive oral pemigatinib (13.5 mg once daily q21) or intravenous chemotherapy (1000 mg/m 2 gemcitabine + 25 mg/m 2 cisplatin d1,8 q21 ≤8 cycles) stratified by previous receipt of 1 chemotherapy cycle, geographic region, and tumor burden. Pemigatinib crossover was allowed for control arm pts progressing on chemotherapy. Primary end point was progression-free survival (PFS). Secondary efficacy, safety, and exploratory end points were also analyzed. Results: After prescreening >4000 pts, only 196 had FGFR2 rearrangement and were screened; 167 were randomized to receive pemigatinib (n=83) or chemotherapy (n=84) before closing the study early due to slow accrual. Baseline characteristics and demographics were similar between arms. Median PFS (mPFS) with pemigatinib versus chemotherapy was 8.3 versus 6.8 mo, respectively (hazard ratio [95% CI], 0.58 [0.39-0.87]; nominal P =.0078); secondary efficacy endpoints generally supported primary results (Table). Median OS was similar, although these results are confounded by FGFR inhibitor administration as second-line treatment. In the crossover group (n=42, second-line pemigatinib), mPFS was 8.1 mo. Safety was consistent with previous results (Table). Exploratory analyses of genetic co-alterations associated with treatment response will be presented. Conclusions: FIGHT-302 was the first phase 3 trial of a targeted therapy for untreated mCCA. Pemigatinb demonstrated superior activity and prolonged mPFS compared with first-line chemotherapy. The results confirm the current management paradigm of pemigatinib administration after disease progression on chemotherapy. Clinical trial information: NCT03656536 . Pemigatinib Gemcitabine + cisplatin mPFS (95% CI), mo a 8.3 (6.5-12.2) 6.8 (6.1-8.3) Objective response rate, n/N (%) a 39/83 (47) 13/84 (15.5) Median duration of response (95% CI), mo a 14.2 (8.7-24.7) 6.3 (4.3-not estimable) Median overall survival (95% CI) a,b , mo 24.4 (18.6-35.9) 25.0 (18.7-34.2) Treatment related TEAEs, n/N c (%) 80/83 (96) 70/73 (96) Serious TEAEs, n/N (%) c,d 23/83 (28) 17/73 (23) Grade ≥3 TEAEs, n/N (%) c 65/83 (78) 49/73 (67) TEAEs leading to treatment discontinuation, n/N (%) c 5/83 (6) 8/73 (11) Fatal TEAE, n/N (%) c,d 3/83 (4) 0 a All randomized pts. b Interpretation limited by second-line treatment with FGFR inhibitor in gemcitabine + cisplatin arm. c Pts who received ≥1 study dose. d None deemed treatment related.

4097 Background: Given a high recurrence rate, surgical resection for localized intrahepatic cholangiocarcinoma (IHCC) is curative in only 30-35% of patients. BILCAP has established a standard of care for adjuvant therapy with monotherapy capecitabine. Gemcitabine, cisplatin and nab-paclitaxel combination chemotherapy (GAP) was associated with a response rate of 45% in biliary cancer and 20% of patients who were previously inoperable underwent margin negative resection. Based on these data, we conducted a neoadjuvant study of GAP for resectable but high-risk IHCC. Methods: A multi-institutional prospective single-arm phase II trial was conducted for patients with resectable high-risk disease, as defined by tumor size > 5cm, multiple tumors, presence of radiographic major vascular invasion, and lymph node involvement. Patients were administered 4 cycles (3 months) of preoperative GAP (gemcitabine 800 mg/m2, cisplatin 25 mg/m2 and nab-paclitaxel 100 mg/m2 on days 1 and 8 of a 21-day cycle) prior to an attempt at curative-intent surgical resection. The primary endpoint was completion of all therapy, including both preoperative chemotherapy and resection. Secondary endpoints were toxicity, radiologic response according to Response Evaluation Criteria in Solid Tumor (RECIST) criteria, RFS, and OS. Thirty evaluable patients provided 73% power to reject a null therapy completion rate of 50%, with a target completion rate of 70% using a one-sided exact test with a Type I error of 0.05. Results: Thirty-seven patients were screened and 30 evaluable patients were enrolled. The trial was sequentially activated at each of the 4 sites from 09/18-02/21 and the final patient was enrolled in 09/21. Median age was 60.5 years and 40% were female. Twenty-three patients (77%, 90% CI: 60.6-88.5%; p = 0.0026) completed all preoperative chemotherapy and underwent surgical resection. Ten patients (33%) experienced grade 3-4 treatment-related adverse events, the most common being neutropenia and diarrhea; 47% required at least one dose reduction. Partial response rate was 23% and disease control rate was 90% (PD: 10%, PR: 23%, SD: 67%). Of the 23 patients who successfully underwent surgical resection, 2 (9%) had minor postoperative complications. Median size of largest tumor was 5.5cm, median number of tumors was 3, and 39% were lymph node positive. Median length of hospital stay was 4 days. There was zero treatment related mortality. Conclusions: This study met its primary endpoint and demonstrated that neoadjuvant gemcitabine/cisplatin/nab-paclitaxel is feasible and safe prior to resection of intrahepatic cholangiocarcinoma and does not adversely impact perioperative outcomes. Continued follow-up for RFS and OS with this treatment strategy is underway and larger validation studies are planned. Clinical trial information: NCT03579771.