Melisi, Davide

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.

4136 Background: NAPOLI 3 (NCT04083235, N = 770), a global, randomized, open-label phase 3 study, demonstrated that NALIRIFOX significantly improved overall survival (OS, primary endpoint) and progression-free survival compared with nab-paclitaxel and gemcitabine in patients with untreated mPDAC. Here, we report an updated analysis of OS. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1) to receive liposomal irinotecan 50 mg/m2 + oxaliplatin 60 mg/m2 + leucovorin 400 mg/m2 + 5-fluorouracil 2400 mg/m2 (NALIRIFOX, n = 383) on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2 (Gem+NabP, n = 387) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence/absence of liver metastases. An updated OS analysis (data cutoff: 3 October 2023) was conducted. Kaplan–Meier methods were used to estimate median (95% confidence interval [CI]) OS and hazard ratios (HRs [95% CI]) were estimated using stratified Cox proportional hazard models. The difference between groups was tested using a stratified log-rank test. Results: The median follow-up for OS was 28.7 months in the NALIRIFOX arm and 29.7 months in the Gem+NabP arm. At data cutoff, 11 patients were still receiving study treatment, all of whom were in the NALIRIFOX arm. With a total of 673 OS events (NALIRIFOX, n = 328; Gem+NabP, n = 345), median OS was 11.1 months (95% CI 10.0–12.1) in the NALIRIFOX arm compared with 9.2 months (8.3–10.6) in the Gem+NabP arm (HR 0.84 [95% CI 0.72–0.98]; nominal p = 0.026). At 12 months and 18 months, survival rates were 45.6% (95% CI 40.5–50.5) and 26.6% (22.2–31.1), respectively, in the NALIRIFOX arm and 39.6% (34.7–44.5) and 20.0% (16.1–24.1), respectively, in the Gem+NabP arm. Conclusions: In this 29-month follow-up of NAPOLI 3, NALIRIFOX continued to demonstrate improved OS compared with Gem+NabP, with 11 patients still receiving the NALIRIFOX regimen. These data confirm NALIRIFOX as a new possible standard of care and reference regimen for the first-line treatment of patients with mPDAC. Clinical trial information: NCT04083235 .

687 Background: The NAPOLI 3 study (NCT04083235, N = 770) reported that NALIRIFOX improved overall survival (OS) vs Gem+NabP with manageable toxicity in 1L treatment of metastatic pancreatic adenocarcinoma. We explored changes in CA19-9 levels and their potential associations with efficacy as an important tumor marker in pancreatic adenocarcinoma. Methods: In NAPOLI 3, CA19-9 was evaluated at baseline and every 8 weeks until patients discontinued study treatment. The detection limit of CA19-9 was 8000 kU/L in this study. The Cox proportional hazards regression and logistic regression were employed to investigate the relationship between CA19-9 decrease and OS, progression-free survival (PFS), and overall response rate (ORR). Results: Patients with evaluable CA19-9 (levels =< 8000) at baseline and additional measurements at weeks 8 and 16 were included in the analysis (NALIRIFOX, n = 179; Gem+NabP, n = 194). The median baseline CA19-9 level was 378.0 and 409.7 kU/L for the NALIRIFOX and Gem+NabP arms, respectively. Overall, patients with (vs without) any CA 19-9 decrease by week 16 had a higher ORR (59.9% vs 35.2%; p = 0.002), a longer median PFS (9.2 vs 6.2 months; p < 0.001) and a longer median OS (14.2 vs 8.7 months; p = 0.005), respectively in a pooled analysis of the treatments. In the NALIRIFOX arm, patients with any CA19-9 decrease by week 16 had a higher confirmed ORR of 65.1% compared with those without at 42.4% ( p < 0.001), a median PFS of 9.5 vs 7.1 months ( p < 0.001) and a median OS of 15.4 versus 8.4 months ( p = 0.004), respectively. In the Gem+NabP arm, patients with CA19-9 decrease by week 16 had a higher ORR of 55.5% compared with those without at 23.8% ( p = 0.012), a median PFS of 7.6 versus 5.8 months ( p < 0.001) and a median OS of 13.7 versus 11.9 months ( p = 0.235), respectively. Conclusions: CA19-9 decrease by week 16 has the potential to be an early prognostic factor for OS, PFS and ORR. The results should be interpreted with caution as a considerable percentage of patients were excluded due to non-evaluable CA19-9 that exceeded the lab detection limit of 8000 kU/L. Clinical trial information: NCT04083235 .

4006 Background: Liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Here, we present results from NAPOLI 3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated mPDAC were randomized (1:1; stratified by Eastern Cooperative Oncology Group [ECOG] performance status, geographic region and presence/absence of liver metastases) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or Gem+NabP on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when at least 543 events were observed using a stratified log-rank test with an overall one-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. Median OS was 11.1 months in the NALIRIFOX group versus 9.2 months in the Gem+NabP group; median PFS was 7.4 months versus 5.6 months. Median (95% CI) duration of response was 7.3 (5.8–7.6) and 5.0 (3.8–5.6) months in patients who received NALIRIFOX and Gem+NabP, respectively. Grade 3/4 treatment-emergent adverse events occurring in at least 10% of patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in patients with mPDAC. The NALIRIFOX safety profile was consistent with the profiles of the regimen components and generally manageable. Clinical trial information: NCT04083235 . [Table: see text]

LBA661 Background: Liposomal irinotecan administered with 5-fluorouracil/leucovorin (5-FU/LV) is approved in the USA and Europe for mPDAC following progression with gemcitabine-based therapy. A phase 1/2 study (Wainberg et al. Eur J Cancer 2021;151:14–24; NCT02551991) demonstrated promising anti-tumor activity in patients with mPDAC who received first-line liposomal irinotecan 50 mg/m2 + 5-FU 2400 mg/m2 + LV 400 mg/m2 + oxaliplatin 60 mg/m2 (NALIRIFOX). Herein, we present results from NAPOLI-3 (NCT04083235), a randomized, open-label, phase 3 study investigating the efficacy and safety of NALIRIFOX compared with nab-paclitaxel + gemcitabine as first-line therapy in patients with mPDAC. Methods: Eligible patients with histopathologically/cytologically confirmed untreated metastatic PDAC were randomized (1:1) to receive NALIRIFOX on days 1 and 15 of a 28-day cycle or nab-paclitaxel 125 mg/m2 + gemcitabine 1000 mg/m2 (Gem+NabP) on days 1, 8 and 15 of a 28-day cycle. Randomization was stratified by ECOG performance status, geographic region and presence or absence of liver metastases. The primary endpoint was overall survival (OS); secondary endpoints were progression-free survival (PFS), overall response rate (ORR) and safety. OS was evaluated when ≥ 543 events were observed using a stratified log-rank test with an overall 1-sided significance level of 0.025. Results: Overall, 770 patients (NALIRIFOX, n = 383; Gem+NabP, n = 387) were included. Baseline characteristics were well balanced between arms. At a median follow-up of 16.1 months, 544 events had occurred. The median OS was 11.1 months in the NALIFIROX arm as compared with 9.2 months in the Gem+NabP arm (HR 0.84 [95% CI 0.71–0.99]; p = 0.04); PFS was also significantly improved (7.4 months vs 5.6 months; HR 0.70 [0.59–0.84]; p = 0.0001). Grade 3/4 treatment-emergent adverse events (TEAEs) with ≥ 10% frequency in patients receiving NALIRIFOX versus Gem+NabP included diarrhea (20.3% vs 4.5%), nausea (11.9% vs 2.6%), hypokalemia (15.1% vs 4.0%), anemia (10.5% vs 17.4%) and neutropenia (14.1% vs 24.5%). Conclusions: First-line NALIRIFOX demonstrated clinically meaningful and statistically significant improvement in OS and PFS compared with Gem+NabP in treatment-naïve patients with mPDAC. The safety profile of NALIRIFOX was manageable and consistent with the profiles of the treatment components. Funding: Funded by Ipsen. Clinical trial information: NCT04083235 .[Table: see text]

4086 Background: Pemigatinib (PEMI), a potent, selective, oral FGFR1-3 inhibitor, has shown efficacy and safety in patients (pts) with CCA and FGFR2 rearrangements/fusions in FIGHT-202 (NCT02924376; objective response rate [ORR], 35.5%; duration of response [DOR], 7.2 months [mo]). Overall survival (OS: 21.1 mo) was not mature in the primary report (Abou-Alfa. Lancet Oncol 2020; cutoff: Mar 22, 2019); herein we report matured efficacy and safety data from FIGHT-202 (cutoff: Apr 7, 2020). Methods: Pts (≥18 y) with known FGF/FGFR alterations and progression after ≥1 prior therapy had FGFR2 rearrangements/fusions (cohort A), other FGF/FGFR alterations (B), or no FGF/FGFR alterations (C). Pts received PEMI 13.5 mg QD (21-d cycle; 2 wks on, 1 wk off) until progression or toxicity. Primary endpoint: independent, centrally confirmed ORR (cohort A); secondary endpoints: ORR (cohorts B, C; cohorts A and B combined); DOR, disease control rate (DCR), progression free survival (PFS), OS, and safety. A post-hoc analysis in cohort A evaluated mOS in responders (pts with complete response [CR] or partial response [PR]) vs non-responders (pts with progressive disease [PD] or stable disease (SD]). Results: At cutoff, 147 pts were enrolled (cohort A, n=108; B, n=20; C, n=17; FGF/FGFR status undetermined, n=2); median follow-up was 30.4 (range, 4.9–38.7) mo and median treatment duration was 5.9 (0.2–36.5) mo. In cohort A, 9.3% of pts remained on therapy at cutoff; in cohorts B and C, all pts had discontinued. Pts discontinued mainly for PD (67.6%, 75%, and 64.7% in cohorts A, B, and C respectively). Independent, centrally confirmed ORR was 37.0%; mOS was 17.5 mo (95% CI, 14.4-22.9) in cohort A (Table 1). mOS for responders (n=40) vs non-responders (n=68) was 30.1 (95% CI, 21.5-NE) mo vs 13.7 (9.6-16.1) mo. Overall, most common all-cause treatment-emergent adverse events (TEAEs) were hyperphosphatemia (58.5%; grade ≥3, 0%), alopecia (49.7%; 0%), diarrhea (46.9%; 3.4%), fatigue (43.5%; 5.4%), nausea (41.5%; 2%), and dysgeusia (40.8%; 0%); 10.2%, 13.6% and 42.2% of pts discontinued, had dose reduction, and treatment interruption due to TEAEs, respectively. Conclusions: These results reinforce the primary data, showing continued, durable responses and sustained tolerability in pts receiving PEMI for CCA harboring FGFR2 rearrangements/fusions. Notably, the matured OS is longer than historical data; OS for responders was more than twice as long vs for non-responders. Clinical trial information: NCT02924376. [Table: see text]