Murphy, Adrian

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]

4069 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ̃20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (mIDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ̃780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.

266 Background: CCA is a rare cancer for which there are limited effective therapies. IDH1 mutations occur in ~20% of intrahepatic CCAs, resulting in production of the oncometabolite D-2-hydroxyglutarate, which promotes oncogenesis. IVO (AG-120) is a first-in-class, oral, small-molecule inhibitor of mutant IDH1 (m IDH1). ClarIDHy aimed to demonstrate the efficacy of IVO vs PBO in pts with unresectable or metastatic m IDH1 CCA. The primary endpoint was met with significant improvement in progression-free survival (PFS) by independent radiology center (IRC) with IVO vs PBO (hazard ratio [HR] = 0.37, p < 0.0001). Objective response rate (ORR) and stable disease for IVO were 2.4% (3 partial responses) and 50.8% (n = 63) vs 0% and 27.9% (n = 17) for PBO. IVO pts experienced significantly less decline in physical and emotional functioning domains of quality of life at cycle 2 day 1 vs PBO pts (nominal p < 0.05). Methods: Pts with m IDH1 CCA were randomized 2:1 to IVO (500 mg PO QD) or matched PBO and stratified by prior systemic therapies (1 or 2). Key eligibility: unresectable or metastatic m IDH1 CCA based on central testing; ECOG PS 0–1; measurable disease (RECIST v1.1). Crossover from PBO to IVO was permitted at radiographic progression. Primary endpoint: PFS by IRC. Secondary endpoints included overall survival (OS; by intent-to-treat), ORR, PFS (by investigator), safety, and quality of life. The planned crossover-adjusted OS was derived using the rank-preserving structural failure time (RPSFT) model. Results: As of 31 May 2020, ~780 pts were prescreened for an IDH1 mutation and 187 were randomized to IVO (n = 126) or PBO (n = 61); 13 remain on IVO. Median age 62 y; M/F 68/119; 91% intrahepatic CCA; 93% metastatic disease; 47% had 2 prior therapies. 70% of PBO pts crossed over to IVO. OS data were mature, with 79% OS events in IVO arm and 82% in PBO. Median OS (mOS) was 10.3 months for IVO and 7.5 months for PBO (HR = 0.79; 95% CI 0.56–1.12; one-sided p = 0.093). The RPSFT-adjusted mOS was 5.1 months for PBO (HR = 0.49; 95% CI 0.34–0.70; p < 0.0001). Common all-grade treatment emergent adverse events (TEAEs, ≥ 15%) in the IVO arm: nausea 41%, diarrhea 35%, fatigue 31%, cough 25%, abdominal pain 24%, decreased appetite 24%, ascites 23%, vomiting 23%, anemia 18%, and constipation 15%. Grade ≥ 3 TEAEs were reported in 50% of IVO pts vs 37% of PBO pts, with grade ≥ 3 treatment-related AEs in 7% of IVO pts vs 0% in PBO. 7% of IVO pts experienced an AE leading to treatment discontinuation vs 9% of PBO pts. There were no treatment-related deaths. Conclusions: IVO was well tolerated and resulted in a favorable OS trend vs PBO despite a high rate of crossover. These data – coupled with statistical improvement in PFS, supportive quality of life data, and favorable safety profile – demonstrate the clinical benefit of IVO in advanced m IDH1 CCA. Clinical trial information: NCT02989857.