Harris, William Proctor

427 Background: Derazantinib, a potent anti- FGFR1-3 oral kinase inhibitor, has shown clinically meaningful anti-tumor activity (21%), durable responses (median, 6.4 months), and progression-free survival (median, 8.0 months) in patients (pts) with FGFR2 fusion (FGFR2F)-positive intrahepatic cholangiocarcinoma (iCCA), and with a manageable toxicity profile. Herein, we report an interim analysis of the clinical efficacy data of derazantinib for pts with iCCA harboring FGFR2 mutations or amplifications (FGFR2M/A), a potential therapeutic option currently not addressed by FGFR inhibitors. Methods: Study FIDES-01 enrolls in a dedicated cohort pts with FGFR2M/A+ advanced iCCA who received previous chemotherapy. Pts receive 300 mg derazantinib daily until disease progression, death or intolerance. The primary endpoint is the proportion of pts alive and free of disease progression at 3 months (PFS3; RECIST 1.1, central imaging review) using a Simon’s two-stage sample-size minimizing statistical design. The interim analysis population comprises 23 pts dosed (intention to treat) who had at least one post-baseline tumor assessment (or clinical progression, or died) by June 3, 2021, using investigator assessments based on RECIST 1.1. Results: To date, 28 pts have been enrolled and dosed. FGFR2M/A observed in these pts included missense point mutations (78%), other short variants (11%) and amplifications (11%). Transition from stage 1 to stage 2 of the study was achieved earlier than planned after 8 (67%) of 12 pts were assessed as PFS3 based on central imaging review. In 23 pts included in this interim analysis for efficacy, the best overall response (investigator assessment) was confirmed partial response in two (8.7%) and stable disease in additional 15 pts (65.2%), resulting in a disease control rate of 73.9% (95% CI, 51.6–89.8). Using Kaplan-Meier analyses, the median PFS was 7.3 months (95%CI, 3.5–16.7) and the probability of being progression-free at 3 months and at 6 months were 76.3% (95%CI, 51.9–89.4) and 50.3% (95%CI, 21.7–73.4), respectively. Clinically meaningful anti-tumor efficacy was observed across all types of genetic aberrations. The safety profile of derazantinib in FGFR2M/A+ iCCA pts was consistent with that previously reported for FGFR2F+ iCCA pts. Conclusions: This interim data in study FIDES-01 suggest that derazantinib treatment provides clinical benefit to pts with advanced iCCA harboring FGFR2M/A who progressed after at least one line of standard chemotherapy. To our knowledge, this is the first report of clinically meaningful anti-tumor efficacy in a prospectively planned cohort of iCCA pts harboring FGFR2M/A. The study is ongoing to accrue 43 patients, assessing derazantinib as a therapeutic option for FGFR2M/A+ iCCA pts after disease progression on first-line treatment. Clinical trial information: NCT03230318.

PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348 ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

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.

e16686 Background: Genetic alterations in the FGFR pathway are emerging as promising therapeutic targets in CCA. The clinical and molecular features of patients (pts) with CCA harboring FGFR genetic alterations are reported here. Methods: A retrospective chart review was performed in pts with CCA who were found to have an FGFR alteration on tumor molecular profiling as part of routine care between 9/2007 and 12/2019. Data on demographics, risk factors, pathology, molecular characteristics, systemic therapies, radiographical response, time on treatment, and overall survival (OS) were collected in a multi-center collaborative effort across seven academic centers. Results: Among 135 pts with FGFR-altered CCA, the median age at diagnosis was 57 years old (range = 25-92 years), and 80 (59.3%) pts were female, 129 (95.6%) had intrahepatic CCA, and 6 (5.6%) had chronic HBV. At presentation, 28.2% of pts had resectable disease, including 65.0% with Stage I-II, 22.5% with Stage III, and 5.0% with Stage IV. At the time of initial diagnosis, CA19-9 was < 35U/mL in 42.6% of pts. Bone metastases were observed in 41 (30.6%) pts with advanced disease. FGFR2 fusions were the most common FGFR alteration (68.2%), followed by FGFR2 mutations (21.5%), FGFR3 mutations (3.7%), FGFR2 rearrangements (1.5%), FGFR1 amplification (1.5%), and FGFR2 amplification (1.5%). The most common FGFR2 fusion partners were BICC1 (28.3%), SORBS1 (4.4%), POC1B (3.3%), and TACC2 (3.3%). The median lines of palliative systemic therapies received was 3 (range = 0-8), and 40/135 (29.6%) pts received a liver-directed therapy. For the 55 (59.8%) pts with FGFR2 fusions who received gemcitabine/cisplatin as first-line palliative systemic therapy, the median time on treatment was 6.2 months (95% CI: 4.1-9.3). The median OS from time of initial diagnosis was 36.1 months (95% CI: 28.3-51.6) in the FGFR2 fusion positive cohort. Among the 92 pts with FGFR2 fusions, 70 (76.1%) pts received an FGFR inhibitor on a clinical trial; 12 (17.1%) were subsequently treated with a second FGFR inhibitor, and 58.3% stayed on the second FGFR inhibitor for ≥4 months. Pts with a BICC1 fusion partner (n = 16) had an overall response rate of 42.9% on FGFR-selective inhibitors compared to 30.8% in non-BICC1 fusion partners (n = 54). Conclusions: Pts with CCA harboring FGFR alterations were found to have a high rate of normal CA19-9, high rate of bone metastases, and short median time on treatment on first-line palliative gemcitabine/cisplatin. Additional comparative studies are necessary to evaluate these findings.

4508 Background: The combination of dual immune checkpoint inhibitors (ICI) T (anti–CTLA-4) and D (anti–PD-L1) showed tolerability with a promising objective response rate (ORR) in the initial cohort of this study (NCT02519348). Subsequent evaluation of pts with solid tumors treated with increasing doses of T suggested priming with a higher dose of T may induce a stronger immune response and enhance anti-tumor activity. Thus, the randomized expansion cohorts comprised 4 arms evaluating T and D as monotherapies and 2 T+D regimens, including a novel T+D regimen featuring a single, priming dose of T. Methods: ICI-naïve pts with aHCC who progressed on, were intolerant to, or refused sorafenib were randomized to one of two T+D combinations: T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Safety was the primary endpoint. ORR by blinded, independent central review using RECIST v1.1, duration of response (DoR), circulating lymphocytes, and overall survival (OS) were assessed. Results: At data cut-off (09/02/2019), 332 pts were enrolled. Median follow-ups were 11.7 months (mo) for T300+D, 14.6 (T75+D), 8.9 (D), and 15.8 (T). Treatment-related adverse event (trAE) incidences are shown (Table); no deaths were attributed to trAEs for T300+D or T. The T300+D arm had the highest confirmed ORR (DoR not reached [NR]) and longest OS (Table). A unique proliferative T cell profile was identified for pts in the T300+D arm, suggesting additive biologic activity for the combination, and showed pts with an OR exhibited high cytotoxic (CD8) counts. Conclusions: The encouraging clinical activity and tolerable safety profile suggest T300+D provides the best benefit-risk profile as opposed to T75+D or monotherapies. The unique pharmacodynamic activity of the T300+D regimen further supports its use in aHCC. T300+D and D are being evaluated in the ongoing phase III HIMALAYA study (NCT03298451) in first-line HCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348 . [Table: see text]