e16150 Background: Immune checkpoint inhibition has demonstrated modest activity in biliary tract carcinoma (BTC). Augmentation of the immune response by ablative procedures to improve efficacy of immune checkpoint inhibition has been previously demonstrated in hepatocellular carcinoma, however the outcome of the combination of immune checkpoint inhibition with tremelimumab (anti-CTLA4) and durvalumab (anti-PD1) with ablation in advanced biliary tract carcinoma is unclear. The primary objective of this study was to establish the efficacy via 6-month progression-free survival (PFS) of combining tremelimumab and durvalumab in patients with advanced BTC either alone or with tumor ablation. Secondary objectives were safety and feasibility of combination treatment. An exploratory objective was overall survival (OS). Methods: Eligible patients had histologically confirmed advanced or unresectable BTC (intra- or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer) who had progressed on, been intolerant to, or refused prior chemotherapy. Disease had to be technically amenable to cryoablation with at least two measurable lesions. Adequate organ function and an ECOG of 0 or 1 were required. Patients were treated with tremelimumab and durvalumab with or without tumor ablation. Tremelimumab and durvalumab were administered intravenously every 28 days for four cycles followed by durvalumab every 28 days until disease progression. Cryoablation was performed on day 36. Patients were imaged every 8 weeks and response was defined per RECIST v 1.1 criteria. Results: In total, 22 patients have been enrolled into the BTC cohort. Half underwent ablation and half received immunotherapy alone. The median age was 59 years (range 21-80). All patients had received prior systemic chemotherapy, locally advanced disease was present in 68% of patients. Median PFS was 2.1m and median OS was 5.6 m. DCR was 45% (SD). Median OS and PFS was similar in the group that received ablation vs immunotherapy alone with a median OS of 6.8 m vs 6.7 m and 2.0 m vs 2.7 m respectively. The most common grade 3- 4 adverse events were lymphopenia (27%), increased AST (41%), increased alkaline phosphatase (32%) and elevated bilirubin (27%). Conclusions: Combination checkpoint inhibition combined with tumor ablative procedures is a safe and effective treatment strategy for patients with advanced BTC, however the addition of ablative therapy may not enhance efficacy in this small cohort of patients. Results illustrate the poor prognosis of advanced BTC and may represent a non-chemotherapeutic approach to treatment in this patient population. Further studies are warranted to identify patient populations most likely to respond to these interventions. Clinical trial information: NCT02821754.
e16689 Background: Immune checkpoint inhibitor therapy has recently been approved for the treatment of patients with Hepatocellular Cancer (HCC). Data on long-term survival is lacking and the predictors of good outcomes are unknown. The combination of locoregional therapies (transarterial chemoembolization or radiofrequency ablation) plus tremelimumab (trem) with or without durvalumab (durva) was studied in patients with advanced HCC. We report the long-term survival and analyze predictors of good response in two trials of immune checkpoint and ablation treatment in advanced HCC. Methods: Adult patients (pts) with pathologically confirmed HCC with advanced or sorafenib refractory disease who satisfied the eligibility criteria were enrolled in the studies (NCT02821754, NCT01853618). They received treatment with trem, 10 mg per kilogram every 4 weeks for six doses followed by 3 monthly infusions (23 pts) or trem 75 mg flat dose every 28 days for four doses and then durva 1500 mg flat dose every 28 days (35 pts). Subtotal radiofrequency or chemoablation was done on day 36. Results: The average overall survival in the 58 pts was 10.1 months (range 0.9 to 74.2 months); 41.6% were alive at 12 months and 5.5 % were alive at 61 months. A select group of patients had exceptional overall survivals up to 67 months. Predictors of improved overall survival included the presence of higher grade immune related (irAEs) (OR 0.235, p = 0.075) and a partial or stable disease response per RECIST. No new late toxic effects were noted during this long term follow up. Conclusions: Impressive overall survival times of up to 68.8 months were observed with ICI and subtotal ablation in patients with advanced HCC; the presence of irAEs and the tumor response per RECIST may be predictive of better overall survivals. To our knowledge this has not been previously reported in the literature. Clinical trial information: NCT02821754,NCT01853618 .
TPS624 Background: The mortality of hepatocellular carcinoma (HCC) is increasing worldwide, but outcome of systemic treatments in advanced HCC is suboptimal. Adoptive T-cell transfer therapy represents a promising field that exploits the ability of T-cells to recognize and eliminate their target. Targeting the tumor-associated antigen glypican- 3 (GPC3) through chimeric antigen receptors (CAR) engineered T cells is a mechanistically rational novel treatment for advanced HCC. This study aims to determine the dose and early signals of GPC3 targeted (CAR)-T cells in advanced GPC3 expressing HCC (NCT05003895). Methods: This phase I first in human dose escalation trial will study the safety and feasibility of CAR (hYP7)- T cells in advanced HCC patients expressing GPC3. Eligibility criteria includes advanced HCC, not candidates for curative interventions, progressed on first line systemic treatment, tumor GPC3 positivity of ³ 25% by IHC, Child-Pugh Class A, ³1 measurable lesion, ECOG 0 or 1, adequate organ and marrow function. ParticipantsÕ T cells collected through leukapheresis will be transduced with a lentivirus encoding the CAR construct to generate CAR expressing T cells. Patients receive a conditioning chemotherapy regimen of cyclophosphamide and fludarabine prior to the infusion of the GPC3 directed CAR-T cells (Table). The trial has a 4-level modified Fibonacci dose escalation with a minimum of 3 patients at each level and a 28-day interval between the first three patients. Response will be assessed by imaging every two months during the first year. Patients undergo close monitoring with safety assessments during the first year and are followed for life. The primary objective is to determine the MTD, DLT, safety and feasibility of anti-GPC3 CAR expressing T- cells in patients with GPC3-expressing advanced HCC. Secondary objectives include best overall response and overall survival. Exploratory objectives are multiple and include studies to evaluate the persistence and peak levels of anti-GPC3 CAR-T cells after infusion. Recruitment began in December 2021 and the two patients at dose level -1 has been treated; the planned sample size is 38 patients. Table 1 Dose Level Anti-GPC3 CAR-T Cyclophosphamide (mg/m2) Fludarabine (mg/m2) Level -1 0.3x106 CAR-T per kg bw 200 30 Level 1 0.3x106 CAR-T per kg bw 300 30 Level 2 1x106 CAR-T per kg bw 300 30 Level 3 3x106 CAR-T per kg bw 300 30. Clinical trial information: NCT05003895 .
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