Gao, Feng

Abstract During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received BT had a higher baseline risk profile than patients who did not receive BT, and these patients, as a group, had inferior outcomes compared with those who did not receive BT. However, after propensity score matching between the 2 groups, there were no statistically significant differences in overall response rate (77% vs 87%; P = .13), complete response rate (58% vs 70%; P = .1), progression-free survival (hazard ratio [HR], 1.25; P = .23), and overall survival (HR, 1.39; P=.09) between the BT group and the no-BT group, respectively. Analyzing the effects of BT in the whole cohort that underwent leukapheresis regardless of receiving axi-cel (intention-to-treat analysis) showed similar results. Radiation BT resulted in outcomes similar to those observed with nonradiation BT. Our findings suggest that BT may be safe without a significant impact on long-term survival for patients who require disease stabilization during the manufacturing period. Moreover, our results suggest that there is no clear advantage to using radiation-based BT over nonradiation-based BT.

4146 Background: Targeting focal adhesion kinase (FAK) renders checkpoint immunotherapy effective in pancreatic ductal adenocarcinoma (PDAC) mouse models. Defactinib is a highly potent oral FAK inhibitor shown to have a tolerable safety profile. We evaluated the safety and recommended phase 2 dose (RP2D) of defactinib in combination with pembrolizumab and gemcitabine for PDAC patients. Methods: We conducted a multicenter, open-label, phase I study with dose escalation and expansion phases. In 3x3 dose escalation, patients with refractory solid tumors were treated at five escalating dose levels of defactinib and gemcitabine to identify a RP2D. In expansion phase, patients with metastatic PDAC who progressed on frontline treatment (refractory cohort) or had treatment response or stable disease (SD) on standard gemcitabine/nab-paclitaxel (maintenance cohort) were treated at RP2D. Pre- and post-treatment tumor biopsies were performed to evaluate changes in tumor immunity. Results: The triple drug combination was well-tolerated with no dose-limiting toxicities. Among 17 treated patients with refractory PDAC, the disease control rate (DCR) was 58.8% with one partial response (PR) and nine SDs and the median progression-free survival (PFS) and overall survival (OS) were 4.2 months and 9.1 months, respectively. Among the evaluable patients in the maintenance cohort, DCR was 63.6% with one PR and six SD. Three patients with SD came off study due to treatment- or disease-related complications. The median PFS and OS were 5.0 months and 8.3 months, respectively. Conclusions: The combination of defactinib, pembrolizumab, and gemcitabine was well-tolerated, had promising preliminary efficacy, and showed increased infiltrative T lymphocytes in post-treatment tumor biopsies. Incorporation of a more potent chemotherapy backbone should be considered to achieve better clinical response in future trial design. Clinical trial information: NCT02546531.

2068 Background: There is a lack of effective therapy for recurrent high-grade meningiomas who relapsed after prior radiation therapy (RT). ETCTN 10186 is a phase I/II study to evaluate the feasibility and preliminary clinical efficacy of combining reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab for recurrent high-grade meningiomas. The preliminary results from the phase I portion are reported here. Methods: Recurrent grade II-III meningioma patients were treated with radiosurgery plus nivolumab with or without ipilimumab. Key eligibility criteria include age ≥ 18 years; ECOG score ≤ 2; tumor diameter 1-5 cm; prior radiation dose ≤ 70 Gy; normal organ function; no active autoimmunity. During the phase I portion, eligible patients were treated according to treatment-escalation schema following the modified 3+3 design (Table 1). The maximum tolerated combination (MTC) will be the regimen at which ≤ 1/6 patients experience dose-limiting toxicity (DLT) within 8 weeks of the start of study therapy. During the phase II portion, a total of 24 evaluable patients will be enrolled at the MTC using Simon’s MiniMax two-stage design. The primary endpoint of the phase I portion is to determine the MTC. Objective radiological responses (ORRs) are defined as per the Macdonald criteria. One cycle of immunotherapy is defined as 4 weeks of nivolumab with or without concurrent ipilimumab. Results: From 7/2019 to 3/2021, 13 patients were enrolled in the phase I, including 6 with regimen A and 7 with regimen B (Table). The median prior RT dose was 56 Gy (18-70) at a median interval of 2.8 years (1.3-13.3). There was no DLT in either cohort, so regimen B was deemed the MTC. The median cycles of immunotherapy completed were not significantly different between cohort A and B (11 vs. 6, p = 0.41, respectively). Three cohort A patients and 2 cohort B patients completed all planned doses of immunotherapy. Most patients stopped due to progression, and only one cohort B patient stopped due to treatment-related toxicity (grade 3 hypophysitis and encephalitis after 6 cycles of immunotherapy). After a median follow-up of 11.1 months, there have been 5 progressions and 4 deaths. The 6 month-PFS and 12 month-PFS rates are 62% and 54%, respectively. Two ORRs have been reported by institutional assessment, and central radiology review is ongoing and will be reported. Conclusions: Reirradiation using fractionated radiosurgery with nivolumab plus or minus ipilimumab are well tolerated for radiation-relapsed high-grade meningiomas. Phase II study of regimen B is currently enrolling. Clinical trial information: NCT03604978. [Table: see text]