Dandapani, Savita

5069 Background: Ra-223 improves the overall survival in patients with mCRPC to the bone. We assessed the safety of standard-of-care Ra-223 in combination with peposertib, a DNA-dependent protein kinase inhibitor, with or without avelumab, an anti-PD-L1 antibody. Methods: Patients with mCRPC and two or more skeletal metastases identified by bone scintigraphy with or without lymph node metastases up to 3 cm in size, but no visceral metastases, were eligible. Progression after progression after at least one androgen receptor pathway inhibitor or taxane was required. Phase 1 consisted of a two-step sequential safety lead-in using a 3+3 design. Step 1 combined 6 standard cycles of Ra-223 (55 kBq/kg), with increasing doses of peposertib: 50, 100, and 200 mg PO bid on days 3-26 of each cycle. Step 2 combined Ra-223 with the maximum tolerated dose of peposertib and added standard avelumab 800 mg IV every 14 days, starting at cycle 2 of Ra-223. Results: A total of 9 patients participated in Step 1, where the maximum tolerated peposertib dose of 200 mg PO bid with Ra-223 was deemed tolerable. A total of 6 patients participated in Step 2 and the combination of Ra-223, peposertib at 200 mg PO bid, and standard avelumab was deemed tolerable. Of the 15 patients in Phase 1, none experienced grade 4 or higher treatment-related toxicities, while 7 experienced grade 3 toxicities, including neutropenia (1), anemia (1), cardiac chest pain (1), fall (1), maculopapular rash (2), and lymphopenia (2). The median (Q1, Q3) PSA velocity from the beginning to the end of treatment was lower for Step 2 versus Step 1: 2.1 (-0.1, 4.6) versus 23.5 (18.6, 77.1) ng/mL/month (p = 0.0067). OS and PFS were calculated with the limitation that the Phase 1 was non-randomized. Median OS was not reached for Step 2, as only 1 of 6 patients had died, versus 15.2 months for Step 1, where 8 out of 9 patients had died (p = 0.0537). The patient who died in Step 2 discontinued therapy prematurely after 3 cycles due to progression and survived 15.2 months (the 5 alive completed all 6 cycles). The median radiographic PFS was 7 months for Step 2 versus 12.7 months for Step 1 (p = 0.8910). Conclusions: The combination of Ra-223 and peposertib, with or without avelumab was well tolerated. The triplet combination showed the most promising results at this early evaluation. We continue to accrue in the randomized Phase II portion of the trial. Clinical trial information: NCT04071236 .

Introduction There is no prospective data to guide the utilization of peri-transplant radiation (PTRT) in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). In retrospective analyses, PTRT has been associated with local disease control, however evidence supporting improved progression free survival (PFS) is less well defined (Milgrom SA et al Cancer. 2017; 123(8):1363-1371). Furthermore, the added benefit of PTRT in the era of recent advancement in salvage strategies, including brentuximab vedotin (BV) and checkpoint inhibitors (CPI), is unclear. In a multicenter, retrospective analysis, we evaluated the impact of PTRT on PFS for patients with R/R cHL. Methods We identified consecutive pts ≥7 years old at time of diagnosis with R/R cHL treated with autologous stem cell transplant (ASCT) at 5 US academic institutions between 2010-2021. PTRT was defined as radiation administered within 3 months of ASCT. The primary objective was to compare the post-ASCT PFS, defined as the time from ASCT to subsequent relapse or death from any cause, between the two groups. Univariable and Multivariable Cox regression was performed to evaluate the impact of various relevant clinical factors on post-ASCT PFS. Results A total of 958 eligible pts were identified ( Table 1). The median age at cHL diagnosis was 31 (range, 7-72). At the time of first relapse/primary refractory disease, 406 (54%) pts had early-stage disease, 167 (24%) pts had bulky disease (≥5.0 cm), 308 (36%) pts had extra-nodal disease, 182 (22%) pts had B-symptoms (B-sx), and 338 (45%) had primary refractory disease. A total of 302 (32%) pts received >1 line of salvage before ASCT. Salvage treatment at any time point before ASCT included chemotherapy only for 457 (48%) patients, BV(+/- chemotherapy) for 308 (32%) patients, and CPI (+/- BV or +/- chemotherapy) for 193 (20%) patients. In total, 239 (24.9%) pts received PTRT, 139 (58.1%) before ASCT and 100 (41.8%) after ASCT. Among pts with available dosing information (23.3%), the median radiation dose administered was 28 Gy. The most common doses administered were 30 Gy in 77 (31.7%) pts, 36 Gy in 62 (27.8%) pts, and 18 Gy in 43 (19.2%) pts. Radiated sites included mediastinum in 172 (80.7%) pts, neck/cervical lymph nodes in 68 (31.9%) pts, and supra/infra clavicular region and axilla, each in 31 (14.6%) pts. Compared to the 719 pts that did not receive PTRT, patients treated with PTRT were more likely to have early stage disease (73% vs 47%, p<0.001), bulky disease (30% vs 22%, p = 0.048), primary refractory disease (56% vs 40%, p <0.001), >1 line of salvage treatment prior to ASCT (40% vs 29%, p<0.001), and <CR prior to ASCT (36% vs 27%, p = 0.007) (Table 1). Patients treated with PTRT were less likely to have RT at initial diagnosis (5.9% vs 22%, p<0.001), extra-nodal disease (19% vs 42%, p<0.001), B-sx (17% vs 25%, p=0.035), salvage treatment that included CPI (11% vs 23%, p<0.001), and BV maintenance (20 vs 31%, p<0.001). After a median follow up from ASCT of 4.5 years (range, 2.4-7.2), 2-year PFS was 76% (73%, 79%) and 5-year PFS was 70% (67%, 73%). In univariable analysis, receipt of PTRT showed non-significant reduced hazard for PFS (HR 0.79, 95% CI 0.59-1.05, p = 0.093) (Figure 1). In a multivariable model, PTRT showed significant association with PFS (HR 0.56, 95% CI 0.36-0.88, p=0.009) when adjusting for other clinically relevant factors at relapse such as stage, B-sx, bulk, primary refractory disease, BV(+/- chemotherapy) or CPI (+/- BV or +/- chemotherapy) in salvage, PET response prior to ASCT, and BV maintenance after ASCT. To determine if specific subgroups benefited from PTRT, we tested for interaction effects between PTRT and clinically relevant factors. Only bulk (HR 0.37, 95% CI 0.16-0.85, p=0.013) and B-sx (HR 0.45, 95% CI 0.20-1.02, p=0.041) showed significant interaction with PTRT.Among pts with bulky disease, 5-year PFS was significantly improved with receipt of PTRT (81% vs 62%, p=0.013). Conclusion In this large multi-center analysis of pts with R/R cHL undergoing ASCT, there was no significant difference in PFS regardless of receipt of PTRT. However, after adjusting for known clinically relevant factors, receipt of PTRT was significantly associated with PFS and was particularly beneficial for patients with bulky disease or B-sx at relapse. We found decreased utilization of PTRT in pts receiving CPI-based salvage; therefore the role for PTRT for pts receiving CPI-based salvage is unclear.