Ansell, Steve M

Background Chimeric antigen receptor (CAR) T-cell therapies have recently been established as an important option for the management of relapsed/refractory (R/R) DLBCL. However, real-world studies suggest that approximately half of all patients (pts) receiving commercial CAR-T therapies will relapse within 6 months. These pts have a poor prognosis, with estimated overall survival (OS) of only 5 months, indicating a significant unmet need. Odronextamab is a novel, off-the-shelf, CD20×CD3 bispecific antibody that has demonstrated activity in both R/R follicular lymphoma and R/R DLBCL. We have previously reported encouraging results with odronextamab from the Phase 1 ELM-1 study (NCT02290951) in pts with R/R DLBCL post CAR-T therapy (Bannerji R, et al. Lancet Haematol. 2022). These results were consistent with the antitumor activity seen in pts with R/R DLBCL from the Phase 2 ELM-2 study (Kim WS, et al. ASH 2022). Here, we present an updated analysis of outcomes in a prespecified cohort of post CAR-T patients from ELM-1. Methods Intravenous odronextamab was administered weekly in 21-day cycles during Cycles (C) 1-4. Revisions to the step-up regimen were reported previously (Bannerji R, et al. Lancet Haematol. 2022). Odronextamab was administered with steroid prophylaxis and step-up doses of 0.7/4/20 mg during C1 to mitigate the risk of cytokine release syndrome (CRS), followed by 160 mg on Days (D) 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg every 2 weeks until disease progression or unacceptable toxicity. Those pts who achieved a complete response (CR) that was durable for ≥9 months transitioned to dosing with 320 mg every 4 weeks. The primary endpoint was objective response rate (ORR), assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DoR), progression-free survival (PFS), and OS. Immune biomarker assessment was an exploratory endpoint. Results As of Dec 20, 2022, 46 pts were treated (safety-evaluable), with 44 pts evaluable for efficacy. For safety-evaluable pts, median age was 63 years (range 27-82), 67% male, 74% Ann Arbor stage III-IV, and 72% were refractory to CAR-T therapy administered in any prior line. 44 pts were evaluable for efficacy after 4.9 months median duration of follow-up. The ORR and CR rate by ICR were 48% (21/44) and 30% (13/44), respectively. Responses were durable, and both median DoR and median duration of CR were not reached. The probability of maintaining a response for 12 months was 62% and the probability of maintaining a CR for 9 months was 86%.A responder analysis of the subgroup of pts who achieved a CR will be presented. The CAR-T treated pts with DLBCL who were evaluable for biomarker analysis (n=10) had lower T-cell counts at baseline compared with CAR-T naive DLBCL pts (n=41 comparable pts who received odronextamab in ELM-2), yet the fold-change of T-cell expansion at C4D15 was greater in CAR-T treated pts versus CAR-T naive pts. T-cell dynamics, such as changes in activation, exhaustion, and memory subsets, will be presented. Safety was generally consistent with that previously reported. Six (13%) pts permanently discontinued odronextamab due to a treatment-emergent AE (device-related infection, pneumonia, dysphagia, gait disturbance, leukemia, and encephalopathy [n=1 each]). The most common treatment-emergent AE was CRS (any grade, 52%). The highest grade of CRS reported was Grade 2, and low-grade CRS events occurred in 46% of pts with the 0.7/4/20 mg step-up regimen. No cases of ICANS were reported in pts with the 0.7/4/20 mg regimen. Grade ≥3 infections occurred in 10 (22%) pts, with no Grade 5 events. No cases of tumor flare were reported. Conclusions Odronextamab monotherapy demonstrates encouraging antitumor activity in heavily pretreated pts who have progressed after CAR-T therapy, with a generally manageable safety profile. Durable CRs were achieved in this difficult-to-treat setting. These data support the potential role of odronextamab in the treatment paradigm for R/R DLBCL. Further studies to evaluate the optimal sequencing and combinations of odronextamab with CAR-T therapy are warranted.

Introduction: Single arm studies incorporating PD-1 blockade and/or brentuximab vedotin (BV) to salvage regimen have produced encouraging results in transplant-eligible relapsed/refractory classic Hodgkin lymphoma (R/R cHL) and are increasingly used in practice. As prospective randomized studies comparing PD1 based salvage to other salvage regimens are lacking, we conducted a retrospective study comparing post-transplant outcomes of R/R cHL patients who received PD1-based regimen and other novel and conventional regimen. Methods: Consecutive adult patients with R/R cHL who received salvage therapy and underwent autologous stem cell transplant (ASCT) between 2010 and 2021 at 5 United States academic institutions were included. Demographics and clinical variables were recorded at relapse by electronic health records review. Study Objectives were post-ASCT progression free survival (PFS) and overall survival (OS). Results: 981 pts of R/R cHL were identified. At relapse, median age was 31 (IQR: 21-43) years, 504 (52%) were male, 323 (49%) had advanced stage, 353 (41%) had extranodal disease (END), 185 (22%) had B symptoms, 345 (45%) were refractory to frontline therapy and 317 (32%) relapsed within a year of frontline therapy.308 (31%) received >1 line of salvage before ASCT. Patients were divided into 3 groups based on salvage therapy received: 1) 195 (20%) patients received a PD-1 agent with or without BV at any point before ASCT (PD-1 group), 2) 312 (32%) patients received BV at any point before ASCT without PD-1 (BV group), and 3) 474 (48%) patients received no novel agent before ASCT (chemo group). PFS was significantly higher in PD1 group (2-yr PFS 93.1 (CI 95: 89.4-96.9)%); compared to BV (2 yr PFS 73.9 (CI 95: 69.1-79.1)% , p <0.0001) or chemo groups (2 yr PFS 71.6 (CI 95: 67.6-75.9)% , p<0.0001). PFS was not different between the BV and chemo groups (p=0.88) (Figure 1). OS was not significantly different between PD-1 group (2 yr OS 96.2 % (CI 95: 93.2-99.2), p=0.06), BV group (2 yr OS 94.3% (CI 95: 91.7-97.0), p=0.2) and chemo group (2 yr OS 91.8% (CI 95: 89.3-94.4)). Amongst pts who were transplanted in complete metabolic response (CMR), we assessed post-ASCT PFS and OS based on salvage therapy received immediately before ASCT. Pts who received PD-1 as last salvage therapy had improved PFS compared to chemo (HR: 0.15 (CI 95: 0.07-0.3), p= <0.0001) and BV (HR: 0.2 (CI 95: 0.08-0.5), p= <0.001). Pts receiving PD-1 immediately before ASCT also had higher OS compared to those receiving chemo (HR: 0.2 (CI 95: 0.05-0.8), p= 0.02) but not BV (HR: 0.8 (CI 95: 0.4-1.3), p=0.1). There was no difference between BV and chemo group in regards to PFS and OS. In multivariable analysis that included time to relapse, B symptoms, END, pre-ASCT response, number of salvage therapy lines before ASCT, year of transplant and BV consolidation, PD-1 salvage therapy had significantly higher PFS compared to chemotherapy (HR: 0.3 (CI 95: 0.2-0.5), p= <0.001). BV group had significantly lower PFS (HR: 3.34 (CI 95: 1.8-6.0), group=0.002) compared to PD1 group. PFS was not different between BV and chemo group (p= 0.7). OS was similar between all 3 groups. Similar PFS and OS were seen among patients receiving PD-1 + BV (n=83) and PD-1 with or without chemo (n =112) (p=0.96 for PFS; p= 0.72 for OS); as well as for patients receiving PD-1 as part of their first salvage therapy (n=151) or later salvage treatments (n=44) (p=0.45 for PFS, p= 0.3 for OS). Patients who received PD1 based regimen as last salvage therapy pre-ASCT had significantly better PFS (HR: 6.8 (CI 95: 2.4-19.2), p= <0.0001) and OS (HR: 10.6 (CI 95: 2.5-44.8), p= 0.0001) compared to patients who received PD1 prior to their last line of salvage therapy per-ASCT. Conclusion: Receipt of PD-1 based salvage therapy at any point before ASCT is associated with significantly improved PFS compared to either BV or chemotherapy-based salvage treatments. In the subgroup of patients transplanted in CMR, PD1 based last salvage regimen were associated with higher PFS compared to chemotherapy and BV and higher OS compared to chemotherapy. PD1 based last salvage therapy pre-ASCT was associated with better survival compared to PD1 prior to last salvage therapy. Results of this study strongly support the use of PD-1 based salvage therapy for patients with R/R cHL. S.D., R.M., H.S contributed equally. R.S., M.M. contributed equally.