Median Prior Lines Of Therapy Research Articles

Chimeric antigen receptor T-cell infusion for large B-cell lymphoma in complete remission: a center for international blood and marrow transplant research analysis.

CD19 CAR T-cell (CAR-T) therapy is commonly administered to patients with relapsed or refractory large B-cell lymphomas (LBCL), but salvage or bridging therapy can sometimes lead to a complete response (CR) prior to infusion. Limited studies have assessed the outcomes of patients infused in CR. A total of 134 patients with LBCL in CR prior to CAR-T infusion were identified from the CIBMTR registry, with median prior lines of therapy of 3 (range 2-9). At two years post-infusion, the probability of progression-free survival was 43.5% (95% CI 34.4-52.8) and the probability of overall survival was 63.8% (95% CI 54.4-72.6). The cumulative incidence rates of non-relapse mortality and relapse/progression at two years were 9.2% (95% CI 4.5-15.4) and 47.3% (95% CI 38.2-56.6), respectively. The rate of grade 3 or higher cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were 2.2% and 8.2%, respectively. In summary, CAR-T in heavily pretreated patients with LBCL who are in CR following two or more lines of prior therapy demonstrate that a subset of patients may remain free of progression at two years. Additionally, the toxicity profile was impressive with very low rates of grade 3 CRS and ICANS.

Abstract PS08-04: Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC)

Abstract PS08-04: Multicenter retrospective cohort study of the sequential use of the antibody-drug conjugates (ADCs) trastuzumab deruxtecan (T-DXd) and sacituzumab govitecan (SG) in patients with HER2-low metastatic breast cancer (MBC)

Abstract PO1-04-03: Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer

Abstract Background: Ibrutinib is a first-in-class inhibitor of Bruton’s tyrosine kinase that has demonstrated potent inhibition of ErbB/HER family receptor tyrosine kinases in preclinical models. Ibrutinib also displays immunomodulatory effects, shifting the profile of the immune response from Th2-type to Th1-type cytokines (Dubovsky et al. 2013), resulting in enhanced antitumor immunity. As there is a need for novel HER2-targeted therapies following progression on established anti-HER2–directed therapies, and as combining multiple HER2-directed agents is more effective than single-agent therapy (Blackwell et al. 2012), this study explored the safety and efficacy of ibrutinib in combination with trastuzumab in patients (pts) with HER2-positive metastatic breast cancer (MBC) (NCT03379428). Trial design: Phase I was a dose-escalation study to define the recommended Phase II dose (RP2D) of ibrutinib plus trastuzumab. The primary objective of Phase II was to define the clinical benefit rate (CBR = complete response [CR] + partial response [PR] + stable disease [SD] ≥ 6 months) of ibrutinib plus trastuzumab; secondary objectives were to determine objective response rate (ORR = CR + PR), overall survival (OS), progression-free survival (PFS), and safety/tolerability. Pts had HER2-positive MBC with measurable disease per RECIST v1.1, disease progression on or within 6 months of completing ado-trastuzumab emtansine (T-DM1) therapy, and ≤4 (Phase I) or ≤5 (Phase II) prior chemotherapy regimens for MBC, with no limit on prior endocrine therapies. Results: 26 pts were treated in Phases I and II: median age, 65.1 y; 15.4% Asian, 15.4% Black, 46.2% Caucasian, 19.2% Hispanic, and 3.8% Other; 46.2% with ECOG performance status (PS) of 0, 42.3% with PS of 1, and 7.7% with PS of 2. Median prior lines of therapy for MBC was 2 (range: 0, 6); median prior lines of therapy in any setting was 4 (range: 1, 9). In any setting, 88.5% of pts had prior treatment (Tx) with trastuzumab, 80.8% had prior Tx with pertuzumab, and 100% had prior Tx with T-DM1. 0% of pts had brain, 38.5% had bone, 23.1% had liver, and 42.3% had lung metastases. All pts were HER2+ by local pathology, 61.5% positive by IHC and 42.3% by FISH; 12 pts had ER+ and/or PR+ and 14 pts had ER-/PR- cancers. The starting dose of ibrutinib for Phase I was 560 mg. Of the 3 pts enrolled at this dose level, all experienced grade 3 or higher adverse events (AEs), with 2 of the pts experiencing serious AEs (grade 4 alanine aminotransferase [ALT] increased and grade 5 respiratory failure). As such, 420 mg of ibrutinib was selected as the RP2D. At the time of data extraction, across Phase I/II, 16 pts (61.5%) experienced a Tx-related adverse event (TRAE). The most common (≥5%) TRAEs of any grade were bruising and rash (each 19.2%); fatigue and thrombocytopenia (each 15.4%); anemia, diarrhea, and edema (each 11.5%); and ALT increased, aspartate aminotransferase increased, blurred vision, ecchymoses, mucositis, nausea, pruritus, and vomiting (each 7.7%). A total of 5 pts (19.2%) experienced grade 3 or 4 TRAEs; no grade 5 TRAEs were reported. 26 pts were treated with ibrutinib and trastuzumab, and 26 pts were in the evaluable population. 1 pt had CR for an ORR of 3.8% (95% CIs: 0.1, 19.6); 9 pts had SD, and 4 pts had SD for ≥6 months for a CBR of 19.2% (95% CIs: 6.6, 39.4). Median OS was 27.1 months (range: 0.30, 27.1), and median PFS was 2.0 months (range: 0.03, 27.1). The PFS rate at 12 months was 34.6% (95% CIs: 15.6, 54.6). Conclusion: Ibrutinib plus trastuzumab had a manageable safety profile; however, the CBR did not reach the protocol-specified goal of 28%, and these results do not support further clinical investigation. An in-depth evaluation of the immune effects of ibrutinib in these pts is ongoing. Citation Format: Joyce O'Shaughnessy, Andrea Glidden, Tracy Locke, Amy Scales. Phase I/II Trial of Ibrutinib Plus Trastuzumab in HER2-Positive Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-04-03.

Abstract RF01-07: The efficacy and safety of tinengotinib in patients with advanced or metastatic HR+/HER2- breast cancer or TNBC

Abstract Background: Tinengotinib is a novel multiple kinase inhibitor that strongly inhibits Aurora A/B, FGFR1/2/3, VEGFRs, JAK1/2, and CSF1R. Here we present the preliminary safety, pharmacokinetic and efficacy data of tinengotinib in patients (pts) with hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) breast cancer (BC) and triple-negative BC (TNBC) from Phase I TT420X2101 (NCT03654547) and Phase Ib/II TT420X1103 (NCT04742959) trials. Methods: Eligible pts with HR+/HER2- BC or TNBC who have no available standard therapeutic treatment options were enrolled to the TT420X2101 and TT420X1103 trials. Tinengotinib was given as monotherapy at different dose levels (5 mg QD, 10 mg QD and 12 mg QD); different dosing schedule (6 mg BID); and as combination (tinengotinib 8 mg QD and Abraxane 100 mg/m2). Recruitment spanned from January 2019 to March 2023. Results: As of June 2023, 36 pts with metastatic BC were treated: 30 with tinengotinib monotherapy at dose levels of 5 mg QD (n=1), 8 mg QD (n=4), 10 mg QD (n=5), 12 mg QD (n=18), 6 mg BID (n=2) and 6 with tinengotinib 8 mg QD in combination with nab-paclitaxel 100 mg/m2. Median age 51 years (range 24-75), ECOG PS 1 in 83.3% of pts, median lines of prior therapy were 5, and 77.8% of pts had prior taxanes. Of 30 pts receiving tinengotinib monotherapy, treatment related adverse events (TRAEs) were reported in 26 (86.7%) pts. 43.4% were Grade (G) 1-2, 43.3% were G3. No G4 or G5 TRAEs were reported. Common TRAEs (≥20%) of tinengotinib monotherapy were hypertension (60.0%), stomatitis (50.0%), palmar-plantar erythrodysesthesia syndrome (46.7%) and diarrhea (20.0%). All six (100%) pts receiving tinengotinib in combination with nab-paclitaxel experienced TRAEs, 16.7% were G1, 66.7% were G3, no G4 TRAEs, and one pt had G5 (pulmonary hemorrhage). Common TRAEs (≥20%) of tinengotinib in combination with nab-paclitaxel were neutrophil count decreased/neutropenia (50.0%), stomatitis (50.0%), hypertension (33.3%), hyponatremia (33.3%), hypokalemia (33.3%), and nausea (33.3%). Twenty-eight pts receiving tinengotinib monotherapy were efficacy evaluable. 11 pts with HR+/HER2- BC achieved objective response rate (ORR) of 45.5%, clinical benefit rate (CBR, CR+PR+SD ≥ 24 weeks) of 54.5% and median progression-free survival (mPFS) of 5.55 (95% CI 1.97-6.18) months. Partial responses were seen in 3 pts with HER2-zero (n=5) and 2 pts with HER2 low (1+/2+) pts (n=6), respectively. 17 pts with TNBC had ORR of 23.5%, CBR of 29.4% and mPFS of 2.73 (95% CI 1.68-6.41) months. In 6 pts treated with tinengotinib in combination with nab-paclitaxel, one out of 2 pts with HR+/HER2- BC achieved PR for 13 weeks as of data cutoff; two out of 4 pts with TNBC had SD. No significant difference in exposure was observed between tinengotinib monotherapy and tinengotinib in combination with nab-paclitaxel. Conclusions: Tinengotinib for the treatment of HR+HER2- BC or TNBC, whether as monotherapy or in combination with nab-paclitaxel, had manageable side effects. Tinengotinib has shown promising clinical benefit in heavily pre-treated pts with refractory HR+HER2- BC or TNBC. Clinical benefit was similar across the subgroups of pts with HR+ HER2-zero and HR+ HER2 low disease. Citation Format: Piha-Paul Sarina, Binghe Xu, Ying Fan, Yuan Yuan, Sayeh Lavasani, Joanne Mortimer, Sanjay Goel, Apostolia Tsimberidou, Nuhad Ibrahim, Sausan Abouharb, Carlos Barcenas, Adaeze lheme, Daniel Karp, Jordi Rodon Ahnert, Ecaterina Dumbrava, Jean Fan, Peng Peng, Caixia Sun, Hui Wang, Katie Hennessy, Ximei Fu, Ruolan Xu, Shumao Ni, Frank Wu, Funda Meric-Bernstam. The efficacy and safety of tinengotinib in patients with advanced or metastatic HR+/HER2- breast cancer or TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF01-07.

Abstract CT071: Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy

Abstract Introduction: Despite therapeutic advances, multiple myeloma remains incurable. BCMA targeting immunotherapies, such as bispecific T-cell engagers (TCE) and autologous CAR-T provide high response rates, but relapses are common. Autologous CAR-T are logistically challenging due to the need for apheresis, prolonged manufacturing and occasional manufacturing failures. Importantly, pts who have progressed after a prior BCMA targeting immunotherapy are an emerging area of high unmet need. Emerging data indicate that autologous CAR-T have lower clinical activity in pts ho have progressed on TCE. Methods: P-BCMA-ALLO1 is an allogeneic CAR-T therapy manufactured from healthy donor T-cells available “off-the-shelf” and being evaluated in a phase 1 clinical trial (P-BCMA-ALLO1-001) in RRMM pts. This primary objective is to determine the maximum tolerated dose of P-BCMA-ALLO1, and the key secondary objective is to investigate the anti-myeloma activity. The pts must have progressed on a prior proteasome inhibitor, immunomodulatory drug and anti-CD38 monoclonal antibody. The study allows enrollment of pts who have received prior BCMA targeting therapy. The study is exploring escalating P-BCMA-ALLO1 doses and several different lymphodepletion chemotherapy (LD) regimens. Here we report the safety and early efficacy results for the 5 pts who were treated with P-BCMA-ALLO1 after having progressed on BCMA targeting CAR-T, TCE or both. These pts were treated in arms P1 (LD: cyclophosphamide (cy) 500 mg/m2 + fludarabine (flu) 30 mg/m2 X 3 days) or arm P2 (LD: cy 1000 mg/m2 + flu 30 mg/m2 X 3 days) at a P-BCMA-ALLO1 dose of > 2 X 106 to <6 X 106 cells/kg. Results: The median pt age was 62 years and median prior lines of therapy was 10. Three pts were treated in arm P2 and 2 in arm P1. Two pts had received prior teclistamab, 2 had received prior CAR-T and 1 had received prior teclistamab and CAR-T. P-BCMA-ALLO1 was well tolerated with no dose limiting toxicities or graft vs. host disease. Three of the five pts developed cytokine release syndrome (all grade (G) 2) and one developed G2 immune effector cell neurotoxicity syndrome. Three of the five pts (60%) achieved clinical responses with all three achieving the best response of very good partial response. The two non-responders had previously received and failed to achieve clinical response with teclistamab. One pt who had previously received both teclistamab and CAR-T achieved VGPR. Conclusion: In conclusion, P-BCMA-ALLO1 is an allogeneic CAR-T that is available “on-demand” with activity in RRMM pts who have progressed following prior BCMA targeted CAR-T and TCE. We believe this is the first such report of an allogeneic CAR-T showing clinical activity in such a pt population with high unmet need. Enrollment is continuing and updated data will be presented at the meeting. Citation Format: Bhagirathbhai Dholaria, Leyla Shune, Andrew Kin, Katherine McArthur, Jeff D. Eskew, Christopher E. Martin, Sabrina Haag, Joanne McCaigue, Hamid Namini, Sam DePrimo, Stacey Cranert, Julia Coronella, Devon Shedlock, Rajesh Belani. Clinical activity of P-BCMA-ALLO1, a B-cell maturation antigen (BCMA) targeted allogeneic chimeric antigen receptor T-cell (CAR-T) therapy, in relapsed refractory multiple myeloma (RRMM) patients (pts) following progression on prior BCMA targeting therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT071.

Abstract CT173: Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma

Abstract Background: IMM0306 is a fusion protein of CD20 monoclonal antibody with the CD47 binding domain of SIRPα on both heavy chains. It exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement. Here, we report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy results of phase I in patients (pts) with relapsed or refractory (R/R) CD20-positive B-cell non-Hodgkin's lymphoma (B-NHL). Methods: Eligible pts with R/R CD20-positive B-NHL were enrolled in this open-label, multicenter phase I/II study (NCT05805943). IMM0306 was administered as monotherapy at escalating doses of 0.04, 0.1, 0.25, 0.5, 0.8, 1.2, 1.6, 2.0 mg/kg intravenously once a week after a 2-week single-dose observation period, until disease progression or intolerable toxicity. Dose-limiting toxicity (DLT) was evaluated in the first 28 days. Safety was evaluated per CTCAE 5.0, PK and PD analysis were also assessed, tumor assessments performed once every 8 weeks by Lugano 2014. Results: As of Nov 21, 2023, 48 pts were enrolled. The median age was 56 years with 30 (62.5%) males. The median prior lines of therapy was 2. All pts received previous anti-CD20 therapy. No DLTs were observed. Recommended phase II dose (RP2D) was determined as 2.0 mg/kg. The most frequent treatment related adverse events (TRAEs) were WBC decreased (66.7%), anemia (64.6%), lymphocyte decreased (58.3%), ANC decreased (47.9%), PLT decreased (45.8%), infusion-related reactions (35.4%). Grade ≥3 TRAEs occurred in 33 (68.8%) pts, the most frequent grade ≥ 3 TRAEs were lymphocyte decreased (56.3%), WBC decreased (18.8%), ANC decreased (18.8%). Eight (16.7%) pts experienced treatment related serious adverse event, including PLT decreased, chest pain and pneumonia. Drug discontinuation due to AEs occurred in 1 pt (G4 PLT decreased occurred at 1.6mg/kg without any bleeding). No AE led to death. IMM0306 exhibited approximate dose-proportional increase in PK exposure from 0.5 to 2.0 mg/kg and no obvious accumulation was observed after repeated dosing. At 1.2 mg/kg, CD47 receptor occupancy on peripheral lymphocytes was saturated, suggesting IMM0306 is well tolerated from perspective of CD47 engagement in high dose cohorts. B-cell counts depleted rapidly at doses ≥ 0.8 mg/kg. Elevated cytokines levels were observed after first dosing of IMM0306, but multiple dosing did not stimulate further cytokine activation. Among 33 pts who received active doses ≥ 0.8 mg/kg, 5 CR (4 follicular lymphoma [FL], 1 marginal zone lymphoma [MZL]), 5 PR (3 FL, 1 MZL, 1 diffuse large B cell lymphoma) and 11 SD were seen. Among 17 FL pts, 7 (41%) responded including 4 CR and 3 PR; among 6 MZL pts, 2 (33.3%) responded including 1 CR and 1 PR. Conclusions: IMM0306 was well-tolerated and with a robust preliminary anti-tumor activity especially in pts with R/R FL and MZL. The phase II study is ongoing. Citation Format: Yuankai Shi, Jianliang Yang, Yongping Song, Keshu Zhou, Zhiming Li, Mingzhi Zhang, Hongmei Jing, Zhen Wang, Li Yu, Qiying Lu, Frank Gan, Wenzhi Tian. Preliminary results from a phase I study of IMM0306 in patients with relapsed or refractory CD20-positive B-cell non-Hodgkin's lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT173.

Abstract CT260: A phase II trial of defactinib combined with avutometinib in patients with metastatic uveal melanoma

Abstract Background: Outcomes remain poor for patients with metastatic uveal melanoma (MUM). Therapies targeting commonly mutated G-protein pathway-associated GNAQ and GNA11 have not been met with clinical success. Recent kinome-wide CRISPR-Cas9 screens revealed that FAK and RAF/MEK co-targeting may provide a new network-based precision therapeutic strategy for MUM treatment. Methods: This is an investigator-initiated, prospective, single-arm, single-institution, phase II study evaluating the combination of a FAK inhibitor (defactinib, VS-6063) with a RAF/MEK inhibitor (avutometinib, VS-6766) for the treatment of MUM [NCT04720417]. Defactinib was given 200mg twice daily and avutometinib was given 3.2mg twice a week. Both drugs were given for 3 weeks on and 1 week off (28-day cycle). The primary endpoint of the study is disease control rate (DCR) including complete response (CR), partial response (PR), and stable disease (SD) as determined by RECIST version 1.1 after two cycles. Secondary endpoints include progression free survival (PFS), overall survival (OS), and safety. The trial was designed using a Simon’s two stage design where in stage I, a total of 8 patients would be accrued and if there are ≤2 overall responses, further enrollment would be stopped with the conclusion that DCR cannot be ≥50%. An additional 10 patients would be accrued in stage II, resulting in a total sample size of 18 patients. Results: Twelve patients with MUM were treated with the combination. Median lines of prior therapy was 2 (range 0-7), with 3 patients (25%) being treatment naïve. After 2 cycles, 6 patients achieved SD (50%) while the other 6 patients developed PD. No patients achieved CR or PR. Median duration of treatment was 2.6 months for all patients, and 5.6 months for patients with SD. With a median follow up of 16.5 months, the median PFS was 2.6 months and median OS was 18.4 months. All adverse events (AE) were Grade 1-2 except one Grade 3 AE of asymptomatic elevated CPK that resolved with holding treatment and did not recur upon restarting. Most common AEs were rash (100%), diarrhea (66.7%), peripheral edema (50%), nausea (50%), fatigue (50%), and blurred vision (41.7%). No dose reductions were required for any patients. Reduction of active ERK (pERK) was observed in 2 patients that achieved SD, but not in 2 patients that had PD. Trial enrollment was stopped early by study sponsors before the anticipated accrual of 18 patients due to no patients having significant reduction in disease. Conclusions: In this phase II study of the combination regimen of FAK and RAF/MEK inhibitors, stable disease was achieved in half of patients with MUM. Treatment was well tolerated with only one transient asymptomatic grade 3 CPK elevation. Further research should seek to elucidate an optimal combination treatment strategy such as FAK and PKC inhibitors for improved blocking of the downstream pathways of GNAQ/GNA11 driver mutations. Citation Format: Rino S. Seedor, Mizue Terai, Amry Majeed, Ryota Tanaka, Andrew E. Aplin, Marlana Orloff, Alfredo A. Molinolo, J Silvio Gutkind, Takami Sato. A phase II trial of defactinib combined with avutometinib in patients with metastatic uveal melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT260.

Abstract CT226: Phase 2 study of oral CCR4 antagonist FLX475 (tivumecirnon) plus pembrolizumab in subjects with head and neck squamous cell carcinoma (HNSCC) previously treated with checkpoint inhibitor

Abstract BACKGROUND: FLX475 (tivumecirnon) is a selective CCR4 antagonist designed to block the recruitment of immunosuppressive regulatory T cells (Treg) into the tumor microenvironment. The FLX475-02 trial (NCT03674567) is a phase 1/2 study of FLX475 as monotherapy and in combination with pembrolizumab in subjects with advanced cancer. Early encouraging data on the biologic effects, safety and antitumor activity of FLX475 have previously been presented. We now present the results from the Phase 2 cohort of combination therapy in subjects with head and neck squamous cell carcinoma (HNSCC) previously treated with checkpoint inhibitor (CPI-experienced). METHODS: Subjects with CPI-experienced, recurrent or metastatic (R/M) HNSCC received FLX475 100 mg orally once daily with pembrolizumab (200 mg IV Q3 weeks). The primary study objectives were safety and tolerability, and antitumor activity. The primary efficacy endpoint was objective response rate (ORR), based on RECIST 1.1 criteria. Additional efficacy endpoints included progression-free survival (PFS). Safety was evaluated as per CTCAE v4.03. Data cutoff was 11DEC2023. RESULTS: For the 32 subjects with HNSCC evaluable for response, median follow-up was 14.8 months (range 2.2-40.1) and median lines of prior therapy were 3 (1-6). Median age of subjects was 59 yrs; 94% were male and 75% were Caucasian. Primary tumor location was oropharynx in 56%. As previously reported, the only adverse event clearly determined to be treatment related to FLX475 to date has been asymptomatic and reversible QT prolongation (managed by dose reduction). Among the subjects evaluable for response regardless of HPV or PD-L1 status (n=32), confirmed partial response (cPR) was observed in 5 subjects (ORR: 15.6%, 95% CI 6-32%). Among the subgroup of subjects whose tumors were HPV positive (n=18), 8 (44%) experienced reduction from baseline in target lesion measurements and cPR was observed in 4 (ORR: 22.2%, 95% CI 9-46%). Among the subgroup of subjects whose tumors expressed PD-L1 (combined positive score [CPS] ≥1%) (n=22), cPR was observed in 4 (ORR: 18.2%, 95% CI 7-39%). At data cutoff, the HPV-positive subgroup median PFS was 2.9 months (95% CI 2-10.3) and 3 subjects were still on treatment. CONCLUSIONS: FLX475, an oral CCR4 antagonist, has previously demonstrated clear monotherapy activity in EBV+ extranodal NK/T-cell lymphoma and promising combination activity with pembrolizumab in EBV+ gastric cancer and CPI-naïve non-small cell lung cancer. In this completed Phase 2 cohort of subjects with CPI-experienced R/M HNSCC, FLX475 in combination with pembrolizumab was shown to be well tolerated and has demonstrated encouraging clinical activity particularly in those with HPV-positive tumors, supporting the continued development of this combination therapy for CPI-experienced HNSCC. Citation Format: Jameel Muzaffar, Kedar Kirtane, Rebecca Redman, Muh-Hwa Yang, Tae Min Kim, Stephen Liu, Ryan Lynch, Julie Brahmer, Patricia LoRusso, Brian Henick, Sung-bae Kim, Yin-Hsun Feng, Michael Chisamore, Paul Kassner, Dirk Brockstedt, Nicole Nasrah, Rakesh Goyal, William Y. Ho, Victoria Villaflor. Phase 2 study of oral CCR4 antagonist FLX475 (tivumecirnon) plus pembrolizumab in subjects with head and neck squamous cell carcinoma (HNSCC) previously treated with checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT226.

Abstract CT144: Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma

Abstract Background: HMPL-523, a selective oral Syk inhibitor, demonstrated encouraging benefit-risk profile in 2 Phase 1 (P1) studies in relapsed/refractory (R/R) lymphoma patients (pts) in USA/Europe (NCT03779113) and China (NCT02857998). In the 16 response-evaluable pts in the dose-escalation portion (Part 1) of study NCT03779113, 4 responses were noted, including complete responses (CRs) in R/R hodgkin lymphoma (HL) and follicular lymphoma (FL) pts (Strati et al. Blood 2021). Here, we report the results from the dose expansion portion (Part 2) of the study NCT03779113. Methods: Safety and efficacy of HMPL-523, at the recommended phase 2 dose (RP2D) of 700 mg QD, was evaluated in lymphoma pts who have exhausted all approved therapy options. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v5.0. Responses were assessed by investigators at weeks 8, 16, and 24, and then every 12 weeks. Results: As of 14 July 2023, 47 pts were enrolled in the Part 2 [25 HL, 9 Peripheral T cell lymphoma (PTCL), 7 Chronic lymphocytic leukemia (CLL), 2 each of FL and Mantle cell lymphoma (MCL), and 1 each with Marginal zone lymphoma (MZL) and Waldenström's macroglobulinemia (WM)]. Median age was 57 (Range:21-93) years, 55% were males, 85% were Caucasian, 47% had ECOG status of 1, 81% were disease stage ≥3 and 17% had B-symptoms at study entry. Median prior lines of therapy was 4 (range 1 - 12); 86% of CLL pts were prior BTK treated and 88% of HL pts had both a PD-1 inhibitor and Brentuximab vedotin. With a median drug exposure of 2.9 months, the overall response rate (ORR) among 41 efficacy evaluable pts was 26.8% and disease control rate (DCR) was 65.9% [4 CR (9.8%), 7 PR (17.1%) and 16 SD (39.0%)]. The median time-to-response was 1.9 months. Among HL pts (N=24), ORR was 25.0% and DCR was 66.7% [2 CR (8.3%), 4 PR (16.7%) and 10 SD (41.7%)]. Among PTCL pts (N=7), ORR and DCR were 42.9% [2 CR (28.6%) and 1 PR (14.3%)]. The median duration of response (DOR) was not reached for HL pts and was 5.7 months (2.0 - NR) in PTCL. Two pts (one each with HL and PTCL) with disease control were taken off treatment to be consolidated with allogenic stem cell transplant. At cut-off, 1 pt each with CLL (N=5 ) and WM (N=1) demonstrated a PR. Serious TEAEs occurred in 18 pts (38.3%), of which 4 (8.5%) were considered treatment-related (TRAE). Grade≥3 TRAEs were noted in 15 pts (31.9%); the most common Grade≥3 TRAEs (>5%) were alanine aminotransferase increase 4 (8.5%) and febrile neutropenia 3 (6.4%). Dose interruption due to TEAEs occurred in 23 pts (48.9%) and dose reduction in 4 pts (8.5%). Two pts (4.3%), 1 each with TEAE of thrombocytopenia and pruritis had drug discontinued. Conclusion: HMPL-523 was well tolerated at the RP2D of 700 mg QD in R/R lymphoma pts. Encouraging proof of activity was demonstrated in heavily pre-treated HL and PTCL pts. Additional studies are needed to evaluate the value of SYK-inhibitor as either monotherapy or combination in these high unmet-need population. Citation Format: Paolo Strati, Eva Gonzalez-Barca, Daniel Morillo, Sairah Ahmed, Dominik Chraniuk, Sirpa Leppa, Fatima de la Cruz Vicente, Piotr Centkowski, Rathi N. Pillai, Shivani Nanda, Alisha Khullar, Marjo Hahka-Kemppinen, Vijayvel Jayaprakash, Giuseppe Gritti. Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT144.

Abstract CT176: OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma

Abstract Introduction: Treatment options are limited for pts with ICI-resistant metastatic melanoma. Investigational unengineered TIL cell therapy has shown promising activity in this setting, but co-administration of systemic high-dose IL2 limits pt eligibility and is associated with safety risks. OBX-115 is an investigational, autologous TIL cell therapy engineered to express membrane-bound IL15 (mbIL15) under pharmacologic regulation by the FDA-approved small-molecule drug acetazolamide (ACZ) using cytoDRiVE® technology, to induce cytokine-driven TIL expansion and persistence without co-administration of IL2. Methods: This Phase 1 first-in-human study (NCT05470283) is assessing the safety, tolerability, and efficacy of the OBX-115 regimen in pts with unresectable or metastatic melanoma progressing after ICI. Initial pts are enrolled into dose-escalation cohorts (n=3 each; maximum doses: Cohort 1 [C1], 30 × 109 cells + ACZ 125 mg; Cohort 2b [C2b], 100 × 109 cells + ACZ 125 mg). OBX-115 is manufactured using the pt’s tumor tissue (procured by surgical excision or core needle biopsy) and infused after completion of cyclophosphamide and fludarabine lymphodepletion. ACZ is administered orally once daily for up to 7 days, with redosing (Week 6, up to 7 days) permitted for pts without radiographic response at Week 6. No systemic IL2 is administered. The primary objective is to evaluate safety (dose-limiting toxicities [DLTs] and treatment-emergent adverse events [TEAEs]). Results: As of 1 December 2023, 6 pts (age, 28-64 y; C1, n=3; C2b, n=3) with ICI-resistant metastatic melanoma completed the DLT-evaluation period. Median lines of prior therapy was 2.5 (range, 1-5). OBX-115 was successfully manufactured for all 6 pts, including from core needle biopsy tumor tissue (n=5). At 20 weeks median study follow-up (range, 11-51 weeks), no DLTs were observed; 3 pts experienced Gr 3 nonhematologic TEAEs (abdominal pain, ALT elevation, hypokalemia, hyponatremia, syncope) and no Gr 4 nonhematologic TEAEs were reported. Four pts received and tolerated ACZ redosing. ORR per RECIST 1.1 was 50% (2 CR, 1 PR, 3 SD); responses were established between Week 6-18 and ongoing at the time of data cut. All pts had consistent reduction of lesions at each assessment through Week 18. One pt developed new metastatic disease (liver) and progressed at Week 24, despite continued target lesion reduction. Updated data will be presented. Conclusions: OBX-115, a one-time, IL2-free, regulatable, engineered TIL cell therapy, was well-tolerated and induced consistently deepening and durable responses, with the potential to fulfill the unmet need in ICI-resistant advanced melanoma. These early results support continued investigation of the OBX-115 regimen in this and an ongoing Phase 1/2 multicenter study (NCT06060613). Citation Format: Rodabe N. Amaria, Jennifer L. McQuade, Michael A. Davies, Isabella C. Glitza Oliva, Steffy Jose, Erik N. Cressman, Ashlynd L. Clausell, Roland Bassett, Sapna Patel, Adi Diab, Hussein A. Tawbi, Michael K. Wong, Alexandra P. Ikeguchi, Madan Jagasia, Giridharan Ramsingh, Prakash Prabhakar, Raina Duan, Parameswaran Hari. OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy induced deepening and durable responses without interleukin 2 (IL2) in patients (pts) with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT176.

Amivantamab monotherapy in relapsed/refractory metastatic colorectal cancer: OrigAMI-1, an open-label, phase 1b/2 study.

135 Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, has shown preclinical activity in colorectal cancer (CRC) models. MET amplification is implicated in driving resistance to anti-EGFR therapies in metastatic CRC (mCRC). We hypothesize that dual, co-inhibition of EGFR and MET with ami could improve outcomes in relapsed/refractory mCRC. Methods: OrigAMI-1 (NCT05379595) is assessing the safety and efficacy of ami as monotherapy in patients (pts) with refractory mCRC in 3 separate cohorts (Table). Eligible pts were wild-type for KRAS, NRAS, BRAF, and EGFR ectodomain by ctDNA testing, without ERBB2/ HER2 amplification. Cohorts A and B included pts with left-sided mCRC without/with prior exposure to anti-EGFR monoclonal antibodies, respectively, and cohort C included pts with right-sided mCRC. Safety population included all pts receiving the recommended phase 2 dose (RP2D; 1050 mg [1400 mg, ≥80kg]). Investigator-assessed response per RECIST v1.1 is reported for evaluable pts with post-baseline disease assessment(s) or who discontinued for any reason. Ami plus FOLFOX or FOLFIRI is being explored in additional cohorts. Results: As of September 4, 2023, 93 pts were treated at RP2D; 89 were response evaluable (median follow-up: 4.4 mo). Median age was 60 years, 66% were male, and median prior lines of therapy were 2, with 94% receiving prior bevacizumab and 69% prior anti-EGFR therapy. Best timepoint responses were: Cohort A: 7/17, 41.2%; Cohort B: 13/54, 24.1%; Cohort C: 1/18, 5.6%. Disease control rates (DCR) were 88.2%, 72.2%, and 77.8% for Cohorts A, B, and C, respectively. Median duration of response (mDoR) for confirmed responders was 7.5 and 7.4 mo for Cohorts A and B, respectively. Treatment is ongoing for the responder in Cohort C. 10/13 responders (77%) remain on treatment. Preliminary biomarker data suggest ami may be active in alterations associated with anti-EGFR antibody resistance (eg, EML4-ALK fusion, PTEN). The most frequent treatment-emergent adverse events were rash (84%) and infusion-related reactions (53%). No new safety signals were observed. Updated results will be presented at the meeting. Conclusions: Ami monotherapy demonstrated promising, durable antitumor activity in refractory mCRC, including pts treated with prior anti-EGFR therapy and pts with right-sided disease. The safety profile of ami in mCRC is manageable and consistent with prior NSCLC experience. Clinical trial information: NCT05379595 . [Table: see text]

Evaluating Tumor-Intrinsic and Patient-Specific Mechanisms of Resistance to Teclistamab in Anti-BCMA Exposed and Naïve Multiple Myeloma

Background: Teclistamab (Tec) is a CD3 x BCMA bispecific antibody granted accelerated FDA approval for treating relapsed/refractory (RR) multiple myeloma (MM) based off the results of the MajesTEC-1 trial (Usmani S, et al. Lancet 2021, Moreau P, et al. N Engl J Med 2022). However, patients with prior exposure to anti-BCMA therapies were excluded from this trial and there is no published data evaluating Tec efficacy in this setting. Additionally, little is known about tumor-intrinsic and patient-specific immunologic predictors of response to Tec. Methods: We performed an IRB-approved analysis of clinical outcomes for 52 commercially treated Tec patients treated as of 07/28/2023 at our center. Results were correlated to pre-treatment BCMA expression measured by immunohistochemistry (IHC). We also profiled peripheral blood T-cells from pre-treatment peripheral blood mononuclear cell (PBMC) samples from a sub cohort of patients via high-dimensional spectral cytometry using a 37-color panel including lineage, exhaustion, and activation markers. Results: Our commercial cohort was older (median age 70 vs 64), more heavily pretreated (median prior lines of therapy 7 vs 5) and had higher incidence of both high-risk cytogenetic abnormalities (33% vs 26%) and extramedullary disease (35% vs 17%) than the MajesTEC-1 population. Additionally, 52% had prior exposure to anti-BCMA therapies, including belantamab mafodotin (31%), anti-BCMA CAR T-cell therapies (37%), and anti-BCMA bispecific antibody therapies (4%), with some having exposure to multiple prior anti-BCMA therapies (17%). Among response evaluable patients (90%), with a median follow-up time of 100 days, the overall response rate (ORR) to Tec was 64% (36% ≥VGPR). Progression free survival (PFS) in patients without prior BCMA therapy was higher than in the anti-BCMA exposed population (median PFS NR vs 102 days, p = 0.032, Figure Panel A). However, the anti-BCMA therapy exposed population was more heavily pretreated (8 vs 5 median prior lines of therapy) and had more patients with high-risk cytogenetic abnormalities (46% vs 19%) and extramedullary disease (42% vs 27%) than the anti-BCMA therapy naïve cohort. No major differences in BCMA expression were noted between responding and non-responding patients or between anti-BCMA exposed and anti-BCMA naïve patients. However, two patients had absent BCMA expression following prior treatment with other BCMA targeting agents and did not respond to Tec. Cytokine release syndrome (CRS) during step-up dosing was strongly associated with Tec efficacy (median PFS NR vs 27 days, p <0.0001), with a 100% ORR for patients with CRS. Immune profiling experiments (Figure Panel B) revealed that Tec responders had peripheral blood enriched for both CD8 + effector memory T-cells (TEM, >6-fold increase, p = 0.0499) and CD8 + effector memory T-cells re-expressing CD45RA (TEMRA, >5-fold increase, p = 0.012) when compared to Tec non-responders. Tec non-responders had peripheral blood enriched for TIGIT + regulatory T-cells (Tregs, 3-fold increase, p = 0.03) when compared to Tec responders. No differences in PD-1, CTLA-4, LAG-3 or TIM-3 expression were observed in Tec responders vs non-responders. Patients with recent relapse from non-BCMA targeting bispecific antibodies (including products targeting FcRH5 or GPRC5D) had peripheral blood enriched for γδ T-cells with high TIGIT expression. Conclusion: Tec is an effective therapy in RRMM with a slightly lower efficacy observed in patients with prior anti-BCMA therapy exposure. PFS reductions among these anti-BCMA exposed patients may be partly due to independent disease associated risk factors. A pre-Tec peripheral blood T-cell population enriched with highly cytotoxic effector T-cells was associated with response to therapy, while suppressive TIGIT +Tregs were associated with nonresponse, suggesting a potential therapeutic role for TIGIT blockade or CD25 + cell depletion to enhance the therapeutic efficacy of bispecific antibodies. Clinical and translational data from additional patients will be presented at the meeting.

Fixed-Duration Pirtobrutinib Combined with Venetoclax ± Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results, Including MRD Data, from the BRUIN Phase 1b Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL). Recent clinical studies have evaluated the safety and efficacy of fixed-duration regimens with venetoclax and cBTKi. While these combinations are effective, their use may be limited by toxicity. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has shown promising safety and efficacy in heavily pretreated relapsed or refractory (R/R) CLL patients (pts). Here, we report the safety and efficacy of fixed-duration pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: Pts with R/R CLL were eligible for pirtobrutinib combined with venetoclax ± rituximab in the phase 1b portion of the multicenter phase 1/2 BRUIN study (NCT03740529). Prior cBTKi therapy was allowed, but not prior venetoclax. Pts were enrolled into sequential cohorts, first in the pirtobrutinib + venetoclax (PV) cohort and then the PV + rituximab (PVR) cohort. Pirtobrutinib 200 mg QD was started on cycle 1 day 1, and venetoclax was started on cycle 2 day 1 with the standard 5-week dose ramp to 400 mg QD target dose. PV was given for up to 24 cycles; each cycle was 28 days. For the PVR cohort, rituximab was given at 375 mg/m 2 on cycle 1 day 1 and then 500 mg/m 2 on day 1 of cycles 2-6. The primary endpoint was safety as assessed by treatment-emergent adverse events (TEAEs) graded according to CTCAE v5.0. Other key endpoints included overall response rate (ORR), progression-free survival (PFS), and minimal residual disease (MRD). Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10,000 nucleated cells (<1x10 -4) in peripheral blood by ClonoSEQ® assay (Adaptive Biotechnologies, Seattle, WA). A data cut of May 5, 2023, was utilized. Results: Fifteen pts received PV, and 10 received PVR. Median age was 66 years (range, 49-77) for those who received PV and 69 (range, 39-78) for those who received PVR. Median prior lines of therapy was 1 (range, 1-2) for the PV cohort and 2 (range 1-4) for the PVR cohort. Most pts had received prior chemotherapy (PV=53%; PVR=60%), CD20 monoclonal antibody (73%; 70%), and cBTKi (73%; 60%). The majority of pts had IGHV unmutated CLL (PV=73%; PVR=89%). ORR was 93.3% (95% CI, 68.1-99.8) for the 15 pts receiving PV and 100% (95% CI, 69.2-100.0) for the 10 pts receiving PVR, with 10 complete responses (PV=7; PVR=3). Median duration of follow-up for PFS was 22.1 months (IQR, 20.1-25.7) for PV and 22.1 months (IQR, 20.7-22.1) for PVR; PFS at 18 months was 92.9% (95% CI, 59.1-99.0) for the 15 pts receiving PV and 80.0% (95% CI, 40.9-94.6) for the 10 pts receiving PVR. The overall uMRD rate at cycle 13 was 70.8% (PV=10; PVR=7) for the 24 evaluable pts, with 87.5% (PV=12; PVR=9) of pts achieving uMRD at some time during the trial and all but one pt sustaining uMRD during subsequent MRD assessments ( Figure). Twenty-two pts discontinued treatment (PV=14; PVR=8); of these, 14 completed all 24 cycles of therapy (PV=9; PVR=5) and 8 discontinued early because of progressive disease (PV=2), adverse events (PVR=2), protocol noncompliance (PV=1), death unrelated to treatment (PVR=1), or other reasons (PV=2). Three pts (PV=1; PVR=2) continue to receive treatment. The median relative dose intensity was similar in both cohorts (PV=97.9%; PVR=98.6%). The most common TEAE of any grade included nausea (PV=60.0%; PVR=40.0%), fatigue (53.3%; 50.0%), and diarrhea (46.7%; 60.0%). The most common grade ≥3 TEAE was neutropenia/neutrophil count decreased (PV=46.7%; PVR=60.0%). Grade ≥3 clinical tumor lysis syndrome occurred during venetoclax dose escalation (PV=2), including a grade 3 case that resolved spontaneously after 24 hours and a grade 4 case that resolved after short-term intravenous fluids. Treatment-related adverse events led to dose reductions in three pts (PV=1; PVR=2) and treatment discontinuation in two pts (PVR=2). Conclusions: Fixed-duration pirtobrutinib combined with venetoclax ± rituximab was well tolerated and demonstrated sufficiently promising efficacy to warrant further investigation in pts with R/R CLL. The BRUIN CLL-322 phase 3 trial comparing PVR vs VR in previously treated CLL is currently enrolling pts (NCT04965493).

Sonrotoclax (BGB-11417) in Combination with Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma with t(11;14): Safety, Efficacy, and Determination of Recommended Phase 2 Dose

Background: B-cell lymphoma-2 (BCL2) family proteins represent attractive therapeutic targets as they play an important role in MM cell survival. In patients with relapsed/refractory (R/R) MM harboring t(11;14) for whom multiple prior lines of therapy failed, single-agent venetoclax, a first generation BCL2 inhibitor, demonstrated antimyeloma activity (Kumar S, et al. Blood. 2017). Dexamethasone, a long-standing mainstay of treatment for MM, increases the expression of both BCL2 and Bim. This results in a greater dependency on BCL2 for tumor survival, ultimately increasing the sensitivity to a BCL2 inhibitor. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency >10x that of venetoclax in biochemical assays. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 trial designed to evaluate safety and efficacy of sonrotoclax as monotherapy, in combination with dexamethasone, or in combination with dexamethasone plus carfilzomib in patients with R/R MM harboring the t(11;14). Here, we report preliminary data from the sonrotoclax plus dexamethasone dose-escalation (DE) cohorts. Methods: Eligible patients have R/R MM that is t(11;14) positive by fluorescence in situ hybridization (per central assessment) who have received 1-7 prior lines of therapy for MM with previous exposure to a proteasome inhibitor and an IMiD agent. In dose escalation, patients received 80, 160, 320, or 640 mg of sonrotoclax daily with 40 mg of dexamethasone weekly until intolerability, disease progression, or death. The primary objectives in the DE cohorts were to assess the overall safety/tolerability profile as well as determine the maximum tolerated dose (MTD)/maximum assessed dose (MAD) and establish the recommended phase 2 dose (RP2D). AEs were reported per CTCAEs v5.0; safety was assessed by a safety monitoring committee (SMC) after a 21-day dose-limiting toxicity (DLT) window for each cohort and was guided by a modified toxicity probability interval method (mTPI-2). Disease responses were assessed per International Myeloma Working Group 2016 criteria. Results: As of May 26, 2023, 19 patients have been enrolled in the 80-, 160-, and 320-mg (n=3 each) and 640-mg (n=10 patients) dose-escalation cohorts. The median age was 68 years (range, 52-81 years). The median prior lines of therapy was 4 (range, 1-12) and 11 patients (58%) failed on a prior anti-CD38 antibody. The most common AEs (>20% of all patients) were insomnia (n=9; 47%), fatigue (n=6; 32%), nausea (n=5; 26%), and arthralgia (n=4; 21%); none of which were severity grade ≥3. Three patients (16%) experienced grade ≥3 treatment-emergent AEs (TEAEs). One patient (33%) in the 160-mg cohort had grade 3 increases in liver enzymes and diarrhea; one patient (10%) in the 640-mg cohort had a grade 3 decrease lymphocyte count and hypokalemia; and one patient (10%) in the 640-mg cohort had grade 3 cataracts and retinal detachment. Three patients experienced COVID-19 (grade 1-2, n=2; grade ≥3, n=1). Three patients experienced TEAEs that led to treatment discontinuation (COVID-19, cancer pain, hematuria; n=1 each). No patient, across all dose levels tested, experienced a DLTs; thus, sonrotoclax 640 mg daily was the determined to be the MAD and the RP2D in combination with dexamethasone. Four patients (21%) died while on study; however, no deaths were determined by the investigators to be associated with study treatment. One patient died from COVID-19 while receiving study therapy; three additional patients died ≥50 days after treatment discontinuation (COVID, progressive disease, and unknown causes, n=1 each). With a median treatment duration of 120 days (range, 30-526), ORR was 58%; 11 patients had a PR or better (n=6, PR; n=2, very good PR; n=2, CR; n=1, stringent CR [sCR]; Figure). The ORR for the 640-mg cohort was 70% (n=3, PR; n=2 VGPR; n=1, CR; n=1, sCR). Nine patients remained on treatment; the longest duration of response was 483 days (20 cycles) which, at data cutoff, was still ongoing. Conclusion: Sonrotoclax plus dexamethasone was generally well tolerated in patients with R/R MM harboring t(11;14) at doses up to 640 mg, and initial safety and efficacy results are promising. The SMC has recommended 640 mg in combination with dexamethasone as the RP2D. Recruitment is ongoing for the sonrotoclax in combination with dexamethasone and carfilzomib dose-finding arms and the sonrotoclax plus dexamethasone indication expansion cohort.

Outpatient Management of CAR-T and Teclistamab for Patients with Lymphoma and Multiple Myeloma

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset >= 3 days from infusion, CRP<100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

A Phase IB/II Study of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (alloBMT) Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, transplant-related toxicity and disease relapse limit survival. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates alternative allograft sources. Following PTCy, cellular immune reconstitution is favorable for strategies to augment anti-tumor immunity. Blinatumomab (blina) is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance post-transplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. A study of 21 B ALL pts demonstrated the feasibility of post-transplant blina but did not improve survival when pts universally remained on immunosuppression for at least 1 cycle of treatment (Gaballa. Blood. 2022). We present results of a phase Ib/II trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL in pts off immunosuppression. Methods: Pts ≥1 month-old with high risk CD19+ B ALL or ≥18 years-old with NHL who underwent alloBMT with PTCy were eligible. Pts had to be 60-180 days post-transplant with count recovery and in remission. Pts had to be off immunosuppression for ≥4 weeks prior to treatment, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Pts could receive 2 cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received 1 cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: The study closed to accrual on January 31, 2023 following enrollment of 42 pts (26 male/16 female) with a median age of 54 (Range 30-73). Among enrolled pts, 19 had Ph-negative B ALL and 23 had B-cell NHL. All pts underwent reduced-intensity conditioning alloBMT using a regimen of fludarabine, cyclophosphamide, and total body irradiation. Median prior lines of therapy were 2 (range 1-6). Additional transplant details are presented in Table 1. All B ALL pts were in an MRD-negative CR by flow cytometry at a sensitivity of 0.01% at alloBMT. All pts received a single cycle of therapy. Pts started blina a median of 137 days post-transplant (range, 90-182). Four pts failed to complete a full cycle due to G4 transaminitis (1), G4 neutropenia (1), relapse (1), and patient preference in the setting of tremors (1). Grade 3 or 4 adverse events felt to be at least possibly related to the study drug included G3 neutropenia (7%), G4 neutropenia (19%), anemia (5%), G3 ALT (5%), G4 AST (2%), G3 AST (2%), and neurotoxicity (7%). Two pts (5%) developed chronic GVHD following blina requiring the resumption of immunosuppression. At a median follow-up of 40 months post-alloBMT, the 3-year relapse-free survival is 73% (95% CI 54-85%) due to a 24% (95% CI 12-39%) incidence of relapse and a 4% (95% CI 0-17%) incidence of non-relapse mortality, as shown in Figure 2. All 3 (100%) relapsed B ALL pts and 2/6 (33%) relapsed B NHL pts presented with CNS involvement. Four pts with CNS relapse (80%) had CNS involvement prior to alloBMT. Among 2 pts who died without relapse, 1 was unrelated to alloBMT, while the other died of therapy-related myeloid neoplasm. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity in pts off immunosuppression. Initial survival outcomes are promising with the majority of relapses involving the CNS. A randomized trial of maintenance with blina after alloBMT with PTCy is needed to confirm efficacy in this high-risk population.

The Role of Intravenous Immunoglobulin (IVIG) in Reducing Infection Risk in Multiple Myeloma (MM) Patients Receiving Immune-Based Therapies: A Single Center Experience

Introduction Immune-based therapies, including the anti-CD38 antibody daratumumab (Dara), and most recently bispecific antibodies (BsAb) targeting CD3 and BCMA, GPRC5D or FCRH5 are increasingly important strategies used to treat Multiple Myeloma. However, there are concerns that the prolonged use of these therapies predisposes patients (pts) to increased rates of infection, partly due to hypogammaglobulinaemia. To this date, most clinical trials on Dara and BsAb do not consistently capture rates of hypogammaglobulinaemia and leaves the use of intravenous immunoglobulin (IVIg) as prophylaxis to individual investigator discretion. There are currently a paucity of studies documenting IVIg as a means to reduce infection risk in these pts. Patient and Methods All patients with MM who started Dara or BsAb therapy at St Vincent's Hospital Melbourne from Jan 2021 to Dec 2022 were included in this retrospective chart review. Patients who received more than 2 months of treatment were included. The evaluation period for each patient began at the time of first Dara or BsAb dose and ended at the cut-off date of 28 th June 2023. The two time periods were “ON IVIg” defined as any time within 30 days of last IVIg administration and “OFF IVIg” defined as any time >30 days from last IVIg administration. The primary outcome was the incidence rate of all grade infections (expressed in events/person-year) during periods of ON IVIg vs OFF IVIg. Secondary outcomes included incidence rate of severe infection (CTCAE Grade 3-5). Incidence rate ratios (IRR) and the corresponding 95% confidence intervals were calculated using the Exact Poisson method. Results A total of 52 Dara or BsAb treated pts were identified of which 7 were excluded due to treatment cessation from progressive disease within 2 months. The remaining 45 pts were included in the study of which 16 were on Dara, 16 on a BCMA BsAb and 13 on a non-BCMA BsAb. All 16 of the patients on Dara received Dara as a triplet combination. Median age was 65 (IQR 59-70), 25 (56%) were male and median prior lines of therapy received was 1 (IQR 1-3). At the start of treatment, 34 pts (76%) had documented hypogammaglobinaemia of which 12 (27%) had severe hypogammaglobinaemia (defined uninvolved IgG <4.0 g/L). Median functional IgG was 5.0 g/L (IQR 3.9-6.5). Eleven pts (24%) were already on IVIG prior to Dara or BsAb therapy and a further 18 (40%) were commenced on IVIG during the course of treatment. At the cut-off date, 30 (67%) pts were still receiving Dara or BsAb therapy. Median time on treatment was of 8.94 months (IQR 5.06-14.30). The proportion of time ON IVIg for the cohort was 53%. Patient receiving BsAb spent a greater proportion of time ON IVG than patients receiving Dara-based therapy (56% vs 42%, p <0.002). There were 95 all grade infections during the evaluated period, most commonly in the respiratory tract; upper respiratory tract infections (36%), lower respiratory tract infections (31%) and COVID-19 (12%). There were 15 documented severe infections of which 10 occurred during the OFF IVIG period. There were no infection related deaths. The median time to first infection from commencement of Dara or BsAb was 3.12 (IQR 1.25-5.61) months. The rate of all grade infections ON IVIG was 1.54 (95% CI 1.07-2.15) per person years and lower compared to 2.56 (1.95-3.29) per person years OFF IVIG with IRR of 0.60 (95% CI 0.39-0.93; p=0.016) (figure 1). Rate of severe infections was 0.22 (0.07-0.51) and 0.43 (0.20-0.78) per person years respectively with IRR of 0.52 (0.14-1.66; p=0.234). BsAb therapy had a higher all grade infection rate vs Dara-based therapy; 2.86 (2.23-3.62) vs 1.39 (0.91-2.03) per person years respectively; IRR 2.06 (1.30-3.38; p=0.001) Conclusion There are high rates of pre-existing hypogammaglobinaemia in MM patients even during early lines of treatment. The use of IVIG during immune-based therapies appears to significantly reduce the yearly rate of all grade infections by 40% in our cohort. Differences between the rates of severe infection ON IVIg and OFF IVIg are not significant due to small number of events. Further prospective studies are needed to confirm these findings, towards an evidence-based approach in IVIg support for patients with myeloma on novel immunotherapies.

Double Step-up Dosing (2SUD) Regimen Mitigates Severe Icans and CRS While Maintaining High Efficacy in Subjects with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL) Treated with AZD0486, a Novel CD19xCD3 T-Cell Engager (TCE): Updated Safety and Efficacy Data from the Ongoing First-in-Human (FIH) Phase 1 Trial

Background: AZD0486 (formerly TNB-486) is a novel, IgG4 fully human CD19xCD3 bispecific TCE incorporating a unique low affinity anti-CD3 moiety designed to reduce cytokine release while retaining potent T-cell mediated cytotoxicity of malignant B cells. A silenced Fc prevents nonspecific binding, antibody-dependent cellular cytotoxicity, and confers a long half-life suitable for intermittent administration. Preliminary clinical activity in Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) was reported [ Hou et al, Blood 2022; Jacobs et al, HemaSphere 2023] following fixed and single step-up dosing (1SUD). We now present focused updated safety data following implementation of 2SUD in the ongoing FIH phase 1 study (NCT04594642). Methods: Patients with R/R CD19+ B-NHL failing ≥2 prior lines of therapy, including prior CD19 CART and/or CD20 TCE, were enrolled. AZD0486 was administered in escalating doses in either no SUD (Day (D)1, D15 0.03-2.4mg), 1SUD (D1 0.27-1 mg, D15 2.4-10 mg), or 2SUD (D1 0.27 mg, D8 1 mg, D15 2.4-7.2 mg, FL/DLBCL only) schedules. AZD0486 was given IV every 2 weeks in 28D Cycles (C) up to 2 years. Monthly dosing was considered for patients in complete response (CR) at C6. Responses were assessed by RECIL 2017 by Central Imaging Review, AEs by CTCAE v5.0, and CRS/ICANS by 2019 ASTCT criteria. Results: As of 03 July 2023, 62 patients (27 DLBCL, 25 FL, 5 mantle cell lymphoma, 4 marginal zone lymphoma, 1 other) received AZD0486 and were evaluable for safety. Median age was 68 (range 22-86), with 58% male, 81% stage III/IV. Median prior lines of therapy was 3 (range 2-16) including 23 (37%) failing CART and 3 (4.8%) failing CD20 TCE. Fifteen (24%) were CD20 negative at study entry. The complete response (CR) rate was 91% (10/11) in patients with FL treated in 2.4 mg dose cohorts and for all FL efficacy evaluable subjects dosed at 2.4mg or above, CR was achieved in 14/17 (83%) with an overall response rate (ORR) of 88%. Median duration of response (DOR) has not beenreached. With the implementation of 2SUD regimen, no Grade 3+ CRS or ICANS events were observed (Table 1). Grade 1-2 CRS events decreased from 62.5% to 22.2% (fixed/1SUD, 15/24 and 2SUD, 4/18). Grade 1-2 ICANS events decreased from 20% (5/24) to 5.6% (1/18), presented mainly as confusion, and typically resolved in 1-2 days. The most common AEs (occurring in >20%) of any grade and regardless of drug causality were CRS (48%), anemia (34%), neutropenia (32%), lymphopenia (29%), ICANS (27%) and decreased WBC (20.9%). Treatment-related events of Grade ≥3 included lymphopenia (24%), neutropenia (15%), ICANS (9.7%) and anemia (3.2%). No treatment related deaths were reported (1 death due to COVID19, unrelated) and no treatment-related AEs lead to discontinuation (1 patient discontinued due to COVID-19, unrelated). Preliminary analysis (TNF-a, IL-6, IL-8, IL-10) suggests a decrease in cytokine levels after target dose with 2 SUD compared to fixed dosing and 1SUD, regardless of target dose. Conclusions: AZD0486 (formerly TNB-486) is an active treatment in patients with advanced R/R B-NHL and has a predictable safety profile characterized by mainly low-grade AEs and fully transient and reversible CRS/ICANS events. The 2 SUD schedule reduced the overall rate of low grade CRS and ICANS (Grade 1-2) and abrogated Grade 3 events further improving the risk/benefit profile of AZD0486. Dose escalation is ongoing to identify the RP2D.

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

A Phase 2 Study of the Fully Oral Combination of ASTX727 (Decitabine/Cedazuridine) Plus Venetoclax for Older and/or Unfit Patients with Acute Myeloid Leukemia

Background: The combination of a hypomethylating agent (HMA) plus venetoclax is the standard of care for patients (pts) with acute myeloid leukemia (AML) who are older (age ≥ 75 yrs) and/or unfit for intensive chemotherapy. ASTX727 (oral decitabine/cedazuridine) is an oral formulation of decitabine with pharmacokinetic AUC equivalent exposures to IV decitabine. We performed a phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax in the frontline (FL) and relapsed-refractory (R/R) settings. Methods: Pts ≥ 18 yrs with WHO 2016-defined AML were eligible. The FL cohort enrolled newly diagnosed pts with ECOG ≤ 3 who were either ≥ 75 yrs or ineligible for intensive chemotherapy due to comorbidities. Pts ≥ 18 yrs and ECOG ≤ 2 were eligible for the R/R cohort. Pts with a history of myelodysplastic syndrome (MDS), including previously treated MDS, were eligible. Treatment consisted of ASTX727 (decitabine/cedazuridine) 35/100 mg PO daily x 5 days and venetoclax 400 mg PO daily (adjusted for azoles) for 28 days during induction (held if blast clearance on day 21 bone marrow examination) and 21 days in consolidation. Dose reductions were permitted for toxicity/tolerability. Therapy was administered in 28-day cycles for up to 24 cycles. Risk stratification and responses were determined per ELN 2022. This study was registered on ClinicalTrials.gov (NCT04746235). Results: 52 pts have been enrolled (42 in the FL and 10 in the R/R cohorts). In the FL cohort, the median age was 79 yrs (range 50-92). 17/42 (40%) pts had antecedent MDS (including 8 [19%] with treated secondary AML) and 6/42 (14%) had therapy-related AML (t-AML). By ELN 2022, 6 (14%) were favorable, 3 (7%) were intermediate, and 33 (79%) were adverse. 9/42 (21%) had complex cytogenetics and 6 (14%) had TP53 mutations. In the R/R cohort (n=10), the median age was 71 yrs (46-75). 2 (20%) pts had antecedent MDS and 2 (20%) had t-AML. By ELN 2022, 3 (30%) were intermediate and 7 (70%) were adverse. 5/10 (50%) had complex cytogenetics and 2/10 (20%) had TP53 mutations. The median prior lines of therapy in the R/R cohort was 2 (1-4), with 5 (50%) pts with 2 or more prior lines of therapy. The median number of cycles given was 3 (1-12). In the FL cohort, the ORR was 67% (28/42 pts: 15 [36%] CR, 11 [26%] CRi, 2 [5%] MLFS). In responding FL pts, measurable residual disease (MRD) by flow cytometry became undetectable in 7/22 (32%) pts with adequate samples. In the R/R cohort, the ORR was 50% (5/10 pts: 3 [30%] CR, 2 [20%] CRi). The median number of cycles to first and best response were 1 (1-4) and 1 (1-7), respectively. At a median follow-up of 12.8 months, the median OS was 12.7 months in the FL cohort and 7.6 months in the R/R cohort (figure A). In pts achieving CR/CRi (n=26 FL and 5 RR), the median RFS was 9.8 months in the FL and 4.6 months in the R/R cohort (figure B). The median DOR was 13.2 and 4.6 months the FL and R/R settings, respectively. 2 (4%) pts (1 FL and 1 R/R) went off protocol to undergo stem cell transplantation. We then stratified the FL pts into 3 genetic groups (group 1: TP53 wt, K/NRAS wt, no FLT3-ITD; group 2: TP53 wt, K/NRAS mut or FLT3-ITD positive; group 3: TP53 mut) as previously described (Döhner, ASH 2022). The median OS in group 1 (n=24), group 2 (n=12), and group 3 (n=6) was 16.2, 9.1, and 1.4 months, respectively. In FL pts achieving CR/CRi, the median RFS in group 1 (n=17), group 2 (n=7), and group 3 (n=2) was 13.2, 8.1, and 9.8 months, respectively. OS in the FL cohort was similar between the pts under 80 yrs (n=21, median 12.7 months) vs those 80+ yrs (n=21, median 14.8 months), p=0.98. The most common grade 3/4 adverse events were neutropenic fever (23%), pneumonia (13%), bacteremia (8%), cellulitis (6%), sepsis (6%), and respiratory failure (6%). 4-wk and 8-wk mortality were 10% and 15%, respectively. The median time to cycle 2 was 38 days (26-70). In pts who experienced count recovery during cycle 1, the median time to platelets > 50 x 10 9/L and absolute neutrophil count > 1.0 x 10 9/L was 23 (18-55) and 42 (28-69) days, respectively. Cycle 2 dose reductions occurred in 27/42 (64%) pts (21 venetoclax dose reductions, 6 both drugs reduced). Of the 29 observed deaths, 15 (52%) occurred in non-responders, 11 (38%) following AML relapse, and only 3 (10%) in pts with ongoing response (1 sepsis, 1 GI hemorrhage, and 1 electing to pursue hospice). Conclusions: In this older and very high-risk population of pts with AML, an entirely oral regimen consisting of ASTX727 and venetoclax was effective and tolerable.