Permanent Treatment Discontinuation Research Articles

Alectinib vs. Lorlatinib in the Front-Line Setting for ALK-Rearranged Non-Small-Cell Lung Cancer (NSCLC): A Deep Dive into the Main Differences across ALEX and CROWN Phase 3 Trials

Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, ‘non-comparative’ assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile.

#636 A phase 4, open label, multicenter prospective study of the safety and efficacy of agalsidase beta in Chinese patients with Fabry disease

Abstract Background and Aims Fabry disease (FD) is a rare inherited lysosomal storage disease caused by pathogenic GLA gene variants which result in a deficiency of the enzymatic activity of α-galactosidase A. Enzyme replacement therapy (ERT) is the mainstay of FD-specific treatment, but there are currently no reported clinical trials of ERT for FD in the Chinese population. This is the first phase 4 study to evaluate the safety and efficacy of ERT for FD in China since the approval of agalsidase beta in China in 2019. Method A 54-week, phase 4, open label, single arm, prospective, post-marketing surveillance (PMS) study of agalsidase beta (NCT05054387) was performed at 6 sites in China. Twenty-two Chinese ERT-naïve FD participants (≥8 years) with estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled and received infusions of agalsidase beta (Fabrazyme®, Sanofi) at a dose of 1.0 mg/kg every 2 weeks for up to 48 weeks. The primary endpoint was safety and tolerability of agalsidase beta. The endpoints of clinical efficacy included the changes of plasma globotriaosylceramide (GL-3), globotriaosylsphingosine (Lyso-GL-3), FD symptoms (including angiokeratoma, hypohidrosis, anhidrosis, abdominal pain, headache, tinnitus, heat tolerance, and activity tolerance), and eGFR from baseline to week 48. A post-hoc subgroup analysis was conducted to explore the differences in ERT efficacy between two subgroups of different ages (<30 years and ≥30 years). Results All 22 patients completed the study intervention. There were 18 males (81.8%) and the mean age of ERT initiation was 29.0 ± 13.5 years. Treatment-related adverse events (AEs) and infusion-associated reactions (IARs) were reported in 8 participants (36.4%), which was less than ∼60% as previously reported for IARs. Most AEs were mild or moderate and no AE caused permanent treatment discontinuation or death. The mean plasma GL-3 and Lyso-GL-3 levels decreased remarkably at week 6 and remained stable throughout the trial, with the mean percentage reduction from baseline to week 6 through week 48 ranged from −34.6% ± 27.4% to ­41.9% ± 14.9% and −58.8% ± 20.2% to ­64.9% ± 12.7%, respectively (Fig. 1a and b). The reduction was more remarkable for the classic male patients (n = 18; GL-3: 7.99 ± 2.19 ug/mL at baseline and 4.31 ± 1.71 ug/mL at week 48, −46.0% ± 18.4%; Lyso-GL-3: 83.11 ± 25.69 ng/mL at baseline and 25.89 ± 13.43 ng/mL at week 48, −67.8% ± 17.6%). Thirteen (59.1%) participants experienced improved FD symptoms at week 48, with no cases of worsening symptoms. The mean eGFR was 115.6 ± 37.3 mL/min/1.73 m2 at baseline and 118.4 ± 42.9 mL/min/1.73 m2 at week 48, with a change of 0.0 ± 12.4 mL/min/1.73 m2 from baseline to week 48 (Fig. 1c). In the subgroup analysis, participants were divided into the younger group with age <30 years (n = 11) and the older group with age ≥30 years (n = 11) according to their age of ERT initiation. At week 48, the reduction of mean plasma GL-3 (−47.1% ± 23.6% vs −22.0% ± 26.0%) and Lyso-GL-3 levels (−72.4 ± 17.3% vs −48.2% ± 19.8%), the stabilization of renal function (the mean change of eGFR from baseline to week 48: 5.2 ± 7.9 mL/min/1.73 m2 vs −5.2 ± 14.1 mL/min/1.73 m2) and the percentage of symptom improvement (81.8% vs. 36.4%) were generally more remarkable in the younger group than in the older group (Table 1). Conclusion This first phase 4 study of ERT for Fabry disease in China demonstrates that agalsidase beta is safe and well tolerated with a relatively low IAR rate, and effective in reducing plasma GL-3 and Lyso-GL-3, improving symptoms, and stabilizing renal function in Chinese patients with FD. Furthermore, the present study implies that patients who initiate ERT at a younger age benefit more from the therapy. Funding: Commercial support - Sanofi Pharmaceuticals.

The effect of semaglutide on body weight in patients with type 2 diabetes mellitus

Obesity is a global health problem associated with various comorbidities and increased mortality. Obesity is of particular importance in relation to the development and progression of type 2 diabetes mellitus (T2DM), being its main pathophysiological factor. Lifestyle changes are the most important mechanism for weight loss, but may not be sufficient for sustainable weight loss. Pharmacologic agents such as glucagon-like peptide-1 receptor agonists (GLP-1 receptor agonists) are recommended as an adjunct to lifestyle interventions to promote and maintain clinically meaningful weight loss and reduce the risk of comorbidities. Since 2005, several GLP-1 agonists have been approved for the treatment of type 2 diabetes, including exenatide (short- and long-acting), lixisenatide, liraglutide, dulaglutide, and semaglutide. Of these, semaglutide (subcutaneous) and liraglutide are currently approved by the US Food and Drug Administration (FDA) for ongoing weight control in patients with or without diabetes. Semaglutide therapy resulted in significant and sustained weight loss and improvement in cardiometabolic risk factors compared with placebo, was well tolerated, and had a safety profile consistent with other GLP-1 agonists. The most common side effects with semaglutide are gastrointestinal events, which were transient, mild to moderate in severity, and usually resolved without permanent discontinuation of treatment.

Abstract PO5-02-14: Clinical-pathological determinant factors to choose between four or six cycles of adjuvant chemotherapy with docetaxel/cyclophosphamide (TC) in a retrospective real-world cohort of HER2-negative breast cancer patients

Abstract Introduction: The long-term severe adverse events associated with anthracyclines, including irreversible cardiotoxicity, myelodysplastic syndromes, and therapy-related leukemias, led researchers to question the risk-benefit of anthracycline-based chemotherapy regimens, especially for patients without axillary lymph node involvement, leading to an increasing trend to omit anthracyclines in adjuvant treatment. Docetaxel plus cyclophosphamide (TC) has replaced doxorubicin plus cyclophosphamide (AC) for lower-risk patients that need adjuvant chemotherapy. However, the optimal number of cycles of adjuvant in patients with node-positive or node-negative breast cancer is currently unknown. Methods: We performed a retrospective cohort study of patients with HER2-negative breast cancer, stage I to III, that received adjuvant docetaxel and cyclophosphamide (TC) for four or six cycles, treated from January 2010 to December 2021. Patients were included from four cancer institutions, both private and public, located in the South, Southeast, and Northeast of Brazil. Objectives: To investigate the clinical-pathological characteristics and survival of earlystage HER2-negative breast cancer patients who received four (TC4) or six cycles (TC6) of adjuvant docetaxel and cyclophosphamide (TC). Results: We collected data from six hundred and ninety-eight patients, 98.7% were female with an average age of 52 years, 51.9% were postmenopausal, 14.6% BRCA gene mutation, 66% had some comorbidity, and only 8.4% were not candidates for anthracyclines. Two hundred and twenty-five patients had public and 473 private health insurance. About 13.2% of the patients were hormone receptor negative (HR-) and 86.8% hormone receptor positive (HR+), 57.4% breast-conserving surgery and 77.7% sentinel lymph node (SL). Five hundred sixty-four (80.8%) patients received TC4 and 134 (19.2%) TC6. We observed that patients who received TC 6 had unfavorable prognostic factors such as: (TC4 vs TC6) previous breast cancer (8.7% vs 16.3%) (p=0.002), invasive ductal carcinoma (IDC) (73.4 vs 86.7%) (p=0.009), histological grade 3 (HG3) (34.9 vs 42.9%) (p= 0,085) conservative surgery (59.4% vs 53%) (p=0144), SL (80.9% vs 62.2%) (p =0.001), Lymph node positive (15% vs 42.3%) (p=0.001), pathological stage II (37.5% vs 50%) (p=0.001).Treatment completion rates were 96.5% and 84.3% for TC4 and TC6, respectively (p=0,02). The incidence of grade 3 or higher toxicity with TC6 (14% vs 21.1%; p= 0,043). Febrile neutropenia was observed in 6.7% of both groups. Grade 3 or higher neuropathy was most common with TC6 (2.2% vs 10.3%; p=0,163). Permanent treatment discontinuation was more frequent in the TC6 group (3.4% vs. 9.8%; p=0,004), as well as late toxicity (3.4% vs. 9.2%; p=0,004). Ninety-four percent of the patients completed the proposed cycles of chemotherapy, 72% received adjuvant radiotherapy and 85.4% received adjuvant hormone therapy, with 42% of these receiving an aromatase inhibitor for 5 years. The median follow-up of the entire cohort was 61 months. There was no difference in the 5-year DFS (77.5% vs. 64.7%; p=0.159) or the 5-year OS (89.5% vs. 70.5%; p= 0,06) between patients treated with TC4 and TC6. Conclusion: TC6 was commonly used for patients with unfavorable prognostic factors as history of previous breast cancer, (IDC), HG III, lymph node positive and stage II. Patients who received TC6 had less chance of completing the treatment and more severe toxicity, especially late peripheral neuropathy. There was no difference in DFS or OS. Citation Format: Mila Kraychete, Marcelle Cesca, Guilherme Almeida, Leonardo Santana, Luciana Leite, Solange M. Sanches, Vladmir Cordeiro de Lima, Rafaela Pirolli, Rafael Manea, Felipe Kaneta, Jean Coutinho, Lucas Vian, Waires Zeviani, Marcio Reis, Luciana Landeiro, Clarissa Mathias, Geila Nunez, Tamara Santana, Monique Tavares. Clinical-pathological determinant factors to choose between four or six cycles of adjuvant chemotherapy with docetaxel/cyclophosphamide (TC) in a retrospective real-world cohort of HER2-negative breast cancer patients [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 PO5-02-14.

Abstract B046: A first-in-human Phase 1a/b of PEP-010, a proapoptotic bifunctional peptide, administered as single agent and in combination with paclitaxel in patients with recurrent and/or metastatic solid cancer: results from the dose escalation study

Abstract Background: PEP-010 is a first-in-class bifunctional peptide that penetrates cells and specifically disrupts the interaction between Caspase9 and PP2A, two proteins involved in the apoptotic cascade, leading to Caspase9-dependent apoptosis in cancer cells. Safety, PK, and preliminary anti-tumor activity from the dose escalation part of a Phase 1a/b study of PEP-010 as a monotherapy and in combination with paclitaxel (P) in recurrent and/or metastatic solid cancer are presented. Methods: PEP-010 was administered as a 3-hour intravenous weekly infusion on 3 consecutive days in patients (pts) with advanced cancer ineligible for standard therapy, in monotherapy (Arm A) or in combination with weekly P (Arm B) for pts eligible for P. In Arm A, pts were enrolled into 8 dose cohorts starting at 0.15 mg/kg up to 15 mg/kg, using an accelerated titration design (first 4 dose levels (DLs)), followed by a 3+3 design. In Arm B, 5 DLs of PEP-010 combined with weekly P (80mg/m²) were explored. The primary objective was the determination of the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of PEP-010 in both arms, based on occurrence of dose-limiting toxicities (DLTs). Secondary objectives were the safety and tolerability profile, PK and preliminary antitumor activity assessed by RECIST1.1. Results: At data cutoff (March 7, 2023), 19 (Arm A) and 15 (Arm B) pts received PEP-010 across 8 and 3 DLs, respectively. Median age was 57 [32-78] years and 56% were female. Median number of prior therapies was 6 [2-13]. A DLT (Grade 2 infusion-related reaction (IRR)) was observed in 1 pt in Arm A at DL 8 (15 mg/kg). In Arm B, 3 pts experienced a DLT at DL 5 mg/kg: 1 Grade 4 neutropenia and 2 IRR (inacceptable Grade 2 and 4). All DLTs led to permanent treatment discontinuation. MTD was defined as 15 mg/kg in Arm A and 2.5 mg/kg in Arm B. Most common adverse events (AE) related to PEP-010 included asthenia (26.5%) and IRR (14.7%) whereas most common AEs related to P included anemia (66.7%), peripheral neuropathy (33.3%), neutropenia (20%), onychopathy (20%), and diarrhea (20%). Median time on treatment was 5.1 weeks [2.1-25.3] in Arm A and 5.3 [3-18] in Arm B. In Arm A, for 7 pts (36.8%) a stable disease (SD) was observed for a median of 2.8 months [0.6-4.5]. In Arm B, 4 (26.7%) confirmed partial responses were observed in pts with ovarian, pancreatic and thyroid adenocarcinomas, and squamous cell lung carcinoma, and 2 pts (13.3%) had SD for a median of 4 months [2.7-9.6]. PK data indicated a proportionally dose-related increase of systemic exposure to PEP-010. No significant accumulation of PEP-010 over time or impact of P combination was observed. Conclusions: Data from the Escalation Part of the Phase 1a/b clinical trial showed an acceptable safety profile of PEP-010 in monotherapy. In combination, the dose of PEP-010 could not be escalated to the same level because of IRR. Preliminary antitumoral activity was observed with PEP-010 in combination with P including in pts who had previously received taxanes. Further clinical development is warranted. Citation Format: Pauline Du Rusquec, Elodie Coquan, Frederique Berger, Keyvan Rezai, Pierre-Emmanuel Brachet, Sophie Postel-Vinay, Zahra Castel-Ajgal, Gregoire Marret, Marie-Paule Sablin, Segolene Hescot, Raphael Sanchez, Anne-Claire Coyne, Claire Bertrand, Clementine Bouchez, Elsa Lafitte, Lucas Frezouls, Carole Mardesson, Abdelkrim Taamma, Chantal Krezel, Laura Dadon, Christophe Le Tourneau. A first-in-human Phase 1a/b of PEP-010, a proapoptotic bifunctional peptide, administered as single agent and in combination with paclitaxel in patients with recurrent and/or metastatic solid cancer: results from the dose escalation study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B046.

Blinatumomab in Combination with Immune Checkpoint Inhibitors (ICIs) of PD-1 and CTLA-4 in Adult Patients with Relapsed/Refractory (R/R) CD19 Positive B-Cell Acute Lymphoblastic Leukemia (ALL): Results of a Phase I Study

Background: Blinatumomab (blina) improves outcomes in R/R CD19+ ALL compared to chemotherapy. However, the overall response rate to blina was 44%, and median overall survival (OS) is just 7.7 mos (Kantarjian. NEJM. 2017). Preclinical studies show increased PD-L1 expression on leukemic blasts potentially contributes to relapse after blina. The addition of PD-1 +/- CTLA-4 blockade to blina leads to increased in vitro T cell proliferation and enhanced cytotoxicity (Feucht. Oncotarget 2016). Thus, blockade of co-inhibitory pathways may enhance blina efficacy in vivo. We describe results of a multi-center phase I study combining blina with immune checkpoint inhibitors (ICIs) targeting PD-1 (nivolumab) +/- CTLA-4 (ipilimumab). Methods: In a dose-escalation study, we evaluated the safety, tolerability, and preliminary efficacy of blina with nivolumab (nivo) +/- ipilimumab (ipi) using a 3+3 design. Pts ³16 years-old with R/R CD19+ B-ALL or mixed phenotype acute leukemia (MPAL) were eligible. Pts ³60 years could be untreated. Table 1 presents the dose escalation schema. Expansion cohorts of 6 pts were planned at the maximum tolerated dose (MTD) for blina + nivo AND blina + nivo + ipi. Pts received up to 5 cycles of blina and 1 year of ICIs. Pts removed from the study during the blina lead-in (days 1-10) were replaced. Dose-limiting toxicities (DLTs) were defined as grade 3+ non-hematologic toxicities requiring the permanent discontinuation of treatment in the first 42 days. Primary endpoints were toxicities and MTD. Secondary endpoints included complete remission (CR), MRD-negativity at a sensitivity of 0.01%, duration of response and OS from treatment initiation. Results: Twenty-seven pts were enrolled to 3 dose levels (14 DLA1, 3 DLB1, and 10 DLB-1) from September 2017-December 2022. Six pts were replaced (4 prior to ICI dosing and 2 requiring subsequent therapy in the DLT window). The median age of enrolled pts was 55 (range 24-84), 14 were male (52%), and median baseline BM blasts were 60% (range 0.2-98%). Baseline characteristics are presented in Table 2. A single DLT (G4 infusion reaction and G3 hypotension) occurred among 6 pts at DLA1. Based on this safety and efficacy data, blina + nivo was expanded to include 6 additional pts without additional DLTs. There were 2 DLTs at DLB1 (G5 pneumonitis and G2 GVHD), which led to de-escalation to DLB-1, where there was 1 DLT (G3 delirium). Grade 2+ immune-related adverse events attributable to ICIs included pneumonitis (G2+G5), rash (G2+G3), transaminitis (G2+G3), colitis (G3), and hypothyroidism (G2). Grade 3+ adverse events attributable to blina included neutropenia (5-G4+3-G3), dysphasia (2-G3), weakness (G3), seizure (G4), and transaminitis (1-G4+4-G3). Among 22 pts evaluable for response, the CR rate was 68% (100% MRD-negative). Among 13 pts with >50% BM blasts at baseline, 62% achieved CR. Pts with B-myeloid MPAL (0/2) and a history of extramedullary disease (1/4) were less likely to respond. Nine responders subsequently relapsed including 3 with isolated extramedullary disease and 2 with CD19-negative disease. As shown in Figure 1, relapse-free survival (RFS) at 1 year was 27% (95% CI 10-46), while OS at 1 year was 63% (95% CI 38-79). Twelve pts underwent allogeneic blood or marrow transplant (alloBMT) following study treatment. At 1 year for alloBMT pts, RFS was 51% (95% CI 19-76) and OS was 61% (95% CI 26-83). Ongoing analyses of changes in T cell subpopulations, co-signaling molecule expression, and single cell RNA seq results will be presented. Conclusions: Combination therapy with blina and ICIs in R/R ALL is safe, feasible, and associated with a high MRD-negative response rate. Long-term survival was promising in comparison to prior results with blina monotherapy, especially following consolidation with alloBMT. A randomized trial of blina +/- nivolumab is needed to confirm the benefit of this combination.

PD-1 Antibody (Sintilimab) Plus Histone Deacetylase Inhibitor (Chidamide) for the Treatment of Refractory or Relapsed Extranodal Natural Killer/T Cell Lymphoma, Nasal Type (r/r ENKTL): Updates of the Phase Ib/II Scent Study

Background Extranodal natural killer/T-cell lymphoma (ENKTL) is a highly aggressive of non-Hodgkin's lymphoma (NHL) closely related to Epstein-Barr virus (EBV), with a higher incidence in Asia than in Europe and North America. Patients with r/r ENKTL have a poor prognosis after failing asparaginase based regimen, and there is lack of effective treatment. Anti-programmed death 1 (anti-PD-1) antibody monotherapy represented a favorable treatment for the patients with rr-ENKTL. ORIENT-4 trial demonstrated sintilimab(anti-PD-1antibody ) was effective and well tolerated in r/r ENKTL. The efficacy of chidamide monotherapy, an oral subtype-selective histone deacetylase inhibitor (HDACi) was reported on the patients with rr-ENKTL . Moreover, accumulating evidences have shown the synergism between epigenetic modulator and PD-1 antibody. In 2020 ASH meeting, we reported the preliminary results of sintilimab plus chidamide (SC) for treatment of r/r ENKTL orally. This report is an update of this trial with cumulative data of approximately 40 months. Methods This multicenter, single-arm, phase Ib/II clinical trial enrolled eligible patients with histologically confirmed r/r-ENKTL failing from asparaginase-based regimen. This study consisted of a Phase Ib (dose escalation) portion followed by a Phase II expansion portion. In the Phase Ib escalation portion, a standard “3+3” design was utilized to identify the maximum tolerated dose (MTD), dose limited toxicity (DLT) and recommended Phase II dosage (RP2D) of chidamide. Patients received oral escalating doses of chidamide (20, 25, 30 mg) twice a week and 200 mg of sintilimab intravenously every 3 weeks. In the phase II expansion portion, patients received six cycles of SC every 3 weeks. Patients with complete response (CR) or partial response (PR) received SC every 3 weeks for up to 1 year, until disease progression, intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigators per RECIL 2017criteria. Key secondary endpoints included time to response (TTR), duration of response (DOR) and progression-free survival (PFS), overall survival (OS) and safety. Adverse events (AEs) were defined according to National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). This trial was registered at ClinicalTrials.gov (NCT 03820596). Results From March 2019 to May 2020, 41 patients were screened, and 37 eligible patients were enrolled. Overall, median age 48 years (range, 20-72), 26 (70.3%) patients with Stage IV, 20 (54.1%) patients with PINK-E score ≥ 3 points, 16 (43.2%) patients received ≥ 2 lines of prior systemic therapy. RP2D of chidamide was 30 mg twice a week. Of 36 response evaluable patients, 21 patients (58.3%) achieved an objective response including 16 (44.4%) patients with CR. The median time to initial response was 6.0 weeks (range, 5.0 to12.4). Cut-off data was July 28, 2023. The median cycles of SC were 6 (range, 2 to 44). Median follow-up time of whole cohort was 38.3 (range, 0.9 to 51.5; Interquartile range [IQR] range 8.5 to 46.3) months, 3-year OS rate was 56% (95% CI: 0.44-0.75, Figure 1 A), median PFS was 23.4 months (Figure 1 B). Twenty-one patients still alive, median follow-up time for this group was 44.9 (IQR 43.2 to 49.3) months. Estimated 4-year PFS rate was 76% (95% CI: 0.51-0.89, Figure 1 C). Median follow-up time of 21 responded(CR+PR) patients was 43.4 (IQR 34.3 to 47.6) months, estimated 4-year DOR was 68% (95% CI: 0.45-0.83, Figure 1 D). Twenty-six (26, 70.3%) patients reported treatment-related AEs (TRAEs). There were no new safety signals were identified after August 2020. The most frequently observed (≥10%) TRAEs were neutropenia (21,56.8%), thrombocytopenia (17, 45.9%), transaminase increased (11, 29.7%), nausea (9, 24.3%). The most frequent Grade (G) ≥3 TRAEs were neutropenia (6, 16.2%) and thrombocytopenia (4, 10.8%). Immune-related AEs were reported in 16 (43.2%) patients including a G4 exfoliative dermatitis, and the most common irAEs were G1 hypothyroidism and rash. TEAEs that led to permanent treatment discontinuation occurred in only one (2.7%) patient. No death was related to the study drug. Conclusion Sintilimab combined with Chidamide showed long-lasting therapeutic effects with manageable toxicity in patients with r/r-ENKTL. Epigenetic modulator can synergize with anti-PD-1 antibody to enhance antitumor activity to r/r-ENKTL.

Results of the Phase II of Epirchop Study, Evaluating the Efficacy of Tazemetostat in Combination with R-CHOP in Elderly Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL): A Lysa Study

Introduction: Tazemetostat (TAZ) is a selective oral EZH2 inhibitor with a favorable safety profile and activity in pts with either EZH2wild type or mutant B-cell NHL. In the phase I part of Epi-RCHOP study, we reported that R-CHOP plus TAZ (Taz-RCHOP) was well tolerated with safety and PK results comparable to R-CHOP alone, and the RP2D of TAZ in combination with RCHOP was consistent with TAZ monotherapy (800mg BID). We report here the efficacy results of the phase II TAZ R-CHOP study (Epi-RCHOP, NCT02889523), in pts 60-80y with newly diagnosed DLBCL. Methods: Pts received 6 R-CHOP every 21 days in combination with continuous TAZ at 800 mg BID, plus 2 cycles of TAZ and R (cycle 7 and 8). Prophylaxis with G-CSF, valaciclovir and trimethoprim sulfamethoxazole were strongly recommended. Primary endpoint was PET-based complete metabolic response rate (CR, Lugano 2014) at end of study treatment (EOT, i.e 8 cycles or at time of permanent treatment discontinuation) (data cut-off was January 30, 2023). Sample size calculation was made with the expectation of an increase of 10% in CR, with an H0 hypothesis of 70% and an H1 assumption of 80%, leading to a theorical sample size of 122 pts, assuming a drop out of 5%. The efficacy set correspond to pts who signed an informed consent and received at least one dose of TAZ. Pts without response assessment (no matter the reason) were considered non-responders. Key secondary objectives were progression free and overall survival. A sensitivity analysis was performed excluding pts who withdrawn their consent (N=112). Analyses were conducted using SAS® version 9.3. Results: From July 31, 2020 to July 18, 2022, 122 pts were enrolled in 27 LYSA centers. Median age was 70 years (60-80), 57% were female, 12% had an ECOG-PS2+, 70.5% a stage IV disease and 19.7% stage III, 66% elevated LDH, 73.8% an IPI of 3-5. Mutational profile was available for 76 pts, of whom 10 (13%) had an EZH2 mutations and 26 (34%) and EZB profile as assessed with LymphGen classifier. One hundred pts (82%) received 8 cycles and 22 had a premature treatment discontinuation (PTD), 12 (9.8%) during the first 2 cycles and 10 (8.2%) between cycle 3 and 8. Reasons for PTD were: consent withdrawal (N=10, including 7 during cycle 1 & 2), adverse events (AE, N=6, including 2 treatment related), death (N=2, both due to septic shock), protocol deviation (N=2), progressive disease (N=1) or physician decision (N=1). Overall, the median percentage of TAZ dose received was 98.4% (mean 77.2%, Q1: 61%; Q3: 100%), and AE led to TAZ interruption in 4.1%, discontinuation in 2.8% and dose reduction in 2.4% of the cases. Mean time between cycles was 21.5 days. In oct 2020, after the inclusion of 22 pts, recommendation to cap vincristine at 1mg was done, due to an excess of constipation. At end of treatment or PTD, 92/122 pts (75.4%, IC95: 66.8-82.8%) achieved CR, 8 (6.6%) PR, 5 (4.1%) had a PD, 2 (1.6%) had died (septic shock) and 15 (12.3%) were not evaluated and considered as non-responders. The primary objective was not met in this efficacy set, with a CR of 75.4% (lower than the H1 at 80%). The sensitivity analysis, excluding the 10 pts that withdrawn their consent (all non-evaluated), showed a CR rate of 82.1% (92/112, IC95: 73.8-88.7%) and PR rate of 7.1%. After a median follow-up of 18.5 months (Range = [0.2; 28.1]), 17/122 pts had a relapse/progression (13.9%) and 12 had died: 4 due to lymphoma, 3 to COVID-19, 4 to AE (2 septic shock, 1 acute myeloid leukemia and 1 heart failure), 1 unknown cause (in CMR). The estimated 18m PFS and OS were 77.7% (IC95: 67.5-85.1%) and 88.8% (IC95: 79.9-93.9%) respectively. Most frequent AE were: neutropenia (53%), anemia (51%), nausea (47%), asthenia (42%), peripheral neuropathy (37%), gastro-intestinal hypomotility (35%), weight loss (28%), vomiting (24%), thrombocytopenia (24%). AE of grade 3 or more occurred in 73% of the pts and were mainly hematological AE with neutropenia (48%, including 6% of febrile neutropenia), anemia (23%), thrombocytopenia (17%) and gastro-intestinal disorder (overall 10.7%). Red blood cell and platelets transfusions were administered in 31% and 11.5% of the pts respectively. Conclusion: R-CHOP plus TAZ is doable. Efficacy results in this trial conducted during the COVID pandemic in a particularly challenging population, suggest that the combination warrant further investigation including correlative studies with molecular subclassification that will be presented.

Efficacy and Safety of Fedratinib in Patients with Myelofibrosis Previously Treated with Ruxolitinib: Results from the Phase 3 Randomized FREEDOM2 Study

Introduction Patients (pts) with myelofibrosis (MF) treated with the Janus kinase inhibitor (JAKi) ruxolitinib (RUX) show spleen volume reduction (SVR) and symptom reduction. However, most develop RUX intolerance or relapsed/refractory (R/R) disease and survival rates after RUX discontinuation are poor. Fedratinib (FEDR) delivered SVR and symptom reduction in the JAKARTA2 and FREEDOM studies (C Harrison et al. Am J Hematol 2020; V Gupta et al. Blood 2022). FREEDOM2 (NCT03952039) was a phase 3, open-label, randomized study to evaluate the safety and efficacy of FEDR compared with best available therapy (BAT) in pts with MF previously treated with RUX. Methods Pts aged ≥ 18 years with primary, post-polycythemia vera, or post-essential thrombocythemia MF with Dynamic International Prognostic Scoring System (DIPSS) score ≥ intermediate-2, splenomegaly (≥ 450 cm 3), platelets ≥ 50 x 10 9/L, peripheral blood myeloblasts < 5%, and normal baseline thiamine, R/R or intolerant to RUX, were randomized 2:1 to FEDR 400 mg/day or BAT in 28-day cycles, with stratification by spleen size, platelet count, and RUX R/R vs intolerant. Crossover to FEDR was permitted for progressive disease or after cycle 6 (EOC6) response assessment. Pts were treated until intolerance or lack of efficacy and followed-up every 3 months until death, withdrawal of consent, or study closure. The primary endpoint was SVR ≥ 35% (SVR35) at EOC6; secondary endpoints included symptom response (≥ 50% reduction in total symptom score measured by Myelofibrosis Symptom Assessment Form), SVR ≥ 25% (SVR25), durability of SVR and symptom response, and safety. Results Overall, 201 pts were initially randomized and treated, 134 and 67 pts in the FEDR and BAT arms, respectively; subsequently, 46 (68.7%) pts from the BAT arm crossed over to FEDR. Median (interquartile range) age was 70 (64-74) years, 52.2% were male, and most had primary MF (54.7%) and intermediate-2 DIPSS risk (76.1%). Assessed by aggregated group, most pts in the BAT arm received RUX (70.1%), hydroxyurea (10.4%), or RUX plus hydroxyurea (7.5%). At the data cutoff of December 27, 2022 (median follow-up, 15 months), pts receiving FEDR had significantly higher rates of SVR35 at EOC6 compared with BAT (35.8% vs 6.0%; P < 0.0001), as well as superior SVR25 at EOC6 and SVR35 during the full treatment course ( Table, Figure). SVR35 benefit with FEDR was observed across subgroups. The FEDR arm also showed higher rates of symptom response at EOC6 compared with BAT (34.1% vs 16.9%; P = 0.0033; Table). Median treatment duration was 43 weeks of FEDR and 24.7 weeks of BAT. During the first 6 cycles in the safety population: 70 (52.2%) pts on FEDR and 20 (29.9%) pts on BAT had dose interruption/reduction; median time to first reduction/interruption was 44.0 days for FEDR and 56.5 days for BAT. Treatment-emergent adverse events (TEAEs) leading to permanent treatment discontinuation occurred in 13 (9.7%) and 4 (6.0%) pts in the FEDR and BAT arms, respectively, during the first 6 cycles. During the first 6 cycles, 132 (98.5%) pts on FEDR and 65 (97.0%) pts on BAT had ≥ 1 TEAE; treatment-related AEs (TRAEs) occurred in 109 (81.3%) and 23 (34.3%) pts in the FEDR and BAT arms, respectively. The most frequently occurring TRAEs with FEDR were diarrhea (38.1% FEDR vs 0.0% BAT) and nausea (32.1% FEDR vs 1.5% BAT); most cases were grade 1/2. Grade 3/4 TRAEs occurred in 52 (38.8%) pts in FEDR and 8 (11.9%) pts in BAT arms, most frequently thrombocytopenia (11.9% FEDR vs 3.0% BAT) and anemia (9.0% FEDR vs 9.0% BAT). In the FEDR arm, 22 (16.4%) pts had thiamine levels below normal range, compared with 2 (3.0%) pts receiving BAT; most cases occurred prior to the study amendment of prophylactic thiamine supplementation. There was a single grade 1 case of suspected Wernicke's encephalopathy in the FEDR arm during cycle 3, which resolved fully 24 hours after thiamine supplementation (0 cases in BAT arm). Two pts each in FEDR and BAT arms had TRAEs of infection. Conclusions In this phase 3 randomized study in pts with MF and prior RUX treatment, FEDR demonstrated superior SVR and symptom response rates compared with BAT. Most pts on BAT received RUX, highlighting a clinical need for an alternative JAKi. Differences in AE and discontinuation rates in the first 6 cycles are consistent with other studies comparing JAKi with BAT. AE mitigation strategies were effective and no new safety concerns for FEDR were identified. Study support Bristol Myers Squibb

Safety of bendamustine for the treatment of indolent non-Hodgkin lymphoma: a UK real-world experience

AbstractBendamustine is among the most effective chemotherapeutics for indolent B-cell non-Hodgkin lymphomas (iNHL), but trial reports of significant toxicity, including opportunistic infections and excess deaths, led to prescriber warnings. We conducted a multicenter observational study evaluating bendamustine toxicity in real-world practice. Patients receiving at least 1 dose of bendamustine with/without rituximab (R) for iNHL were included. Demographics, lymphoma and treatment details, and grade 3 to 5 adverse events (AEs) were analyzed and correlated. In total, 323 patients were enrolled from 9 National Health Service hospitals. Most patients (96%) received bendamustine-R, and 46%, R maintenance. Overall, 21.7% experienced serious AEs (SAE) related to treatment, including infections in 12%, with absolute risk highest during induction (63%), maintenance (20%), and follow-up (17%) and the relative risk highest during maintenance (54%), induction (34%), and follow-up (28%). Toxicity led to permanent treatment discontinuation for 13% of patients, and 2.8% died of bendamustine-related infections (n = 5), myelodysplastic syndrome (n = 3), and cardiac disease (n = 1). More SAEs per patient were reported in patients with mantle cell lymphoma, poor preinduction performance status (PS), poor premaintenance PS, and abnormal preinduction total globulins and in those receiving growth factors. Use of antimicrobial prophylaxis was variable, and 3 of 10 opportunistic infections occurred despite prophylaxis. In this real-world analysis, bendamustine-related deaths and treatment discontinuation were similar to those of trial populations of younger, fitter patients. Poor PS, mantle cell histology, and maintenance R were potential risk factors. Infections, including late onset events, were the most common treatment-related SAE and cause of death, warranting extended antimicrobial prophylaxis and infectious surveillance, especially for maintenance-treated patients.

Tazemetostat in Combination with R-CHOP in Patients with High-Risk, Frontline Follicular Lymphoma (Epi-RCHOP): A Phase II Study from the Lysa

Background: Tazemetostat (TAZ), an enhancer of zeste homolog 2 (EZH2) inhibitor, is approved by the US Food and Drug Administration for the treatment of patients with relapsed/refractory (R/R) follicular lymphoma (FL) whose disease has mutant (MT) EZH2 and who have received ≥2 prior therapies or with R/R FL who have no satisfactory alternative treatment options. We previously reported that the RP2D of TAZ in combination with R-CHOP was 800mg BID in the phase 1 part of Epi-RCHOP study (NCT02889523). Here, we report results of the phase 2 part evaluating TAZ with R-CHOP + rituximab maintenance in a cohort of previously untreated high-risk FL patients. Methods: patients were eligible if aged 18-80 years, had histologically confirmed FL grade 1-3A, high-risk FLIPI (score of 3-5) and were in need of treatment according to GELF criteria. Induction treatment consisted in 6 cycles of RCHOP every 21 days and TAZ 800mg BID every day, starting on day 2 of cycle 1, plus 2 additional 21 days cycles of rituximab+TAZ (cycle 7 and 8). Responses were assessed at end of induction (EOI), and responders then received maintenance 1 (TAZ 6 mo + rituximab 12 mo) and maintenance 2 (12 mo of rituximab alone).The primary efficacy endpoint was PET-based complete response rate based on local assessment at the end of induction or at permanent treatment discontinuation, as determined by Cheson IWG 2014 Lugano Classification (Deauville scale 1-3); in addition bone marrow biopsy (BMB) was mandatory at EOI if involved at baseline and complete metabolic response (CMR) patients with missing assessment at EOI classified as partial responders. Sample size calculation was made with the expectation of an increase of 13% in CR, with an H0 hypothesis of 67% and an H1 assumption of 80%, leading to a theorical sample size of 62 pts, assuming a drop out of 10%. Initial assumption was that CR rate should be >76.4% to consider the combination eligible for further clinical evaluation in high risk FL patients. Results: As of June 14, 2022, 62 patients were enrolled between Aug2020 and Apr2022 across 20 centers (including a drop-out of 12 patients, 70 were enrolled in France, 4 in Belgium). Disease characteristics included: males 61.3%, median age 64.5 years, FLIPI 3/4/5 in 61.3%/32.3%/6.5%, EZH2 mutated 17.3% (n=9/46 assessed had EZH2 mutation; 16 undertermined), BM involvement 68.3%, circulating FL cells in 21%, and increased LDH in 50%. Fifty eight (93%) patients completed induction and initiated maintenance 1, 44 (71%) initiated maintenance 2. Fourteen patients permanently discontinued treatment: 4 before EOI not related to PD (2 COVID19 disease, 1 late onset neutropenia and 1 stopped therapy but accepted FU), and 9 after EOI (5 PD, 2 COVID19 disease, 1 neutropenia, 1 paralytic ileus and 1 patient's refusal). At EOI, 79% (95%CI 66.8; 88.3%) achieved complete metabolic response (CMR) and 16.2% PMR for an overall metabolic response rate of 95.2%, however, according to the stringent protocol definition, 16 patients who achieved CMR had no BMB assessment at EOI and were downgraded to PR leading to 53.2% CR and 41.9% PR rate at EOI. Complete response rates were significantly higher in EZH2 mutants (8/9 CMR 88.9%) versus 17/37 (45.9%) in EZH2 wild-type (WT) patients (Fisher exact test p=0.027). Figure 1 shows the AEs reported by more than 10% of patients. The most common grade 3-4 TEAEs were neutropenia (53.2%, only 3.2% febrile), thrombocytopenia (17.7%), anemia (16.1%). Serious AEs occurred in 14 patients, the two most frequent being Covid19 disease (6.5%) and gastrointestinal hypomotility (6.5%). This latter AE was the most frequent non-hematologic event (40.3%), followed by peripheral neuropathy (35.5%). After amending vincristine dose (Oct2020), 30 digestive AEs were reported (16 related to TAZ, mostly grade 1-2, only 1 grade 3, no sequelae). No SPM was observed. With a median follow-up of 19 months, 7 relapses (5 EZH2 WT and 2 undetermined) including 5 needing subsequent treatment and 2 deaths occurred (1 Covid19 disease, 1 after PD). Median PFS and median DOR were not reached and appeared to be similar irrespective of EZH2 status, 18-months PFS and OS rates were 89.3% and 98.3% respectively. Conclusions: Although the primary endpoint was not met due to missing BM assessments, TAZ + RCHOP combination demonstrated a promising complete metabolic response rate of 79% in this high-risk frontline FL population, with a manageable safety profile, after vincristine dose was reduced.

Long-Term Evaluation of Luspatercept in Erythropoiesis-Stimulating Agent (ESA)-Intolerant/Refractory Patients (pts) with Lower-Risk Myelodysplastic Syndromes (LR-MDS) in the Phase 3 MEDALIST Study

Background: Pts with LR-MDS receiving luspatercept in the phase 3 MEDALIST trial previously reported durable, long-term red blood cell (RBC) transfusion independence (RBC-TI) (Fenaux P, et al. J Clin Oncol 2022;40[suppl 16]. Abstract 7056). MEDALIST pts were eligible to enroll in a follow-up study to evaluate long-term efficacy and safety. Aims: To report long-term efficacy and safety outcomes in ESA-refractory/intolerant pts with LR-MDS treated with luspatercept in the MEDALIST trial with an additional 26 mo of follow-up from the final MEDALIST data cutoff. Methods: Eligible pts were ≥ 18 y of age; IPSS-R-defined Very low-, Low-, or Intermediate-risk MDS with ring sideroblasts; were refractory, intolerant, or unlikely to respond to ESAs, and required regular RBC transfusions. Pts were randomized 2:1 to luspatercept (starting dose 1.0 mg/kg, with titration up to 1.75 mg/kg) or placebo. Efficacy outcomes include RBC-TI ≥ 8 wk and ≥ 16 wk. Cumulative duration of response was determined by Kaplan-Meier (KM) analysis. Rates of longest single and cumulative duration of RBC-TI ≥ 1 y and exposure-adjusted incidence rates (EAIR) of treatment-emergent adverse events (TEAEs) and AEs of special interest (AESIs) were calculated. Rates of high-risk (HR)-MDS and acute myeloid leukemia (AML) progression were calculated from LR-MDS diagnosis to HR-MDS/AML diagnosis, or to last HR-MDS/AML follow-up date for pts who did not progress. Results: As of January 2, 2023, 11 pts remained on luspatercept treatment; 8 pts randomized to luspatercept and none from placebo continued in post-treatment follow-up. The median (range) follow-up time was 39.9 (2.8-76.0) mo for luspatercept arm pts and 38.7 (1.7-68.6) mo for placebo arm pts. The median (range) duration of treatment was 50.9 (5.9-332.9) wk for luspatercept pts and 24.0 (9.0-103.0) wk for placebo pts. Seventy-five of 153 (49.0%) luspatercept pts achieved RBC-TI ≥ 8 wk during the entire treatment period and 53/75 (70.7%) had ≥ 2 response periods with a median cumulative duration of 110.14 wk (95% confidence interval [CI], 53.71-154.14; Figure A). Overall, 31/75 (41.3%) luspatercept pts had the longest RBC-TI duration ≥ 1 y, and 44/75 (58.7%) had a cumulative RBC-TI duration ≥ 1 y. In total, of the 48/153 (31.4%) pts receiving luspatercept who achieved RBC-TI ≥ 16 wk during the entire treatment period, 32/48 (66.7%) had ≥ 2 response periods with a median cumulative duration of 129.29 wk (95% CI, 79.86-240.43). Grade 3/4 treatment-related TEAEs were reported in 14/153 (9.2%; EAIR, 5.3 per 100 pt-y [PYs]) and 3/76 (3.9%; EAIR, 6.6 per 100 PYs) luspatercept and placebo pts, respectively; TEAEs of any grade leading to permanent treatment discontinuation were reported in 24/153 (15.7%; EAIR, 8.6 per 100 PYs) luspatercept and 6/76 placebo pts (7.9%; EAIR, 13.0 per 100 PYs). The most common TEAEs of any grade reported in > 5% of luspatercept pts were fatigue (47/153 [30.7%]; EAIR, 22.1 per 100 PYs; vs placebo, 11/76 [14.5%]; EAIR, 27.1 per 100 PYs), diarrhea (47/153 [30.7%]; EAIR, 23.5 per 100 PYs; vs placebo, 8/76 [10.5%]; EAIR, 18.4 per 100 PYs), asthenia (41/153 [26.8%]; EAIR, 18.8 per 100 PYs; vs placebo, 9/76 [11.8%]; EAIR, 21.5 per 100 PYs), peripheral edema (40/153 [26.1%], EAIR, 17.6 per 100 PYs; vs placebo, 13/76 [17.1%]; EAIR, 32.0 per 100 PYs), and back pain (38/154 [24.7%]; EAIR, 16.8 per 100 PYs; vs placebo, 5/76 [6.6%]; EAIR, 11.7 per 100 PYs; Figure B). During the entire treatment period, 26/44 (59.1%), 9/23 (39.1%), and 12/86 (14.0%) pts who received ≤ 1 mg/kg, 1.33 mg/kg, and 1.75 mg/kg luspatercept, respectively, reported fatigue of any grade. No new progression to HR-MDS or AML events have been reported since the last data cutoff (Santini V et al. Blood 2022;140[suppl 1]:4079-4081). Conclusions: Pts with LR-MDS who received luspatercept for > 2 years longer than in the original MEDALIST study, continued to experience sustained periods of RBC-TI with more than half of pts experiencing cumulative RBC-TI for ≥ 1 year. The long-term safety profile of luspatercept is consistent with previous shorter-term reports, and AEs were mostly lower grade with rates of fatigue decreasing with increasing luspatercept dose. These data demonstrate the long-term efficacy and safety of luspatercept in pts with LR-MDS intolerant/ineligible for ESA treatment.

Efficacy, safety, and correlative biomarkers of bintrafusp alfa in recurrent or metastatic nasopharyngeal cancer patients: a phase II clinical trial.

The strategy of dual blockade of TGF-β and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients. In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n=2; partial response, n=7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced≥grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n=9, 23.7%) and secondary malignancies (n=4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFβ1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P=0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR. Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning. The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.

Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma

Introduction: While combination of stereotactic body radiotherapy (SBRT) and immunotherapy are promising, their efficacy and safety have not been compared with SBRT-alone in patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included 100 patients with nonmetastatic, unresectable HCC in two hospitals. Eligible patients had tumor nodules ≤3 and Child-Pugh liver function score of A5 to B7. Seventy patients received SBRT-alone, and 30 patients underwent combined SBRT and immunotherapy (SBRT-IO). Overall survival (OS), time to progression (TTP), overall response rate (ORR), and toxicity were analyzed. We adjusted for the potential confounding factors using propensity score matching. Results: The median tumor size was 7.3 cm (range, 2.6–18 cm). Twenty-five (25%) of patients had vascular invasion. Before propensity score matching, the 1-year and 3-year OS rate was 89.9% and 59.8% in the SBRT-IO group and 75.7% and 42.3% in SBRT-alone group (p = 0.039). After propensity score matching (1:2), 25 and 50 patients were selected from the SBRT-IO and SBRT-alone group. The 1-year and 3-year OS was 92.0% and 63.9% in the SBRT-IO group versus 74.0% and 43.3% in the SBRT-alone group (p = 0.034). The 1-year and 3-year TTP was better in SBRT-IO group (1-year: 68.9% vs. 58.9% and 3-year: 61.3% vs. 32.5%, p = 0.057). The ORR of 88% (complete response [CR]: 56%, partial response [PR]: 22%) in SBRT-IO arm was significantly better than 50% (CR: 20%, PR: 30%) in the SBRT-alone arm (p = 0.006). Three patients (12%) developed ≥grade 3 immune-related treatment adverse events (n = 2 hepatitis, n = 1 dermatitis) leading to permanent treatment discontinuation. Conclusion: Adding immunotherapy to SBRT resulted in better survival with manageable toxicities. Prospective randomized trial is warranted.

Efficacy and safety of isatuximab plus bortezomib, lenalidomide, and dexamethasone in patients with newly diagnosed multiple myeloma ineligible/with no immediate intent for autologous stem cell transplantation

Patients with newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation (ASCT) have lower survival rates and may benefit from frontline regimens that include novel agents. This Phase 1b study (NCT02513186) evaluated preliminary efficacy, safety, and pharmacokinetics (PK) of isatuximab, an anti-CD38 monoclonal antibody, combined with bortezomib-lenalidomide-dexamethasone (Isa-VRd) in patients with NDMM ineligible for/with no intent for immediate ASCT. Overall, 73 patients received four 6-week induction cycles of Isa-VRd, then maintenance with Isa-Rd in 4-week cycles. In the efficacy population (n = 71), the overall response rate was 98.6%, with 56.3% achieving a complete response or better (sCR/CR), and 36/71 (50.7%) patients reaching minimal residual disease negativity (10−5 sensitivity). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 79.5% (58/73) of patients but TEAEs leading to permanent study treatment discontinuation were reported in 14 (19.2%) patients. Isatuximab PK parameters were within the previously reported range, suggesting that VRd does not alter the PK of isatuximab. These data support additional studies of isatuximab in NDMM, such as the Phase 3 IMROZ study (Isa-VRd vs VRd).

Efficacy and safety of tunlametinib in patients with advanced NRAS-mutant melanoma: A multicenter, open-label, single-arm, phase 2 study.

9510 Background: NRAS-mutant melanoma is an aggressive subtype with worse prognosis. However, no targeted therapy has been approved to date worldwide. Tunlametinib (HL-085), a novel, potent, selective, oral small-molecule MEK1/2 inhibitor, has showed a favorable pharmacokinetics profile, acceptable tolerability and encouraging antitumor activity in the phase 1 study (BMC Med. 2023 Jan 4;21(1):2). Methods: This is an ongoing, multicenter, open-label, single-arm, phase 2 pivotal registration study. Patients (pts) with NRAS-mutant unresectable stage III or IV melanoma were enrolled and received tunlametinib 12 mg orally twice daily. A historical control of objective response rate (ORR) of 10% was predefined for sample size estimation (100 pts, assuming loss to follow-up rate of 5%) and efficacy evaluation. The primary endpoint was the confirmed ORR per RECIST v1.1 assessed by independent radiology review committee. Results: A total of 100 pts were enrolled. All pts were included in the safety analysis set and 95 pts were included in the full analysis set (FAS) for efficacy analysis. At cut-off date (August 17, 2022), median follow-up was 7.9 months (95% CI: 6.6, 9.8). In the FAS, the median age was 58.0 years (range: 24 to 84). Sixty-four pts (67.4%) had received prior immunotherapy (PD-1/PD-L1 inhibitor). Fifty-six pts (58.9%) were acral melanoma, 16 (16.8%) mucosal melanoma and 12 (12.6%) skin melanoma. Fourteen pts (14.7%) were stage III and 81 (85.3%) stage IV. The most frequent NRAS mutation types were Q61R (40.0%), Q61K (29.5%) and G12D (9.5%). Confirmed ORR was 34.7% (95%CI: 25.3%, 45.2%). Median progression-free survival was 4.2 months (95%CI: 3.5, 5.6), overall survival was immature, and 1-year survival rates was 57.2% (95% CI, 44.7%, 67.8%). Subgroup analysis showed that, in pts who had previously received immunotherapy, the confirmed ORR was 39.1% (95% CI: 27.1%, 52.1%). The most frequent treatment related adverse events (TRAEs) were increased blood creatine phosphokinase (CK), diarrhea, peripheral oedema, facial oedema and increased aspartate aminotransferase. Grade ≥3 TRAEs occurred in 68 pts (68.0%), of which 38.0% (38/100) were increased blood CK. Most of pts with CK elevation are asymptomatic and can be managed by dose interruption or reduction without permanent treatment discontinuation. No treatment-related death was reported. Conclusions: Tunlametinib was well tolerated and demonstrated encouraging treatment response rate in pts with advanced NRAS-mutant melanoma. These results indicate that tunlametinib could be a promising treatment option for NRAS-mutant melanoma, even for those immunotherapy failed pts. Clinical trial information: NCT05217303 .

Maintenance therapy with carfilzomib, pomalidomide, and dexamethasone (KPd) in high-risk myeloma patients (pts): A phase 2 study with a safety run-in.

8001 Background: High-risk pts derive survival benefit from combination maintenance (PI and IMiD) strategies. We have evaluated the safety and efficacy of the next generation PI (carfilzomib) and IMiD (pomalidomide) in combination with dexamethasone in high-risk myeloma (NCT03756896). Methods: Newly diagnosed high-risk myeloma pts that have achieved ≥PR post-ASCT were included. High-risk myeloma was defined by the presence of t(4;14) in 27.6%, t(14;16) in 17.2%, del17p in 58.6% pts by FISH or CTG or presence of ≥20% circulating cells (pPCL) in 6.9%. Double-hit myeloma (as defined by presence of ≥2 high-risk cytogenetic abnormalities including gain of 1q) was seen in 58.6% of pts. Each cycle is 28 days. Carfilzomib 20/56 mg/m2 IV was given on days 1,8,15 and pomalidomide 2 mg PO on days 1 to 21 and dexamethasone 40 mg PO was administered on days of carfilzomib. Statistical analysis was conducted using SAS Version 9.4. Results: After the safety run in the first 3 pts, 26 additional pts were enrolled. Median age was 60 years (range, 46−75); 58.6% male and 58.6% black. At diagnosis, 65.5% had RISS stage 3 disease. 54.5% of whites and 64.7% of blacks had double-hit disease. Median time from diagnosis and from transplant to study entry was 9.3 (range, 6.08-12.42) and 2.89 (range, 2-8.51) months, respectively. At study entry, ≥CR and ≥VGPR rates were 24.1% and 68.9%, respectively, which deepened to 79.3% and 100% while on study. The median time to best response was 2.07 months (range, 1.22-14.26). Of the 15 pts with available MRD data, MRD (10-5) and (10-6) were achieved in 80% and 53.3%, respectively. After a median follow-up of 25.8 months, 36 month PFS was 63.2% (95% CI 38.3-80.3%) and 36 month OS was 72.4% (44.2-88.0%). Double-hit disease was an independent predictor for progression and death. Among these high risk patients, RISS did not show any statistical significance. While there is no PFS difference by race, the 36 month OS for black pts was inferior compared to whites (61.1% [23.1-84.7%] vs 85.7% [33.4%-97.9%], log rank 0.05). At data cut-off, 37.9% of pts were still receiving treatment; most common reason for permanent treatment discontinuation was progressive disease (27.6%). Among the 6 pt deaths, the most common cause of death was progressive disease (83.3%). Most common (≥20%) TEAEs were fever (37.9%), fatigue (34.5%), diarrhea (27.6% [G3/4, 3.4%]), nausea (24.1%), cough (20.7%), muscle cramps (20.1%), acneiform rash (20.1%). TEAEs of interest were cardiac (10.3% [G3/4, 3.4%]), cataracts (17.2% [G3/4, 17.2%]), neutropenia (6.9% [G3/4, 6.9%]) and anemia (10.3% [G3/4, 0%]). Conclusions: In pts with high-risk myeloma, KPd maintenance deepened responses. MRD negativity (10-5) was attained in 80% of pts. Despite the encouraging results in this cohort of high-risk patients, PFS and OS among double-hit pts remains poor, warranting newer strategies aimed at remission sustenance. Clinical trial information: NCT03756896 .

Elranatamab, a B-cell maturation antigen (BCMA)-CD3 bispecific antibody, for patients (pts) with relapsed/refractory multiple myeloma (RRMM): Extended follow up and biweekly administration from the MagnetisMM-3 study.

8039 Background: MagnetisMM-3 (NCT04649359) is an open-label, multicenter, registrational phase 2 study evaluating the efficacy and safety of elranatamab monotherapy in pts with RRMM; pts naïve to BCMA-directed therapies were enrolled in Cohort A. Methods: Eligible pts were refractory to at least 1 PI, 1 IMiD, and 1 anti-CD38 antibody. Pts received SC elranatamab in 28-d cycles with step-up doses of 12 mg on C1D1 and 32 mg on C1D4 followed by 76 mg QW beginning C1D8. Pts treated for 6 cycles and achieving partial response (PR) or better with response persisting ≥2 mo were switched to 76 mg Q2W, 46 and 58 pts are included in the Q2W efficacy and safety analyses, respectively. Results: Overall, 123 pts received elranatamab. Median pt age was 68.0 y (range, 36−89), 63.4% of pts had an ECOG PS ≥1 and median prior lines of therapy was 5.0 (2−22); 96.7% and 42.3% of pts were triple-class- and penta-drug refractory, respectively. At data cutoff (~12 mo after last pt initial dose), the median follow up was 12.8 mo (0.2−22.7); 34.1% of pts remained on treatment. Most common reasons for permanent treatment discontinuation were progressive disease (39.0%) and adverse events (AE; 13.8%). Objective response rate per blinded independent central review (BICR) was 61% (95% CI 51.8−69.6), with 39 (31.7%) pts with complete response (CR) or stringent CR (sCR); very good partial response (VGPR) and PR were achieved in 29 (23.6%) and 7 (5.7%) pts, respectively. MRD-negativity (threshold 10–5) was achieved by 92.0% (n = 23/25) of evaluable pts. Median duration of response (mDOR) has not been reached (95% CI 12.9−NE) and DOR at 12 mo was 74.1% (95% CI 60.5−83.6). In pts with CR/sCR or VGPR, mDOR was not reached by 12 mo; in pts with PR, mDOR was 5.2 mo (95% CI 1.6−NE). There were 46 responders by BICR who switched to Q2W dosing ≥24 wk prior to the data cut-off; among these pts, 80.4% maintained/improved their response ≥24 wk after the switch. Median progression-free and overall survival have not been reached by 12 mo, and the respective rates (95% CI) at 12 mo were 57.1% (47.2−65.9) and 62.0% (52.8−70.0). Most common Grade 3/4 treatment emergent AEs were hematologic; Grade 3/4 non-hematologic events reported in ≥5% of pts were COVID-pneumonia (10.6%), hypokalemia (9.8%), pneumonia (7.3%), sepsis (6.5%), hypertension (6.5%), ALT increased (5.7%), and SARS-COV-2 test positive (5.7%). Among pts who switched to Q2W dosing, the incidence of Grade 3/4 AEs decreased by > 10% after the switch. Conclusions: Elranatamab remains efficacious and well tolerated in pts with RRMM after > 1 y of follow-up. Updated analysis with a median follow up of ~15 mo, the longest of all phase 2 BCMA-CD3 bispecific antibody studies, including the outcome of pts who switched to the Q2W dosing, will be presented. These results support continued elranatamab development for pts with MM. Clinical trial information: NCT04649359 .

Efficacy and safety of elranatamab in patients with relapsed/refractory multiple myeloma (RRMM) and prior B-cell maturation antigen (BCMA)-directed therapies: A pooled analysis from MagnetisMM studies.

8008 Background: Studies in the MagnetisMM program (MM-1, NCT03269136; MM-3, NCT04649359; MM-9, NCT05014412) enrolled pts treated with prior BCMA-directed therapies. A pooled analysis from these studies evaluated the efficacy and safety of elranatamab in pts with RRMM and prior exposure to BCMA-directed therapy. Methods: Eligible pts received at least 1 PI, 1 IMiD, 1 anti-CD38 antibody, and 1 BCMA-directed therapy (ADC and/or CAR-T cells). Pooled analysis included pts in MM-1 (n = 13) who received SC elranatamab 215−1000 µg/kg; MM-3 (n = 64) and MM-9 (n = 9) who received the RP2D, SC 76 mg QW. Efficacy endpoints were assessed by investigator per IMWG criteria. TEAEs were graded by CTCAE (MM-1, v4.03; MM-3 & MM-9, v5.0); CRS and ICANS were graded by ASTCT criteria. Results include data up through ~10 months after last pt initial dose in all pooled studies. Results: In total, 86 pts were included. Median age was 66.0 y (range, 40−84); 47.7% male. At baseline, 69.8% had an ECOG PS ≥1; 24.4% had high risk cytogenetics; 54.7% had extramedullary disease. Pts received a median of 7.0 (3−19) prior lines of therapy, including BCMA-directed ADC (67.4%), CAR T-cells (41.9%), 9.3% received both. 96.5% and 54.7% of pts were triple-class and penta-drug refractory, respectively; among pts who received ADC and CAR-T cells respectively, 79.3% and 27.8% were refractory to ADC and CAR-T cells. After a median follow-up of 10.3 mo (0.3−32.3), median duration of treatment was 3.3 mo (0.03−30.4). At data cut-off, 24.4% of pts remained on treatment; most common reason for permanent treatment discontinuation was progressive disease (44.2%). ORR was 45.3% (95% CI 34.6−56.5), with ≥CR achieved in 17.4% of pts. ORR for pts with prior BCMA-directed ADC and CAR-T cells was 41.4% (95% CI 28.6−55.1) and 52.8% (95% CI 35.5−69.6), respectively. Among responders, median time to objective response was 1.9 mo (0.3−9.3). Median DOR was not reached by 10 mo; the DOR rate at 9 mo was 72.4% (95% CI 54.7−84.2). DOR rate (95% CI) for pts with prior BCMA-directed ADC and CAR-T cells were 67.3% (43.1−83.0) and 78.9% (53.2−91.5) at 9 mo, respectively. Median PFS was 4.8 mo (95% CI 1.9−7.7), and median OS was not reached by 10 mo, with a rate of 60.1% (95% CI 48.9−69.6) at 9 mo. Most common (≥25% of pts) TEAEs were CRS (65.1% [G3 1.2%]), anemia (59.3% [G3/4, 46.5%]), neutropenia (44.2% [G3/4, 40.7%]), thrombocytopenia (40.7% [G3/4, 29.1%]), diarrhea (33.7% [G3/4, 0%], and lymphopenia (32.6% [G3/4, 30.2%]). ICANS was reported in 5.8% (G3, 2.3%) of pts. Conclusions: In pts with RRMM and prior exposure to BCMA-directed therapies, elranatamab was efficacious and well tolerated; no new safety signals were observed vs the BCMA-naïve population. Results support treatment with elranatamab in pts with RRMM post BCMA-directed therapy. Clinical trial information: NCT03269136 , NCT04649359 , NCT05014412 .

Phase II study of crizotinib in patients with MET amplification and MET exon 14 deletion: Results from NCI-MATCH ECOG-ACRIN trial (EAY131) subprotocols C1 and C2.

3108 Background: The NCI-Molecular Analysis for Therapy Choice (MATCH) platform trial enrolled patients with solid tumors, lymphomas, or multiple myeloma to trials of targeted therapies based on matching genomic alterations. Subprotocols C1 and C2 evaluated MET tyrosine kinase inhibitor crizotinib in pts with MET amplification ( METamp; C1) or MET Exon 14 mutation/deletion ( METex14; C2). Methods: Pts whose tumors had METamp or METex14 were eligible for C1 and C2, respectively. Results were confirmed by MATCH Oncomine assay if possible; C2 explored METex14 quantification at DNA level retrospectively using cases with sufficient tissue for analysis of DNA mutations surrounding MET exon 14 and control samples with a variable amount of MET exon 14 counts using Anchored Multiplex PCR. Pts in C1 and C2 received crizotinib orally BD daily in 28-day cycles until progression or unacceptable toxicity. Tumor assessment occurred every 2 cycles. Primary endpoint was ORR; PFS; secondary endpoints: 6-month PFS, OS, and predictive biomarkers. Results: C1 enrolled 44 pts, of which 28, representing a variety of histologies, were eligible, received treatment, and included in the primary efficacy analysis as prespecified by protocol; GI (n=17) and lung (n=7) were most common. Median age: 67 (range 28- 82), 9 pts were women. Median MET copy number was 16.8 (min 7.1, max 78.0). Of 28 pts, 4 had PR; 10 had SD, 13 had PD as best response; disease control rate (DCR) 50% (14/28); one pt was unevaluable. ORR was 14% (4/28, 90% CI: 5.0%-29.8%). Median PFS was 3.4 mo (90% CI: 1.8–3.7); median OS 7.1 mo (90% CI: 5.0–11.5). 4 pts with confirmed PR were lung (n=2), GI (n=1), melanoma (n=1); 1 pt had SD >6 mo (NSCLC). Most pts had ≥1 co-occurring gene alteration (n=27; 96%), TP53 co-mutation most frequently (n=23, 82%); 21 pts had ≥3 co-occurring mutations. C2 enrolled 20 pts, 14 evaluable received treatment: GI (n=5); lung (n=6); other (n=3). Median age for the 14 pts was 68 (range 57-78); 6 pts were women, 9 (64%) had ≥3 lines of prior therapy. Most pts had ≥1 co-occurring gene alteration (n=13; 93%, range 1-4); TP53 co-mutations were frequent (n=7, 50%). Of 14 pts, 2 had PR (both NSCLC); 4 had SD, 4 had PD as best response, and DCR was 43% (6/14). 2 pts had SD >6 mo (1 lung, 1 bladder). ORR was 14% (2/14, 90% CI: 2.6%-38.5%). Median PFS 2.0 mo (90% CI: 1.4–4.1). On quantification by Met count ≥50,000 mPFS 8.8 months (90% CI: 2.1–NA), MET count <50,000 mPFS 1.7 mo (90% CI: 1.1–3.7). All lung cancer pts with confirmed PR/SD >6 mo had documented MET count >50,000. Most common reason for permanent treatment discontinuation was disease progression. No new toxicity signals were identified. Conclusions: We demonstrate clinical activity using crizotinib across tumors in patients with METampand METex14. In METex14, differentiating true pathogenic variants from low-level splice variant transcripts may be clinically meaningful. Clinical trial information: NCT02465060 .