Impact of extended interval dosing of immune checkpoint inhibitors in lung cancer patients during the COVID-19 pandemic

Background The COVID 19-pandemic has led physicians to change their approach to treating non-small cell lung cancer (NSCLC) to reduce hospital stays for patients. Objectives We aimed to assess the toxicity and efficacy of extended interval (EI) dosing of immune checkpoint inhibitors (ICIs) compared to standard dosing (SD). Methods In this retrospective two-center study, we included patients with stage III/IV NSCLC who were treated with ICIs with or without maintenance pemetrexed during the month before March 2020. Adverse events and efficacy were collected until June 2021. Toxicity and survival were assessed using multivariate Cox models. Results Among the 134 patients identified (8 stage III and 126 stage IV;66 first line and 60 second or subsequent lines), 70.9% received EI dosing. In the EI group, 12.6% of patients developed grade 3 or 4 immune-related adverse events versus 15.4% in the SD group (P- value = 0.8). Treatment was definitively discontinued due to toxicity in 9 patients in the EI group and in 5 in the SD group (P-value =0.5). Overall survival was not associated with dosage regimen or toxicity analyzed as a time-dependent variable. Conclusions Our study suggests that EI dosing of ICIs did not affect toxicity and overall survival in lung cancer patients.

Indian Multicenter Phase Ii Randomised Controlled Study Comparing Post Stem Cell Maintenance Regimen for Newly Diagnosed Multiple Myeloma (Impose Bortecon Study)

Introduction: Autologous stem cell transplant (ASCT) remains the backbone therapeutic modality with the highest progression-free survival (PFS) and overall survival (OS) benefit even in the era of the novel agents in newly diagnosed multiple myeloma (NDMM). The survival post-transplant can be prolonged using maintenance therapies. The regimen with maximum benefit is still debated, with bortezomib showing PFS benefit even in the high-risk myeloma. Aims & Objectives: This randomized phase II trial is aimed at studying the efficacy (as measured by overall survival (OS), progression- free survival (PFS)), and safety of post-ASCT different maintenance regimens in patients with NDMM. Material(s) and Method(s): Multicentric open-label interventional study with randomized allocation, parallel assignment, with intention-totreat analysis. Recruitment was prospective starting 01 Jan 2017, including all NDMM patients eligible for the study. Remission status was evaluated at D100 and every 6 months for 2y post-ASCT, including MRD analysis by multicolor flow cytometry (MFC) and PET/CT. The four arms included (Arm-A) bortezomib alone (V), (Arm-B) bortezomib in combination with cyclophosphamide and dexamethasone (VCD), (Arm-C) bortezomib in combination with lenalidomide (VR), and (Arm-D) Lenalidomide starting D100 till 2y post-ASCT. Adverse events with CTACE grade<2 were defined as non-serious and the rest as serious. JMP ver. 13 was used for statistical analysis and p<0.05 was considered significant. Kaplan Meier statistics was used for survival analysis. Result(s): A total of 123 patients have enrolled of which 92 patients completed the study protocol and the rest 31 patients were excluded because of protocol deviation due to the COVID pandemic. The median age of the study population was 54.5y (35-76y) with a male preponderance (67%). There was no statistically significant difference between the four arms on the log-rank test in the OS (p-0.99), clinical PFS (p-0.65), biochemical PFS (p-0.6), or MFC-based PFS (p-0.83). There was a statistically significant difference between the four arms on the log-rank test (p-0.0185) on PET/CT-based PFS (PFS being in a descending order VCD>V>VR>R regimen). The all-cause mortality of the study participants was 19.57% (n-18) and the difference in deaths among the various groups was not statistically significant (p-0.85). The tolerability, serious and non-serious adverse were significantly higher amongst Arm D patients. Conclusion(s): We conclude that there was no difference in OS between the different regimens. Patients on Lenalidomide-only therapy had significantly inferior Imaging-PFS.

A Modified Regimen of 21-day Nab-Paclitaxel Plus Gemcitabine in Locally Advanced or Metastatic Pancreatic Cancer: A Retrospective Real-World Study.

BACKGROUND: It is 1 of the standard treatment options for metastasis pancreatic cancer to receive nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1, 8 and 15 every 28 days. Some patients showed intolerance and inconvenience to this therapeutic regimen. Thus, we conducted this retrospective real-world study to determine the efficacy and tolerability of a modified 21-day nab-paclitaxel plus gemcitabine (nab-P/Gem) regimen for the first-line treatment of locally advanced or metastatic pancreatic cancer. METHODS: Patients with locally advanced and metastatic pancreatic cancer treated with nab-paclitaxel (125 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 every 21-day at West China Hospital and Shang Jin Hospital of Sichuan University from Mar 2018 to Dec 2021 were reviewed retrospectively. Clinical characteristics of patients were collected. The progression-free survival, overall survival, objective response rate, disease control rate, and toxicity were evaluated. RESULTS: A total of 113 patients who received the modified regimen of 21-day nab-P/Gem chemotherapy were included. The median overall survival was 9.3 months and the median progression-free survival was 4.4 months. The objective response rate and disease control rate were 18.6% and 56.7%, respectively. The median relative dose intensity for this modified regimen was 65%. The adverse events were mild to moderate, and the most common grade 3 or 4 treatment-related adverse events were neutropenia (21%) and leukopenia (16%). CONCLUSIONS: Our study showed that this modified regimen of 21-day nab-P/Gem for locally advanced and metastatic pancreatic cancer had comparable efficacy and tolerable toxicity. This treatment may provide a considerable option for pancreatic cancer patients who desire a modified schedule. The modified regimen of 21-day nab-P/Gem is also an option worth considering during the coronavirus disease 2019 pandemic for minimizing the number of visits and limiting the risk of exposure.

CARTITUDE-2 Cohort A: Updated Clinical Data and Biological Correlative Analyses of Ciltacabtagene Autoleucel (cilta-cel) in Lenalidomide-Refractory Patients With Progressive Multiple Myeloma (MM) After 1-3 Prior Lines of Therapy (LOT)

Context: CARTITUDE-2 (NCT04133636) Cohort A is assessing cilta-cel in lenalidomide-refractory patients with progressive MM after 1-3 prior LOT. Objective(s): To present updated results from CARTITUDE-2 Cohort A. Design(s): Phase 2, multicohort study. Patient(s): Lenalidomide-refractory patients with progressive MM after 1-3 prior LOT (PI and IMiD included) and no previous exposure to BCMA-targeting agents. Intervention(s): Single cilta-cel infusion (target dose 0.75x106 CAR+ viable T-cells/kg) after lymphodepletion Main Outcome Measure(s): Primary endpoint was minimal residual disease (MRD) negativity at 10-5. Management strategies were used to reduce risk of movement/neurocognitive adverse events (MNTs). Pharmacokinetics (PK) (Cmax/Tmax of CAR+T-cell transgene levels), cytokine release syndrome (CRS)-related cytokines over time, peak cytokine levels by response/CRS, association of cytokine levels with immune effector cell-associated neurotoxicity syndrome (ICANS), and CAR+T-cell CD4/CD8 ratio by response/CRS/ICANS are being evaluated. Result(s): As of January 2022 (median follow-up [MFU] 17.1 months), 20 patients (65% male;median age 60 years;median 2 prior LOT;95% refractory to last LOT) received cilta-cel. Overall response rate was 95% (90% >=complete response;95% >=very good partial response). Median times to first and best response were 1.0 month and 2.6 months, respectively. All 16 MRD-evaluable patients achieved MRD negativity at 10-5. Median duration of response was not reached. At 12 months, event-free rate was 79% and progression-free survival rate was 75%. 95% of patients had CRS (gr3/4 10%);median time to onset was 7 days and median duration was 3 days. Neurotoxicity was reported in 30% of patients (5 gr1/2;1 gr3/4) and ICANS in 15% (all 3 gr1/2);1 patient had gr2 facial paralysis. No MNTs were observed. 1 death occurred due to COVID-19 (treatment-related), 2 due to progressive disease, and 1 due to sepsis (not treatment-related). Preliminary PK analyses showed peak CAR-T cell expansion at day 10.5;median persistence was 153.5 days. Conclusion(s): At MFU of 17.1 months, a single cilta-cel infusion resulted in deep and durable responses in lenalidomide-refractory MM patients with 1-3 prior LOT. We will present updated PK/cytokine/CAR-T subset analyses and clinical correlation to provide novel insights into biological correlates of efficacy/safety in this population. Copyright © 2022 Elsevier Inc.

The case against censoring of progression-free survival in cancer clinical trials - A pandemic shutdown as an illustration.

BACKGROUND: Missing data may lead to loss of statistical power and introduce bias in clinical trials. The Covid-19 pandemic has had a profound impact on patient health care and on the conduct of cancer clinical trials. Although several endpoints may be affected, progression-free survival (PFS) is of major concern, given its frequent use as primary endpoint in advanced cancer and the fact that missed radiographic assessments are to be expected. The recent introduction of the estimand framework creates an opportunity to define more precisely the target of estimation and ensure alignment between the scientific question and the statistical analysis. METHODS: We used simulations to investigate the impact of two basic approaches for handling missing tumor scans due to the pandemic: a "treatment policy" strategy, which consisted in ascribing events to the time they are observed, and a "hypothetical" approach of censoring patients with events during the shutdown period at the last assessment prior to that period. We computed the power of the logrank test, estimated hazard ratios (HR) using Cox models, and estimated median PFS times without and with a hypothetical 6-month shutdown period with no patient enrollment or tumor scans being performed, varying the shutdown starting times. RESULTS: Compared with the results in the absence of shutdown, the "treatment policy" strategy slightly overestimated median PFS proportionally to the timing of the shutdown period, but power was not affected. Except for one specific scenario, there was no impact on the estimated HR. In general, the pandemic had a greater impact on the analyses using the "hypothetical" strategy, which led to decreased power and overestimated median PFS times to a greater extent than the "treatment policy" strategy. CONCLUSION: As a rule, we suggest that the treatment policy approach, which conforms with the intent-to-treat principle, should be the primary analysis to avoid unnecessary loss of power and minimize bias in median PFS estimates.

[Multiple myeloma: response to treatment and survival of patients according to the interim analysis of the Russian observational, retrospective-prospective, multicenter cohort study (MULTISPECT)].

AIM: The primary objective of the interim analysis of the MULTISPECT study was to evaluate the short-term efficacy of the treatment and long-term outcomes in cohorts of primary and pretreated patients with multiple myeloma (MM) receiving treatment in actual clinical practice in various regions of the Russian Federation. Secondary objectives were a description of the main characteristics of patients; analysis of the most commonly used therapy regimens of the 1st and later lines and the sequence of their changes; evaluation of the response to therapy. Additional objectives included evaluation of the effect of the new COVID-19 coronavirus infection on the course of MM in patients. MATERIALS AND METHODS: The study is an observational retrospective-prospective multicenter cohort study. For its implementation, a structured database of patients with MM was used, provided by hematologists of the centers affiliated for the study. RESULTS: The study included 1,294 patients (cohort 1 806, cohort 2 488). In both cohorts, patients aged 6069 years were in the majority. 3 lines of therapy (L1, L2, L3) were used for cohort 1; in cohort 2, the 4th line of therapy was also used in 2 patients. The therapy regimens were analyzed for 290 (22.41%) of all patients in the study. Responses to therapy were analyzed for 214 patients of cohort 1 and 109 patients of cohort 2. Autologous and allogeneic hematopoietic stem cell transplantations were carried out for a limited proportion of patients in both cohorts. At the end of the study and upon presentation of its results, the status of patients was the following: 96% of patients in cohort 1 and 89% in cohort 2 were alive. The therapy regimens in both cohorts were characterized by variability. The most commonly used regimens in each of the lines of therapy have been identified. The most used therapy regimen in patients with MM of both cohorts was the VCD-regime. Rd-regime in cohort 1 and RD-regime in cohort 2 were the second most frequent used regimens. In patients of both cohorts, the therapy regimens including Bortezomib were most often used. CONCLUSION: The variety of therapy regimens used to treat MM in actual clinical practice may be due to the factors of availability of new medicines and updated recommendations for the treatment of the disease. Further, in the context of this study, a more detailed analysis of the efficacy of certain therapy regimens in the 1st and later lines on progression free survival and overall survival of MM patients should be carried out.

Comparison of abiraterone acetate and prednisolone (AAP) or combination enzalutamide (ENZ) + AAP for metastatic hormone sensitive prostate cancer (mHSPC) starting androgen deprivation therapy (ADT): Overall survival (OS) results of 2 randomised phase III trials from the STAMPEDE protocol

Background: AAP or ENZ added to ADT improves outcomes for mHSPC. Any benefit of combining ENZ & AAP in this disease setting is uncertain. Methods: STAMPEDE is a multi-arm, multi-stage (MAMS), platform protocol conducted at 117 sites in the UK & Switzerland. 2 trials with no overlapping controls randomised mHSPC patients (pts) 1:1 to ADT +/- AAP (1000mg od AA + 5mg od P) or AAP + ENZ (160mg od). Treatment was continued to progression. From Jan 2016 docetaxel 75mg/m2 3-weekly with P 10mg od was permitted + ADT. Using meta-analysis methods, we tested for evidence of a difference in OS and secondary outcomes (as described previously: failure-free, metastatic progression-free, progression-free & prostate cancer specific survival) across the 2 trials using data frozen 3 Jul 2022. All confidence intervals (CI) 95%. Restricted mean survival times (RMST) restricted to 84 months (m). Results: Between Nov 2011 & Jan 2014, 1003 pts were randomised ADT +/- AAP & between Jul 2014 & Mar 2016, 916 pts were randomised ADT +/- AAP + ENZ. Randomised groups were well balanced across both trials. Pt cohort: age, median 68 years (yr), IQR 63, 72;PSA prior to ADT, median 95.7 ng/ml, IQR 26.5, 346;de novo 94%, relapsed after radical treatment, 6%. In AAP + ENZ trial, 9% had docetaxel + ADT. OS benefit in AAP + ENZ trial, HR 0.65 (CI 0.55‒0.77) p = 1.4×10-6;in AAP trial, HR 0.62 (0.53, 0.73) p = 1.6×10-9. No evidence of a difference in treatment effect (interaction HR 1.05 CI 0.83‒1.32, p = 0.71) or between-trial heterogeneity (I2 p = 0.70). Same for secondary end-points. % (CI) of pts reporting grade 3-5 toxicity in 1st 5 yr: AAP trial, ADT: 38.5 (34.2-42.8), + AAP: 54.4 (50.0-58.8);AAP + ENZ trial, ADT: 45.2 (40.6 – 49.8), + AAP + ENZ: 67.9 (63.5 – 72.2);most frequently increased with AAP or AAP + ENZ = liver derangement, hypertension. At 7 yr in AAP trial (median follow-up: 95.8m), % (CI) pts alive with ADT: 30 (26, 34) versus with ADT + AAP: 48 (43, 52);RMST: ADT: 50.4m, ADT + AAP: 60.6m, p = 6.6 x 10-9. Conclusions: ENZ + AAP need not be combined for mHSPC. Clinically important improvements in OS when adding AAP to ADT are maintained at 7 yr. Clinical trial identification: NCT00268476. Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at University College London. Funding: Cancer Research UK, Medical Research Council, Janssen, Astellas. Disclosure: G. Attard: Financial Interests, Personal, Invited Speaker: Janssen, Astellas, AstraZeneca;Financial Interests, Personal, Advisory Board: Janssen, Astellas, Novartis, Bayer, AstraZeneca, Pfizer, Sanofi, Sapience, Orion;Financial Interests, Personal, Royalties, Included in list of rewards to discoverers of abiraterone: Institute of Cancer Research;Financial Interests, Institutional, Research Grant: Janssen, Astellas;Non-Financial Interests, Principal Investigator: Janssen, Astellas;Non-Financial Interests, Advisory Role: Janssen, AstraZeneca. W.R. Cross: Financial Interests, Personal, Invited Speaker, Speaker fee: Myriad Genetics, Janssen, Astellas;Financial Interests, Personal, Advisory Board, Advisory Board fee: Bayer;Financial Interests, Institutional, Research Grant, Research grant: Myriad Genetics. S. Gillessen: Financial Interests, Personal, Advisory Board, 2018: Sanofi, Roche;Financial Interests, Personal, Advisory Board, 2018, 2019: Orion;Financial Interests, Personal, Invited Speaker, 2019 Speaker's Bureau: Janssen Cilag;Financial Interests, Personal, Advisory Board, 2020: Amgen;Financial Interests, Personal, Invited Speaker, 2020: ESMO;Financial Interests, Personal, Other, Travel Grant 2020: ProteoMEdiX;Financial Interests, Institutional, Advisory Board, 2018, 2019, 2022: Bayer;Financial Interests, Institutional, Advisory Board, 2020: Janssen Cilag, Roche, MSD Merck Sharp & Dohme, Pfizer;Financial Interests, Institutional, Advisory Board, 2018: AAA International, Menarini Silicon Biosystems;Financial Interests, Institutional, Advisory Board, 2019, 2020: Astellas Pharma;Financial Interests, Institutional, Advisory B ard, 2019: Tolero Pharmaceuticals;Financial Interests, Personal, Invited Speaker, 2021, 2022: SAKK, DESO;Financial Interests, Institutional, Advisory Board, 2021: Telixpharma, BMS, AAA International, Novartis, Modra Pharmaceuticas Holding B.V.;Financial Interests, Institutional, Other, Steering Committee 2021: Amgen;Financial Interests, Institutional, Advisory Board, 2021, 2022: Orion, Bayer;Financial Interests, Personal, Invited Speaker, 2021: SAKK, SAKK, SAMO - IBCSG (Swiss Academy of Multidisciplinary oncology);Financial Interests, Personal, Advisory Board, 2021: MSD Merck Sharp & Dhome;Financial Interests, Personal, 2021: RSI (Televisione Svizzera Italiana);Financial Interests, Institutional, Invited Speaker, 2021: Silvio Grasso Consulting;Financial Interests, Institutional, Other, Faculty activity 2022: WebMD-Medscape;Financial Interests, Institutional, Advisory Board, 2022: Myriad genetics, AstraZeneca;Financial Interests, Institutional, Invited Speaker, 2022: TOLREMO;Financial Interests, Personal, Other, Travel support 2022: AstraZeneca;Financial Interests, Institutional, Funding, 2021, Unrestricted grant for a Covid related study as co-investigator: Astellas;Non-Financial Interests, Advisory Role, 2019: Menarini Silicon Biosystems, Aranda;Non-Financial Interests, Advisory Role, Continuing: ProteoMediX. C. Pezaro: Financial Interests, Personal, Advisory Board, Ad board Dec 2020: Advanced Accelerator Applications;Financial Interests, Personal, Advisory Board, Aug 2021: Astellas;Financial Interests, Personal, Advisory Board, Oct 2021: Bayer;Financial Interests, Personal, Invited Speaker, Sept-Oct 2020: AstraZeneca;Financial Interests, Personal, Invited Speaker, Oct 2020: Janssen;Financial Interests, Personal, Advisory Board, July-Sept 2022: Pfizer. Z. Malik: Financial Interests, Personal, Advisory Board, advisry board for new hormonal therapy for breast cancer: sanofi;Financial Interests, Institutional, Invited Speaker, research grant for CHROME study: sanofi;Other, Other, support to attend meetings or advisory boards in the past: Astellas,Jaansen,Bayer;Other, Other, Sponsorship to attend ASCO meeting 2022: Bayer. M.R. Sydes: Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training sessions for clinicians (no discussion of particular drugs): Janssen;Financial Interests, Personal, Invited Speaker, Speaker fees at clinical trial statistics training session for clinicians (no discussion of particular drugs): Eli Lilly;Financial Interests, Institutional, Research Grant, Educational grant and drug for STAMPEDE trial: Astellas, Janssen, Novartis, Pfizer, Sanofi;Financial Interests, Institutional, Research Grant, Educational grant and biomarker costs for STAMPEDE trial: Clovis Oncology. L.C. brown: Financial Interests, Institutional, Research Grant, £170k educational grant for the FOCUS4-C Trial from June 2017 to Dec 2021: AstraZeneca;Financial Interests, Institutional, Funding, Various grants awarded to my institution for work undertaken as part of the STAMPEDE Trial: janssen pharmaceuticals;Non-Financial Interests, Other, I am a member of the CRUK CERP funding advisory panel and my Institution also receive grant funding from CRUK for the STAMPEDE and FOCUS4 trials: Cancer Research UK. M.K. Parmar: Financial Interests, Institutional, Full or part-time Employment, Director at MRC Clinical Trials Unit at UCL: Medical Research Council Clinical Trials Unit at UCL;Financial Interests, Institutional, Research Grant: AstraZeneca, Astellas, Janssen, Clovis;Non-Financial Interests, Advisory Role, Euro Ewing Consortium: University College London;Non-Financial Interests, Advisory Role, rEECur: University of Birmingham;Non-Financial Interests, Advisory Role, CompARE Trial: University of Birmingham. N.D. James: Financial Interests, Personal, Advisory Board, Advice around PARP inhibitors: AstraZeneca;Financial Interests, Personal, Advisory Board, Prostate cancer therapies: Janssen, Clovis, Novartis;Financial Interests, Institutional, Expert Testimony, Assisted with submissions regarding licencing for abiraterone: Janssen;Financial Interests, Personal, Advisory Board, Docetaxel: Sanofi;Financial Interests, Institutional, Expert Testimony, Providing STAMPEDE trial data to facilitate licence extensions internationally for docetaxel: Sanofi;Financial Interests, Personal, Advisory Board, Bladder cancer therapy: Merck;Financial Interests, Personal, Advisory Board, Advice around novel hormone therapies for prostate cancer: Bayer;Financial Interests, Personal, Invited Speaker, Lecture tour in Brazil August 2022 - speaking on therapy for advanced prostate cancer: Merck Sharp & Dohme (UK) Limited;Financial Interests, Institutional, Invited Speaker, Funding for STAMPEDE trial: Janssen, Astellas;Financial Interests, Institutional, Invited Speaker, Funding for RADIO trial bladder cancer: AstraZeneca. All other authors have declared no conflicts of interest.

HER2 copy number variation in non-small cell lung cancer (NSCLC)

Background: The value of increased HER2 gene copy number (GCN) in NSCLC is unclear. In this study we defined its frequency and characterized a cohort of patients harboring it. Methods: Patients with stage IIIB/IV NSCLC enrolled in the Gustave Roussy MSN study (NCT02105168) between Oct. 2009 and Feb. 2016 were screened by FISH (positivity defined as HER2 GCN to centromeres ratio ≥ 2) and tested for other molecular alterations. Descriptive analyses of clinical-pathological data were performed, progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method. Results: HER2 FISH tested positive in 22 of 250 screened patients (9%). Median age was 60 years (range 47-80), 68% (n=15) were male, 91% (n=20) were current or former tobacco smokers (median exposure 47 pack-year), 64% (n=14) had adenocarcinoma, 18% (n=4) squamous cell and 18% (n=4) large cell carcinoma. 91% (n=20) had an ECOG PS of 0 or 1. Stage IV with extra-thoracic involvement was the most common clinical presentation (64%, n=14). Overall, 95% of patients (n=21) had 1 or 2 metastatic sites at diagnosis (bone 32%, lung 27%, nodes 18%, liver 18%, brain 18%). In 9 patients (41%) 12 concurrent molecular alterations were detected: 5 KRAS mutation (3 G12C, 1 G12D, 1 G61H), 2 HER2 exon 20 insertion, 1 EGFR exon 19 deletion, 1 BRAF V600E mutation, 1 ALK rearrangement, 1 FGFR1 and 1 MET amplification. 18 patients received first-line platinum-based chemotherapy, with 33% (95% CI 16-56) objective response rate and 83% (95% CI 61-94) disease control rate. After a median follow-up of 28 months (95% CI 23-45), median PFS and OS were 5.9 (95% CI 3.4-11.0) and 15.3 (95% CI 10.3-NR) months, respectively. Median PFS was longer in patients with higher GCN. As further line of treatment, 5 patients received trastuzumab: 4 in combination with chemotherapy and 1 as monotherapy, with 1 stabilization of disease as best response. 3 patients received nivolumab (1 partial response and 1 stable disease) and 3 a targeted therapy (anti ALK, EGFR, BRAF). Conclusions: Increased HER2 GCN was found in 9% of patients with unresectable NSCLC, was not correlated to particular clinical characteristics, but frequently occurred with other molecular alterations. Its clinical actionability and the correlation with protein expression deserve further characterization. Clinical trial identification: NCT02105168. Legal entity responsible for the study: Gustave Roussy. Funding: Has not received any funding. Disclosure: M. Tagliamento: Other, Personal, Other, Travel grants: Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly;Other, Personal, Writing Engagements, Honoraria as medical writer: Novartis, Amgen. E. Auclin: Financial Interests, Personal, Advisory Board: Amgen, Sanofi. E. Rouleau: Financial Interests, Institutional, Advisory Board: AstraZeneca, Roche, Amgen, GSK;Financial Interests, Institutional, Invited Speaker: Clovis, BMS;Financial Interests, Institutional, Funding, Data base: AstraZeneca. A. Bayle: Non-Financial Interests, Institutional, Other, Principal/Sub-Investigator of Clinical Trials: AbbVie, Adaptimmune, Adlai Nortye USA Inc, Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Astex Pharmaceuticals, AstraZeneca Ab, Aveo, Basilea Pharmaceutica International Ltd, Bayer Healthcare Ag, Bbb Technologies Bv, BeiGene, BicycleTx Ltd, Non-Financial Interests, Institutional, Research Grant: AstraZeneca, BMS, Boehringer Ingelheim, GSK, INCA, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi;Financial Interests, Institutional, Other, drug supplied: AstraZeneca, Bayer, BMS, Boehringer Ingelheim, GSK, MedImmune, Merck, NH TherAGuiX, Pfizer, Roche. F. Barlesi: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Sanofi-Aventis, Seattle Genetics, Takeda;Non-Financial Interests, Principal Investigator: AstraZeneca, BMS, Merck, Pierre Fabre, F. Hoffmann-La Roche Ltd. D. Planchard: Financial I terests, Personal, Advisory Board: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Samsung, Celgene, AbbVie, Daiichi Sankyo, Janssen;Financial Interests, Personal, Invited Speaker: AstraZeneca, Novartis, Pfizer, priME Oncology, Peer CME, Samsung, AbbVie, Janssen;Non-Financial Interests, Principal Investigator, Institutional financial interests: AstraZeneca, BMS, Merck, Novartis, Pfizer, Roche, Daiichi Sankyo, Sanofi-Aventis, Pierre Fabre;Non-Financial Interests, Principal Investigator: AbbVie, Sanofi, Janssen. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. L. Mezquita: Financial Interests, Personal, Advisory Board: Takeda, AstraZeneca, Roche;Financial Interests, Personal, Invited Speaker: Roche, BMS, AstraZeneca, Takeda;Financial Interests, Personal, Research Grant, SEOM Beca Retorno 2019: BI;Financial Interests, Personal, Research Grant, ESMO TR Research Fellowship 2019: BMS;Financial Interests, Institutional, Research Grant, COVID research Grant: Amgen;Financial Interests, Institutional, Invited Speaker: Inivata, Stilla. All other authors have declared no conflicts of interest.

Net treatment benefit of OSE2101 in HLA-A2+ non-small cell lung cancer (NSCLC) patients after failure to immune checkpoint inhibitors (IO) in phase III Atalante-1 randomized trial

Background: OSE2101 (Tedopi) is an anticancer vaccine that increased overall survival (OS) (HR 0.59, p=0.017) versus Standard of Care Chemotherapy in the population of interest (PoI N=118) of patients with IO secondary resistance after sequential CT-IO (ESMO 2021 #47LBA). The Net Treatment Benefit (NTB) is an original method combining efficacy and safety endpoints to test the overall improvement in health outcome between 2 treatments (Buyse M. Stat Med 2010). NTB was assessed in the overall population (N=219) from whom OS improvement of OSE2101 (HR 0.86, p=0.35) was lower than in PoI. Methods: NTB was tested by comparing prioritized outcomes using Generalized Paired Wise Comparisons (GPC). The prioritized outcomes were OS, then time to worsening ECOG (threshold=2 months) followed by severe adverse events, progression free survival (shorter vs. longer than 2 months) and Quality of Life (threshold=5 points on Global Health Status of EORTC-QLQC30). Analysis was stratified using the 3 strata of the study (histology, best response to 1rst line, line of prior IO) and enrollment time (before vs during COVID-19). Sensitivity analyses used no stratification, different thresholds of clinical relevance and PoI. Results: In the primary analysis (1088 pairs), NTB was 19% and reached statistical significance in favor of OSE2101 (p=0.035). In unstratified analysis (11120 pairs), NTB was 11% (p=0.188). In the PoI (388 pairs), NTB was 22% (p stratified=0.074) and 28% (p=0.014) in unstratified analysis (3040 pairs). Although the primary analysis was statistically positive, results were not consistent in some sensitivity analyses due to the limited sample size and the impact of stratification factors. Conclusions: An overall improvement in health outcome was observed with OSE2101 in the overall population of advanced NSCLC after IO failure with a NTB of 19% over SoC. In PoI with IO secondary resistance after CT-IO, the NTB was 22%. Post-hoc analyses are ongoing intended to explain the variability of NTB and will be detailed. Clinical trial identification: EudraCT: 2015-003183-36;NCT02654587. Editorial acknowledgement: We thank Pierre Attali (Medical Expert, MD) for his support in the writing of the . Legal entity responsible for the study: Ose Immunotherapeutics. Funding: Ose Immunotherapeutics. Disclosure: M.E. Buyse: Financial Interests, Personal, Officer, Chief Scientific Officer: IDDI;Financial Interests, Personal, Invited Speaker, Board Member: CluePoints;Financial Interests, Personal, Stocks/Shares: IDDI, CluePoints. F. Montestruc: Financial Interests, Personal, Member of the Board of Directors, CEO of the Company: eXYSTAT SAS;Financial Interests, Institutional, Other, Statistician Consultant: AbbVie, Biocodex, Geneuro, Gensight, Guerbet, Imcheck, Ose Immunotherapeutics, Pfizer, Takeda;Non-Financial Interests, Personal, Other, Statistician Consultant and Training: Institut Pasteur. J. Chiem: Financial Interests, Personal, Full or part-time Employment: IDDI. V. Deltuvaite-Thomas: Financial Interests, Personal, Full or part-time Employment: IDDI. S. Salvaggio: Financial Interests, Personal, Full or part-time Employment, Working as a statistician: International Drug Development Institute. M.R. Garcia Campelo: Financial Interests, Personal, Advisory Role: Roche/Genentech, MSD Oncology, AstraZeneca, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, Janssen Oncology;Financial Interests, Personal, Speaker’s Bureau: Roche, AstraZeneca, Bristol-Myers Squibb, Pfizer, Novartis, Takeda, Boehringer Ingelheim, MSD Oncology, Sanofi/Aventis, Janssen Oncology, Amgen;Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Roche/Genentech, MSD Oncology, Pfizer. F. Cappuzzo: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, PharmaMar, Mirati, Novocure, OSE, and MSD;Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, BMS, Pfizer, Takeda, Lilly, Bayer, Amgen, Sanofi, Mirati, PharmaMar, Novocure, OSE, Galecto and MS . S. Viteri Ramirez: Financial Interests, Personal, Advisory Board: Merck Healthcare KGAA Germany, Bristol Myers Squibb S.A. U, Puma Biotechnology;Financial Interests, Personal, Invited Speaker: Takeda Farmaceutica España SA, MSD de España SA, AstraZeneca Farmaceutica Spain, Roche Farma SA;Financial Interests, Personal, Expert Testimony: Reddy Pharma Iberia SAU. W. Schuette: Financial Interests, Personal, Other, Honoraria: Roche, MSD, Novartis;Financial Interests, Personal, Advisory Role: Roche, MSD, Novartis. A. Zer: Financial Interests, Personal, Invited Speaker: Roche, BMS, MSD, Takeda, Pfizer, Novartis;Financial Interests, Personal, Advisory Board: AstraZeneca, Steba, Oncohost;Financial Interests, Personal, Stocks/Shares: Nixio;Financial Interests, Institutional, Research Grant: BMS. S. Comis: Financial Interests, Personal, Full or part-time Employment: Ose Immunotherapeutics. B. Vasseur: Financial Interests, Personal, Full or part-time Employment: Ose Immunotherapeutics;Financial Interests, Personal, Other, Actions: Ose Immunotherapeutics. R. Dziadziuszko: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Seattle Genetics, Pfizer, Takeda, Regeneron, MSD, Bristol Myers-Squibb, PharmaMar, Bayer;Financial Interests, Personal, Invited Speaker: Boehringer Ingelheim, Foundation Medicine;Financial Interests, Personal, Expert Testimony: Novartis;Financial Interests, Personal and Institutional, Invited Speaker: Roche, AstraZeneca, MSD, Amgen, Celon Pharma, Pfizer, Novartis, Brsitol Myers-Squibb, Eli Lilly, Loxo;Financial Interests, Invited Speaker: BeiGene, Ardigen, Ose Immunotherapeutics;Financial Interests, Personal and Institutional, Other, Subinvestigator and ad hoc Consultant: PDC* line Pharma;Non-Financial Interests, Institutional, Product Samples: Novartis, Pfizer, AstraZeneca, Roche;Other, Travel: Roche, Bristol Myers-Squibb, AstraZeneca. G. Giaccone: Financial Interests, Personal, Advisory Board: Novartis;Financial Interests, Institutional, Research Grant: Karyopharm. B. Besse: Financial Interests, Institutional, Funding: 4D Pharma, AbbVie, Amgen, Aptitude Health, AstraZeneca, BeiGene, Blueprint Medicines, Boehringer Ingelheim, Celgene, Cergentis, Cristal Therapeutics, Daiichi Sankyo, Eli Lilly, GSK, Janssen, Onxeo, Ose Immunotherapeutics, Pfizer, Roche-Genentech, Sanofi, Takeda, Tolero Pharmaceuticals;Financial Interests, Institutional, Research Grant: Chugai Pharmaceutical, EISAI, Genzyme Corporation, Inivata, Ipsen, Turning Point Therapeutics. E. Felip: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Janssen, Medical Trends, Merck Sharp & Dohme, Pfizer, Puma, Sanofi, Takeda, Merck Serono, Peptomyc, Regeneron, Syneos Health, F. Hoffmann-La Roche;Financial Interests, Personal, Invited Speaker: AstraZeneca, Bristol Myers Squibb, Eli Lilly, Medscape, Merck Sharp & Dome, Peervoice, Pfizer, Springer, Touch Medical, Amgen, F. Hoffmann-La Roche, Janssen, Medical Trends, Merck Serono;Financial Interests, Personal, Invited Speaker, Independent member: Grifols;Financial Interests, Institutional, Invited Speaker, Clinical Trial: F. Hoffmann-La Roche Ltd, Merck Sharp & Dohme Corp, AstraZeneca AB, Daiichi Sankyo Inc, Exelixis Inc, Merck KGAA, Janssen Cilag International NV, GlaxoSmithKline Research & Development Limited, AbbVie Deutschland GmbH & Co KG, Novartis Farmaceutica SA, Bayer Consumer Care AG, Takeda Pharmaceuticals International, Boehringer Ingelheim International GmbH, Pfizer S.L.U., Amgen Inc, Bristol-Myers Squibb International Corporation (BMS), Mirati Therapeutics Inc;Non-Financial Interests, Leadership Role, President Elect (2021-2023): SEOM (Sociedad Espanola de Oncologia Medica);Non-Financial Interests, Member, Member of ESMO Nominating Committee and Compliance Committee: ESMO;Non-Financial Interests, Leadership Role, Member of Board of Directors and the Executive Committee (2017-Sept 2021): IASLC (International Association for the Study of Lung Cancer);Non-Fina cial Interests, Member of Scientific Committee: ETOP (European Thoracic Oncology Platform). All other authors have declared no conflicts of interest.

The safety and efficacy of surufatinib for the treatment of advanced neuroendocrine tumors: A prospective, multicenter, real-world study

Background: Surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1, and CSF-1R) has exhibited encouraging antitumor activity for the treatment of advanced neuroendocrine tumors (including NEN and NEC) in multiple registration studies. Here, we report the preliminary results of advanced neuroendocrine tumors of an ongoing, multicenter, real-world study of surufatinib + MDT (ChiCTR2100049999). Challenges in tumor clinical trials management in the face of the COVID-19 resurgence period in Shanghai. Methods: In this multicenter, single-arm real-world study, adults (18-80) with advanced neuroendocrine tumors (including NEN and NEC) were eligible and received surufatinib (300mg orally, QD) with MDT（multidisciplinary collaborative diagnosis and treatment). The primary endpoint was progression-free survival (PFS) per RECIST 1.1. We minimized the interruptions caused by the pandemic using telemedicine platforms for all patients. This included online consultations, follow-up drug distributions, and health management services. Results: Twenty-three pts were enrolled, with 20 NEN and 3 NEC. At the data cutoff date (April 10, 2022), 15 pts had at least one post-baseline tumor assessment;of them, the confirmed ORR (95%CI) was 20% (4.3-48.1), and DCR (95%CI) was 93.33% (68.1-99.8). Median PFS (mPFS) (95%CI): 10.640 mo (3.796-17.484);median OS: not reached and median duration of follow up was 6.870 mo (6.797-6.943). A pNET patient (NO. 010007) was interrupted by asymptomatic COVID-19 infection 9 mo after enrollment. There are no interruptions caused by COVID-19 for other patients. An NEC patient treated with single agent had a 5.85 mo PFS, evaluated as NE, in whom target lesion resected after baseline. In overall pts (n=23), most commonly (≥3 pts) with hemorrhage, anemia, hypertension, proteinuria, and abdominal pain. Three pts had TRAEs that led to treatment discontinuation. Conclusions: Surufatinib + MDT exhibited promising efficacy and manageable toxicity in pts with advanced neuroendocrine tumors. Now and in the future, it is necessary to design regulatory changes in telehealth adoption for clinical trial design in the pandemic era. Clinical trial identification: ChiCTR2100049999. Legal entity responsible for the study: The authors. Funding: Hutchison MediPharma Limited. Disclosure: All authors have declared no conflicts of interest.

Progression-free survival (PFS) and overall survival (OS) in advanced/recurrent (AR) mismatch repair deficient/microsatellite instability–high or proficient/stable (dMMR/MSI-H or MMRp/MSS) endometrial cancer (EC) treated with dostarlimab in the GARNET study

Background: Dostarlimab is a programmed death 1 (PD-1) inhibitor approved in the EU as a monotherapy in patients (pts) with dMMR/MSI-H AR EC that has progressed on or after platinum-based chemotherapy;and in the US as a monotherapy in pts with dMMR AR EC that has progressed on or after platinum-based chemotherapy or dMMR solid tumors that have progressed on or after prior treatment, with no satisfactory alternative treatment options. We report on PFS and OS in 2 expansion cohorts of the GARNET trial that enrolled pts with EC. Methods: GARNET is a multicenter, open-label, single-arm phase 1 study. Pts were assigned to cohort A1 (dMMR/MSI-H EC) or A2 (MMRp/MSS EC) based on local immunohistochemistry assessment. Pts received 500 mg of dostarlimab IV every 3 weeks for 4 cycles, then 1000 mg every 6 weeks until disease progression, discontinuation, or withdrawal. PFS and OS are secondary efficacy endpoints. Results: 153 pts with dMMR/MSI-H and 161 pts with MMRp/MSS EC were enrolled and treated. The efficacy-evaluable population included 143 pts with dMMR/MSI-H EC and 156 pts with MMRp/MSS EC with measurable disease at baseline and ≥6 mo of follow-up. Median follow-up was 27.6 mo for dMMR/MSI-H and 33.0 mo for MMRp/MSS EC (Table). For pts with dMMR/MSI-H EC, median PFS (mPFS) was 6.0 mo, with 3-year estimated PFS rate of 40.1%. With 37.3% of pts experiencing an event, mOS was not reached;estimated 3-year OS was >50%. For pts with MMRp/MSS EC, mPFS was 2.7 mo. mOS was 16.9 mo with 68.9% of pts experiencing an event. Safety has been previously reported. [Formula presented] Conclusions: Dostarlimab demonstrated durable antitumor activity in dMMR/MSI-H and MMRp/MSS AR EC. dMMR/MSI-H was associated with longer PFS and OS than MMRp/MSS as expected. Clinical trial identification: NCT02715284. Editorial acknowledgement: Writing and editorial support, funded by GlaxoSmithKline (Waltham, MA, USA) and coordinated by Heather Ostendorff-Bach, PhD, of GlaxoSmithKline, was provided by Shannon Morgan-Pelosi, PhD, and Jennifer Robertson, PhD, of Ashfield MedComms, an Ashfield Health company (Middletown, CT, USA). Legal entity responsible for the study: GlaxoSmithKline. Funding: GlaxoSmithKline. Disclosure: A.V. Tinker: Financial Interests, Institutional, Sponsor/Funding: AstraZeneca;Financial Interests, Personal, Other: AstraZeneca, Eisai, GlaxoSmithKline. B. Pothuri: Financial Interests, Institutional, Funding: AstraZeneca, Celsion, Clovis Oncology, Eisai, Genentech/Roche, Karyopharm, Merck, Mersana, Takeda Pharmaceuticals, Tesaro/GSK;Financial Interests, Personal, Other: Arquer Diagnostics, AstraZeneca, Atossa, Clovis Oncology, Deciphera, Elevar Therapeutics, Imab, Mersana, Tesaro/GSK, Merck, Sutro Biopharma, Tora, GOG Partners;Financial Interests, Personal, Advisory Board: Arquer Diagnostics, AstraZeneca, Atossa, Deciphera, Clovis Oncology, Eisai, Elevar Therapeutics, Imab, Merck, Mersana, Sutro Biopharma, Tesaro/GSK, Toray;Financial Interests, Personal, Leadership Role: GOG Partners, NYOB Society Secretary, SGO Clinical Practice Committee Chair, SGO COVID-19 Taskforce Co-Chair. L. Gilbert: Financial Interests, Institutional, Funding: Alkermes, AstraZeneca, Clovis, Esperas, IMV, ImmunoGen Inc, Karyopharm, Merck Sharp & Dohme, Mersana, Novocure GmbH, OncoQuest Pharmaceuticals, Pfizer, Roche, Tesaro;Financial Interests, Personal, Other: Merck, Alkermes, AstraZeneca, Eisai, Eisai-Merck, GlaxoSmithKline. R. Sabatier: Financial Interests, Institutional, Funding: AstraZeneca, Eisai;Financial Interests, Personal, Other: AstraZeneca, GlaxoSmithKline, Novartis, Pfizer, Roche;Non-Financial Interests, Personal, Other: AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Pfizer, Roche. J. Brown: Financial Interests, Personal, Advisory Role: Caris, Clovis, Eisai, GlaxoSmithKline;Financial Interests, Personal, Funding: GlaxoSmithKline, Genentech. S. Ghamande: Financial Interests, Personal, Advisory Role: Seattle Genetics;Financial Interests, Personal, Speaker’s Bureau: GlaxoSmithKline;Financial Interests, Institutional, Funding: Abbv e, Advaxis, Bristol Myers Squibb, Clovis, Genentech, GlaxoSmithKline, Merck, Roche, Seattle Genetics, Takeda. C. Mathews: Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Deciphera, Moderna, GSK, Regeneron, Seattle Genetics;Financial Interests, Personal, Advisory Board: IMAB biopharma. D. O'Malley: Financial Interests, Personal, Advisory Board: AstraZeneca, Tesaro/GSK, Immunogen, Ambry, Janssen/J&J, Abbvie, Regeneron, Amgen, Novocure, Genentech/Roche, GOGFoundation, Iovance, Eisai, Agenus, Merck, SeaGen, Novartis, Mersana, Clovis, Elevar, Takeda, Toray, INXMED, SDP Oncology (BBI), Arquer Diagnostics, Roche Diagnostics MSA, Sorrento, Corcept Therapeutics, Celsion Corp;Financial Interests, Personal, Funding: AstraZeneca, Tesaro/GSK, Immunogen, Janssen/J&J, Abbvie, Regeneron, Amgen, Novocure, Genentech/Roche, VentiRx, Array Biopharma, EMD Serono, Ergomed, Ajinomoto Inc, Ludwig Cancer Research, Stemcentrx, Inc, Cerulean Pharma, GOGFoundation, Bristol-Myers Squibb Co, Serono Inc, TRACON Pharmaceuticals, Yale University, New Mexico Cancer Care Alliance, INC Research, Inc, inVentiv Health Clinical, Iovance, PRA Intl, Eisai, Agenus, Merck, GenMab, SeaGen, Mersana, Clovis, SDP Oncology (BBI);Financial Interests, Personal, Other: Myriad Genetics, Tarveda. V. Boni: Financial Interests, Personal, Advisory Board: OncoArt, Guidepoint Global;Financial Interests, Personal, Speaker’s Bureau: Solti;Financial Interests, Personal, Other: START, Loxo, IDEAYA Biosciences;Financial Interests, Institutional, Research Grant: Sanofi, Seattle Genetics, Loxo, Novartis, CytomX Therapeutics, Pumo Biotechnology, Kura Oncology, GlaxoSmithKline, Roche/Genentech, Bristol-Myers Squibb, Menarini, Synthon, Janssen Oncology, Merck, Lilly, Merus, Pfizer, Bayer, Incyte, Merus, Zenith Epigenetics, Genmab, AstraZeneca, Seattle Genetics, Adaptimmune, Alkermes, Amgen, Array BioPharma, Boehringer Ingelheim, BioNTech AG, Boston Biomedical. A. Gravina: Financial Interests, Personal, Other: Gentili, Pfizer. S. Banerjee: Financial Interests, Personal, Advisory Board: Amgen, Genmab, Immunogen, Mersana, Merck Sereno, MSD, Roche, Tesaro, AstraZeneca, GSK, Oncxerna;Financial Interests, Personal, Invited Speaker: Clovis, Pfizer, Tesaro, AstraZeneca, GSK, Takeda, Amgen, Medscape, Research to Practice, Peerview;Financial Interests, Personal, Stocks/Shares: PerciHealth;Financial Interests, Institutional, Research Grant: AstraZeneca, GSK, Tesaro;Non-Financial Interests, Principal Investigator, Phase II clinical trial Global lead, ENGOTov60/GOG3052/RAMP201: Verastem;Non-Financial Interests, Principal Investigator, ENGOT-GYN1/ATARI phase II international trial (academic sponsored): Astrazeneca;Non-Financial Interests, Advisory Role: Epsilogen;Non-Financial Interests, Other, Member of membership committee: ESGO;Non-Financial Interests, Advisory Role, Medical advisor to UK ovarian cancer charity: Ovacome Charity;Non-Financial Interests, Other, Received research funding from UK based charity I have provided medical advice (non-remunerated): Lady GardenFoundation Charity. R. Miller: Financial Interests, Personal, Other: AZD, Clovis Oncology, Ellipses, GlaxoSmithKline, MSD, Shionogi, AZD, GlaxoSmithKline;Financial Interests, Personal, Speaker’s Bureau: AZD, Clovis Oncology, GSK, Roche. J. Pikiel: Financial Interests, Personal, Other: Amgen, Clovis Oncology, GlaxoSmithKline, Incyte, Novartis, Odonate Therapeutics, Pfizer, Regeneron, Roche. M.R. Mirza: Financial Interests, Personal, Advisory Board: AstraZeneca, Biocad, GSK, Karyopharm, Merck, Roche, Zailab;Financial Interests, Personal, Invited Speaker: AstraZeneca, GSK, Karyopharm;Financial Interests, Personal, Stocks/Shares: Karyopharm;Financial Interests, Institutional, Research Grant: GSK, AstraZeneca, ultimovacs, Apexigen;Financial Interests, Institutional, Invited Speaker: Deciphera;Non-Financial Interests, Advisory Role: Ultimovacs, Apexigen. T. Duan: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. G. Antony: Financial Interests, Personal, Fu l or part-time Employment: GlaxoSmithKline. S. Zildjian: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. E. Zografos: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. J. Veneris: Financial Interests, Personal, Full or part-time Employment: GlaxoSmithKline. A. Oaknin: Financial Interests, Personal, Advisory Board: AstraZeneca, Clovis Oncology, Deciphera Pharmaceuticals, Genmab, GSK, Immunogen, Mersana Therapeutics, PharmaMar, Roche, Tesaro, Merck Sharps & Dohme de España, SA, Agenus, Sutro, Corcept Therapeutics, EMD Serono, Novocure, prIME Oncology, Sattucklabs, Itheos, Eisai, F. Hoffmann-La Roche,;Financial Interests, Personal, Other, Travel and accomodation: AstraZeneca, PharmaMar, Roche;Financial Interests, Institutional, Funding: Abbvie Deutschland, Advaxis Inc., Aeterna Zentaris, Amgen, Aprea Therapeutics AB, Clovis Oncology Inc, EISAI limited LTD, F. Hoffmann –La Roche LTD, Regeneron Pharmaceuticals, Immunogen Inc, Merck, Sharp & Dohme de España SA, Millennium Pharmaceuticals Inc, PharmaMar SA, Tesaro Inc., Bristol Myers Squibb;Non-Financial Interests, Leadership Role, Executive Board member as a Co-Chair: GEICO;Non-Financial Interests, Leadership Role, Phase II Committee and Cervix Cancer Committee Representative on behalf of GEICO: GCIG;Non-Financial Interests, Officer, Chair of Gynaecological Track ESMO 2019. Scientific Track Member Gynaecological Cancers ESMO 2018, ESMO 2020, ESMO 2022. Member of Gynaecological Cancers Faculty and Subject Editor Gyn ESMO Guidelines.: ESMO;Non-Financial Interests, Member: ESMO, ASCO, GCIG, SEOM, GOG.

Niraparib plus aromatase inhibitors (AI) for germinal mutated BRCA1/2 (gBRCAm) or homologous recombination-deficient (HRd), hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC): LUZERN interim analysis

Background: The poly(ADP-ribose) polymerase inhibitor niraparib showed clinical activity in advanced gBRCAm ovarian and breast cancers. LUZERN aims to assess the effectiveness of niraparib plus AI in HR+/HER2–, AI-resistant ABC with a pathogenic variant in homologous recombination-related genes. Here we report findings from the stage 1 interim analysis. Methods: This open-label, single-arm, Simon’s 2-stage, phase II trial is enrolling HR+/HER2– ABC patients (pts) with gBRCAm (cohort A;n=6 in stage 1, n=7 in stage 2) and gBRCA wild-type/HRd (cohort B;n=9 in stage 2). Pts had to have received ≤1 prior line of chemotherapy for ABC, 1–2 prior lines of endocrine therapy for early or ABC with secondary endocrine resistance to the last AI regimen. Pts receive niraparib (200/300mg daily orally) plus AI (same agent given with the prior regimen) on each 28-day cycle. Primary endpoint: clinical benefit rate (CBR) as per RECIST 1.1. Secondary endpoints: overall response rate, progression-free survival (PFS), and safety per CTCAE 5.0. If ≥1/6 pts experienced clinical benefit, the trial should proceed to stage 2. Results: Six pts were enrolled in stage 1. Median age was 46 years (range 32–76), 66.7% of pts had visceral disease, and 83.3% had received prior CDK4/6 inhibitor-containing regimen for ABC. At data cut-off, 50.0% of pts were ongoing and median duration of treatment was 4.6 months (range 2.4–5.7). One patient achieved complete response, meeting the criterion to proceed to stage 2. Median investigator-assessed PFS was 5.3 months (95%CI 3.9–NA). The most frequent adverse events (AEs) of any grade (G) were nausea (3 [50.0%]), neutropenia (2 [33.3%];16.7% G3), constipation (2 [33.3%]), and vomiting (1 [16.7%]). Serious AEs occurred in 3 pts (50.0%;G3 COVID-19 pneumonia;G3 pseudomonal bacteriemia;G2 sacral pain). No treatment-related discontinuations/deaths were reported. Conclusions: Niraparib plus AI showed preliminary activity with a tolerable safety profile in gBRCAm HR+/HER2– AI-resistant ABC pts. Based on the steering committee recommendation, enrolment in cohorts A and B is ongoing. Clinical trial identification: ClinicalTrials.gov identifier: NCT04240106. Legal entity responsible for the study: MEDSIR. Funding: GlaxoSmithKline. Disclosure: J.Á. García Saenz: Financial Interests, Personal, Advisory Board: Seagen, Gilead;Financial Interests, Personal, Invited Speaker: Novartis, Celgene, Eli Lilly, Eisai, AstraZeneca, Daiichi Sankyo, MSD, Exact Sciences;Financial Interests, Institutional, Funding: AstraZeneca. J. De la Haba Rodriguez: Financial Interests, Personal, Other, Consultant and Advisory Role, Research Funding and Speaking: Pfizer, Novartis, Roche, Lilly;Financial Interests, Personal, Other, grant support: Pfizer. J.E. Ales Martínez: Financial Interests, Personal, Other, travel grant: Pfizer;Financial Interests, Personal, Research Grant: MEDSIR. E. Alba Conejo: Financial Interests, Personal, Advisory Role: Roche, Novartis, Pfizer, Lilly, BMS, Astrazeneca, Pierre Fabre, Daiichi, Exact Sciences;Financial Interests, Personal, Research Grant: Pfizer. J. Balmaña: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer;Financial Interests, Institutional, Other, Steering committee member: AstraZeneca;Financial Interests, Institutional, Principal Investigator: Medsir, Pfizer. J.M. Perez Garcia: Financial Interests, Personal, Advisory Role: Lilly,Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics, Medsir;Financial Interests, Personal, Other, travel expenses: Roche. M. Sampayo-Cordero: Financial Interests, Personal, Other, honoraria: Medsir, Syntax for Science, Optimapharm, and Ability pharma;Financial Interests, Personal, Research Grant: Medsir;Financial Interests, Personal, Other, travel expenses: Medsir, Syntax for Science, Optimapharm, and Roche;Financial Interests, Personal, Other, consultant: Medsir, Syntax for Science, and Optimapharm;Financial Interests, Personal, Speaker’s Bureau: Medsir;Financial Interests, Personal, Full or part-time Employment: Me sir. A. Malfettone: Non-Financial Interests, Personal, Full or part-time Employment: MEDSIR. J. Cortés: Financial Interests, Personal, Advisory Role: Roche, Celgene, Cellestia, Astrazeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks;Financial Interests, Personal, Other, honoraria: Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo;Financial Interests, Institutional, Research Grant: Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F.Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London.;Financial Interests, Personal, Stocks/Shares: MEDSIR, Nektar Pharmaceuticals, Leuko (relative);Financial Interests, Personal, Other, travel, accomodation: Roche, Novartis, Eisai, pfizer, Daiichi Sankyo, Astrazeneca. A. Llombart Cussac: Financial Interests, Personal, Leadership Role: Eisai, Celgene, Lilly, Pfizer, Roche, Novartis, and MSD;Financial Interests, Personal, Stocks/Shares: MEDSIR and Initia-Research;Financial Interests, Personal, Advisory Role: Lilly, Roche, Pfizer, Novartis, Pierre-Fabre, GenomicHealth, GSK;Financial Interests, Personal, Speaker’s Bureau: Lilly, AstraZeneca, and MSD;Financial Interests, Personal, Research Grant: Roche, Foundation Medicine, Pierre-Fabre, and Agendia;Financial Interests, Personal, Other, travel compensation: Roche, Lilly, Novartis, Pfizer, and AstraZeneca. All other authors have declared no conflicts of interest.

Primary endpoint analysis of a randomized phase II of darolutamide or capecitabine in patients with triple-negative androgen receptor-positive advanced breast cancer (UCBG3-06 START trial)

Background: A subgroup of triple negative breast cancer (TNBC) expresses the androgen receptor (AR). In this trial we evaluated the efficacy and tolerability of the AR inhibitor darolutamide (D) or capecitabine (C) in patients (pts) with advanced AR-positive TNBC (NCT03383679). Methods: Pts with centrally reviewed AR-positive (≥ 10% by immunohistochemistry) TNBC treated with up to one line of chemotherapy for advanced disease were eligible. They were randomized in a 2:1 ratio to receive D 600 mg twice daily or C 1000 mg/m2 twice daily 2-weeks on/ 1-week off, until progression or unacceptable toxicity. Primary endpoint was clinical benefit rate (CBR) at 16 weeks and was assessed in the eligible population and in the sensitivity analysis population (pts with delayed tumour assessment performed in the context of COVID pandemic). Main secondary endpoints included objective response rate, overall survival, progression-free survival (PFS) and safety. Results: A total of 254 pts from 45 centres were screened;94 pts were randomized (61 in D arm, 33 in C arm) from April 2018 to July 2021. A clinical benefit was observed in D arm in 13 of 53 evaluable pts (CBR at 16 weeks 24.5%;95% CI: 12.9%-36.1%) including 2 PR and 1 CR and in C arm in 11 of 23 evaluable pts (CBR at 16 weeks 47.8%;95% CI: 27.4%-68.2%). In the sensitivity analysis, a clinical benefit was observed in D arm in 17 of 58 evaluable patients (CBR ≥ 16 weeks 29.3%;95% CI: 17.6%-41.0%) and in C arm in 19 of 32 evaluable patients (CBR ≥ 16 weeks 59.4%;95% CI: 42.3%-76.4%). 7 pts presented with drug-related serious adverse events: 3 in D arm and 4 in C arm. In D arm, asthenia (26.7%), nausea (25%) and ASAT increase (21.7%) were the most common adverse events, the majority being grade 1 or 2, similar to previous safety data. Median PFS were 1.8 months (CI 95% 1.7-3.1) and 3.6 months (1.8-9.1) in D arm and C arm respectively. Other secondary endpoints will be presented at the meeting. Conclusions: Despite not reaching the pre-specified CBR, darulotamide demonstrated clinical activity with significant benefit for a group of patients. A research program to identify predictive biomarkers of sensitivity is ongoing. Clinical trial identification: EudraCT: 2017-002284-18 NCT03383679. Legal entity responsible for the study: UNICANCER. Funding: BAYER. Disclosure: All authors have declared no conflicts of interest.

ADDITION OF IXAZOMIB TO POMALIDOMIDE AND DEXAMETHASONE IMPROVES PROGRESSION-FREE SURVIVAL FOR MULTIPLE MYELOMA PATIENTS PROGRESSING ON LENALIDOMIDE AS PART OF 1ST LINE THERAPY: ALLIANCE A061202

Background: Lenalidomide (LEN) maintenance and continuous LEN-based induction therapy until disease progression have become standard of care for frontline therapy of multiple myeloma (MM). As such, an increasing number of patients (pts) in need of 2nd line therapy have LEN-refractory disease. Optimal treatment in this setting has not been rigorously assessed in randomized studies. The phase I portion of Alliance A061202 demonstrated the safety of the ixazomib-pomalidomide-dexamethasone (IXA-POM-DEX) combination for the treatment of pts with LEN and proteasome inhibitor (PI)-refractory MM. Aims: In the randomized phase II portion, we evaluated the addition of IXA to POM-DEX for PI naïve / sensitive pts progressing on LEN as part of 1st line therapy. The primary endpoint was progression-free survival (PFS). Key secondary endpoints included overall response rate (ORR), depth of response, survival and safety. Methods: Pts were randomized 1:1 to IXA-POM-DEX or POM-DEX and stratified by prior bortezomib exposure, International Staging System stage (1 and 2 vs 3) and the presence of high-risk cytogenetics. POM was administered at 4 mg on days 1-21;IXA 4 mg on days 1, 8 and 15;and DEX 20 mg (>75 years (yrs)) or 40 mg (≤75 yrs) on days 1, 8, 15 and 22 of a 28-day cycle. Treatment was continued until disease progression, the emergence of unacceptable side effects or withdrawal of treatment consent. Results: 38 and 39 eligible pts were assigned to IXA-POM-DEX and POM-DEX, respectively. The median age was 66 yrs (range 41-83) and 64 yrs (range 52-85). A planned first interim analysis was conducted after 43 out of 57 required events had occurred. PFS favored the IXA-POM-DEX arm (one-sided log rank test value = 4.6345, p=0.03134 [< p-value boundary of 0.058]), yielding a hazard ratio of 0.528 (upper 90% bound = 0.777). A stratified log-rank test found that PFS was superior for the triplet after adjusting for stratification factors (one-sided stratified log rank test value = 5.8371;p=0.0157), adjusted hazard ratio 0.451 (upper 90% bound = 0.694). The ORR favored IXA-POM-DEX (63.2% vs 43.6%, p=0.0853), and the ≥very good partial response was 26.3% vs 5.1%, respectively (p=0.01). The clinical benefit rate (ORR + minimal response rate) was 73.7% and 56.4%. The most common grade 3/4 adverse events included lymphopenia, neutropenia, anemia, and fatigue in 40%, 37%, 16% and 16% of IXAPOM-DEX-treated pts and 26%, 21%, 13%, and 15% of POM-DEX-treated pts. Therapy was discontinued for disease progression in 47.4% of pts on IXA-POM-DEX and 76.9% of pts on POM-DEX and for adverse events in 7.9% and 7.7% of pts, respectively. Summary/Conclusion: The addition of IXA to the POM-DEX backbone improved the depth of response and PFS for pts relapsing on LEN as part of 1st line therapy. Hematologic toxicity was increased with the addition of IXA, but side effects were manageable. The ease of administration of this all-oral combination allowed for safer, uninterrupted treatment during the COVID pandemic. Our results should be confirmed in phase III trials but lend support for this regimen as part of 2nd line therapy for this patient population.

CLINICAL EFFICACY AND TOLERABILITY OF VENETOCLAX PLUS RITUXIMAB IN RELAPSED OR REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA - REAL WORLD ANALYSIS OF POLISH ADULT LEUKEMIA STUDY GROUP

Background: The introduction of venetoclax into clinical practice has improved the outcome of patients with relapsed/refractory chronic lymphocytic leukemia (RR-CLL). The results of the MURANO trial published in March 2018 showed significantly longer progression-free survival (PFS) and overall survival (OS) in RR-CLL patients treated with venetoclax and rituximab (VEN-R) comparing to bendamustine and rituximab (BR) and resulted in the approval of VEN-R in the therapy of RR-CLL in the European Union and the United States. It should be noted that the results of registration studies often do not correspond with the data from real-life observations. Aims: To study the clinical efficacy and safety profile of VEN-R treatment in RR-CLL patients outside clinical trials. Methods: We performed retrospective analysis of RR-CLL patients treated with VEN-R in hematology centers of the Polish Adult Leukemia Study Group (PALG) from 2019 to 2021. Results: Clinical data of 117 RR-CLL patients treated with VEN-R were collected. Median patient age upon initiation of VEN-R therapy was 67 years (range 33 - 84 years). Seventy-two patients (61.5%) were men. Median Cumulative Illness Rating Scale (CIRS) was 6 (range 2 -16). Patients were treated with a median of 2 (range 1-9) previous lines of therapy, whereas 32 patients (27.4%) had relapsed following the first line of treatment. Overall, 25 patients (21.4%) had 17p deletion, whereas TP53 mutation was identified in 13 patients (11.1%). The median follow-up was 9.96 months (range 0.27 -29.13). The overall response rate (ORR) was 95.2%. Seventeen patients (14.5%) achieved complete remission (CR), 83 (70.9%) partial remission (PR), while in 5 patients (4.3%) disease progression was noted. In the patients with 17p deletion (n=22) or TP53 mutation (n=11), CR and PR were observed in 4 (12.1%) and 29 (87.9%) patients, respectively. The median PFS in the whole cohort was 20.8 (95% CI 18.43 -not reached) months and the median OS was not reached. In our study none of the analyzed clinico-pathological factors had significant impact on ORR, PFS and OS. During the follow-up time four (3.4%) cases of Richter transformation were diagnosed. There were 18 deaths recorded during the course of observation;3 (16.7%) due to disease progression and 7 (38.9%) due to COVID-19 infection. The others were due to infections other than SARS-CoV-2 (n=3, 16.7%) and the cause of death could not be specified in five cases (27.8%). Eighty-three patients (70.9%) remain on treatment, while treatment was discontinued in thirty-four cases (29.1%). Reasons for therapy discontinuation included patient's death (52.9%), treatment-related cytopenias (17.6%), disease progression (14.7%), Richter's transformation (11.8%), autoimmune hemolytic anemia (5.9%), diarrhea (2.9%) and infections (8.8%). In one case treatment discontinuation was due to consent withdrawal and one patient was lost to follow-up. The following adverse events of VEN-R treatment were reported during the study: all grade neutropenia (71.8% with grade 3/4 in 55.6%), anemia (51.3%), thrombocytopenia (47%), pneumonia (9.4%), neutropenic fever (6.8%), autoimmune hemolytic anemia (4.3%), immune thrombocytopenic purpura (1.7%), diarrhea (4.3%) and in one case exacerbation of heart failure was observed. Summary/Conclusion: In this retrospective analysis the outcomes of treatment with the VEN-R regimen in real-life setting were worse than those reported in the MURANO trial.

LISOCABTAGENE MARALEUCEL (LISO-CEL) AS SECOND-LINE THERAPY FOR R/R LARGE B-CELL LYMPHOMA (LBCL) IN PATIENTS NOT INTENDED FOR HSCT: PRIMARY ANALYSIS FROM THE PHASE 2 PILOT STUDY

Background: Patients with relapsed or refractory (R/R) LBCL after first-line treatment who are unable to undergo high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) hae poor outcomes and limited treatment options. Aims: PILOT (NCT03483103) ealuated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as second-line treatment in patients with R/R LBCL not intended for HSCT. Methods: Eligible patients were adults with R/R LBCL after first-line treatment who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria as follows: age ≥ 70 years, Eastern Cooperatie Oncology Group performance status (ECOG PS) of 2, diffusing capacity for carbon monoxide ≤ 60%, left entricular ejection fraction < 50%, creatinine clearance < 60 mL/min, or alanine aminotransferase/aspartate aminotransferase > 2 × the upper limit of normal. Bridging therapy was allowed. Patients receied lymphodepletion with cyclophosphamide and fludarabine, followed 2-7 days later by liso-cel infusion at a target dose of 100 × 106 CAR+ T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria. Neurological eents (NE) were defined as inestigator-identified neurological aderse eents related to liso-cel and graded using the National Cancer Institute Common Terminology Criteria for Aderse Eents, ersion 4.03. The primary endpoint was objectie response rate (ORR) per independent reiew committee;all patients had ≥ 6 months of follow-up from first response. Results: Of 74 patients who underwent leukapheresis, 61 receied liso-cel and 1 receied nonconforming product (ie, product wherein one of the CD8 or CD4 cell components did not meet one of the requirements to be considered lisocel). Common reasons for preinfusion dropout included death and loss of eligibility (5 each). For liso-cel-treated patients, median age was 74 years (range, 53-84;79% ≥ 70 years) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectiely;26% had ECOG PS of 2 and 44% had Hematopoietic Cell Transplantation-specific Comorbidity Index score ≥ 3. After first-line treatment, 54% were chemotherapy refractory, 21% relapsed within 12 months, and 25% relapsed after 12 months;51% of patients receied bridging chemotherapy. Median (range) onstudy follow-up was 12.3 months (1.2-26.5). ORR and complete response rate were 80% and 54%, respectiely (Table). Median duration of response and progression-free surial were 12.1 months and 9.0 months, respectiely. Median oerall surial has not been reached. The most frequent treatment-emergent aderse eents (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade 3 CRS in 1 patient (2%) and no grade 4/5 CRS eents. Any-grade NEs were seen in 31% (n = 19) of patients;grade 3 NEs occurred in 5% (n = 3) of patients and no grade 4/5 NEs were reported. Seen percent (n = 4) receied tocilizumab only, 3% (n = 2) receied corticosteroids only, and 20% (n = 12) receied both tocilizumab and corticosteroids for treatment of CRS and/or NEs. Oerall, grade ≥ 3 TEAEs occurred in 79% (n = 48) of patients, with grade 5 TEAEs in 2 patients (both due to COVID-19). Two patients (3%) had grade 3/4 infections and 15 (25%) had grade ≥3 neutropenia at Day 29. Summary/Conclusion: In the PILOT study, liso-cel as second-line treatment in patients with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable oerall and complete responses, with no new safety concerns. (Table Presented).

ZANUBRUTINIB IN OLDER PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) MARGINAL ZONE LYMPHOMA (MZL): SUBGROUP ANALYSIS OF THE MAGNOLIA STUDY

Background: MZL is the second most common lymphoma in older pts. Choosing an optimal treatment can be challenging because of patient-or disease-related risk factors and treatment-related toxicities (Curr Opin Oncol. 2019;31(5):386-393). Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition, which may improve efficacy outcomes and minimize toxicities, such as cardiac arrythmias and bleeding events. Zanubrutinib received accelerated approval from the United States FDA for the treatment of pts with R/R MZL (Haematologica . 2022;107(1):35-43). Aims: We aim to present a subgroup analysis of efficacy and safety of zanubrutinib in pts aged ≥65 years with R/R MZL enrolled in MAGNOLIA (BGB-3111-214;NCT03846427). Methods: MAGNOLIA is a phase 2, multicenter, single-arm study of adults with R/R MZL who had received ≥1 line of therapy including ≥1 CD20-directed regimen. All were treated with zanubrutinib 160 mg twice daily until disease progression or unacceptable toxicity. Use of long-term antiplatelet and anticoagulation agents was permitted. The primary endpoint was overall response rate (ORR;complete response [CR] and partial response [PR]) determined by an independent review committee (IRC) in accordance with the Lugano classification. Secondary endpoints include ORR by investigator assessment (INV), duration of response (DOR), progression-free survival (PFS), and safety. All pts gave informed consent. Results: As of 18 January 2021, a total of 68 pts were enrolled (Table). Forty (61%) pts were ≥65 years old with a median age of 73 (range, 65-85);18 pts were ≥75 years old. Median number of prior therapies was 2 (range, 1-6) and 10 (25%) pts were refractory to last therapy. Most pts received prior rituximab + cyclophosphamide + vincristine + prednisone (48%) or bendamustine + rituximab (30%), while 5 (13%) pts received rituximab monotherapy. MZL subtypes included extranodal (n=17, 43%), nodal (n=14, 35%), and splenic (n=8, 20%). Median duration of treatment was 14.4 months (mo;range, 0.9-19.6). At a median follow-up of 15.8 mo (range, 2.8-21.8), ORR by IRC was 75% (CR 25%, PR 50%;Table). Responses were observed in all subtypes, with an ORR of 71%, 86%, and 75% in extranodal, nodal, and splenic subtypes, respectively (CR 41%, 21%, and 0%, respectively). Median DOR and PFS were not reached;15-month PFS was 87% and 12-month DOR was 93%. Most (63%) pts are continuing zanubrutinib. Treatment discontinuation due to disease progression was 28% by INV. Most common treatmentemergent adverse events (AEs) observed in ≥20% of pts include contusion (28%), diarrhea (25%), and constipation (20%). Grade ≥3 neutropenia occurred in 5% of pts. The most common infection was upper respiratory tract infection (10%). Two (5%) pts discontinued zanubrutinib due to unrelated fatal AEs (COVID-19 pneumonia and myocardial infarction in a patient with pre-existing coronary artery disease). Atrial fibrillation/flutter and hypertension occurred in 2 (5%) pts each and did not lead to treatment discontinuation. No pts required dose reductions, or experienced major or serious hemorrhage. Image: Summary/Conclusion: The safety profile of zanubrutinib observed in older pts was consistent with previously published results (Clin Cancer Res . 2021;27(23):6323-6332). Zanubrutinib was well tolerated and effective, as demonstrated by a high response rate and durable disease control in older pts with R/R MZL.

UPDATE AND FOLLOW-UP OF NEWLY DIAGNOSED MULTIPLE MYELOMA (NDMM) WITH HIGH-RISK CYTOGENETIC (HRC)

Background: Despite therapeutic strategies improvement, there is still a subgroup of NDMM patients (pts) that pose a clinical challenge, whose represents a <20%, we refer to HRC. HRC Pts are associated with a poor prognosis and aggressive course, although, recent studies propose different clinical evolution according to the cytogenetic alteration (CA). IMWG identified a 4-year progression free survival (PFS) of 12% and OS of 35%. Aims: Describe our clinical experience and therapeutic management, also the clinical-biochemical alterations at diagnosis in a heterogeneous NDMM HRC's cohort. Evaluate survival curves according to HRC. Methods: Descriptive and retrospective analysis, using clinical and analytical NDMM HRC patient's data from 2009 to 2022 at Guadalajara University Hospital. 61/201 pts were selected in the MM treatment (tto) protocols. FISH results were not found in <30% NDMM, due to lack of metaphases or no request. Pts with t(4;14), t(14;16), gain 1q, t(14;20), plasmablastic leukemia and/or del(17p13) were classified as HRC. Survival data and Pearson (P) correlation were used. P value <0.05 was considered significant. Results: Total HRC NDMM 61 pts were analyzed. 21 of 61 pts (35%) were diagnosed with stage monoclonal gammopathy of undetermined significance (MGUS) prior to HRC NDMM, with a mean 4 years (y) (IR 2-10 y), greater % representation of MGUS were del17p (38), gain 1q (48), t (14;16) (4,5) and del17p + gain1q (9,5). Clinical characteristics data at diagnosis according to HRC are shown in Table 1. Pts receiving 1st line were 100% (61), 90,2% of the pts received bortezomib (V) - based induction, of them 29% (n=16) were treated with alkylating agents, 49,1% (n=27) received IMIDs and 18,2% (n=10) V with dexamethasone (d), plus two of these pts received regimens composed of 3xVCd + 3xVPd and the other dara-VRd. 25 pts (40,98%) were transplant eligible (TPH). 2nd line, 32 pts (52,5%), (n=3) VTD-PACE, (n=6) daratumumab (n=1 alone, 3 R, 1 V, 1 K), (n=1) Kdexa, (n=1) Pocydex and (n=9) V plus 3 IMIDs, 2 alkylating, 2 P or 2 alone and (n=12) IMIDs and alkylatings in combination. 5 pts (8,2) were TPH (1 alogenic). 3rd line, 16 pts (26,2), just 3 pts were TPH. 4th line, 7 pts (11,4), 1 pts were TPH. 5th line, 4 pts (6,5). 6th line, 2pts (3,3). In the last lines, the use of triplets with pomalidomide, karfilzomib or intensive chemotherapy prevail. After a median follow-up of 3 y (IR 1,6-6,2) from diagnosis, pts had relapsed at least one time (60,6%) and more than 3 times (11,5%), and 25 had died (40,9%), 16 of them due to infections (14 bacteremia, 2 COVID), 5 cardiorespiratory arrest and 3 due to progression. (Image 1) represents PFS y OS for only 5 CA, as data were no representative in other CA. Correlation between ISS and ISS-R data were only able to execute in HRC gain1q, due to lack of sample in other CA. We found a P coefficient of 0.568399 or 56.83% (p- <0.00578, CI 95%). Summary/Conclusion: Our case series continues with a longer survival curve compared to those commented in other studies. As cytogenetic abnormalities (t(4;14), t(14;16), t(14;20) and gain1q), similar % of representation are described as Kumar. Nat Rev Clin Oncol. 2018, except for del(17p), 23% vs 10%. From the second line, the probability of receiving a new line, the duration of tto and the interval without tto decreased with each line of tto. As treatment lines progress, therapeutic combinations are more heterogeneous and less concordant. A further longer follow-up and higher HRC NDMM pts's recruitment will be necessary to clarify the response to tto regimens based on individual cytogenetic groups.

QUALITY OF LIFE AND CLINICAL OUTCOMES IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM) TREATED WITH IXAZOMIB-LENALIDOMIDE-DEXAMETHASONE (IRD): RESULTS OF A REAL-WORLD EVIDENCE STUDY

Background: Comprehensive evaluation of new treatment regimens in RRMM patients both from physician's and patients' perspective is worthwhile. Aims: We aimed to evaluate clinical and patient-reported outcomes during IRd treatment as ≥ 2nd line in RRMM patients in a multicenter real-world evidence study. Methods: Adult patients with RRMM who have been assigned IRd as ≥2nd line treatment were enrolled in 18 centers of Russian Federation from April 2019 till May 2020. Treatment response was evaluated by IMWG 2011 criteria. For assessment of adverse events (AEs) NCI CTCAE v. 4.0 was used. Patients filled out RAND SF-36 and ESAS-R questionnaires at baseline, at 1 and 3 mos, and thereafter every 3 mos till 18 mos after IRd treatment onset. Statistical analysis of patient-reported outcomes was conducted using GEE with adjustment to age, gender and baseline quality of life (QoL). Duration of response (DOR), progression-free (PFS) and overall survival (OS) from the start of IRd treatment were evaluated using Kaplan-Meyer method. Results: In total, 40 patients with RRMM were enrolled into the study: median age - 64 years (range, 33-80), 35% males. Durie-Salmon stage at study entry: II/III - 40/60%, ECOG status 0/1 - 70%, 2/3 - 30%. Median time since initial MM diagnosis - 55 mos (range, 2.0-99.0). Median number of lines of prior therapy - 3 (range, 1-7). Comorbidities were revealed in 65% patients;median Charlson Comorbidity index - 2 (range, 0-5);95% patients had bone complications. The median duration of IRd treatment - 7.5 mos (IQR, 3.9-18.0). Two-thirds of the patients (28/39) responded to therapy. The overall response rate was 46.2% (95%CI: 30.6-61.8), median DOR - 16.3 mos (95%CI: 15.4-17.3). Among them 3 patients achieved complete response, 1 - stringent complete response, 2 - very good partial response, 12 - partial response. Ten patients had minor response. Clinical benefit rate - 71.8% (95%CI: 57.7-85.9). Six patients (15.4%) had stable disease and 4 (10.3%) progressed upon therapy. Median PFS was 10.6 mos (95%CI: 6.3-16.3). During the entire period of the study 5 deaths were registered: 3 were related to progression, 2 - because of COVID-19. Median OS was not reached. One-year OS rate was 85.2% (95%CI: 71.0-99.0). AEs were revealed in 55% patients: grades 1-2 AEs - 15 patients;grades 3-4 AEs - 7 patients;SAEs - 3 patients (neurological toxicity, gastric bleeding, hypotension and diarrhea). Baseline QoL was dramatically impaired by the majority of SF- 36 scales;42% patients experienced severe/critical QoL impairment. At baseline all the patients experienced symptoms;85% with moderate-to severe symptoms (≥4 scores on the scale from 0 to 10). The most prevalent and severe symptoms were tiredness (98%), drowsiness (90%), pain (82%) and shortness of breath (80%). During IRd treatment QoL was stable or improved. Physical and role physical functioning, general health, vitality and mental health significantly improved as compared to baseline (GEE, p<0.05). Twice increase of Integral QoL Index was observed - 0.27 at baseline vs 0.48 at 18 mos (p<0.05). Severity of pain, tiredness and nausea meaningfully decreased during IRd treatment as compared to baseline (GEE, p<0.05). Total ESAS-R score decreased by 10 points at 18 mos of therapy as compared to baseline - 31 vs 21 (GEE, p<0.05). Summary/Conclusion: In summary, results obtained in a real-world evidence study confirmed RCTs data that IRd regimen is an effective treatment in RRMM patients. This treatment is accompanied with definite improvement of QoL. Our results demonstrate benefits of IRd, both from physician's and patient's perspective.