Absence Of Disease Progression Research Articles

Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer (MBC) with a somatic BRCA1/2mutation identified in a cell-free DNA or tumor tissue genotyping assay.

TPS1143 Background: PARP inhibitors are approved for germline BRCA1/2mutant MBC but the applicability of these well-tolerated oral targeted therapies is limited, as germline BRCA1/2mutations account for 5% of breast cancer. We demonstrated that pathogenic somatic BRCA1/2mutations are detectable in cell-free DNA and tumor tissue genotyping assays in a subset of HER2- MBC, in patients who are not known germline BRCA1/2carriers. In a circulating tumor cell culture model derived from a patient with a pathogenic somatic BRCA1 mutation, we demonstrated that the growth inhibitory effect of a PARP inhibitor paralleled germline BRCA1/2mutant cultures. We hypothesize that somatic BRCA1/2mutations may be amenable to PARP inhibition. In this study, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2mutant MBC. The results may expand the population of patients who benefit from PARP inhibitors. Methods: In this phase II investigator-initiated clinical trial, 30 patients with HER2- MBC with pathogenic somatic BRCA1/2mutations (in the absence of a known germline BRCA1/2mutation) identified in a CLIA certified cell-free DNA or tumor tissue genotyping assay are being enrolled at 7 academic centers. Mutations are vetted for pathogenicity by genetic counselors using validated genomic databases such as ClinVar. Patients with metastatic triple-negative or hormone receptor positive (HR)+/HER2- breast cancer who received ≥1 prior therapy in the metastatic setting are eligible. Any number of prior therapies are acceptable, including a prior platinum (in absence of disease progression). Patients must have adequate baseline performance status and organ function. Patients are treated with talazoparib 1 mg/day until disease progression. Disease assessments occur at baseline and every 3 months via CT chest, abdomen, and pelvis, and bone scan. The primary endpoint is progression free survival (PFS) via RECIST 1.1. This study has 81% power to demonstrate the 12-week PFS is ≥53% (4% alpha). Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory endpoints, determined using serial cell-free DNA collected at baseline and monthly, include identifying resistance mutations, and evaluating the impact of mutant allele fraction and BRCA1/2reversion mutations on response. The Cancer Risk B (CR-B) assay, a novel method to identify double-strand break repair mutations in circulating blood cells, will be correlated with response. The study (NCT03990896) is open at Massachusetts General Hospital, University of California San Francisco, MD Anderson, Emory, Northwestern, and Vanderbilt and will open at Cornell, with 17 patients enrolled as of 2/2024. Clinical trial information: NCT03990896 .

A phase II study of liposomal irinotecan-based chemotherapy with or without PD-1 inhibitor in patients with unresectable locally advanced or metastatic biliary tract cancer.

e15077 Background: Clinical outcomes for advanced biliary tract cancer (BTC) patients (pt) progressed on first-line therapy remain dismal. Liposomal irinotecan (LI) (HE072) is a formulation encapsulating I in a lipid bilayer vesicle and was approved in China in September 2022. It was used with 5-fluorouracil (5-FU) and leucovorin (LV) for patients with metastatic pancreatic cancer progressing on gemcitabine treatment. We conducted an phase II study to investigate HE072 in combination with 5-FU and LV with or without a novel PD-1 inhibitor SG001 in patients with advanced BTC progressed on prior gemcitabine-based chemotherapy. Methods: This is a multi-center, non-randomized, open label phase II study in pts with unresectable locally advanced or metastatic BTC. Key inclusion factors were ECOG PS 0-1, prior gemcitabine-based chemotherapy, evidence of disease progression with at least one measurable lesion and adequate haematological/organ function. Key exclusion factor was brain metastases. Pts were treated with liposomal irinotecan (70 mg/m2) plus LV (400 mg/m2f) and 5-FU (2400 mg/m2) with or without SG001 (240mg) IV every 2 weeks for up to 2 years in absence of disease progression or unacceptable toxicity. Tumor assessments based on RECIST 1.1 were performed every 6 weeks by investigators. Primary endpoint was objective response rate (ORR). Secondary endpoints include progression free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Results: As of April 25, 2023, 17 BTC pts were enrolled into liposomal irinotecan-based chemotherapy arm (n = 7) and liposomal irinotecan-based chemotherapy plus SG001 arm (n = 10). ORR and DCR were 14.3% and 71.4% for chemotherapy arm, 20% and 40% for chemotherapy+ SG001 arm. Median OS and PFS for chemotherapy arm was 11.5(95% CI, 3.9-NE) and 4.2(95% CI, 1.4-NE) months, and for chemotherapy+PD-1 arm was 15.3 (95% CI, 3.6-17.0) and 3.8(95% CI, 1.4-6.9) months. All pts experienced treatment-related adverse events (TRAEs). The incidence of grade≥3 TRAEs was 58.8%(10/17), which occurred in 57% (4/7) of pts treated in chemotherapy arm vs 60% (6/10) in chemotherapy+SG001 arm. Among all patients, the most frequent grade ≥3 TRAEs were fatigue (29.4%), neutropenia (23.5%) and leukopenia (23.5%). One grade 4 TRAE leading to dose reduction in liposomal irinotecan was febrile neutropenia in chemotherapy arm. There were no treatment-related deaths. Conclusions: These preliminary results suggested that liposomal irinotecan plus 5-FU and LV was well-tolerated and showed promising and durable clinical activity in advanced BTC pts progressed on first-line treatment. Combined use of SG001 further improved clinical outcome in these pts without increased toxicity. Combination of liposomal irinotecan, 5-FU, LV and PD-1 inhibitor is a treatment strategy which is worthy of further exploration.

Abstract PO4-19-06: Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer with a somatic BRCA1/2 mutation present in cell-free DNA or tumor tissue genotyping

Abstract Background: PARP inhibitors improve both progression free survival (PFS) and patient quality of life in germline BRCA1/2 mutant metastatic breast cancer (MBC), which accounts for 5-10% of breast cancer, leading to their approval in this setting. We have previously shown that a subset of patients with MBC who are not germline BRCA1/2 carriers may harbor pathogenic somatic BRCA1/2 mutations that are identified by cell-free DNA and/or tumor tissue genotyping. In our prior work, we developed a circulating tumor cell culture from a patient with MBC harboring a pathogenic somatic BRCA1 mutation, and demonstrated that a PARP inhibitor induced cell growth inhibition similar to germline BRCA1/2 mutant cultures. Thus, we hypothesize that a PARP inhibitor may be effective in treating somatic BRCA1/2 mutant MBC. In this clinical trial, we are studying the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Our work may help expand the clinical application of PARP inhibitors in MBC. Trial Design: This phase II investigator-initiated clinical trial is enrolling 30 patients with MBC who have a pathogenic somatic BRCA1/2 mutation identified by a CLIA certified cell-free DNA and/or tumor tissue genotyping assay. Patients are treated with the PARP inhibitor talazoparib 1 mg/day until progression of disease. Imaging (CT chest, abdomen and pelvis, and bone scan) occurs for disease assessment at baseline and every 3 months. Cell-free DNA is collected at baseline and then monthly to evaluate changes in the genomic environment. Patients also undergo the Cancer Risk B (CR-B) assay, a novel flow variant assay to identify double-strand break repair mutations in circulating blood cells, at baseline. Eligibility Criteria: Patients must have MBC with a pathogenic somatic BRCA1/2 mutation identified in a cell-free DNA and/or tumor tissue genotyping assay, with pathogenicity confirmed by a genetics counselor using validated genomic databases such as ClinVar. Patients may have triple-negative (receipt of at least 1 prior chemotherapy) or hormone receptor positive/HER2- MBC (receipt of at least 1 prior hormone therapy). Patients must not be known germline BRCA1/2 carriers. Any number of prior therapies including a prior platinum (in absence of progressive disease on a platinum) are allowed, but patients should not have received a prior PARP inhibitor. Patients must have adequate organ function and performance status. Specific Aims: The primary aim is to determine PFS (RECIST 1.1). Secondary aims include determining the objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory aims include evaluating serial changes in BRCA1/2 mutant allelic frequency in cell-free DNA, understanding the impact of BRCA1/2 reversion mutations in cell-free DNA, comparing pre- and post-treatment cell-free DNA results to understand changes in the genomic environment, studying the CR-B assay positivity rate, and correlating these biomarker analyses with treatment response. Statistical Methods: This study has 81% power to demonstrate that the 12-week PFS is 53% or higher. In contrast, there is a 4% (alpha) probability of concluding that the 12-week PFS is ≥ 53% if the true 12-week PFS is 30% or lower. If 14 or more of 30 total patients achieve PFS > 12 weeks, the null hypothesis (12-week PFS ≤ 30%) will be rejected. Present accrual and target accrual: This study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, University of California San Francisco, Emory, Northwestern, and Vanderbilt. As of 7/2023, 14/30 patients are enrolled. Funding: This study is funded by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu. Citation Format: Neelima Vidula, Senthil Damodaran, Manali Bhave, Hope Rugo, Ami N. Shah, Erica Blouch, Nathan Royce Ruffle-Deignan, Ogadinma Ogbenna, Lisa E. Flaum, Massimo Cristofanilli, Joseph Sparano, Harry Ostrer, Vandana Abramson, Nora Horick, Aditya Bardia. Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer with a somatic BRCA1/2 mutation present in cell-free DNA or tumor tissue genotyping [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 PO4-19-06.

Современный подход к лечению склероатрофического лихена и его осложнений.

Introduction. One of the reasons for the development of urethra stricture in men is Lichen sclerosis, and its role in the development of panurethral narrowing of the urethra comes to the fore. With timely diagnosis and adequate treatment, it is possible to anticipate the development of complications of this disease. At the moment, there are a large number of approaches to the treatment of lichen sclerosis and its complications. Purpose. To study and summarize the currently available options for treatment of lichen sclerosis and its complications, as well as to determine the vector of further research. Materials and methods. The search results were analyzed in the scientific databases eLibrary, PubMed, according to the following. keywords: «lichen sclerosus», «urethral stricture», «meatal stenosis». The search was carried out regardless of the date and language of publication. After analyzing the literature, 47 works were selected for review that most fully reflect the topic of diagnosis and treatment of lichen sclerosis and its complications. Results. Lichen sclerosus is a complex, recurrent disease, the etiology of which is currently not completely clear. It is clear that patients require careful monitoring during and after treatment, since the disease is chronic and relapsing. This article presents research data on the safety and effectiveness of various methods of treating lichen sclerosus: from topical application of topical glucocorticosteroids, calcineurin inhibitors and retinoids to multi-stage urethroplasty. It has been shown that with timely treat-ment and timely prescribed conservative therapy, the likelihood of relief of clinical symptoms and absence of disease progression is quite high. If the urethra is involved in the process, it is necessary to resort to surgical intervention, and the method of treatment is determined individually and depends on the clinical picture and extent of the disease. Thus, if the external opening of the urethra is damaged, classical meatotomy does not bring the desired clinical effect, which is why it is necessary to resort to the original Malone technique. For strictures of the penile and bulbous urethra, good results are shown by single- and multi-stage urethroplasty using the oral mucosa. In some severe cases, the operation of choice is perineostomy. Conclusion. Lichen sclerosus is a serious problem leading to a decrease in the quality of life of patients. Treatment of lichen sclerosus requires an integrated approach with the participation of dermatologists and urologists, which can improve the effectiveness of treatment for patients with both isolated lesions of the foreskin and involvement of the urethra.

The involvement of the hepatic artery is a risk factor for unresectability after neoadjuvant treatment in borderline pancreatic adenocarcinoma

IntroductionBorderline Resectable Pancreatic Ductal Adenocarcinoma (BR-PDAC) benefits from neoadjuvant treatment (NAT) with the intent of surgical salvage in the absence of disease progression during chemotherapy (CT) or chemoradiotherapy (CRT). Scarce literature exists about prognostic factors of resectability at the time of diagnosis or during neoadjuvant treatment, especially regarding vascular relationships. MaterialsWe reviewed our prospective BR-PDAC cohort to determine resectability predictors. We collected data about clinical baseline characteristics, vessels’ involvement, type of NAT, CA19-9 evolution, and radiological outcome. We performed a descriptive analysis and a logistic regression model to define resectability predictors; we finally compared overall survival (OS) and progression-free survival (PFS) for those predictors. ResultsOne hundred patients started NAT, with a resection rate of 44 % (40 pancreaticoduodenectomies, 4 distal pancreatectomies). The most frequent vessel relationship was the abutment of the superior mesenteric artery (44 %), and 26 patients had ≥2 vessels involved. Prognostic factors of resectability were CA19-9 response >10 % (OR 3.07, p = 0.016) and Hepatic Artery involvement (OR 0.21, p = 0.026). Median overall survival was better for CA19-9 responders than for non-responders (20.9 months and 11.8 months respectively, p < 0.001), and similar to normalized CA19-9 (25.0 months, p = 0.48). There were no differences in terms of OS or PFS with the involvement of the HA (17.7 vs 17.1 months, p = 0.367; and 8.7 vs 12.0 months, p = 0.267). ConclusionThe involvement of the Hepatic Artery seems to confer a worse prognosis regarding resectability. A decrease of only >10 % of CA19-9 is a predictive factor for resectability and better overall and progression-free survival.

Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.

BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

A Propensity Score-Matched Analysis on the Outcomes of Brexucabtagene Autoleucel from Zuma-2 Study and Allogeneic Stem Cell Transplantation from the EBMT Database in Relapsed and Refractory Post-Btki Mantle Cell Lymphoma

Introduction Brexucabtagene autoleucel (brexu-cel), an autologous anti-CD19 CAR T-cell therapy, is approved in the US for the treatment of relapsed/refractory (r/r) mantle cell lymphoma (MCL) and in Europe for r/r MCL after ≥2 prior lines of therapies, including Bruton's tyrosine kinase inhibitor (BTKi). The pivotal ZUMA-2 trial demonstrated very good efficacy of brexu-cel in r/r MCL and tolerable safety including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (Wang et al. J Clin Oncol. 2022). Allogeneic stem cell transplantation (alloSCT) is potentially curative but is associated with high treatment related mortality (TRM) and clinically significant graft-versus-host disease (GvHD). The optimal choice of treatment between brexu-cel and alloHCTs is unclear. We conducted a propensity score matched (PSM) analysis of brexu-cel and alloSCT in patients (pts) with r/r MCL. Methods Pts from ZUMA-2 were matched with alloSCT pts from the EBMT database. Selection criteria to identify pts in the EBMT registry were: r/r MCL diagnosis and receipt of alloSCT from 2010 to 2020, age ≥18 years, prior treatment with anti-CD20, prior anthracycline- or bendamustine containing regimens, and prior BTKi. We performed a 1:1 nearest neighbor matching without replacement, balanced for 5 baseline parameters: age, sex, number of prior treatment lines, time from diagnosis to cellular immunotherapy, and prior autologous stem cell transplantation (autoSCT). The primary endpoint was overall survival (OS) from cellular immunotherapy. The following secondary endpoints were analyzed: progression-free survival (PFS), TRM, defined as incidence of deaths which are related to the treatment and occurred in absence of disease progression, and rate of GvHD. Competing risks were defined as relapse, progression or treatment-unrelated death for TRM, and death for GvHD. The EBMT registry includes pts who actually underwent alloSCT. To characterize the dropout rate prior to cellular therapy, we conducted a multicenter intent-to-treat (ITT) analysis and identified 77 pts with r/r MCL for whom an unrelated donor search was initiated and an alloSCT was intended. Results Sixty-four of 68 pts from the ZUMA-2 cohort were included in the study; 4 pts were excluded because of inability to anonymize. A total of 270 pts who had undergone alloSCT and met eligibility criteria were identified in the EBMT registry. Patient characteristics between the brexu-cel and the alloSCT cohorts were imbalanced. Brexu-cel pts were older (p&amp;lt;0.001), had more prior lines of treatment (median 3 vs 2, p&amp;lt;0.001), had less prior autoSCT (41% vs 71%, p&amp;lt;0.001), and had longer time between diagnosis and treatment (53 vs 40 months, p=0.01). After 1:1 PSM matching, criteria were well balanced between cohorts. Median follow-up time was 36.5 and 46.4 months for the brexu-cel and the matched alloSCT cohort, respectively. PFS and long-term OS were similar between both cohorts (Fig. 1A). However, the risk of death within the first 12 months was significantly lower in the brexu-cel cohort vs the alloSCT cohort (logistic regression with inverse probability of censoring weighting, risk ratio=0.5, 95% confidence interval [CI] 0.3-0.9, p=0.02). This was mainly attributable to the significantly higher TRM rate in the alloSCT cohort (alloSCT vs brexu-cel: cause specific hazard ratio=7.7, 95% CI 1.9-31.6, p=0.005, Fig. 1B). The cumulative incidence of acute GvHD grade ≥3 at 3 months and chronic GvHD at 24 months was 17.9% (95% CI 9.1-29.0%) and 44.3% (95% CI 30.6-57.2%), respectively. In our ITT analysis, the dropout rate was significantly higher in the cohort intended to receive alloHCT (23%, [18/77]) vs the cohort intended to receive brexu-cel (8% [6/74]; Fisher test, p=0.01). For alloSCT, failure to proceed to cellular therapy was related to progression in 13%, change of patient's preference in 5% and ineligibility in 4%; in the brexu-cel cohort this was due to manufacturing failures in 4% and progression in 3%. Conclusion Brexu-cel is an effective treatment in pts with r/r MCL post-BTKi with a superior safety profile compared with alloSCT, as indicated by lower 12-month mortality, lower TRM, and absence of chronic GVHD-related morbidity. Despite efforts to match pts between the cohorts, the inherent limitations of this study, such as incongruent data sources and case selection bias, have to be considered. Additional analyses will be presented.

Real-World Tisagenlecleucel Outcomes in Richter-Transformed Chronic Lymphocytic Leukemia: A Center for International Blood & Marrow Transplant Research (CIBMTR) Analysis

Background: Richter transformation (RT) is a rare but serious transformation of chronic lymphocytic leukemia (CLL) into an aggressive lymphoma, most commonly large B-cell lymphoma (LBCL). There is currently no standard therapy for RT lymphoma and median overall survival (OS) is estimated to be only 8-12 months. Tisagenlecleucel is an autologous CD19-directed chimeric antigen receptor (CAR)-T cell therapy approved for the treatment of r/r LBCL in patients who have received ≥2 lines of prior therapy. Here, we describe the efficacy and safety of tisagenlecleucel in patients with RT in a real-world setting with a median follow-up (infusion to data cutoff) of 31 months. Methods: Data were collected as part of a noninterventional, prospective, longitudinal study using the CIBMTR registry. All patients were treated in the United States, Canada, or Israel. Efficacy outcomes analyzed included overall response rate (ORR), progression-free survival (PFS), and OS. Safety outcomes included the incidence and severity of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 4, 2023, 48 patients with RT received a single tisagenlecleucel infusion. The median age at infusion was 68 years (range, 39-83). Fifty-eight percent of patients were ≥65 years old. The median number of all prior lines of therapy was 3 (range, 1-8); 42% of patients received ibrutinib as a prior therapy. No information confirming clonal relation of LBCL to CLL in evaluated patients was available. Fifty percent of patients had primary refractory disease. Prior to infusion, 46% of patients were reported to have elevated lactate dehydrogenase (LDH). Two patients who received tisagenlecleucel infusion, and were alive at data cutoff, had not yet reached 100 days post-infusion and were therefore not evaluable for efficacy and safety. Among the 46 patients evaluated for efficacy and safety, the ORR (complete response [CR] + partial response) was 63% (95% CI, 47.5-76.8) and CR rate was 50% (n=23). In total, 23 patients (23/46, 50%) experienced disease relapse, 17 within 6 months of infusion (Figure). Twelve- and 24-month PFS were 43% and 39%, respectively; 12- and 24-month OS rates were 51% and 44%, respectively. Among 23 patients with a best overall response of CR, 57% remained in remission at data cutoff. The most common adverse events of any grade were CRS (78%), hypogammaglobinemia (46%), and ICANS (35%). Grade 3/4 CRS was reported in 11% of patients. No patient experienced grade 5 CRS. CRS was managed with tocilizumab in 81% of cases. Grade 3 ICANS was reported in 9% of patients. No grade 4/5 ICANS events were observed. Two patients went on to receive a stem cell transplant following tisagenlecleucel infusion. In total, 25 deaths were reported. The most common cause of death was progressive disease (13/48, 27%). Twelve patients (12/48, 25%) died in the absence of disease progression. Causes of non-relapse-related mortality included infection (including COVID-19, n=5), respiratory failure (n=2), malignant neoplasm (n=2), prior malignancy (n=1), multiorgan dysfunction (n=1), and severe veno-occlusive disease (n=1). Conclusions: In the largest cohort of patients with RT receiving treatment in a real-world setting, tisagenlecleucel resulted in a high overall response rate and durable survival. The incidences of CRS and ICANS were similar to other real-world reports of tisagenlecleucel for patients with LBCL. Overall, these findings demonstrate that tisagenlecleucel could be considered a potential treatment option for patients with RT who have a high unmet medical need.

Mosunetuzumab and Polatuzumab Vedotin Demonstrates Preliminary Efficacy in Elderly Unfit/Frail Patients with Previously Untreated Diffuse Large B-Cell Lymphoma

Background: Treatment options for elderly unfit/frail (U/F) patients (pts) with diffuse large B-cell lymphoma (DLBCL) are often limited due to comorbidities or functional decline. Less toxic, efficacious alternatives to full-dose chemoimmunotherapy (CIT) are needed. Mosunetuzumab (Mosun) is a first-in-class CD20xCD3 T-cell engaging bispecific antibody that redirects T cells to eliminate B cells. Mosun monotherapy has demonstrated efficacy, durable complete responses (CR), and manageable safety in U/F pts with untreated DLBCL (NCT03677154; Olszewski et al. ASH 2022). Subgroup analysis from an ongoing Phase Ib/II study (NCT03671018) of Mosun plus polatuzumab vedotin (Pola; M-Pola) in pts with relapsed/refractory DLBCL demonstrated efficacy and a manageable safety profile in pts ≥65 years (yrs) (Olszewski et al. ASH 2022). We report preliminary efficacy and safety data from the M-Pola cohort of study NCT03677154 in elderly U/F pts with newly diagnosed DLBCL. Methods: Eligible pts were ≥80 yrs, or 65-79 yrs and ineligible for full-dose CIT/unfit per simplified Geriatric Assessment (sGA; Merli et al. J Clin Oncol 2021) ( Table). Pre-phase prednisone was allowed. Pts were enrolled in two safety cohorts with escalating doses of Mosun subcutaneous (SC; Cohort 1 and 2), followed by an expansion (Exp) phase. Pts received Cycle (C) 1 step-up dosing with Mosun SC on Day (D) 1/8/15 (Cohort 1: 5/15/45mg; Cohort 2 and Exp: 5/45/45mg) then 45mg on D1 of C2-8 plus 1.8mg/kg intravenous Pola on D1 of C1-6. Pts with CR stopped Mosun after 8 cycles; pts with partial response (PR) or stable disease could continue Mosun for up to 17 cycles in the absence of progressive disease (PD). Primary endpoints included safety and objective response rate (ORR) by independent review committee (IRC; assessed by positron emission tomography-computed tomography [Lugano 2014 criteria]) at end of treatment (EOT). CR rate, progression-free survival, and overall survival were secondary endpoints (IRC- and investigator [INV]-assessed). Best overall response (BOR) and EOT responses are reported in pts who received first treatment with a sufficient time interval to be eligible for the relevant response evaluation. Cytokine release syndrome (CRS) was assessed by ASTCT criteria (Lee et al. Biol Blood Marrow Transplant 2019). Results: Pts were enrolled from Feb 2021 to Jan 2023. As of the clinical cutoff date (CCOD; Feb 17, 2023), 108 pts received M-Pola (Cohort 1: n=7; Cohort 2: n=13; Exp: n=88). Median age was 81 yrs (range: 66-94); 52% of pts were female; 81% had an ECOG PS of 0-1; and 66% had Ann Arbor stage III-IV disease. Per sGA, 59% were unfit and 40% frail ( Table). Median (range) number of cycles was 7.5 (1-14) for Mosun and 6 (1-6) for Pola. Most frequent treatment-emergent adverse events (AEs) (≥20%) were neutropenia (32%), CRS (30%), and injection site reaction (20%). Grade (Gr) 3-4 AEs occurred in 43% of pts (most frequent: neutropenia [28%]). Serious AEs occurred in 41% of pts; most frequent (≥5%) were CRS (14%) and infections (21%), including COVID-19 pneumonia (10%) and COVID-19 infection (7%). Most CRS events occurred in C1; 30/32 pts had Gr 1-2 events; two pts had Gr 3 events. All CRS events resolved within a median of 2 days (range: 1-6); management included tocilizumab (7/32) and corticosteroids (3/32). AEs leading to discontinuation of Mosun or Pola occurred in 15% and 12% of pts, respectively. Fatal AEs occurred in 15 pts (14%): eight COVID-19/COVID-19 pneumonia events; two unexplained deaths; and one event each of Staphylococcal bacteremia, sepsis, pneumonia, pulmonary embolism, and suicide. Range of onset date for fatal AEs was D8-251. At the CCOD, median follow-up was 7.5 months (range: 0-21). In 90 evaluable pts from Cohort 2 and Exp, BOR and best CR rate per INV were 80% (72/90) and 61% (55/90), respectively. EOT response assessments per INV in 56 evaluable pts showed ORR in 55% (31/56); CR in 45% (25/56); PD in 9% (5/56); PR in 11% (6/56); and 36% (20/56) without EOT assessment (withdrawal of consent: 4/20; AEs: 13/20; early discontinuation per INV: 2/20; PD in C1: 1/20) ( Figure). Conclusions: Chemotherapy-freeM-Pola demonstrated preliminary efficacy in elderly U/F pts with previously untreated DLBCL. Overall, the safety profile of M-Pola was consistent with that of the individual drugs. However, COVID-19 remains a high risk in elderly U/F pts treated for DLBCL. Biomarker analyses and long-term follow-up data will be presented.

Efficacy of the Allosteric MEK Inhibitor Trametinib in Relapsed and Refractory Juvenile Myelomonocytic Leukemia: A Report from the Children's Oncology Group

Background: Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm of infants and toddlers. Upfront therapies typically include high-dose cytarabine or azacitidine, but the only definitive treatment is hematopoietic stem cell transplantation (HSCT). While HSCT cures ~50% of patients, the prognosis is dismal for those who relapse. In the absence of a second HSCT, patients who relapse have a 2-year overall survival of ~10%. JMML is initiated by germline and somatic driver mutations in NF1, KRAS, NRAS, PTPN11, and CBL. These mutations converge on Ras signaling, leading to elevated levels of active Ras-GTP in specific cell lineages. Genetically engineered mouse (GEM) models accurately model key molecular, biologic, and biochemical features of JMML. Preclinical trials of the allosteric MEK inhibitors in Kras and Nf1 mutant mice demonstrated dramatic phenotypic responses with reduction in white blood cell counts, resolution of splenomegaly, and reversion to normal erythropoiesis. Based on the promising efficacy signal in GEM models, we evaluated trametinib, an orally bioavailable allosteric inhibitor of MEK1/2, in a prospective clinical trial in children with relapsed or refractory JMML to determine the overall response rate to trametinib. Results: Ten infants and children with JMML (median age 23.6 months) were enrolled and all were evaluable for safety and efficacy. Patients received age-adjusted dosing of trametinib for 28-day cycles and could remain on study for up to 12 cycles in the absence of disease progression or toxicity. A clonal Ras pathway mutation was confirmed in the blood and/or bone marrow of all patients. The objective response rate was 50% (two complete and three partial clinical responses). Four patients proceeded to HSCT after receiving protocol therapy and remain alive in complete remission with undetectable levels of the Ras pathway mutation identified at enrollment. Three additional patients completed 12 cycles of trametinib and continue to receive off-protocol therapy 6-24 months later with no change in the variant allele frequency of the underlying Ras pathway mutation. The remaining three patients had progressive disease with two demonstrating molecular evolution by the end of cycle 2. Paired pre- and post-trametinib RNASeq and proteomic analyses confirmed on-target biochemical effects of trametinib with down-regulation of both Ras/MAPK pathway related gene expression and MEK1/2 kinase activity, respectively. To gain deeper insight into how trametinib might affect distinct populations of hematopoietic cells, we generated single cell RNASeq data before and after treatment. The most prominent finding was a reduction in the proportions of classical and non-classical monocytes and broad downregulation of immune-related pathways in all cell populations. However, the downregulation of MAPK signaling genes was confined to specific cell types including, macrophages, classical monocytes, and granulocyte-monocyte progenitors, which uniquely displayed downregulated KRAS-related signatures following treatment. High DNA methylation and the presence of &amp;gt;1 mutation at enrollment correlated with lack of response to trametinib. Conclusions: We conducted an open label, phase 2 trial of trametinib in children with relapsed or refractory JMML. This is the first completed study of a MEK inhibitor in any hematologic malignancy in children. The trial met its primary objective and demonstrated a 50% objective response rate with 70% of patients bridging to a successful HSCT or completing the maximum 12 cycles permitted on study. The three patients who completed 12 cycles continue to receive trametinib off study for as long as 2 years. Although limited by a small number of patients, the long-term survival, and correlative molecular analyses from this trial raise provocative questions about whether certain patients with JMML might be spared the long-term adverse health risks of genotoxic HSCT conditioning regimens based on favorable molecular characteristics at diagnosis. This hypothesis will now be tested in a national, risk-stratified therapeutic trial (NCT05849662) of trametinib in combination with azacitidine in newly diagnosed patients. The authors would like to acknowledge funding and support from: NCTN Operations Center Grant (U10CA180886), NCTN Statistics &amp; Data Center Grant (U10CA180899), and the St. Baldrick's Foundation.

Efficacy and safety of neoadjuvant nab-paclitaxel plus gemcitabine therapy in patients with borderline resectable pancreatic cancer: A multicenter single-arm phase II study (NAC-GA trial).

Nab-paclitaxel plus gemcitabine is a standard treatment for metastatic/locally advanced pancreatic cancer. The effectiveness of neoadjuvant therapy with nab-paclitaxel plus gemcitabine (GnP-NAT) in patients with borderline resectable pancreatic cancer (BRPC) remains unclear. This single-arm phase II trial included 61 patients with BRPC that were treated with two cycles of GnP-NAT, (nab-paclitaxel 125 mg/m2 and gemcitabine 1000 mg/m2), on days 1, 8, and 15 over a 4-week period, which comprised one cycle. The primary endpoint was overall survival time. In the absence of disease progression, patients underwent planned pancreatectomy. Median overall survival, the primary endpoint, was 25.2 months, and the median recurrence-free survival was 12.3 months. The overall rate of grade 3/4 events was 73.8%. One patient, who had a history of radiation therapy for past esophageal cancer, died from exacerbation via pneumonia. The overall resection rate was 73.8% (n = 45), and the R0 resection rate was 63.9% (n = 39). Overall, postoperative complications were found in 19 patients (42%) with 24 events, and nine patients (20%) with nine events ≥ grade IIIa, based on Dindo's classification. This protocol treatment is thought to be a feasible, safe, and promising treatment regimen, but we caution against its use in patients with a history of interstitial lung disease and/or prior pulmonary irradiation. The survival data from this study suggest the need for further investigations of GnP-NAT efficacy in patients with BRPC, as well as prospective evaluation of adverse events. UMIN Clinical Trials Registry, UMIN000024154 and ClinicalTrials.gov, NCT02926183.

Short intravenous amphotericin B followed by oral posaconazole using a simple, stratified treatment approach for diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis: a prospective cohort study

ObjectivesTo evaluate the efficacy and safety of short-course intravenous amphotericin B followed by sustained release posaconazole tablets for diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis. MethodsThis prospective, pragmatic study included adults with diabetes or COVID-19-associated rhino-orbito-cerebral mucormycosis. Patients received short (7–14 days) or long (15–28 days) intravenous antifungal therapy (short intravenous antifungal treatment [SHIFT] or long intravenous antifungal treatment [LIFT], respectively) depending on the presence or absence of brain involvement. All patients received step-down posaconazole tablets, debridement, and glycemic control. The primary outcome was the treatment success at week 14, which was determined by assessing survival and the absence of disease progression through clinical evaluation and nasal endoscopy. Log-binomial regression analysis (risk ratio and 95% CI) was performed to assess factors associated with the primary outcome. ResultsIntravenous therapy was administered to 251 participants: SHIFT, 205 (median duration, 13 days); LIFT, 46 (median duration, 22 days). Treatment success at 3 months was 88% (217/248; 95% CI, 83–91%): SHIFT group, 93% (189/203; 89–96%); LIFT group, 62% (28/45; 47–76%). All-cause mortality was 12% (30/251): SHIFT group, 6% (13/205); LIFT group, 37% (17/46). Age (aRR [95% CI]: 1.02 [1.00–1.05]; p 0.027), diabetic ketoacidosis at presentation (2.32 [1.20–4.46]; p 0·012), glycated haemoglobin A1c (1.19 [1.03–1.39]; p 0.019), stroke (3.93 [1.94–7.95]; p 0·0001), and brain involvement (5.67 [3.05–10.54]; p < 0.0001) were independently associated with unsuccessful outcomes. Discussion: Short intravenous amphotericin B with step-down posaconazole tablets should be further studied as primary treatment option for diabetes or COVID-19-associated mucormycosis in randomized controlled trials.

Osmotic blood-brain barrier disruption with mannitol followed by methotrexate, rituximab, and carboplatin in treating patients with newly diagnosed primary central nervous system lymphoma.

2077 Background: Osmotic blood-brain barrier disruption (BBBD) uses intra-arterial (IA) mannitol to open the neuro-vascular unit to enhance delivery of therapeutic agents to the brain. We report the results of a multi-institutional, single arm, phase 2 study evaluating the efficacy and safety of BBBD-enhanced chemotherapy in combination with immunotherapy in patients with newly diagnosed primary central nervous system lymphoma (PCNSL). PCNSL is a rare non-Hodgkin’s lymphoma that is limited to the brain, cerebrospinal fluid, spinal cord and/or the vitreoretinal compartment. Methods: Non-immunocompromised subjects with newly diagnosed PCNSL received rituximab IV over 5 hours on day 1. On days 2 and 3, under general anesthesia in the angiography suite, subjects received IA mannitol immediately followed by IA methotrexate over 10 minutes, and then IA carboplatin over 10 minutes. Subjects received sodium thiosulfate IV for hearing protection at 4 and 8 hours after each carboplatin dose. Treatment was repeated every month for up to 12 courses in the absence of disease progression or unacceptable toxicity. Per institutional recommendations, further accrual was terminated during the COVID-19 pandemic. Contrast MRI was used for response assessment based on IPCG criteria. Results: Twenty subjects (10 F, 10 M, Median KPS = 80; range 40-100) received a median of 8 cycles at 3 US institutions. Sixteen radiographic complete responses (80%) and 1 partial response were documented, 3 subjects were not evaluable (2 withdrew consent and 1 unrelated death). Median PFS was 55.2 months (95% CI :10.3 – not reached) and Median Overall survival was 82.8 months (95% CI :19.8-145.8). Fourteen patients (82% of evaluable patients) had grade 3 or 4 adverse events (AE). Grade 4 AEs (n = 14 in n = 7 patients) included neurologic toxicities (ischemia, cervical cord inflammation, neuropathy) and blood/bone marrow toxicities (lymphopenia, neutropenia, granulocytopenia). There were no treatment-related deaths. Conclusions: We demonstrate the feasibility of performing BBBD in a multi-institutional setting with excellent PFS and OS in patients without whole brain radiation or autologous transplant. Our CR rates, PFS and OS are comparable to other IV high-dose MTX regimens, with acceptable toxicity profile and no documented treatment-related deaths. Clinical trial information: NCT00293475 .

A first-in-human phase I trial of a novel peptide vaccine LabVax 3(22)-23 and adjuvant GM-CSF sargramostim in patients with refractory labyrinthin-expressing adenocarcinomas.

e14660 Background: Labyrinthin (Lab) is a novel tumor-specific protein expressed on the cell surface of the majority of adenocarcinomas of various cancer types. LabVax 3(22)-23 contains 4 synthetic Lab-based peptides designed to elicit both B-cell and T-cell responses. We hypothesized that vaccination against labyrinthin could elicit strong immune responses against Lab-positive adenocarcinomas in cancer patients (pts). This single institution, first-in-human, phase I trial (UCDCC#296) evaluated the feasibility and safety of LabVax 3(22)-23 and adjuvant GM-CSF sargramostim in pts with Lab-positive metastatic or recurrent adenocarcinoma of any primary tumor site after standard-of-care therapies. Methods: Eligible pts were &gt;18 years of age, had metastatic adenocarcinomas of any histology, Lab expression on their tumor cells by immunohistochemistry, adequate end organ function, and performance status (PS) 0-1. Pts received GM-CSF subcutaneously and LabVax 3(22)-23 intradermally on weeks 1, 2, 4, 8, and 12 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, pts were/are followed every 3 months for 1 year. The primary objective was to assess the toxicity per CTCAE V5.0. Dose limiting toxicity (DLT) was defined as grade ≥ 2 allergic and autoimmune reaction, grade ≥ 3 injection site reaction, any grade 3 toxicities lasting &gt;1 week, or any grade ≥ 4 toxicities. Results: All 10 pts were accrued: median (range) age, 52 (34-73) yrs; female/male, 6/4; White/Asians/Hispanic, 7/2/1; PS 1: 100%. Tumor types included colon or rectum (8), ovarian (1), and scalp (1). Median number (range) of prior line systemic therapies, 4 (1-8). The treatment has been well tolerated without any DLT or drug-related severe adverse effect. As of February 10, 2023, 2 pts completed all 5 treatments with stable disease as the best tumor response, and 1 pt is scheduled for last treatment. Seven pts discontinued treatment early due to tumor progression, 3 pts after 4 treatments and 4 pts after 3 treatments. OS has not matured yet. RNA sequencing analysis of peripheral blood mononuclear cells (PBMCs) of first two pts revealed LabVax 3(22)-23 modulated the activity of immune cells and PD-1 pathway. Other correlative studies are ongoing for the effect of LabVax 3(22)-23 on various immune responses (cytokines, anti-Lab antibody production). Conclusions: LabVax 3(22)-23 and GM-CSF were well tolerated in these heavily pre-treated patients with Lab-expressing, refractory adenocarcinomas. Based on preclinical synergism with pembrolizumab, this dose and injection schedule will be tested in a phase II open label study of LabVax 3(22)-23 and GM-CSF in combination with pembrolizumab in patients with refractory lung adenocarcinomas and adenocarcinomas of all other tumor types. Clinical trial information: NCT051013560 .

Ropeginterferon versus Standard Therapy for Low-Risk Patients with Polycythemia Vera

BackgroundWhether phlebotomy alone can adequately maintain target hematocrit in patients with low-risk polycythemia vera (PV) remains elusive.MethodsIn a phase 2 open-label randomized trial, we compared ropeginterferon alfa-2b (ropeg; 100 μg every 2 weeks) with phlebotomy only regarding maintenance of a median hematocrit level (≤45%) over 12 months in the absence of progressive disease (primary end point). In follow-up, crossover to the alternative treatment group was allowed if the primary end point was not met.ResultsIn total, 127 patients were enrolled (ropeg: n=64; standard group: n=63). The primary end point was met in 81% and 51% in the ropeg and standard groups, respectively. Responders continued the assigned treatment until month 24 and maintained response in 83% and 59%, respectively (P=0.02). Ropeg responders less frequently experienced moderate/severe symptoms (33% vs. 67% in the standard group) and palpable splenomegaly (14% vs. 37%) and showed normalization of ferritin levels and blood counts. Nonresponders at 12 months crossed over to the standard (n=9) or ropeg (n=23) group; in patients switched to ropeg only, 7 of 23 met the response criteria in 12 months, and phlebotomy need was high (4.7 per patient per year). Discontinuation because of adverse events occurred in seven patients treated with ropeg.ConclusionsIn this 24-month trial, ropeg was superior to phlebotomy alone in maintaining hematocrit on target. No dose-limiting side effects or toxicities were noted; 9.2% of patients on ropeg and no patients on standard treatment developed neutropenia. (Funded by AOP Health and others; ClinicalTrials.gov number, NCT03003325.)

Discontinuation of anti-PD1 in advanced melanoma: an observational retrospective study from the Italian Melanoma Intergroup

BackgroundImmunotherapy has improved the survival of patients with stage IV melanoma. In responders, clinical benefits may be long-lasting and persist even after treatment discontinuation. The optimal duration of anti-PD1 (anti-Programmed cell death-1) therapy in metastatic melanoma patients remains to be elucidated. Moreover, limited data are available on clinical outcomes of patients that discontinued anti-PD1 immunotherapy in a real-life setting. The aim of this study was to evaluate the progression-free survival (PFS) in patients with metastatic melanoma who interrupted anti-PD-1 treatment in the in the absence of disease progression. MethodsWe retrospectively reviewed patients with advanced/metastatic melanoma treated with anti-PD1 immunotherapy at 23 Italian Melanoma Intergroup (IMI) centres. The study investigated the risk of relapse in patients who stopped anti-PD1 therapy due to CR (Complete response), treatment-related toxicity, or by their own choice after a long period of treatment. Clinical and biological factors associated with or without recurrence were evaluated. ResultsThe study population included 237 patients. The median age of patients was 68.9 years (standard deviation: 13; range 33–95). The median time on treatment was 33 months (standard deviation: 18, 7; range 1–98). Among the 237 patients, 128 (54%) interrupted the anti-PD1 for CR, 74 patients (31.2%) for adverse events (37 patients in CR, 27 patients in partial response (PR), ten patients in stable disease (SD), and 35 patients (14.8%) by their own choice (12 patients in CR, 17 patients in PR, and 6 patients in SD). After a mean follow-up of 21 months (range 1–81), PFS after anti-PD1 discontinuation was 85.7%. Thirty-four patients (14.3%) developed disease progression after a median of 12 months (range 1–35): ten patients (29.4%) after discontinuation in CR, 17 patients (50%) after discontinuation for treatment-related toxicity (seven in CR, five in PR, five in SD), and seven (20.6%) after discontinuation due to the patient’s decision (two in CR, four in PR, one in SD). Only 7.8% of patients who interrupted in CR (10/128), along with 23% of patients who interrupted for limiting toxicity (17/74) and 20% of patients who interrupted by their own choice (7/35), developed recurrence. Regarding patients who discontinued therapy because of CR, we observed a negative association between recurrence and site of primary melanoma, especially mucosal sites (p = <0.05, HR (Hazard ratio) 15.57 IC (confidence interval) 95% 2.64–91.73). Moreover, M1b patients who achieved a CR showed a lower number of relapses (p = <0.05, HR 3.84 IC 95% 1.40–8.48). ConclusionsThis study shows in a real-life setting that, with anti-PD-1 therapy, long-lasting responses, can be maintained after anti-PD1 interruption. In 70.6% of cases, recurrences were observed among patients who did not obtain a CR at treatment discontinuation.

Abstract OT1-11-01: Phase II study of talazoparib, a PARP inhibitor, in somatic BRCA1/2 mutant metastatic breast cancer identified by cell-free DNA or tumor tissue genotyping

Abstract Background: PARP inhibitors are currently approved for the treatment of germline BRCA1/2 mutant metastatic breast cancer (MBC), which accounts for 5-10% of breast cancer. We hypothesize that a PARP inhibitor may also have efficacy in somatic BRCA1/2 mutant MBC, expanding the potential clinical applicability of PARP inhibitors. We previously demonstrated that somatic BRCA1/2 mutations can be identified by both cell-free DNA and tumor tissue genotyping in a subset of patients with MBC who are not germline BRCA1/2 carriers. Furthermore, a PARP inhibitor was demonstrated to induce cell growth inhibition in a circulating tumor cell culture model generated from a patient with pathogenic somatic BRCA1 mutant MBC (Vidula, Dubash, CCR, 2020). In this trial, we are evaluating the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Trial Design: This phase II investigator-initiated clinical trial is enrolling 30 patients with somatic BRCA1/2 mutant MBC identified via cell-free DNA or tumor tissue genotyping. Patients are treated with talazoparib, a PARP inhibitor, until disease progression. At baseline and every 3 months, patients undergo CT chest, abdomen, and pelvis, and a bone scan for disease assessment. Patients undergo blood collection at baseline for the Cancer Risk B (CR-B) assay, a novel flow variant assay to assess double-strand break repair mutations in circulating blood cells (Syeda, 2017) and monthly blood collection for cell-free DNA analysis to evaluate changes in the genomic environment. Eligibility Criteria: Patients with MBC with a pathogenic somatic BRCA1/2 mutation identified by cell-free DNA or tumor tissue genotyping are eligible. Both patients with triple-negative breast cancer (≥ 1 prior chemotherapy) or hormone receptor positive/HER2- MBC (≥ 1 prior hormone therapy) are eligible. Patients should not be known germline BRCA1/2 carriers. There is no limit on prior therapies including receipt of a prior platinum (in the absence of disease progression on prior platinum). A prior PARP inhibitor is not allowed. Adequate performance status and organ function are needed. Specific Aims: Primary aim is progression-free survival (PFS) assessed by RECIST 1.1. Secondary aims include objective response rate and toxicity assessed by NCI CTCAE v 5.0. Exploratory aims include assessing impact of BRCA1/2 reversion mutations in cell-free DNA, studying serial changes in BRCA1/2 mutant allelic frequency in cell-free DNA, comparing pre- and post-treatment cell-free DNA results to identify changes in the genomic environment, assessing the CR-B assay positivity rate, and correlating these biomarker analyses with patient response. Statistical Methods: This study uses a two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS &amp;gt; 12 weeks) in 53% patients (4% alpha). Accrual: This study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, University of California San Francisco, and Emory, with pending activation at Northwestern, Cornell, and Vanderbilt. Five patients are enrolled as of 7/2022. Funding: This study is supported by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Senthil Damodaran, Erica L. Blouch, Nora Horick, Nathan Royce Ruffle-Deignan, Manali Bhave, Ami N. Shah, Leticia Varella, Vandana Abramson, Joseph Sparano, Leif Ellisen, Ishraq Alim, Harry Ostrer, Hope Rugo, Aditya Bardia. Phase II study of talazoparib, a PARP inhibitor, in somatic BRCA1/2 mutant metastatic breast cancer identified by cell-free DNA or tumor tissue genotyping [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-11-01.

Short and long-term prognostic value of intraoperative motor evoked potentials in brain tumor patients: a case series of 121 brain tumor patients.

Iatrogenic neurologic deficits adversely affect patient outcomes following brain tumor resection. Motor evoked potential (MEP) monitoring allows surgeons to assess the integrity of motor-eloquent areas in real-time during tumor resection to lessen the risk of iatrogenic insult. We retrospectively associate intraoperative transcranial and direct cortical MEPs (TC-MEPs, DC-MEPs) to early and late post-operative motor function to prognosticate short- and long-term motor recovery in brain tumor patients undergoing surgical resection in peri-eloquent regions. We reviewed 121 brain tumor patients undergoing craniotomies with DC-MEP and/or TC-MEP monitoring. Motor function scores were recorded at multiple time-points up to 1year postoperatively. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated at each time point. The sensitivity, specificity, PPV, and NPV of TC-MEP in the immediate postoperative period was 17.5%, 100%, 100%, and 69.4%, respectively. For DC-MEP monitoring, the respective values were 25.0%, 100%, 100%, and 68.8%. By discharge, sensitivity had increased for both TC-MEP and DC MEPs to 43.8%, and 50.0% respectively. Subset analysis on patients without tumor recurrence/progression at long term follow-up (n = 62pts, 51.2%) found that all patients with stable monitoring maintained or improved from preoperative status. One patient with transient intraoperative TC-MEP loss and permanent DC-MEP loss suffered a permanent deficit. Brain tumor patients who undergo surgery with intact MEP monitoring and experience new postoperative deficits likely suffer transient deficits that will improve over the postoperative course in the absence of disease progression.

Safety and Tolerability of Pirtobrutinib Monotherapy in Patients with B-Cell Malignancies Who Were Previously Intolerant to a Covalent BTK Inhibitor: Results from the Phase 1/2 BRUIN Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have markedly improved outcomes in several B-cell malignancies. Despite this progress, treatment discontinuation due to cBTKi intolerance remains a significant barrier, ultimately limiting efficacy. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients (pts) with poor-prognosis B-cell malignancies following prior therapy, including prior cBTKi (Mato et al. Lancet, 2021). Here, we evaluated the safety and tolerability of pirtobrutinib monotherapy specifically in pts with relapsed/refractory (R/R) B-cell malignancies who were intolerant to a prior cBTKi. Methods: For this analysis, pts with R/R B-cell malignancies enrolled to the multicenter phase 1/2 BRUIN study (NCT03740529) with documented intolerance to prior cBTKi were analyzed. Intolerance was defined as having discontinued any prior cBTKi due to persistent/recurrent adverse events as assessed by the physician, in the absence of progressive disease. Pirtobrutinib monotherapy was administered once daily in 28-day cycles until disease progression or discontinuation due to toxicity. Analyses were performed descriptively. Results: As of 31 January 2022, 566 pts (CLL/SLL, n=276; MCL, n=150; other NHL, n=140) treated with pirtobrutinib had received a prior cBTKi-containing regimen (prior lines of cBTKi containing regimens: 1 regimen, n=454; 2 regimens, n=93; ≥3 regimens, n=19). Among these 566 pts, 123 (22%) pts (CLL/SLL, n=79; MCL, n=20; other NHL, n=24) discontinued a prior cBTKi due to toxicity. This cBTKi intolerant cohort had received one or more of the following: ibrutinib (n=118, 96%), acalabrutinib (n=29, 24%), or zanubrutinib (n=6, 5%). At the time of enrollment to BRUIN, the median age for pts with prior cBTKi intolerance was 70 years (IQR: 64-75), and ECOG PS was 0, 1 and 2 in 58%, 35%, and 7% of pts, respectively. The most common adverse events (AEs) leading to prior cBTKi discontinuation were cardiac disorders [n=40, 33%; primarily atrial fibrillation (n=31, 25%)], infections (n=13, 11%), neutropenia (n=12, 10%), rash (n=12, 10%), bleeding/hemorrhage (n=11, 9%), arthralgias/myalgias (n=10, 8%), gastrointestinal disorders [n=9, 7%; diarrhea (n=6, 5%)], and fatigue (n=8, 7%). In these 123 pts with prior cBTKi intolerance, median time on pirtobrutinib treatment was 11 months (IQR, 4-18), with 63% (n=78) of pts remaining on pirtobrutinib at the time of data cut-off date. Of the 45 pts who had discontinued pirtobrutinib, the majority did so for progressive disease (62%, n=28). Overall, 9 (7%) pts discontinued pirtobrutinib for AEs which showed no particular pattern. Discontinuations related to pirtobrutinib occurred in 4 pts (1 each) including: myalgia, neutropenia, rash maculo-papular, and staphylococcal sepsis, and discontinuations unrelated to pirtobrutinib occurred in 5 pts (1 each) including: anxiety, abdominal pain and blood alkaline phosphatase increase, chronic respiratory failure, pneumonia, and COVID-19 and dyspnea. Treatment-emergent adverse events (TEAEs) on pirtobrutinib were manageable with dose reductions in 10 pts (8%) primarily due to neutropenia (n=6). The median pirtobrutinib relative dose intensity was 98% (IQR, 92-100). Pirtobrutinib TEAEs recurring in the same patient and same AE category as those leading to prior cBTKi intolerance are listed in the Table. Overall recurrence of a grade ≥3 pirtobrutinib TEAE in the same patient and category as that leading to prior cBTKi discontinuation was observed in only 13% (n=16/123) of pts. Conclusions: Pirtobrutinib monotherapy was safe and well-tolerated in the majority of pts with B-cell malignancies with documented intolerance to prior cBTKi therapy. Most pts did not experience high-grade recurrence of the AE that led to discontinuation of the prior cBTKi, and among those who did, none discontinued pirtobrutinib for this AE. Pirtobrutinib may be an important consideration to extend the benefit of BTK inhibition among pts with intolerance to a prior cBTKi. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Phase II INTERACT-ION study: ezabenlimab (BI 754091) and mDCF (docetaxel, cisplatin, and 5-fluorouracil) followed by chemoradiotherapy in patients with Stage III squamous cell anal carcinoma.

BackgroundChemoradiotherapy alone is the standard treatment for locally advanced squamous cell anal carcinoma (SCAC). However, up to 50% of patients will experience recurrence; thus, there is a need for new treatments to improve outcomes. Modified docetaxel, cisplatin and 5-fluorouracil (mDCF) is a treatment option for first-line metastatic SCAC, having shown efficacy in the Epitopes-HPV01 and -02 trials (NCT01845779 and NCT02402842). mDCF treatment also plays a role in the modulation of anti-tumor immunity, suggesting it may be a good combination partner for immunotherapy in patients with SCAC. Anti-programmed death protein-1 (PD-1) immunotherapy has been shown to be effective in metastatic SCAC. We therefore designed the INTERACT-ION study to assess the combination of mDCF with ezabenlimab (BI 754091), an anti-PD-1 antibody, followed by chemoradiotherapy, in patients with Stage III SCAC.MethodsINTERACT-ION is a pivotal, open-label, single-arm phase II study in patients with treatment-naïve Stage III SCAC. Patients will receive induction treatment with mDCF (docetaxel 40 mg/m2 and cisplatin 40 mg/m2 on Day 1, 5-fluorouracil 1200 mg/m2/day for 2 days) every 2 weeks for 4 cycles and ezabenlimab (240 mg given intravenously) every 3 weeks for 3 cycles. In the absence of disease progression at 2 months, two additional cycles of mDCF and one additional cycle of ezabenlimab will be administered. Patients with radiological objective response, pathological complete/near-complete response and biological complete response will then receive an involved-node radiotherapy with intensity-modulated radiation therapy and concurrent chemotherapy, followed by ezabenlimab alone for seven cycles. All other patients will receive standard chemoradiotherapy. The primary endpoint is the clinical complete response rate 10 months after the first cycle of mDCF plus ezabenlimab. Major secondary endpoints are major pathological response and biological complete response after induction treatment. An extensive ancillary biomarker study in tumor tissue and peripheral blood will also be conducted.DiscussionThe addition of immunotherapy to chemotherapy is an area of active interest in metastatic anal cancer. This pivotal study will evaluate this combination in the locally advanced setting. Ancillary biomarker studies will contribute to the understanding of predictors of response or resistance to treatment.Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT04719988, identifier NCT04719988.