Montefiore Einstein Comprehensive Cancer Center

PURPOSE Revumenib, an oral, small molecule inhibitor of the menin-lysine methyltransferase 2A (KMT2A) interaction, showed promising efficacy and safety in a phase I study of heavily pretreated patients with KMT2A -rearranged ( KMT2Ar ) acute leukemia. Here, we evaluated the activity of revumenib in individuals with relapsed/refractory (R/R) KMT2Ar acute leukemia. METHODS AUGMENT-101 is a phase I/II, open-label, dose-escalation and expansion study of revumenib conducted across 22 clinical sites in five countries (ClinicalTrials.gov identifier: NCT04065399 ). We report results from the phase II, registration-enabling portion. Individuals age ≥30 days with R/R KMT2Ar acute leukemia or with AML and nucleophosmin 1 ( NPM1 ) mutation were enrolled. Revumenib was administered once every 12 hours, at 163 mg (95 mg/m 2 if weight <40 kg) with a strong cytochrome P450 inhibitor, in 28-day cycles. The primary end points were the rate of complete remission (CR) or CR with partial hematologic recovery (CR + CRh) and safety. At a prespecified interim analysis, safety was assessed in all KMT2Ar treated patients; efficacy was assessed in those with centrally confirmed KMT2Ar . The separate NPM1 cohort of the trial is ongoing. RESULTS From October 1, 2021, to July 24, 2023, N = 94 patients (median [range] age, 37 [1.3-75] years) were treated. Grade ≥3 adverse events included febrile neutropenia (37.2%), differentiation syndrome (16.0%), and QTc prolongation (13.8%). In the efficacy-evaluable patients (n = 57), the CR + CRh rate was 22.8% (95% CI, 12.7 to 35.8), exceeding the null hypothesis of 10% ( P = .0036). Overall response rate was 63.2% (95% CI, 49.3 to 75.6), with 15 of 22 patients (68.2%) having no detectable residual disease. CONCLUSION Revumenib led to high remission rates with a predictable safety profile in R/R KMT2Ar acute leukemia. To our knowledge, this trial represents the largest evaluation of a targeted therapy for these patients.

The achievement of complete hematologic remission (CR) is a prerequisite for cure in acute myeloid leukemia (AML). The conventional definition of CR, based on the morphologic recognition of ≤ 5% of leukemic blasts in the BM, does not provide sufficient insight into the quality of the response. Despite CR rates of 50%-80% (depending on age), the majority of patients with AML relapse within 3-5 years from diagnosis. Therefore, there is great need of more sensitive prognostic factors that can predict relapse. Minimal residual disease (MRD), defined as any measurable disease or leukemia detectable above a certain threshold (defined by the methodology applied), predicts failure to maintain a morphologic CR and affects survival negatively. AML is lagging behind acute lymphoblastic leukemia with respect to the implementation of MRD criteria for guidance during therapy. AML is particularly disadvantaged compared with acute lymphoblastic leukemia in that approximately half of AML patients lack a molecular target suitable for MRD monitoring. The detection of altered antigen (Ag) expression by leukemic myeloblasts is a valid alternative to DNA- or RNA-based MRD assays. Although associated with presenting prognostic factors (eg, cytogenetics and genotype), MRD represents the collective end result of all of the cellular mechanisms that determine a patient's response to a given therapy. Therefore, MRD has 2 potential roles in AML treatment: (1) as a posttherapy prognosticator used to assign patients to optimal postinduction/consolidation therapy, and (2) as an early surrogate end point for the evaluation of therapy efficacy.

PURPOSE: SRC-family kinases (SFK) are involved in numerous oncogenic signaling pathways. A phase 2 trial of dasatinib, a potent oral tyrosine kinase inhibitor of SFKs, was carried out in patients with human epidermal growth factor receptor 2-positive (HER2+) and/or hormone receptor-positive (HR+) advanced breast cancer. EXPERIMENTAL DESIGN: Patients with measurable tumors and progression after chemotherapy and HER2 and/or HR-targeted agents in adjuvant or metastatic settings (maximum of two prior metastatic setting regimens) received twice daily dasatinib. Primary endpoint was Response Evaluation Criteria in Solid Tumors-defined response rate. Secondary endpoints included toxicity and limited pharmacokinetics. RESULTS: Seventy patients (55 years median age) were treated, 83% of HER2+ patients had received prior HER2-directed therapy, and 61% of HR+ patients had received prior endocrine therapy in the advanced setting. Dasatinib starting dose was reduced from 100 to 70 mg twice daily to limit toxicity. Median therapy duration was 1.8 months in both dose groups and most discontinuations were due to progression. Of 69 evaluable patients, three had confirmed partial responses and six had stable disease for 16 weeks or more (disease control rate = 13.0%); all nine of these tumors were HR+ (two were also HER2+). The most common drug-related toxicities were gastrointestinal complaints, headache, asthenia, and pleural effusion. Grade 3-4 toxicity occurred in 37% of patients and was comparable between doses; drug-related serious adverse events were less frequent with 70 mg twice daily than 100 mg twice daily. CONCLUSION: Limited single-agent activity was observed with dasatinib in patients with advanced HR+ breast cancer.

Local ablative therapies, including surgery or stereotactic radiotherapy (SABR), are becoming an integral component in the treatment of oligometastatic disease in non-small-cell lung cancer. In this review, we summarize recent randomized evidence supporting progression-free survival and overall survival benefits of local ablation in these patients, as well as upcoming phase III data which should help us better understand the ideal treatment conditions and provide more insight into the oligometastatic state. Since practical management of oligometastatic disease in non-small-cell lung cancer can be challenging, we discuss a modern framework to identify patient, tumor, and treatment characteristics that can best guide management.

Cancer driver mutations often show distinct temporal acquisition patterns, but the biological basis for this, if any, remains unknown. RAS mutations occur invariably late in the course of acute myeloid leukaemia, upon progression or relapsed/refractory disease1–6. Here, by using human leukaemogenesis models, we first show that RAS mutations are obligatory late events that need to succeed earlier cooperating mutations. We provide the mechanistic explanation for this in a requirement for mutant RAS to specifically transform committed progenitors of the myelomonocytic lineage (granulocyte–monocyte progenitors) harbouring previously acquired driver mutations, showing that advanced leukaemic clones can originate from a different cell type in the haematopoietic hierarchy than ancestral clones. Furthermore, we demonstrate that RAS-mutant leukaemia stem cells (LSCs) give rise to monocytic disease, as observed frequently in patients with poor responses to treatment with the BCL2 inhibitor venetoclax. We show that this is because RAS-mutant LSCs, in contrast to RAS-wild-type LSCs, have altered BCL2 family gene expression and are resistant to venetoclax, driving clinical resistance and relapse with monocytic features. Our findings demonstrate that a specific genetic driver shapes the non-genetic cellular hierarchy of acute myeloid leukaemia by imposing a specific LSC target cell restriction and critically affects therapeutic outcomes in patients. We find that RAS-mutant leukaemia stem cells are resistant to venetoclax, driving clinical resistance and relapse with monocytic features.

2505 Background: ALRN-6924 is a cell-penetrating stapled alpha-helical peptide designed to equipotently disrupt the interaction between the p53 tumor suppressor protein and its endogenous inhibitors, murine double minute X (MDMX) and 2 (MDM2). For TP53 wild-type (WT) tumors, pharmacological disruption of this interaction offers a means to restore p53-dependent cell cycle arrest and apoptosis, resulting in antitumor efficacy via a novel mechanism. Methods: The study evaluated safety, PK, PD and anti-tumor effects of ALRN-6924 in patients (pts) with advanced solid tumors or lymphomas in a standard 3+3 design. Pts received ALRN-6924 IV once weekly for 3 consecutive wks on a 28-day cycle (arm A), or 2/wk for 2 consecutive wks on a 21-day cycle (arm B). Results: As of Dec 2016, 69 pts were enrolled with median age 61 yrs (25-78). Pts received a median of 2 (1-19) cycles in arm A [0.16-4.4 mg/kg] and 3 (1-19) cycles in arm B [0.32-2.7 mg/kg]. ALRN-6924 showed a t 1/2 of 5.5 hours, dose-dependent PK, and an increase in serum macrophage inhibitory cytokine-1. Treatment-related AEs seen in 96% of pts were primarily grade 1 and 2; most frequent were GI side effects, fatigue, anemia, and headache. DLTs were G3 fatigue at 3.1 mg/kg, and G3 hypotension, G3 alkaline phosphatase elevation, G3 anemia and G4 neutropenia at 4.4 mg/kg all in 5 pts in arm A. No G3/4 thrombocytopenia was observed. All DLTs resolved with dose hold. Infusion-related reactions were seen in 7 pts, with 3 treatment discontinuations. The RP2D was determined to be at MTD: 3.1 mg/kg QW for 3 wks every 28 days. In 55 pts evaluable for efficacy, disease control rate (DCR) was 45%, including 2 CR (Peripheral T-cell Lymphoma [PTCL], Merkel Cell Carcinoma), 2 PRs (Colorectal Cancer, Liposarcoma) and 21 pts with SD. In WT TP53 pts who initiated ALRN-6924 at ≥0.8 mg/kg, DCR was 57%. 9 pts remain on treatment post data cutoff including 3 pts exceeding 1 year of treatment. Conclusions: ALRN-6924 was well tolerated and demonstrated intriguing anti-tumor activity in this first-in-human phase I trial. An expansion phase IIa cohort in PTCL opened in August 2016 using 3.1 mg/kg (arm A) and is currently enrolling. Clinical trial information: NCT02264613.

The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, we report that the release of mt-dsRNA into the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP). Inhibition of the mitochondrial RNA polymerase, the dsRNA sensors RIGI and MDA5, or the master inflammatory signaling protein MAVS, all result in reduced expression of the SASP, while broadly preserving other hallmarks of senescence. Moreover, senescent cells are hypersensitized to mt-dsRNA-driven inflammation due to their reduced levels of PNPT1 and ADAR1, two proteins critical for mitigating the accumulation of mt-dsRNA and the inflammatory potency of dsRNA, respectively. We find that mitofusin MFN1, but not MFN2, is important for the activation of the mt-dsRNA/MAVS/SASP axis and, accordingly, genetic or pharmacologic MFN1 inhibition attenuates the SASP. Finally, we report that senescent cells within fibrotic and aged tissues present dsRNA foci, and inhibition of mitochondrial RNA polymerase reduces systemic inflammation associated to senescence. In conclusion, we uncover the mt-dsRNA/MAVS/MFN1 axis as a key driver of the SASP and we identify novel therapeutic strategies for senescence-associated diseases. The escape of mitochondrial double-stranded dsRNA (mt-dsRNA) into the cytosol has been recently linked to a number of inflammatory diseases. Here, the authors show that the release of mt-dsRNA to the cytosol is a general feature of senescent cells and a critical driver of their inflammatory secretome, known as senescence-associated secretory phenotype (SASP).

PURPOSE: Standard therapy for locally advanced non-small-cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy followed by adjuvant durvalumab. For biomarker-selected patients with LA-NSCLC, we hypothesized that sequential pembrolizumab and risk-adapted radiotherapy, without chemotherapy, would be well-tolerated and effective. METHODS: Patients with stage III NSCLC or unresectable stage II NSCLC and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible for this trial. Patients with a PD-L1 tumor proportion score (TPS) of ≥50% received three cycles of induction pembrolizumab (200 mg, once every 21 days), followed by a 20-fraction course of risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic volume exceeding 20 cc, 48 Gy delivered to smaller lesions), followed by consolidation pembrolizumab to complete a 1-year treatment course. The primary study end point was 1-year progression-free survival (PFS). Secondary end points included response rates after induction pembrolizumab, overall survival (OS), and adverse events. RESULTS: Twenty-five patients with a PD-L1 TPS of ≥50% were enrolled. The median age was 71, most patients (88%) had stage IIIA or IIIB disease, and the median PD-L1 TPS was 75%. Two patients developed disease progression during induction pembrolizumab, and two patients discontinued pembrolizumab after one infusion because of immune-related adverse events. Using RECIST criteria, 12 patients (48%) exhibited a partial or complete response after induction pembrolizumab. Twenty-four patients (96%) received definitive thoracic radiotherapy. The 1-year PFS rate is 76%, satisfying our efficacy objective. One- and 2-year OS rates are 92% and 76%, respectively. The most common grade 3 adverse events were colitis (n = 2, 8%) and esophagitis (n = 2, 8%), and no higher-grade treatment-related adverse events have occurred. CONCLUSION: Pembrolizumab and risk-adapted radiotherapy, without chemotherapy, are a promising treatment approach for patients with LA-NSCLC with a PD-L1 TPS of ≥50%.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can involve the bone marrow, peripheral blood, skin, lymph nodes, and the central nervous system. Though more common in older adults, BPDCN has been reported across all age groups, including infants and children. The incidence of pediatric BPDCN is extremely low and little is known about the disease. Pediatric BPDCN is believed to be clinically less aggressive but often with more dissemination at presentation than adult cases. Unlike adults who almost always proceed to a hematopoietic stem cell transplantation in first complete remission if transplant-eligible, the majority of children can be cured with a high-risk acute lymphoblastic leukemia-like regimen. Hematopoietic stem cell transplantation is recommended for children with high-risk disease, the definition of which continues to evolve, or those in relapse and refractory settings where outcomes continue to be dismal. Novel agents used in other hematologic malignancies and CD123 targeted agents, including chimeric antigen receptor T-cells and monoclonal/bispecific antibodies, are being brought into research and practice. Our goal is to provide a comprehensive review of presentation, diagnosis, and treatment by review of pediatric cases reported for the last 20 years, and a review of novel targeted therapies and therapies under investigation for adult and pediatric patients.

Purpose: Brain metastases are common among adult patients with solid malignancies and are increasingly being treated with stereotactic radiosurgery (SRS). As more patients with brain metastases are becoming eligible for SRS, there is a need for practical review of patient selection and treatment considerations. Methods and Materials: Two patient cases were identified to use as the foundation for a discussion of a wide and representative range of management principles: (A) SRS alone for 5 to 15 lesions and (B) a large single metastasis to be treated with pre- or postoperative SRS. Patient selection, fractionation, prescription dose, treatment technique, and dose constraints are discussed. Literature relevant to these cases is summarized to provide a framework for treatment of similar patients. Results: Treatment of brain metastases with SRS requires many considerations including optimal patient selection, fractionation selection, and plan optimization. Conclusions: Case-based practice guidelines developed by the Radiosurgery Society provide a practical guide to the common scenarios noted above affecting patients with metastatic brain tumors.

ABSTRACT: The prognosis for relapsed or refractory (R/R) nucleophosmin 1-mutated (NPM1m) acute myeloid leukemia (AML) is poor and represents an urgent unmet medical need. Revumenib, a potent, selective menin inhibitor, was recently approved for the treatment of R/R acute leukemia with a KMT2A translocation in patients aged ≥1 year based on results from the phase 1/2 AUGMENT-101 study. Here, we present results from patients with R/R NPM1m AML enrolled in the phase 2 portion of AUGMENT-101. Enrolled patients received revumenib with or without a strong CYP3A4 inhibitor every 12 hours in 28-day cycles. Primary end points were rate of complete remission (CR) or CR with partial hematologic recovery (CRh; CR + CRh), safety, and tolerability. Secondary end points included overall response rate (ORR) and duration of response. As of 18 September 2024, 84 patients received ≥1 dose of revumenib. Median age was 63 years; 1 patient was aged <18 years. The protocol-defined, efficacy-evaluable population for the primary analysis included 64 adult patients (≥3 previous lines of therapy, 35.9%; previous venetoclax, 75.0%). The CR + CRh rate was 23.4% (1-sided P = .0014); the ORR was 46.9%. Median duration of CR + CRh was 4.7 months. Of 30 responders, 5 (16.7%) proceeded to hematopoietic stem cell transplant (HSCT) and 3 resumed revumenib after HSCT. Treatment-related adverse events led to treatment discontinuation in 4 patients (4.8%). Revumenib demonstrated clinically meaningful responses in this heavily pretreated, older population with NPM1m AML, including remissions that enabled HSCT. The safety profile of revumenib was consistent with previously reported results. This trial was registered at www.clinicaltrials.gov as #NCT04065399.

PURPOSE: To determine the efficacy and toxicity of the protein kinase C inhibitor bryostatin-1 plus paclitaxel in patients with advanced pancreatic carcinoma. METHODS: Each treatment cycle consisted of paclitaxel 90 mg/m by intravenous infusion over 1 hour on days 1, 8, and 16, plus bryostatin 25 mcg/m as a 1-hour intravenous infusion on days 2, 9, and 15, given every 28 days. Patients were evaluated for response after every 2 treatment cycles, and continued therapy until disease progression or prohibitive toxicity. The primary objective was to determine whether the combination produced a response rate of at least 30%. RESULTS: Nineteen patients with locally advanced or metastatic pancreatic adenocarcinoma received a total of 52 cycles of therapy (range: 1-10). Patients received the combination as first-line therapy for advanced disease (N = 5) or after prior chemotherapy used alone or in combination with local therapy. No patients had a confirmed objective response. The median time to treatment failure was 1.9 months (95% confidence intervals: 1.2, 2.6 months). Reasons for discontinuing therapy included progressive disease or death in 14 patients (74%) or because of adverse events or patient choice in 5 patients (26%). The most common grade 3 to 4 toxicities included leukopenia in 26%, anemia in 11%, myalgias in 11%, gastrointestinal bleeding in 11%, infection in 10%, and thrombosis in 10%. CONCLUSION: The combination of weekly paclitaxel and bryostatin-1 is not an effective therapy for patients with advanced pancreatic carcinoma.

Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual . ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines . Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See the Appendix for disclaimers and other important information ( Appendix 1 and Appendix 2 , online only). Updates are published regularly and can be found at https://ascopubs.org/nsclc-da-living-guideline .

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ∼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.

4005 Background: If 5FU/Capecitabine sensitized radiotherapy (RT) is beneficial in the adjuvant (adj) management of PA after adj chemotherapy (chemo) is controversial. NRG/RTOG 0848 was designed to address this issue. Methods: This was a 2 step NCTN randomized (rndmzd) trial. Step 1 rndmzd patients (pts) to 5 cycles of gemcitabine +/- Erlotinib. Step 2 rndmzd pts to a 6 th cycle of the same chemo +/- 5FU/Capecitabine with 50.4 Gy in 28 fractions RT (chemo+CRT). Step 1 eligibility included: R0/R1 resection, M0, ECOG PS 0-1, CA19-9≤180. Step 2 eligibility included &gt; 4 cycles chemo (gem, gem combo, (m)FOLFIRINOX). RT included real time 3D/IMRT treatment (RX) plan review, scoring, and approval. At Step 2, pts stratified by nodal status (+ vs -), CA19-9 (≤90 vs &gt; 90-180), surgical margins (R0 vs R1), and adjuvant chemo. Primary endpoint was OS. Secondary endpoints are DFS and AEs (CTCAEv4). Assuming 17 months median OS (chemo) and hypothesized 22.5 months (chemo+CRT), sample size was 354 pts (HR = 0.76, 80% power, 1-sided α = 0.05, 316 OS events). Due to lower than projected event rate, trial was amended to report at the earlier of (a) 316 observed OS events or (b) 5 years of follow-up time from Step 2 accrual closure (265 OS events, 72% power, same α). OS and DFS were estimated by Kaplan-Meier and arms compared using log-rank test. Multivariable analyses (MVA) used Cox proportional hazards models. Results: Accrual began 11/2009; closed 10/2018. 354 pts rndmzd (174 chemo, 180 chemo+CRT). Median follow-up for all &amp; alive pts = 2 &amp; 7 years, respectively, with 270 OS events. Median age 63, 45% female, 81% white, 13% AA. 83% R0, 26% node negative, 96% CA19-9 &lt; 90. 13% of chemo+CRT pts did not receive RT. AEs were comparable (grade 4: 10% [chemo] vs 11% [chemo+CRT] and 1 grade 5 AE in each arm). Univariate OS/DFS results shown in Table. In initial MVA, RX, CA19-9, surgical margins were not statistically significantly associated with OS or DFS, but nodal status (OS, DFS) and race (OS) were. In further analyses, significant interactions were found between RX and nodal status for both OS and DFS. Node negative pts treated with chemo+CRT had better outcome than chemo pts; node positive pts did not (Table). Conclusions: Chemo+CRT did not improve OS overall, but did improve DFS. Both OS and DFS were improved with Chemo+CRT in node negative pts. Chemo+CRT did not increase Gr 4 or 5 AEs compared to chemo. Clinical trial information: NCT01013649 . [Table: see text]

Background: Most patients (pts) with histone-lysine N-methyltransferase 2A (KMT2A)-rearranged (KMT2Ar) acute leukemia, relapse after conventional chemotherapy and hematopoietic stem cell transplant (HSCT). Remission rates after relapse (complete remission [CR], 5%) and median overall survival (2.4 mo) in ≥2nd salvage therapies in adults remain low (Blood Cancer J. 2021;11[9]:162). In KMT2Ar leukemia, interaction of menin with KMT2A fusion proteins is a key driver of leukemogenesis. However, no therapies targeting the menin-KMT2A interaction have been approved. Revumenib (SNDX-5613; rev), a small-molecule inhibitor of menin-KMT2A interactions, demonstrated preliminary efficacy and safety in a phase 1 study of R/R KMT2Ar and nucleophosmin 1-mutated (NPM1m) acute leukemias. We report topline efficacy and safety for pts with R/R KMT2Ar acute leukemia treated with rev in a pivotal phase 2 study (AUGMENT-101; NCT04065399). Methods: Pts aged ≥30 days with R/R KMT2Ar acute leukemia were enrolled in cohort A (acute lymphoblastic leukemia [ALL]/mixed phenotype acute leukemia [MPAL]) and B (acute myeloid leukemia [AML]); cohort C continues to enroll pts with NPM1m and is not included in this analysis. Pts received rev (163 mg or 95 mg/m2 if body weight &amp;lt;40 kg) q12h with a strong cytochrome P450 3A4 inhibitor orally in 28-day cycles. Treatment continued until unacceptable toxicity or lack of at least morphological leukemia-free state (MLFS) after 4 cycles of treatment. Phase 2 primary objectives were safety and tolerability of rev and CR+CR with partial hematologic recovery (CRh) rate. Key secondary endpoints included composite CR rate (CRc, CR+CRh+CR with incomplete platelet recovery [CRp]+CR with incomplete count recovery [CRi]) and overall response rate (ORR, CRc+MLFS+partial remission). A planned interim analysis (IA) of pooled adult and pediatric pts with KMT2Ar acute leukemia was conducted. Results:As of July 24, 2023, 94 pts with R/R KMT2Ar acute leukemia received ≥1 dose of study drug and were included in the safety analysis (Table 1). Median age was 37.0 y (range, 1.3-75.0). Of the 94 pts, 23 (24.5%) were aged &amp;lt;18 y and 13 (13.8%) were aged ≥65 y. Seventy-eight (83%) had AML and 16 (17.0%) had ALL or MPAL. Over half of pts were female; 17.5% of pts were non-White. Pts were heavily pretreated (median 2 [range, 1-11] prior lines of therapy), with 41 pts (43.6%) having received ≥3 prior lines. Fifty-four pts (57.4%) had refractory relapse disease (unresponsive to most recent salvage treatment), and 47 pts (50%) had prior HSCT. Treatment-related adverse events (TRAEs) were reported in 81.9% of the safety population. Most common TRAEs (≥20%) were nausea (27.7%), differentiation syndrome (26.6%), and QTc prolongation (23.4%). Grade ≥3 TRAEs were observed in 51 pts (54.3%), the most common being differentiation syndrome (16.0%), febrile neutropenia (13.8%), and QTc prolongation (13.8%) (Table 2). Overall, 6.4% of pts discontinued therapy due to TRAEs; none discontinued rev due to differentiation syndrome or QTc prolongation. The pooled efficacy population for the IA (n=57) included all phase 2 pts with centrally confirmed KMT2Ar and ≥5% blasts in bone marrow at baseline who had received ≥1 dose of study drug and started treatment on or before the 38th adult AML efficacy evaluable patient. The IA was specified to occur when the 57 patients have had the opportunity to be followed for 6 months. After median follow-up of 6.1 mo, 13 pts (22.8% [95% confidence interval (CI), 12.7-35.8]) achieved CR+CRh, surpassing the predefined IA efficacy boundary for the pooled KMT2Ar population; CR+CRh rate was similar in adult and pediatric pts. Median duration of CR+CRh was 6.4 mo (95% CI, 3.4-not reached). CRc was 43.9% (95% CI, 30.7-57.6); ORR was 63.2% (95% CI, 49.3-75.6). Most pts with a CR or CRh response, and for whom measurable residual disease (MRD) status was reported, achieved MRD negativity (7/10, 70.0%); most pts with CRc and MRD reported also achieved MRD negativity (15/22, 68.2%). Fourteen of 36 responders (38.9%) proceeded to HSCT, with half resuming rev post HSCT. Conclusions: Rev demonstrated clinically meaningful results in a heavily pretreated KMT2Ar population, including high ORR and rates of MRD negativity and subsequent HSCT. At IA, this pivotal study met its primary endpoint and the KMT2Ar cohorts were stopped early for efficacy.

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

While therapies targeting CD19 by antibodies, chimeric antigen receptor T cells (CAR-T), and T cell engagers have improved the response rates in B cell malignancies, the emergence of resistant cell populations with low CD19 expression can lead to relapsed disease. We developed an in vitro model of adaptive resistance facilitated by chronic exposure of leukemia cells to a CD19 immunotoxin. Single-cell RNA-Seq (scRNA-Seq) showed an increase in transcriptionally distinct CD19lo populations among resistant cells. Mass cytometry demonstrated that CD22 was also decreased in these CD19lo-resistant cells. An assay for transposase-accessible chromatin with sequencing (ATAC-Seq) showed decreased chromatin accessibility at promoters of both CD19 and CD22 in the resistant cell populations. Combined loss of both CD19 and CD22 antigens was validated in samples from pediatric and young adult patients with B cell acute lymphoblastic leukemia (B-ALL) that relapsed after CD19 CAR-T-targeted therapy. Functionally, resistant cells were characterized by slower growth and lower basal levels of MEK activation. CD19lo resistant cells exhibited preserved B cell receptor signaling and were more sensitive to both Bruton's tyrosine kinase (BTK) and MEK inhibition. These data demonstrate that resistance to CD19 immunotherapies can result in decreased expression of both CD19 and CD22 and can result in dependency on BTK pathways.

PURPOSE The development of targeted therapeutics has revolutionized treatment for elderly patients with AML. Two doublet regimens are approved in the frontline setting for intensive chemotherapy (IC)–ineligible AML: venetoclax (VEN) in combination with hypomethylating agent (HMA) therapy and azacitidine (AZA) plus ivosidenib (IVO) specifically for IDH1 -mutated AML. Although both regimens have improved AML outcomes, most patients will either not respond to frontline therapy or relapse, with dismal salvage outcomes. METHODS We herein report on 60 newly diagnosed IC-ineligible patients treated at our institution with triplet regimens for isocitrate dehydrogenase ( IDH )–mutant AML. Patients received either AZA + VEN + IVO on NCT03471260 ( IDH1 -mutated patients only) or oral decitabine + VEN + IVO/enasidenib on NCT04774393 (arms for IDH1- and IDH2 -mutant disease, respectively). RESULTS The triplet regimens were well tolerated with low early mortality (n = 1 [2%] in 60 days) and a similar safety profile to HMA + VEN and isocitrate dehydrogenase inhibitor doublet regimens. The composite complete remission rate (CRc) was 92% (55/60), with an overall response rate of 95% (57/60). With a median follow-up of 27.4 months, the median overall survival (OS) has not yet been reached. The 2-year OS was 69% with a 2-year cumulative incidence of relapse of 24%. Patients with treated-secondary AML (tsAML) experienced inferior outcomes with a CRc of 71% (12/17) and a 2-year OS of 34%; the 2-year OS was 84% in patients without tsAML. Nineteen patients (32%) transitioned to stem cell transplant, and 51% remain on study. CONCLUSION Given the excellent outcomes of IDH-triplet therapy for newly diagnosed, IC-ineligible IDH -mutant AML, further prospective studies comparing IDH-triplet versus IDH-doublet regimens are warranted.

PurposeNo Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study.Methods and MaterialsThis study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients’ blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria.ResultsFifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient.ConclusionsOur results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy. No Food and Drug Administration-approved intervention exists for oral mucositis (OM) from chemoradiotherapy (CRT) used to treat head and neck cancers. RRx-001 is a hypoxia-activated, cysteine-directed molecule that affects key pathways involved in OM pathogenesis. This phase 2a, multi-institutional trial was designed to assess the safety and feasibility of 3 schedules of a fixed concentration of RRx-001; a standard-of-care arm was included to identify potential signals of efficacy for further study. This study enrolled patients with oral cavity and oropharynx squamous cell carcinoma receiving definitive or postoperative cisplatin-based CRT. Patients were randomized into 4 cohorts. In arms 1 to 3, RRx-001 was coinfused with patients’ blood at differing intervals. Arm 4 was a control cohort of patients treated with CRT alone. Trained evaluators assessed OM using a standardized data collection instrument twice weekly during treatment and then until resolution. OM severity was scored centrally using World Health Organization criteria. Safety outcomes were assessed using National Cancer Institute - Common Terminology Criteriav4 benchmarks. Long-term tumor response was defined by Response evaluation criteria in solid tumors v1.1 criteria. Fifty-three patients were enrolled, with 46 and 45 individuals contributing safety and efficacy data, respectively. There were no severe adverse events attributed to the study drug. Across all 3 active arms, the study drug was infused fully per protocol in 86% of patients. All 3 RRx-001 treatment cohorts appeared to demonstrate a similar or lower OM duration relative to control; arm 1 had the lowest median duration of severe oral mucositis (SOM), 8.5 days versus 24 days in controls among patients who developed at least 1 day of SOM. There were no locoregional failures in any patient. Our results support the safety and feasibility of RRx-001 as an intervention to mitigate SOM. Additional studies are planned to confirm its efficacy.