Issa GC, Cuglievan B, El Hajjar G
… +29 more, Jen WY, Bataller A, Short NJ, DiNardo CD, Alvarado Y, Loghavi S, Duose DY, Zhang B, Furudate K, Ning J, Xiao L, Mouhayar E, Pinto A, Bidikian A, Thompson E, Daver N, Garcia-Manero G, Farhat A, McCall D, Kadia TM, Abbas HA, Tan S, Bazinet A, Jabbour E, Montalban-Bravo G, Ravandi F, Takahashi K, Andreeff M, Kantarjian HM
PURPOSE: Revumenib is an oral inhibitor of menin-KMT2A, a key dependency in acute myeloid leukemia (AML) with rearrangement (), mutation (), or rearrangement (). Preclinical studies suggest synergy with BCL2 inhibitio...PURPOSE: Revumenib is an oral inhibitor of menin-KMT2A, a key dependency in acute myeloid leukemia (AML) with rearrangement (), mutation (), or rearrangement (). Preclinical studies suggest synergy with BCL2 inhibition. METHODS: In this phase I-II study, we evaluated an all-oral regimen of revumenib, decitabine/cedazuridine, and venetoclax in patients 12 years and older with relapsed or refractory AML. Decitabine/cedazuridine was given on days 1-5, venetoclax on days 1-14, and revumenib twice daily on days 1-28. The primary objectives were to determine the recommended phase II dose (RP2D) and to assess efficacy according to the composite complete remission (CRc) rate. RESULTS: Forty-two patients were enrolled (median age, 40 years; range, 12-82) including 40% with 38% with , and 21% with Patients had a median of two prior lines of therapy; 52% had prior venetoclax. The RP2D of revumenib was 160 mg twice daily with a strong CYP3A4 inhibitor. Grade ≥3 adverse events included febrile neutropenia (36%), lung infection (21%), and thrombocytopenia (21%). Differentiation syndrome occurred in 10% (5% grade 3) and resolved with glucocorticoids. The CRc rate was 71%, and the CR or complete remission with partial hematologic recovery (CR/CRh) rate was 60%, with measurable residual disease negativity by flow cytometry in 80% of these patients. The median duration of CR/CRh for all patients was 10.5 months, not reached in , 10.7 months in , and 5.9 months in . Emergent mutations in the menin-binding site occurred in 13%. CONCLUSION: This combination was associated with high response rates and durable remissions, with an acceptable safety, in heavily pretreated patients with AML harboring alterations susceptible to menin inhibition.
Yang C, Jia Q, Zhao C
… +22 more, Yang X, Wei H, Liu T, Jiao J, Wu Z, Zhao J, Xu W, Zhou Z, Wan W, Zou W, Zhu Z, Ma X, Chen Q, Guo W, Zhu D, Tan T, Lou Y, Ye J, Xing J, Zhang H, Yuan Z, Xiao J
Qi C, Liu C, Gong J
… +22 more, Wang X, Wang Z, Xu T, Liu D, Zhang P, Li J, Zhang M, Zhang X, Lu M, Zhou J, Lu Z, Peng Z, Cao Y, Yuan J, Wang Y, Lu X, He T, Ding Y, Wu F, Liu D, Li J, Shen L
PURPOSE: The clinical efficacies of third- or later-line therapies for metastatic colorectal cancer (CRC) are extremely limited. The purpose of this study was to evaluate the safety and efficacy of a chimeric antigen rec...PURPOSE: The clinical efficacies of third- or later-line therapies for metastatic colorectal cancer (CRC) are extremely limited. The purpose of this study was to evaluate the safety and efficacy of a chimeric antigen receptor T (CAR T) cell targeting guanylyl cyclase 2C (GUCY2C) that was steadily expressed in all stages of CRC in a phase I study. PATIENTS AND METHODS: This was an open-label, single-center, phase I study, consisting of a 3 + 3 pattern dose-escalation phase and a dose-expansion investigation. Tumor tissues were histologically confirmed positive for GUCY2C expression. Four dose levels were tested in the dose-escalation phase, including 3 × 10 (DL1), 6 × 10 (DL2), 12 × 10 (DL3), and 20 × 10 (DL4) CAR T cells. The primary end points were safety and tolerability within 28 days after the first infusion. RESULTS: In dose-escalation phase, dose-limiting toxicity was not observed. DL3 was chosen for dose-expansion study. A total of 20 patients with metastatic CRC were infused with GUCY2C CAR T after lymphodepletion, and only one patient (5.0%) showed grade 3 cytokine release syndrome and neurotoxicity. Grade 3 diarrhea occurred in 11 patients (55.0%). Of 19 evaluable patients, the objective response rate (ORR) was 26.3%, with all responding patients in DL3 and DL4 groups. Of 10 patients in the DL3 group, the ORR was 40.0% and the median progression-free survival time (mPFS) was 7.0 months. Among patients showing medium-to-high GUCY2C expression in the DL3 group, the ORR achieved 50.0% and the mPFS was 9.0 months. CONCLUSION: GUCY2C CAR T showed acceptable safety profile and high response rate in patients with third- or later-line CRC, and the clinical efficacy was associated with CAR T dose level.
Hurvitz SA, Layman RM, Curigliano G
… +24 more, André F, Cristofanilli M, Kim SB, Martínez Rodríguez JL, Nadal JC, Kim GM, Lo L, Remolina-Bonilla YA, Rosselli G, Emile G, Korbenfeld E, Puig JM, Wesolowski R, Martin M, Ring A, Han HS, Giordano A, Mutka SC, Moss K, Suzuki S, Sullivan B, Gorbatchevsky I, Pistilli B, VIKTORIA-1 Study Group
Meng Y, Liu Y, Lin M
… +23 more, Wang L, Mu Y, Yang L, Du Y, Liu X, Chen Y, Tian S, Zhou Q, Zhuang X, Li Z, Liu J, Fang S, Fan W, Mao Y, Zhang L, Wu H, Yan F, Weng J, Zhao J, Long X, Liu L, Zhou J, Zhang J
PURPOSE: Guideline-recommended 4-day dexamethasone (DEX) for highly emetogenic chemotherapy (HEC) raises toxicity and immunotherapy interference concerns. We tested whether DEX reduction or omission with netupitant/palon...PURPOSE: Guideline-recommended 4-day dexamethasone (DEX) for highly emetogenic chemotherapy (HEC) raises toxicity and immunotherapy interference concerns. We tested whether DEX reduction or omission with netupitant/palonosetron (NEPA) plus olanzapine (OLZ) is noninferior to standard DEX. PATIENTS AND METHODS: In this open-label, randomized phase III noninferiority trial across 28 Chinese centers, adults receiving HEC received NEPA (day 1) plus OLZ (days 1-4) and were randomly assigned to standard DEX (12 mg day 1, 8 mg days 2-4), DEX-sparing (6 mg day 1 only), or DEX-free (no DEX). The primary end point was complete response (CR; no emesis/no rescue medication) from 0 to 120 h. Noninferiority margin was -12% (one-sided α = .025). RESULTS: Of 644 randomly assigned patients (median age 54.9 years; 66.0% female), stratified analysis showed overall CR rates of 72.4% for standard, 72.2% for DEX-sparing (stratified risk difference [RD], -0.2% [95% CI, -8.7 to 8.5]; = .005), and 70.1% for DEX-free (stratified RD, -2.2% [95% CI, -10.7 to 6.4]; = .014). Both met noninferiority, confirmed in per-protocol analysis. Steroid-related toxicities were significantly lower with DEX-sparing and DEX-free regimens versus standard. CONCLUSION: NEPA plus OLZ with reduced (6 mg day 1 only) or no DEX is noninferior to standard 4-day DEX for chemotherapy-induced nausea and vomiting prevention in HEC, supporting steroid-sparing strategies particularly relevant in the chemo-immunotherapy era.
Scherpereel A, Baas P, Nowak AK
… +17 more, Tsao AS, Fujimoto N, Peters S, Mansfield AS, Popat S, Aragon YB, Talbot T, Grossi F, Kowalski D, Kaplan MA, Cardona AF, Soomro R, Hu N, Lee A, Ip V, Hung YH, Zalcman G
Bose P, Ali H, Al-Ali HK
… +22 more, Garcia-Gutierrez V, Grosicki S, Grudeva-Popova Z, Harrison C, Hong J, Hou HA, Kwiatek M, Loschi M, Passamonti F, Patriarca A, Podoltsev N, Rampal R, Tantravahi S, Urian LG, Chai Y, Taverna P, Mark T, Sadiq A, Rangwala R, Vachhani P, Mascarenhas J, SENTRY Trial Investigators
PURPOSE: Ruxolitinib improves splenomegaly and symptoms in myelofibrosis (MF) but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in MF. We evaluated selinexo...PURPOSE: Ruxolitinib improves splenomegaly and symptoms in myelofibrosis (MF) but lacks reliable clonal burden reduction. Selinexor, an oral inhibitor of exportin 1, has demonstrated activity in MF. We evaluated selinexor plus ruxolitinib versus ruxolitinib alone in Janus kinase inhibitor-naïve MF. METHODS: In this double-blind, phase III trial, patients were randomly assigned (2:1) to receive selinexor plus ruxolitinib or placebo plus ruxolitinib. Coprimary end points were spleen volume reduction ≥35% (SVR35) and absolute mean change in total symptom score (AbsTSS; excluding fatigue) from baseline to week 24. RESULTS: A total of 353 patients were randomly assigned. At week 24, SVR35 was achieved in 49.8% of the selinexor plus ruxolitinib group versus 28.0% of the placebo plus ruxolitinib group (difference, 21.8 percentage points; odds ratio, 2.58 [95% CI, 1.60 to 4.17]; < .0001). Differences were evident by week 12 and through week 36. The AbsTSS coprimary end point was not met; however, symptom scores improved from baseline in both groups (-9.9 selinexor plus ruxolitinib, -10.9 placebo plus ruxolitinib), with no significant between-group difference. At a median follow-up of approximately 12 months, the overall survival (OS) hazard ratio was 0.43 ([95% CI, 0.19 to 1.00]; nominal = .022). Grade ≥3 adverse events (AEs) occurred in 70.1% and 50.0% of patients in the selinexor plus ruxolitinib or placebo plus ruxolitinib groups, respectively, most commonly anemia, thrombocytopenia, and neutropenia. Nausea was more frequent with selinexor but predominantly low-grade and early. CONCLUSION: In patients with JAK inhibitor-naïve MF, selinexor plus ruxolitinib met its coprimary end point of improved SVR35 but did not meet the AbsTSS coprimary end point, compared with placebo plus ruxolitinib. An early OS difference was observed. The safety profile was consistent with known AE profiles of the individual agents.
Cancer treatment is evolving from organ-based classification toward biomarker-driven precision medicine, culminating in the development of tumor-agnostic therapies approved based on molecular characteristics, irrespectiv...Cancer treatment is evolving from organ-based classification toward biomarker-driven precision medicine, culminating in the development of tumor-agnostic therapies approved based on molecular characteristics, irrespective of tumor origin. Since the US Food and Drug Administration's landmark 2017 approval of pembrolizumab for microsatellite instability-high tumors, nine tumor-agnostic drugs have been approved, offering unprecedented treatment options for patients with rare cancers and actionable genomic alterations. However, this scientific breakthrough has revealed profound global implementation challenges. We reviewed the current landscape of tumor-agnostic drug approvals, regulatory pathways, and implementation experiences across multiple regions, including Europe, Asia-Pacific, Latin America, Africa, and the Middle East. Barriers to access were examined across regulatory, reimbursement, infrastructure, and workforce domains to inform a conceptual framework for implementation. Access remains inconsistent even in high-resource settings, with fewer than 50% of eligible patients receiving matched therapies. In Europe, centralized regulatory approval through the European Medicines Agency contrasts sharply with fragmented national reimbursement decisions, creating delays in access. Asia-Pacific nations demonstrate rapid growth in tumor-agnostic approvals and drug development capacity, although significant urban-rural disparities persist. Latin America, Africa, and areas in the Middle East face fundamental barriers, including limited testing infrastructure, workforce shortages, and competing health care priorities. To address these challenges, we propose a four-pillar framework for equitable implementation: comprehensive biomarker testing capability, innovative clinical trial designs with decision-support systems, harmonized regulatory approval and reimbursement mechanisms, and investment in genomically competent workforce development. International initiatives including Project Orbis and cross-border trial consortia demonstrate promising models for regulatory convergence. Realizing the transformative potential of tumor-agnostic therapies requires coordinated global strategies that bridge the divide between genomic innovation and geographic accessibility, ensuring all patients benefit regardless of socioeconomic status or location.