Bhoj VG, Kaminski M, Zhao H
… +34 more, Jackson K, Wang W, Liu C, Montgomery RA, Ali N, Mangiola M, Spitzer TR, Safa K, Pattanayak V, Taj R, Chiu J, Bui TM, Sonnenberg EM, Markmann JF, Milone MC, June CH, Siegel DL, Fraietta JA, Gonzalez V, Locci M, Palmer M, Monos D, Hwang WT, Sledge T, Bridges ND, Goldstein JS, Odim J, Sweet SC, Besharatian BD, Hussain SM, Brown NK, Kamoun M, Garfall AL, Naji A
N Engl J Med
· 2026 Jun · PMID 42235014
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HLA sensitization poses a major challenge to kidney transplantation for patients with end-stage kidney disease, especially for highly sensitized candidates. Attempts at antibody elimination (desensitization) have had inc...HLA sensitization poses a major challenge to kidney transplantation for patients with end-stage kidney disease, especially for highly sensitized candidates. Attempts at antibody elimination (desensitization) have had inconsistent efficacy and have often failed to produce sustained reductions in anti-HLA antibodies in patients with the highest level of sensitization (calculated panel-reactive antibody score, ≥99.9%). We now report the results for the safety run-in cohort of a multicenter phase 1 clinical study evaluating the safety and efficacy of combined CD19-targeted and B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T cells in eliminating the cellular sources of preformed anti-HLA antibodies (ClinicalTrials.gov number, NCT06056102). Kidney transplantation was performed in two highly sensitized candidates after desensitization with the use of dual CAR T-cell therapy.
Roboz GJ, Zeidan AM, Mannis GN
… +20 more, Montesinos P, Arnan M, Savona MR, Odenike O, McCloskey JK, Amin HV, Fathi AT, Bernal Del Castillo T, Rodríguez-Macías G, Liesveld JL, Im AP, Cerny J, Gentile TC, Oganesian A, Chan D, Wan Y, Dijkstra M, Keer HN, Griffiths EA, DiNardo CD
N Engl J Med
· 2026 Jun · PMID 42235013
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BACKGROUND: For patients with acute myeloid leukemia (AML) who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, b...BACKGROUND: For patients with acute myeloid leukemia (AML) who are 75 years of age or older or who are ineligible for intensive induction chemotherapy, azacitidine or decitabine plus venetoclax is the standard of care, but parenteral administration imposes a burden on patients and providers. Oral decitabine-cedazuridine, approved in Europe for AML, has pharmacokinetic properties equivalent to those of intravenous decitabine but provides limited survival benefit as monotherapy. METHODS: In this phase 1-2, open-label, multicenter, nonrandomized trial, we assigned patients with newly diagnosed AML who were 75 years of age or older or who were ineligible for intensive chemotherapy to receive oral decitabine-cedazuridine plus oral venetoclax. To mitigate myelosuppression observed in phase 1, schedule adjustments were encouraged in phase 2b after bone marrow blast clearance. The primary end points were the venetoclax area under the curve from 0 to 24 hours and maximum observed concentration with or without decitabine-cedazuridine (measures of drug interaction) on days 5 and 15 of cycle 2 (phase 1-2a) and complete response (phase 2a-b). RESULTS: A total of 189 patients were enrolled (30 patients in phase 1, 58 patients in phase 2a, and 101 patients in phase 2b). No drug-drug interactions were observed between decitabine-cedazuridine and venetoclax. In the pivotal phase 2b, the percentage of patients with a complete response was 47% (95% confidence interval [CI], 36 to 57), the percentage with a complete response or complete response with incomplete hematologic recovery was 63% (95% CI, 53 to 73), and median overall survival was 15.5 months (95% CI, 7.6 to could not be estimated). Common adverse events of grade 3 or higher in phase 2b were anemia (in 30% of the patients), neutropenia (in 26%), and febrile neutropenia (in 25%). Mortality was 3% at 30 days and 10% at 60 days. CONCLUSIONS: Among patients with newly diagnosed AML who were ineligible for intensive chemotherapy, all-oral decitabine-cedazuridine plus venetoclax caused no drug interactions and resulted in a complete response in nearly half the patients, with myelosuppressive effects. (Funded by Taiho Oncology; ASCERTAIN-V ClinicalTrials.gov number, NCT04657081.).
Stone JH, Buttgereit F, Saraux A
… +23 more, Schmidt WA, Dejaco C, Spiera R, Dasgupta B, Drescher E, Jordan A, Novosad L, Nakagomi D, Koyama Y, Duran-Barragan S, Tracey G, Ruyssen-Witrand A, Rubbert Roth A, Fang J, Ng J, Hiremath R, Raffner R, Martin R, Napoletano S, Huang S, Storim J, Patekar M, REPLENISH Investigators
N Engl J Med
· 2026 Jun · PMID 42234540
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BACKGROUND: Polymyalgia rheumatica is a common inflammatory disease characterized by pain and stiffness in the shoulders and hips. Glucocorticoids are the first-line treatment, but relapses and glucocorticoid-related tox...BACKGROUND: Polymyalgia rheumatica is a common inflammatory disease characterized by pain and stiffness in the shoulders and hips. Glucocorticoids are the first-line treatment, but relapses and glucocorticoid-related toxic effects are common, which underscores the need for effective alternatives. Secukinumab is a fully human monoclonal antibody that selectively inhibits interleukin-17A. METHODS: We enrolled patients with recently relapsed polymyalgia rheumatica and randomly assigned them, in a 1:1:1 ratio, to receive secukinumab at a dose of 300 mg (SEC-300 group), secukinumab at a dose of 150 mg (SEC-150 group), or placebo for 52 weeks. Patients in all the groups also received prednisone on a tapering schedule for 24 weeks. The primary outcome was sustained remission at week 52, defined as remission (the absence of signs or symptoms attributable to polymyalgia rheumatica and no new diagnosis of giant-cell arteritis that warranted escape or rescue treatment) that was sustained from week 12 until week 52. The annual cumulative glucocorticoid dose was a secondary outcome. Safety was also assessed. RESULTS: A total of 381 patients underwent randomization, and 127 were assigned to each group. At 52 weeks, sustained remission was observed in 41.2% (95% confidence interval [CI], 32.8 to 49.7) of the patients in the SEC-300 group, in 40.6% (95% CI, 32.2 to 49.0) of those in the SEC-150 group, and in 20.4% (95% CI, 13.6 to 27.2) of those in the placebo group (P<0.001 for the comparison of each secukinumab dose with placebo). The mean adjusted annual cumulative glucocorticoid dose was 1603.7 mg in the SEC-300 group, 1683.2 mg in the SEC-150 group, and 2093.0 mg in the placebo group. Serious adverse events occurred in 13.5% of the patients in the SEC-300 group, in 15.9% in the SEC-150 group, and in 14.2% in the placebo group. Nasopharyngitis, hypersensitivity reactions, urinary tract infections, fungal infections, and back pain were more common in the secukinumab groups than in the placebo group. CONCLUSIONS: Among patients with relapsed polymyalgia rheumatica, treatment with secukinumab plus a 24-week glucocorticoid taper resulted in a higher percentage of patients with remission and in lower cumulative glucocorticoid doses than a glucocorticoid taper alone. (Funded by Novartis; REPLENISH ClinicalTrials.gov number, NCT05767034.).
Della-Torre E, Baker MC, Zhang W
… +32 more, Perugino CA, Katz G, Tanaka Y, Khosroshahi A, Kleger A, Schleinitz N, Martinez-Valle F, Schulze-Koops H, Nakayamada S, Rebours V, Okazaki K, Dong L, Carruthers M, Chen LYC, Frulloni L, Meysami A, Takahashi H, Kawano M, Liu Y, Saeki T, Ebbo M, Alexander T, González García A, Karadag O, Maślińska M, Quinn SM, Poma A, Wells A, Greene TJ, Stone JH, Culver EL, INDIGO Trial Investigators
N Engl J Med
· 2026 Jun · PMID 42233621
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BACKGROUND: IgG4-related disease is a chronic fibroinflammatory condition that can affect virtually any organ system. Glucocorticoid agents are a cornerstone of therapy but are limited by toxic effects, and relapse is co...BACKGROUND: IgG4-related disease is a chronic fibroinflammatory condition that can affect virtually any organ system. Glucocorticoid agents are a cornerstone of therapy but are limited by toxic effects, and relapse is common after discontinuation. Obexelimab is a bifunctional monoclonal antibody that inhibits B-cell activity through coengagement of CD19 and FcγRIIb without inducing B-cell depletion. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, patients with active IgG4-related disease received subcutaneous obexelimab at a dose of 250 mg or placebo once weekly for 52 weeks. For patients in both groups, glucocorticoids were tapered in a standardized schedule to discontinuation at week 8. The primary end point was the time to the first flare of IgG4-related disease for which rescue therapy was required, as determined by both the investigator and the independent adjudication committee. Key secondary end points included complete remission at week 52 and the cumulative dose of glucocorticoid rescue therapy through week 52. RESULTS: From January 2023 through November 2024, a total of 194 patients underwent randomization (with 97 assigned to each group). The time to the first disease flare that required rescue therapy was significantly longer with obexelimab than with placebo (hazard ratio, 0.44; 95% confidence interval, 0.28 to 0.71; P<0.001); flares were reported in 26 patients (26.8%) in the obexelimab group and in 53 patients (54.6%) in the placebo group. Obexelimab showed a significant benefit over placebo with respect to all the key secondary end points, including complete remission (37.1% vs. 19.6%, P = 0.005) and the cumulative dose of glucocorticoid rescue therapy (329.5 mg vs. 929.8 mg, P = 0.004). Adverse events included arthralgias (in 19.6% of the patients in the obexelimab group vs. 11.3% of those in the placebo group), hypersensitivity (in 16.5% vs. 11.3%), and diarrhea (in 11.3% vs. 6.2%). Serious adverse events occurred in 10.3% of the patients in the obexelimab group and in 18.6% of those in the placebo group. CONCLUSIONS: Among patients with active IgG4-related disease, weekly obexelimab treatment led to a significantly lower risk of disease flare and significantly less glucocorticoid exposure than placebo. (Funded by Zenas BioPharma; INDIGO ClinicalTrials.gov number, NCT05662241.).
Wu YL, Hochmair M, Yang Y
… +17 more, Yang XN, Tsuboi M, Paz-Ares L, Yang JC, Wu L, Kim HR, Rieke DT, Johnson M, Besse B, Sharma N, Maeda P, Peterson P, Lin BK, Frimodt-Moller B, Goldman J, Drilon A, LIBRETTO-432 Trial Investigators
N Engl J Med
· 2026 May · PMID 42223087
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BACKGROUND: Selpercatinib, a highly selective, potent, and central nervous system-penetrant rearranged during transfection (RET) inhibitor, is approved for fusion-positive advanced or metastatic non-small-cell lung canc...BACKGROUND: Selpercatinib, a highly selective, potent, and central nervous system-penetrant rearranged during transfection (RET) inhibitor, is approved for fusion-positive advanced or metastatic non-small-cell lung cancer (NSCLC). The efficacy and safety of selpercatinib in early-stage NSCLC are unknown. METHODS: We conducted a phase 3, double-blind trial involving patients with fusion-positive NSCLC who had received definitive therapy with curative intent (surgery or radiotherapy with adjuvant systemic anticancer therapy, if applicable). Patients were randomly assigned to receive adjuvant selpercatinib or placebo for up to 3 years. The primary end point was investigator-assessed event-free survival in patients with stage II or IIIA disease. Secondary end points were investigator-assessed event-free survival in patients with stage IB, II, or IIIA disease; event-free survival as assessed by blinded independent central review; overall survival; and safety. RESULTS: A total of 151 patients were assigned to receive selpercatinib (75 patients) or placebo (76 patients). Median follow-up was 24 months and 27 months in the respective groups. Among 109 patients with stage II or IIIA disease, 2-year investigator-assessed event-free survival was 92% with selpercatinib and 61% with placebo (hazard ratio for disease recurrence, progression, or death, 0.17; 95% confidence interval [CI], 0.06 to 0.51; P<0.001). Event-free survival as assessed by blinded independent central review was consistent with investigator-assessed event-free survival. Among the 151 patients with stage IB, II, or IIIA NSCLC, investigator-assessed event-free survival at 2 years was 94% with selpercatinib and 70% with placebo (hazard ratio for disease recurrence, progression, or death, 0.17; 95% CI, 0.06 to 0.49; P<0.001). The most common adverse events during the treatment period were increased levels of alanine aminotransferase and aspartate aminotransferase (grade ≥3 in 17% and 19% of patients, respectively, in the selpercatinib group). Three deaths occurred, all in the placebo group, owing to disease progression. CONCLUSIONS: Among patients with stage II or IIIA fusion-positive NSCLC, event-free survival was significantly longer with adjuvant selpercatinib than with placebo. (Funded by Lilly; LIBRETTO-432 ClinicalTrials.gov number, NCT04819100.).
Taplin ME, Gleave M, Shore ND
… +21 more, Lopez-Gitlitz A, Kretschmer A, Efstathiou E, Nguyen PL, Damião R, Kamoto T, Ross A, Briganti A, Hadaschik BA, Heidenreich A, Juárez Soto Á, Ye H, Gotto G, Rooney B, Tian SK, Wetherhold L, Miladinovic B, McCarthy SA, Evans CP, Kibel AS, PROTEUS Investigators
N Engl J Med
· 2026 May · PMID 42223077
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BACKGROUND: Radical prostatectomy is potentially curative in patients with high-risk localized or locally advanced prostate cancer; however, relapse occurs within 5 years in up to 50% of patients. METHODS: We conducted a...BACKGROUND: Radical prostatectomy is potentially curative in patients with high-risk localized or locally advanced prostate cancer; however, relapse occurs within 5 years in up to 50% of patients. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial in which patients with newly diagnosed high-risk localized or locally advanced prostate cancer were randomly assigned in a 1:1 ratio to receive androgen-deprivation therapy (ADT) plus apalutamide (240 mg per day) or ADT plus placebo for 6 cycles (28 days each) before and after radical prostatectomy with pelvic lymph-node dissection. The dual primary end points were a composite of pathological complete response or minimal residual disease (defined as a pathological stage of ypT2 or lower, with a tumor size of ≤5 mm in the greatest dimension) and metastasis-free survival, as assessed with conventional imaging or prostate-specific membrane antigen positron-emission tomography. Secondary end points included event-free survival, first subsequent treatment, and distant metastasis (assessed in time-to-event analyses), as well as safety. RESULTS: A total of 2109 patients underwent randomization: 1057 were assigned to receive ADT plus apalutamide, and 1052 to receive ADT plus placebo. The median follow-up was 61.7 months. The percentage of patients with a pathological complete response or minimal residual disease was significantly higher in the apalutamide group than in the placebo group (8.9% vs. 1.0%; odds ratio, 10.17; 95% confidence interval [CI], 5.27 to 19.64; P<0.001), as was the percentage of patients with metastasis-free survival (probability of metastasis-free survival at 5 years, 78.2% vs. 73.5%; hazard ratio for distant metastasis or death, 0.80; 95% CI, 0.67 to 0.96; P = 0.02). Event-free survival, time to the first subsequent treatment, and time to distant metastasis significantly favored ADT plus apalutamide over ADT plus placebo (P<0.001 for all between-group comparisons). Grade 3 or 4 adverse events occurred in 39.6% of the patients in the apalutamide group and in 31.0% of those in the placebo group, with the difference between the groups driven primarily by a higher incidence of rash in the apalutamide group. CONCLUSIONS: Perioperative treatment with ADT plus apalutamide was associated with better oncologic outcomes of radical prostatectomy in patients with high-risk localized or locally advanced prostate cancer than treatment with ADT plus placebo. Adverse events were more common in the apalutamide group than in the placebo group. (Funded by Johnson & Johnson; PROTEUS ClinicalTrials.gov number, NCT03767244.).
O'Reilly EM, Wainberg ZA, Hendifar AE
… +18 more, Borad MJ, Pietrantonio F, Pant S, Hammel P, Cremolini C, Manji GA, Oberstein PE, Garrido-Laguna I, Springfeld C, Azad NS, Ueno M, Chui SY, Zhang Y, Patel H, Lee Y, Salman Z, Wolpin BM, RASolute 302 Trial Investigators
N Engl J Med
· 2026 May · PMID 42223072
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BACKGROUND: Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogen...BACKGROUND: Current therapies offer limited benefit for patients with previously treated metastatic pancreatic ductal adenocarcinoma (mPDAC). Aberrant activation of the RAS pathway is the key driver of PDAC, with oncogenic mutations present in more than 90% of cases. Daraxonrasib is an oral RAS(ON) multiselective, tri-complex inhibitor of the active guanosine triphosphate-bound state of mutant and wild-type RAS. METHODS: In this phase 3, international, open-label, randomized trial, we randomly assigned patients with previously treated mPDAC to receive daraxonrasib or chemotherapy of the investigator's choice. The dual primary end points were overall survival and progression-free survival in the subpopulation of patients with G12 mutations (the G12 population). Key secondary end points included overall survival and progression-free survival in the overall population (which included patients with G12, G13, or Q61 mutations or with no mutation identified) and objective response and patient-reported quality of life in the G12 and overall populations. Safety was also assessed. RESULTS: A total of 500 patients, including 91.8% with G12 mutations, were randomly assigned to receive daraxonrasib (248 patients) or chemotherapy (252 patients). The median overall survival in the G12 population was 13.2 months with daraxonrasib and 6.6 months with chemotherapy, and the median overall survival in the overall population was 13.2 months and 6.7 months, respectively; the hazard ratio was 0.40 in both populations (P<0.001). The median progression-free survival in the G12 population was 7.3 months with daraxonrasib and 3.5 months with chemotherapy, and that in the overall population was 7.2 months and 3.6 months, respectively; the hazard ratios were 0.45 and 0.49, respectively (P<0.001 for both comparisons). Adverse events that occurred after the start of treatment were reported in all the patients in the daraxonrasib group and in 97.7% of those in the chemotherapy group; the incidence of adverse events of grade 3 or higher was 61.8% and 69.6%, respectively. Treatment-related adverse events that led to treatment discontinuation occurred in 1.2% of the patients in the daraxonrasib group and in 11.2% of those in the chemotherapy group. CONCLUSIONS: Among patients with previously treated mPDAC, treatment with daraxonrasib led to significantly longer overall survival and progression-free survival than chemotherapy. (Funded by Revolution Medicines; RASolute 302 ClinicalTrials.gov number, NCT06625320.).
Agarwal N, Matsubara N, Azad AA
… +16 more, Saad F, Mateo J, Jiang S, Ye D, Voog E, Shore ND, Çil T, Vulsteke C, Chung HJ, Zschäbitz S, Laird AD, Zhang X, Nandoskar P, Chetcuti SF, Wang F, Fizazi K
N Engl J Med
· 2026 May · PMID 42223064
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BACKGROUND: A previous trial involving patients with metastatic prostate cancer that was resistant to androgen pathway modulation (formerly referred to as castration-resistant) showed that adding talazoparib to enzalutam...BACKGROUND: A previous trial involving patients with metastatic prostate cancer that was resistant to androgen pathway modulation (formerly referred to as castration-resistant) showed that adding talazoparib to enzalutamide significantly improved imaging-based progression-free survival and overall survival, with the greatest benefit observed in the cohort with alterations in homologous recombination repair genes. METHODS: In this ongoing, phase 3, double-blind trial assessing talazoparib in patients with metastatic androgen pathway modulation-sensitive [APMS] prostate cancer harboring alterations in homologous recombination repair genes, we randomly assigned patients in a 1:1 ratio to receive talazoparib at a dose of 0.5 mg plus enzalutamide at a dose of 160 mg once daily (talazoparib group) or placebo plus enzalutamide at a dose of 160 mg once daily (control group). Randomization was stratified according to disease status (new or relapsed), disease volume (high or low), and (vs. non-) mutation status. The primary end point was investigator-assessed imaging-based progression-free survival. The key secondary end point was overall survival. RESULTS: A total of 300 patients were assigned to the talazoparib group and 299 to the control group. At 3 years, progression-free survival was 77% in the talazoparib group and 56% in the control group (hazard ratio for disease progression or death, 0.48; 95% confidence interval [CI], 0.36 to 0.65; P<0.001). In this interim analysis, overall survival at 3 years was 78% in the talazoparib group and 72% in the control group (hazard ratio for death, 0.77; 95% CI, 0.56 to 1.04). Serious adverse events were reported in 42% and 32% of the patients in the talazoparib group and the control group, respectively. In the talazoparib group, the most common adverse events were anemia, fatigue, and decreased neutrophil count, and the most common event of grade 3 or higher was anemia, reported in 51% of the patients; two treatment-related deaths occurred. CONCLUSIONS: Talazoparib added to enzalutamide led to significantly better imaging-based progression-free survival than placebo plus enzalutamide among patients with metastatic APMS prostate cancer harboring alterations in homologous recombination repair genes. Serious adverse events were more common with talazoparib plus enzalutamide than with placebo plus enzalutamide. (Funded by Pfizer; TALAPRO-3 ClinicalTrials.gov number, NCT04821622.).