NEJM original articles

Background. Sacituzumab tirumotecan (sac-TMT) is an antibody-drug conjugate targeting trophoblast cell-surface antigen 2 that has shown significant survival benefits in patients with EGFR-mutated non-small-cell lung cancer (NSCLC) that has progressed after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and platinum-based chemotherapy.

Methods. In this phase 3 trial, we enrolled patients with EGFR-mutated locally advanced or metastatic nonsquamous NSCLC that had progressed after EGFR-TKI therapy. The patients were randomly assigned, in a 1:1 ratio, to receive sac-TMT monotherapy or pemetrexed plus platinum-based chemotherapy. The primary end point was progression-free survival as assessed by blinded independent review. Overall survival was a hierarchically tested key secondary end point. In the interim analysis of progression-free survival as assessed by blinded independent review, sac-TMT monotherapy met the prespecified criterion for significance (two-sided P<0.0001); we report here the prespecified final analysis of progression-free survival and the preplanned interim analysis of overall survival.

Results. Overall, 376 patients underwent randomization, with 188 assigned to each group. After a median follow-up of 18.9 months, the median progression-free survival was 8.3 months in the sac-TMT group and 4.3 months in the chemotherapy group (hazard ratio for disease progression or death, 0.49; 95% confidence interval [CI], 0.39 to 0.62). Overall survival was significantly longer with sac-TMT than with chemotherapy (hazard ratio for death, 0.60; 95% CI, 0.44 to 0.82; two-sided P = 0.001); 18-month overall survival was 65.8% and 48.0%, respectively. Treatment-related adverse events of grade 3 or higher occurred in 58.0% of patients receiving sac-TMT and in 53.8% of those receiving chemotherapy, with the most common being a decreased neutrophil count (39.9% vs. 33.0%); treatment-related serious adverse events occurred in 9.0% and 17.6%, respectively.

Conclusions. In patients with EGFR-mutated advanced or metastatic NSCLC that had progressed after previous EGFR-TKI therapy, progression-free survival and overall survival outcomes were significantly better with sac-TMT than with platinum-based chemotherapy. (Funded by Sichuan Kelun-Biotech Biopharmaceutical; OptiTROP-Lung04 ClinicalTrials.gov number, NCT05870319.).

Background. The primary analysis of this trial showed that first-line treatment with osimertinib plus chemotherapy with a platinum-based agent and pemetrexed led to significantly longer progression-free survival than osimertinib monotherapy among patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC). Results from the planned final analysis of overall survival are needed.

Methods. In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced NSCLC who had not previously received treatment for advanced disease to receive either osimertinib (80 mg once daily) plus chemotherapy with pemetrexed (500 mg per square meter of body-surface area) and a platinum-based agent (cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or osimertinib monotherapy (80 mg once daily). The key secondary end point was overall survival.

Results. A total of 557 patients were randomly assigned to the osimertinib plus platinum-pemetrexed group (279 patients) or the osimertinib monotherapy group (278 patients). The median overall survival was 47.5 months in the osimertinib plus platinum-pemetrexed group and 37.6 months in the osimertinib monotherapy group (hazard ratio for death, 0.77; 95% confidence interval, 0.61 to 0.96; P = 0.02). Grade 3 or higher adverse events of any cause were reported in 70% of the patients in the osimertinib plus platinum-pemetrexed group and in 34% of the patients in the osimertinib monotherapy group; adverse events leading to the discontinuation of osimertinib were reported in 12% and 7%, respectively.

Conclusions. Among patients with EGFR-mutated advanced NSCLC, first-line treatment with osimertinib plus platinum-pemetrexed led to significantly longer overall survival than osimertinib monotherapy and was associated with an increased risk of reversible adverse events of grade 3 or higher. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Background. Tividenofusp alfa, comprising iduronate-2-sulfatase fused to an engineered transferrin receptor-binding Fc domain, has been developed to treat neurologic and peripheral manifestations of mucopolysaccharidosis type II (MPS II), a rare lysosomal disorder causing progressive multisystem and neurologic decline.

Methods. We conducted a phase 1-2, open-label study in which male participants up to 18 years of age with MPS II received weekly intravenous tividenofusp alfa for 24 weeks, followed by an 80-week safety extension and a 157-week open-label extension. The primary objective was to evaluate the safety of tividenofusp alfa. Secondary objectives were to evaluate central nervous system and peripheral effects as assessed by cerebrospinal fluid (CSF) and urinary heparan sulfate levels, adaptive behavior (as assessed with the Vineland Adaptive Behavior Scales), and liver volume.

Results. A total of 47 male participants were enrolled. At the 24-week primary analysis, all 47 participants reported at least one adverse event that emerged during the treatment period, most commonly infusion-related reactions. Pyrexia, urticaria, and vomiting were the most frequently reported symptoms of infusion-related reactions, occurring in more than 40% of the participants, despite routine premedication. Three participants had serious treatment-related adverse events; all continued to receive treatment. CSF and urinary heparan sulfate levels appeared to be reduced from baseline by 91% and 88%, respectively. Across all study periods, adverse events remained common. Reductions in heparan sulfate levels appeared to be maintained through week 153, adaptive behavior stabilized or improved, and liver volumes normalized or remained normal.

Conclusions. In participants with MPS II, tividenofusp alfa treatment was commonly associated with adverse events. Heparan sulfate, the primary substrate that accumulates in the CSF and urine in persons with MPS II, appeared to decrease to levels within the range of unaffected children. A randomized trial is ongoing to further evaluate these effects. (Funded by Denali Therapeutics; ClinicalTrials.gov number, NCT04251026; EudraCT number, 2019-004909-27.).

Background. Patients with plasmacytomas that are noncontiguous with bone marrow (true extramedullary myeloma) are at high risk for disease progression or relapse. Phase 1 of the RedirecTT-1 study showed promising efficacy with dual-antigen targeting of myeloma with talquetamab (anti-G protein-coupled receptor family C group 5 member D) plus teclistamab (anti-B-cell maturation antigen) in patients with triple-class-exposed relapsed or refractory multiple myeloma, including those with true extramedullary myeloma.

Methods. In this phase 2 study, we investigated talquetamab plus teclistamab exclusively in patients with drug-resistant, true extramedullary myeloma. The primary end point was overall response, evaluated with the use of functional imaging. Secondary end points included the duration of response, progression-free survival, overall survival, and safety.

Results. A total of 90 patients were enrolled in the study and received treatment (median follow-up, 12.6 months). A response occurred in 79% of the patients (95% confidence interval [CI], 69 to 87). Among the patients with a response, the percentage with a response duration of at least 12 months was 64% (95% CI, 48 to 76). At 12 months, progression-free survival was 61% (95% CI, 50 to 71), and overall survival was 74% (95% CI, 63 to 83). Common adverse events of any grade included oral symptoms, such as dysgeusia, dry mouth, and dysphagia (in 87% of the patients); cytokine release syndrome (in 78%); and nonrash skin effects (in 69%). Grade 3 or 4 adverse events (most commonly hematologic events) occurred in 76% of the patients; 31% had grade 3 or 4 infection. A nonfatal adverse event led to discontinuation of one or both agents in 6% of the patients. Among 10 deaths that occurred during follow-up, 5 were due to infection and 5 were considered to be related to the study treatment.

Conclusions. Most patients with drug-resistant, true extramedullary myeloma had a response with talquetamab plus teclistamab. The incidence of adverse events of grade 3 or above was high and was consistent with previous observations for each agent as monotherapy. (Funded by Johnson & Johnson; RedirecTT-1 ClinicalTrials.gov number, NCT04586426.).