Background Immunotherapy targeting the programmed cell death (ligand)-1 (PD-[L]1) pathway has improved outcomes in patients with advanced/metastatic non-small cell lung cancer (NSCLC) without actionable genomic alterations (AGAs), especially those with high PD-L1 expression (≥50% of tumor cells [TC]). However, some patients have primary or acquired resistance to treatment and new therapeutic strategies are needed to address this. Datopotamab deruxtecan (Dato-DXd), a trophoblast cell surface antigen 2 (TROP2)-directed antibody–drug conjugate, and rilvegostomig, a bispecific anti-PD-1/anti-TIGIT antibody, have shown promising efficacy and manageable safety profiles in patients with advanced or metastatic NSCLC. Methods and design TROPION-Lung10 (NCT06357533) is a phase 3, open-label, multicenter, randomized study evaluating the efficacy and safety of first-line Dato-DXd plus rilvegostomig versus standard-of-care pembrolizumab in patients with advanced/metastatic nonsquamous NSCLC with PD-L1 TC expression ≥50% and without AGAs. Approximately 675 adults with nonsquamous stage IIIB/C or IV NSCLC not amenable to curative surgery or definitive chemoradiation, PD-L1 TC ≥50%, and no AGAs will be enrolled. Patients will be randomized (2:1:2) to receive Dato-DXd (6 mg/kg intravenously [IV] every 3 weeks [Q3W]) plus rilvegostomig (750 mg IV Q3W), rilvegostomig alone (750 mg IV Q3W), or pembrolizumab (200 mg IV Q3W for up to 35 cycles/24 months). The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and overall survival (OS) in the TROP2 normalized membrane ratio (NMR) biomarker-positive population for Dato-DXd plus rilvegostomig versus pembrolizumab. The key secondary endpoints are PFS by BICR per RECIST v1.1 and OS in the full analysis set (FAS). Other secondary endpoints include the objective response rate and duration of response by BICR per RECIST v1.1, PFS2, patient-reported outcomes in the TROP2 NMR-positive population and FAS, and safety. Discussion TROPION-Lung10 will assess first-line Dato-DXd plus rilvegostomig in patients with advanced/metastatic NSCLC with high PD-L1 expression and without AGAs. Clinical trial registration ClinicalTrials.gov , identifier NCT06357533.

BackgroundTriple-negative breast cancer is an aggressive breast cancer subtype, and there remains an unmet need to improve outcomes in patients with previously untreated, programmed death ligand 1 (PD-L1)–positive, locally advanced unresectable or metastatic triple-negative breast cancer.MethodsIn this phase 3, open-label, international trial, we randomly assigned patients in a 1:1 ratio to receive sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included overall survival, objective response (complete or partial response) and duration of response as assessed by blinded independent central review, and safety.ResultsA total of 443 patients were randomly assigned to receive sacituzumab govitecan plus pembrolizumab (221 patients) or chemotherapy plus pembrolizumab (222 patients). The median progression-free survival was 11.2 months (95% confidence interval [CI], 9.3 to 16.7) with sacituzumab govitecan plus pembrolizumab and 7.8 months (95% CI, 7.3 to 9.3) with chemotherapy plus pembrolizumab (hazard ratio for disease progression or death, 0.65; 95% CI, 0.51 to 0.84; two-sided P<0.001). Data for overall survival were immature. The percentage of patients with an objective response was 60% (95% CI, 53 to 66) with sacituzumab govitecan plus pembrolizumab and 53% (95% CI, 46 to 60) with chemotherapy plus pembrolizumab; among patients with a response, the median duration of response was 16.5 months (95% CI, 12.7 to 19.5) and 9.2 months (95% CI, 7.6 to 11.3), respectively. Adverse events of grade 3 or higher occurred in 71% of the patients receiving sacituzumab govitecan plus pembrolizumab and in 70% of those receiving chemotherapy plus pembrolizumab; the incidence of treatment discontinuation due to adverse events was 12% and 31%, respectively. Adverse events leading to death occurred in 3% of the patients in each group.ConclusionsSacituzumab govitecan plus pembrolizumab led to significantly longer progression-free survival than chemotherapy plus pembrolizumab among patients with previously untreated, PD-L1–positive, advanced triple-negative breast cancer. (Funded by Gilead Sciences; ASCENT-04/KEYNOTE-D19 ClinicalTrials.gov number, NCT05382286.)

The telomerase vaccine UV1 combined with ipilimumab and nivolumab versus ipilimumab and nivolumab in advanced melanoma (INITIUM): A randomized open-label phase 2 study.

Aumolertinib as adjuvant therapy in resected EGFR-mutated non-small-cell lung cancer (ARTS): a double-blind, multicentre, randomised, controlled, phase 3 trial.

ABSTRACTThe role of perioperative immunotherapy as a chemotherapy-free option for patients with resectable mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) colon cancer is evolving, with early-phase neoadjuvant studies reporting favorable long-term outcomes. AZUR-2 is an ongoing global, Phase III, open-label, randomized study evaluating the efficacy of perioperative dostarlimab monotherapy compared with standard of care (SoC) (adjuvant chemotherapy or surveillance) in adult patients with previously untreated, pathologically confirmed, radiologically evaluable T4N0 or Stage III resectable dMMR/MSIH colon adenocarcinoma. Patients will be randomized 2:1 to receive neoadjuvant dostarlimab 500 mg every 3 weeks (4 cycles), followed by surgery, then adjuvant dostarlimab 1000 mg every 6 weeks (6 cycles), or to receive immediate surgery followed by SoC. The primary endpoint is event-free survival assessed by blinded independent central review. The key secondary endpoint is overall survival; additional secondary endpoints include pathological response assessed by residual viable tumor determined by local assessment, safety, and tolerability.Clinical trial registration: NCT05855200 (www.clinicaltrials.gov).

Programmed cell death 1 (PD-1) inhibitors have been the standard first-line treatment for advanced melanoma; however, their clinical benefit in advanced melanoma predominantly of acral subtype remains unclear. To evaluate the efficacy and safety of toripalimab (a PD-1 inhibitor) vs dacarbazine as the first-line treatment in advanced melanoma predominantly of acral subtype. This multicenter, open-label, positive-control phase 3 randomized clinical trial enrolled patients with advanced melanoma from January 22, 2018, to July 12, 2023. Eligible patients had histologically confirmed stage III or IV melanoma and no prior systemic therapy for advanced melanoma. Data were analyzed from September 23 to November 27, 2023. Patients were randomized (1:1) to receive toripalimab, 240 mg, every 2 weeks for up to 2 years, or dacarbazine, 1000 mg/m2, every 3 weeks until disease progression or intolerable toxic effects. Patients in the dacarbazine group were allowed to receive toripalimab after radiographic disease progression. Progression-free survival (PFS) assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors, version 1.1. The analysis included 256 patients (median [range] age, 58 [18-85] years; 113 females [44.3%] and 142 males [55.7%]), among whom 160 participants (62.7%) had acral melanoma; 127 were randomized to receive toripalimab and 128 to dacarbazine (1 patient was excluded for Good Clinical Practice violation). The median (range) follow-up period was 11.8 (0.1-62.5) months. Toripalimab significantly reduced the risk of disease progression or death by 29.2% (hazard ratio, 0.71; 95% CI, 0.53-0.95; P = .02) compared with dacarbazine as assessed by BICR . Consistent PFS benefit was observed in most predefined subgroups, including patients with acral subtype. The BICR-assessed objective response rate of 11.0% (95% CI, 6.2%-17.8%) vs 8.6% (95% CI, 4.4%-14.9%), and the median duration of response of 13.8 (95% CI, 5.9-not evaluable) months vs 6.9 (95% CI, 3.8-not evaluable) months, respectively, also favored toripalimab over dacarbazine. Grade 3 or worse treatment-related adverse events occurred in 36 patients (28.3%) receiving toripalimab, with the most common (≥3%) being increased lipase (11 patients [8.7%]), anemia (5 patients [3.9%]), increased γ-glutamyltransferase (4 patients [3.1%]), hyponatremia (4 patients [3.1%]), and increased blood triglycerides (4 patients [3.1%]). This phase 3 randomized clinical trial found that as a first-line treatment for advanced melanoma predominantly of acral subtype, toripalimab showed a significant PFS benefit over dacarbazine and an acceptable safety profile. ClinicalTrials.gov Identifier: NCT03430297.

Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial.

Nivolumab plus docetaxel versus placebo plus docetaxel for androgen receptor pathway inhibitor-pretreated and chemotherapy-naive metastatic castration-resistant prostate cancer (CheckMate 7DX): a double-blind, randomised, phase 3 trial.

An unmet treatment need remains for relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL), including the follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL) subtypes. The PI3K/AKT/mTOR pathway is dysregulated and associated with poor prognosis in NHL. The AKT inhibitor capivasertib has preclinical activity in hematologic malignancy models. NCT05008055 was a modular, open-label, multicenter phase II study that examined oral capivasertib monotherapy in patients with R/R B-cell NHL who had received ≥2 prior lines of therapy. Patients had R/R FL (Cohort 1A), MZL (Cohort 1B), or MCL (Cohort 1C). Capivasertib 480 mg twice daily was administered orally 4 days on/3 days off. The primary objective was to determine the objective response rate (ORR) by blinded independent central review. 30 patients were enrolled (of 272 planned). The ORRs for patients with R/R FL, MZL, and MCL were 18.8% (3/16), 33.3% (1/3), and 30% (3/10), respectively; 62.5% (10/16) of patients with R/R FL had stable disease. Baseline tumor PTEN expression was deficient/undetectable in the two patients who had a complete response and three of five patients who had a partial response. The most common capivasertib-related adverse events (AEs) were diarrhea (63.3%), nausea (20%), vomiting (13.3%), and hyperglycemia (10%). Capivasertib-related grade ≥3 AEs or serious AEs were observed in 9 and 3 patients, respectively. The study was terminated early with a small sample size, limiting interpretation, although antitumor activity was limited. Future studies of capivasertib in hematologic malignancies would likely require biomarker-directed patient selection and/or combination therapy.

Treatment for advanced non-small cell lung cancer (NSCLC) with activating mutations in HER2 relies on chemo-immunotherapy in the first-line setting, which fails to address the underlying human epidermal growth factor receptor 2 (HER2)-driven biology. This unmet need is fueling a shift toward HER2-targeted therapies for this patient population and for earlier lines of therapy. The European Society for Medical Oncology (ESMO) Congress 2025, held in Berlin, Germany, from October 17th–21st, included discussions of recent advances in the first-line treatment of HER2-mutant NSCLC. Among the highlights was the presentation of first-line data from the Beamion LUNG-1 Phase Ib expansion study evaluating zongertinib, an oral, HER2-selective tyrosine kinase inhibitor (TKI), in treatment-naive patients with advanced HER2-mutant NSCLC. The study demonstrated a confirmed objective response rate (ORR) of 77% by blinded independent central review (BICR), with a median time to response of 1.4 months. The study also demonstrated early signs of durability, with a 6-month duration of response (DoR) rate of 80% and a 6-month progression-free survival (PFS) rate of 79%. The safety profile of first-line zongertinib was manageable, with mostly low-grade treatment-related adverse events (TRAE) and a low incidence of interstitial lung disease (ILD)/pneumonitis (3%, both Grade 2). Additionally, ESMO 2025 featured data from SOHO-01, which evaluated another oral HER2 TKI, sevabertinib, in treatment-naive patients, further signaling a shift in the first-line treatment of HER2-mutant NSCLC from chemotherapy with or without immunotherapy to HER2-targeted therapies.

Consolidation durvalumab following no progression on concurrent chemoradiotherapy (cCRT) is standard of care for unresectable stage III non-small-cell lung cancer (NSCLC). However, in clinical practice many patients receive sequential CRT (sCRT). The PACIFIC-5 trial aimed to evaluate the efficacy and safety of consolidation durvalumab for unresectable stage III NSCLC following no progression on cCRT or sCRT. This randomised, double-blind, placebo-controlled, phase III trial enrolled patients aged ≥ 18 years with unresectable stage III NSCLC, regardless of PD-L1 expression or sensitising EGFR or ALK aberrations, without disease progression after cCRT or sCRT. Patients were randomised (2:1) to durvalumab 1500mg or placebo intravenously every 4 weeks (stratified by tumour PD-L1 expression and prior treatment) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was progression-free survival (PFS) by blinded independent central review in the modified intention-to-treat population (mITT). Secondary endpoints included overall survival (OS) in the mITT and safety. The safety analysis set include patients who received at least one dose of study treatment. Of 407 patients randomised to receive durvalumab (n = 272) or placebo (n = 135), 405 received at least one dose of durvalumab (n = 271) or placebo (n = 134). The mITT comprised 381 patients randomised to durvalumab (n = 252) or placebo (n = 129). Durvalumab showed statistically significant improvement in PFS versus placebo in the mITT (median [95% confidence interval {CI}], 14.0 [10.9-18.0] vs. 6.5 [5.4-13.8] months; hazard ratio [95% CI], 0.75 [0.58-0.99]; p = 0.038). There was a trend toward improved OS with durvalumab versus placebo in the mITT (median [95% CI], 38.3 [28.9-42.8] vs. 32.5 [20.6-40.4] months; hazard ratio [95% CI], 0.87 [0.66-1.17]; p = 0.346 [interim analysis]). Among the safety analysis set, maximum grade 3 or 4 adverse events of any cause occurred in 26.9% (73/271) and 23.9% (32/134) and 1.5% (4/271) and 0% (0/134) had treatment-related adverse events leading to death for durvalumab and placebo, respectively. PACIFIC-5 met its primary endpoint of improved PFS after either cCRT or sCRT. Follow-up for overall survival is ongoing. NCT03706690.

Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive, HER2-negative breast cancer: final overall survival analysis of the phase III TROPION-Breast01 study.

Fuzuloparib with or without apatinib in patients with HER2-negative metastatic breast cancer with germline BRCA1/2 mutations (FABULOUS): interim analysis of a multicentre, three-arm, open-label, randomised, phase 3 trial.

Background:Osimertinib is the preferred treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) in several settings; however, disease progression is common, and treatment options after progression are limited. Datopotamab deruxtecan (Dato-DXd), an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 (TROP 2) monoclonal antibody conjugated to a potent topoisomerase I inhibitor via a plasma-stable linker, has demonstrated efficacy in advanced NSCLC, including previously treated EGFR-mutated advanced NSCLC. Combining osimertinib and Dato-DXd may overcome heterogeneous osimertinib resistance mechanisms and limit tumor progression.Objectives:TROPION-Lung15 is an ongoing, phase III, open-label, sponsor-blind, multicenter, randomized trial evaluating Dato-DXd ± osimertinib versus chemotherapy in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib.Methods and design:Approximately 630 patients with histologically/cytologically confirmed non-squamous NSCLC, documented epidermal growth factor receptor tyrosine kinase inhibitor-sensitive mutations, and radiologic progression on prior osimertinib monotherapy will be enrolled. Patients will be randomized 1:1:1 to Dato-DXd (6 mg/kg intravenously every 3 weeks), osimertinib (80 mg orally once daily) plus Dato-DXd, or platinum-doublet chemotherapy, stratified by the history/presence of brain metastases (yes vs no), prior osimertinib therapy (adjuvant vs post-chemoradiotherapy/first-line vs second-line), and race. Treatment will continue until radiological progression (per Response Evaluation Criteria in Solid Tumors version 1.1), unacceptable toxicity, or another discontinuation criterion is met. The dual primary endpoints are progression-free survival (PFS) by blinded independent central review (BICR) for osimertinib + Dato-DXd and PFS by BICR for Dato-DXd alone versus chemotherapy. Secondary endpoints include overall survival, central nervous system PFS by BICR, and safety/tolerability.Ethics:The study is approved by independent ethics committees/institutional review boards at each center. Patients will provide written informed consent.Discussion:TROPION-Lung15 will assess Dato-DXd ± osimertinib in patients with EGFR-mutated advanced NSCLC and disease progression on prior osimertinib. Data from this study could lead to a new treatment option in this setting.Trial registration:ClinicalTrials.gov identifier: NCT06417814 (date of registration: May 13, 2024).

Integrin beta-6 (IB6) is a tumor-associated membrane protein involved in many cellular processes, including wound healing and tissue remodeling. While IB6 expression is constitutively low in healthy tissues, high IB6 expression in numerous cancers, including non-small cell lung cancer (NSCLC), is associated with poor outcomes. In a phase I study, the novel IB6-directed vedotin-based antibody-drug conjugate sigvotatug vedotin (SV) showed manageable safety and encouraging efficacy as a monotherapy and in combination with pembrolizumab in patients with advanced solid tumors, including NSCLC. Based on those results, the phase III Sigvie-003 study is evaluating SV plus pembrolizumab compared with pembrolizumab monotherapy as first-line treatment in adult patients with locally advanced, unresectable, or metastatic NSCLC with high programmed cell death ligand 1 expression (tumor proportion score ≥50%). Here, we describe the design of the Sigvie-003 study, which is an open-label, randomized, controlled phase III study. Approximately 714 patients will be randomized 1:1. The dual primary endpoints are progression-free survival as assessed by blinded independent central review per Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; secondary endpoints include additional efficacy, safety and tolerability, pharmacokinetics, and immunogenicity endpoints.Clinical trial registration: NCT06758401 (https://clinicaltrials.gov/study/NCT06758401).

Final Analysis Results and Patient-Reported Outcomes From DESTINY-Lung02-A Dose-Blinded, Randomized, Phase 2 Study of Trastuzumab Deruxtecan in Patients With HER2-Mutant Metastatic NSCLC.

Peri-operative tislelizumab plus neoadjuvant chemotherapy for patients with resectable non-small cell lung cancer: final analysis of the randomized RATIONALE-315 trial.

Randomized, double-blind, phase III LEAP-003 study of first-line lenvatinib plus pembrolizumab versus placebo plus pembrolizumab for unresectable or metastatic melanoma.

First-line serplulimab plus chemotherapy with or without HLX04 versus chemotherapy in locally advanced or metastatic non-squamous non-small-cell lung cancer (ASTRUM-002): a randomised, double-blind, multicentre phase 3 trial.

Pooled analysis by best confirmed response to trastuzumab deruxtecan and related biomarkers in patients with HER2-positive metastatic breast cancer from DESTINY-Breast01, DESTINY-Breast02, and DESTINY-Breast03.