BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) demonstrated significant long-term survival and response benefits in patients with previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 2...BACKGROUND: Nivolumab plus ipilimumab (NIVO + IPI) demonstrated significant long-term survival and response benefits in patients with previously untreated advanced renal cell carcinoma (aRCC) in the phase III CheckMate 214 trial (NCT02231749). We report final efficacy and safety results with 9.3 years median follow-up. PATIENTS AND METHODS: Patients (N = 1096) were randomized to NIVO 3 mg/kg plus IPI 1 mg/kg every 3 weeks × four doses, followed by NIVO (3 mg/kg or 240 mg every 2 weeks or 480 mg every 4 weeks); or sunitinib (SUN) (50 mg) once daily (4 weeks on, 2 weeks off). ENDPOINTS: overall survival (OS), and independent radiology review committee-assessed progression-free survival and objective response rate in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk (primary), intention-to-treat (secondary), and IMDC favorable-risk (exploratory) patients. RESULTS: With a median (range) follow-up of 9.3 years (8.6-9.9 years), the hazard ratio (95% confidence interval) for OS with NIVO + IPI versus SUN was 0.71 (0.62-0.82) in intention-to-treat patients, 0.69 (0.59-0.81) in intermediate/poor-risk patients, and 0.80 (0.59-1.09) in favorable-risk patients; 108-month OS probabilities were 31.4% versus 19.5%, 30.2% versus 18.7%, and 35.3% versus 21.8%, respectively. Progression-free survival probabilities at 96 months were 22.7% versus 9.0% (intention-to-treat), 25.4% versus 8.5% (intermediate/poor risk), and 12.5% versus 11.3% (favorable risk). Probabilities of remaining in response at 96 months with NIVO + IPI versus SUN were 48.0% versus 19.0% (intention-to-treat), 50.0% versus 23.0% (intermediate/poor risk), and 36.0% versus not estimable (favorable risk). Incidence of any-grade (grade 3-4) treatment-related adverse events (AEs) was 94.1% (48.6%) with NIVO + IPI versus 97.6% (64.1%) with SUN. Exploratory post hoc analyses reported include descriptive analyses of OS by immune-mediated AE discontinuation status. CONCLUSIONS: In the longest phase III follow-up of a first-line checkpoint inhibitor combination in aRCC (>9 years), NIVO + IPI maintained a substantial survival benefit with durable responses versus SUN. Grade 3-4 treatment-related AEs were lower with NIVO + IPI versus SUN at 9 years. NIVO + IPI remains a first-line standard of care in aRCC.
BACKGROUND: In DESTINY-Breast06, trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) versus physician's choice of chemotherapy (TPC) for patients with hormone receptor (HR)-positive, human epidermal g...BACKGROUND: In DESTINY-Breast06, trastuzumab deruxtecan (T-DXd) improved progression-free survival (PFS) versus physician's choice of chemotherapy (TPC) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-low/-ultralow metastatic breast cancer (mBC), without new safety signals. We report additional analyses exploring outcomes for patients with characteristics that affect prognosis. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd (5.4 mg/kg) once every 3 weeks or TPC. Subgroups were specified post hoc from the intent-to-treat population (N = 866). Outcomes were PFS, objective response rate (ORR), and duration of response (DOR) by blinded independent central review via RECIST 1.1. Time from randomization until second progression or death (PFS2) by investigator and safety were also assessed. RESULTS: Within subgroups, baseline disease characteristics and prior therapies were balanced across treatments. Median PFS (95% confidence interval) favored T-DXd versus TPC regardless of time to progression (TTP) on prior first-line endocrine therapy (ET) + cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i): <6 months: 14.0 (11.2-15.9) versus 6.5 (4.2-8.4) months for T-DXd versus TPC; 6-12 months: 13.2 (8.6-16.4) versus 6.9 (4.3-10.4) months; >12 months: 12.9 (9.8-17.1) versus 8.2 (6.9-10.9) months. A consistent PFS benefit with T-DXd over TPC was observed for patients with primary or secondary endocrine resistance, and across indicators of high or low disease burden (defined as visceral/non-visceral disease, presence/absence of liver metastases, three or more/less than three disease sites, and >median/≤median baseline tumor size). In all subgroups, confirmed ORR favored T-DXd (36.7% to 67.7%) versus TPC (16.7% to 37.5%), and median DOR (confirmed response) was longer with T-DXd. T-DXd also prolonged PFS2 versus TPC across subgroups. Safety profiles of T-DXd and TPC in subgroups were consistent with the overall safety population. CONCLUSIONS: These data support T-DXd as a broadly efficacious treatment for patients with HR-positive, HER2-low/-ultralow mBC after one or more ETs, regardless of TTP on prior first-line ET + CDK4/6i, endocrine resistance, or disease burden.
Riess JW, Yu HA, Le X
… +18 more, de Langen AJ, Cho BC, Piotrowska Z, Hendriks LEL, Morabito A, Bonanno L, Brustugun OT, Halvorsen TO, Kim YJ, Marrone KA, Shiraishi Y, Goldman JW, Ambrose H, Smith PE, FraenkeI PG, Tang KH, Lehman JM, Goldberg SB
BACKGROUND: ORCHARD (NCT03944772) was a phase II platform study conducted to characterize resistance mechanisms and evaluate novel treatment combinations following progressive disease (PD) on first-line osimertinib. Dato...BACKGROUND: ORCHARD (NCT03944772) was a phase II platform study conducted to characterize resistance mechanisms and evaluate novel treatment combinations following progressive disease (PD) on first-line osimertinib. Datopotamab deruxtecan (Dato-DXd) is an anti-TROP2 antibody-drug conjugate approved as monotherapy in EGFR-mutated advanced non-small-cell lung cancer (NSCLC). We report final data from the osimertinib plus Dato-DXd module. METHODS: Eligible patients had EGFR-mutated advanced NSCLC and PD on first-line osimertinib. Patients received oral osimertinib (80 mg once daily) plus intravenous Dato-DXd (4 or 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1. Secondary endpoints were progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. RESULTS: Sixty-nine patients received study treatment. Among patients in the 4 mg/kg (N = 35) and 6 mg/kg (N = 34) cohorts, respectively, confirmed ORR was 43% [80% confidence interval (CI) 32% to 55%] and 36% (80% CI 25% to 49%); median PFS was 9.5 months (95% CI 7.2-9.8 months) and 11.7 months (95% CI 8.3-21.7 months); median DoR was 6.3 months (95% CI 3.8-8.1 months) and 20.5 months [95% CI 6.2 months-not calculable (NC); estimated median of at least 16 months]; and median OS was 19.8 months (95% CI 13.5-23.3 months) and 26.2 months (95% CI 14.8 months-NC; estimated median greater than or equal to the 4 mg/kg cohort). In the 4 mg/kg and 6 mg/kg cohorts, respectively, grade ≥3 adverse events (AEs) were reported in 49% and 76% of patients; AEs leading to Dato-DXd dose reduction in 23% and 59%; and adjudicated interstitial lung disease/pneumonitis in 3% and 15%. CONCLUSIONS: Osimertinib plus Dato-DXd demonstrated clinical benefit in patients with EGFR-mutated advanced NSCLC who progressed on first-line osimertinib. AEs in the 6 mg/kg cohort were of higher frequency and severity but could be managed with prophylaxis, careful monitoring, and dose reduction. The safety profile was consistent with the known profiles of the individual drugs. Considering the overall benefit-risk profile, 6 mg/kg is suggested as the preferred Dato-DXd starting dose for combining with osimertinib 80 mg. CLINICAL TRIAL NUMBER: ClinicalTrials.govNCT03944772.
BACKGROUND: The primary analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 1333/PEACE-3 study demonstrated that enzalutamide plus radium-223 (Ra223) improved radiological progression-free...BACKGROUND: The primary analysis of the European Organisation for Research and Treatment of Cancer (EORTC) 1333/PEACE-3 study demonstrated that enzalutamide plus radium-223 (Ra223) improved radiological progression-free survival (rPFS) compared with enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint was rPFS, while overall survival (OS) was a key secondary endpoint. Interim OS results were reported at the time of primary analysis. Here, we report the final OS analysis. PATIENTS AND METHODS: From November 2015 to March 2023, 446 patients were randomly assigned to receive enzalutamide alone or enzalutamide combined with six cycles of Ra223. Co-administration of bone-protecting agents (BPAs) became mandatory for all patients from March 2018. Final analysis of OS was triggered on 1 May 2025. RESULTS: With a median follow-up of 58 months and 317 reported deaths, the hazard ratio (HR) was 0.76 [95% confidence interval (CI) 0.60-0.96, P = 0.0096] for OS in favor of the enzalutamide + Ra223 arm, reaching the predefined level of statistical significance of <0.0248. Median OS was 32.6 months (95% CI 29.3-38.2 months) in the enzalutamide arm (n = 224) and 38.2 months (95% CI 33.1-44.8 months) in the combination arm (n = 222). The HR for rPFS was 0.71 (95% CI 0.57-0.89). Grade ≥3 treatment-emergent adverse events (TEAEs) increased from 57.6% to 69.3% in the combination arm, as did treatment-related grade ≥3 TEAEs (18.8% versus 28.9%), with the most frequent being hypertension. CONCLUSIONS: The final analysis of this study confirmed that the combination of enzalutamide with Ra223 significantly improved not only rPFS but also OS as first-line therapy for mCRPC versus enzalutamide alone. Co-administration of a BPA is required to reduce skeletal complications.
BACKGROUND: Primary results from COSMIC-313 demonstrated significantly longer progression-free survival (PFS) with first-line cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in pat...BACKGROUND: Primary results from COSMIC-313 demonstrated significantly longer progression-free survival (PFS) with first-line cabozantinib plus nivolumab and ipilimumab versus placebo plus nivolumab and ipilimumab in patients with advanced renal cell carcinoma. Final efficacy and safety results, as well as data from exploratory biomarker analyses, are reported here. PATIENTS AND METHODS: The design, participants, and primary-endpoint PFS outcomes have been reported previously for this phase III, double-blind, randomized (1 : 1) study of cabozantinib or placebo plus nivolumab and ipilimumab in adults with previously untreated, advanced clear cell renal cell carcinoma. The secondary endpoint was overall survival (OS) in the intention-to-treat population. Exploratory biomarker analyses investigated the potential association between immune cell types and gene signatures with clinical outcomes. RESULTS: After a median follow-up of 45.0 months, the updated median PFS in the cabozantinib (triplet) arm was longer than in the placebo (doublet) arm (16.6 versus 11.2 months; hazard ratio 0.82, 95% confidence interval 0.69-0.98). There was no significant difference in median OS (hazard ratio 1.02, 95% confidence interval 0.85-1.23, P = 0.84), and the safety profile was consistent with the earlier analysis (grade 3/4 treatment-related adverse events occurred in 75% and 43% of patients in the triplet and doublet arms, respectively). In patients with higher levels of M2-like macrophages, the triplet regimen was associated with significantly improved PFS and OS compared with the doublet regimen. Responders in the triplet arm exhibited elevated angiogenic signatures and reduced immune-related pathways, while responders in the doublet arm had robust immune activation. CONCLUSIONS: Long-term results from COSMIC-313 continue to demonstrate a PFS benefit with the addition of cabozantinib to nivolumab and ipilimumab. There was no OS benefit and no new safety signals were observed. Exploratory biomarker analyses suggest adding cabozantinib to nivolumab and ipilimumab improves survival in patients with high levels of M2-like macrophages.
Saini KS, Koopman M, Martins-Branco D
… +50 more, Bossi P, Braendegaard Winther S, Brahmi M, Braña I, Calvo E, Castelo-Branco L, Colombo I, de Azambuja E, De Ruysscher D, Dienstmann R, Dingemans AC, Ekholm M, Gallois C, Golfinopoulos V, Grande E, Halabi S, Le Rhun E, Le Saux O, Leighl NB, Lonardi S, Lorenzen S, Lorusso D, Minniti G, Mountzios G, Oldenburg J, Oosting SF, Osterlund P, Perez-Gracia JL, Pellat A, Piperno-Neumann S, Plummer R, Porta C, Punie K, Ray-Coquard I, Remon J, Ruhlmann CH, Rutkowski P, Siu LL, Stacchiotti S, Suarez C, Suijkerbuijk K, Taieb J, Trapani D, Valachis A, van Laarhoven HWM, Vogel A, Zer A, Pentheroudakis G, Delaloge S, Twelves C
Enumeration of lines of therapy (LoT) is critical across oncology for ensuring optimal patient care, establishing uniform eligibility for clinical trial enrolment, standardising use of real-world data and pooling data fo...Enumeration of lines of therapy (LoT) is critical across oncology for ensuring optimal patient care, establishing uniform eligibility for clinical trial enrolment, standardising use of real-world data and pooling data for research purposes. Building on an earlier proposal for assigning LoT in oncology, the European Society for Medical Oncology (ESMO) developed the ESMO adaptation of Lines of Systemic Therapy (EnLiST) framework applicable to solid tumours across the full range of common clinical settings. A Delphi process was adopted to reach a consensus between expert representatives of multiple stakeholder perspectives including medical oncologists, clinical trialists, regulators, academics, patient advocates, experts from the pharmaceutical industry and clinical research organisations, artificial intelligence professionals, funding body specialists and ethicists. EnLiST provides a set of standard definitions, the format of reporting LoT, the minimum required data to be recorded and guidelines for assigning LoT. In EnLiST, a LoT is separately assigned to systemic anticancer therapies in the early (eLoT), advanced (aLoT) and investigational (iLoT) settings; each expressed as two numerals separated by a decimal point (e.g. 1.0). A change in systemic anticancer therapy results in either a 'New' LoT, a 'Modified' LoT, or the 'Same' LoT. A New LoT results from clinical progression of disease or lack of adequate tumour response, and is recorded as the next sequential value to the left of the decimal point (e.g. following LoT 1.0, the New LoT will be LoT 2.0). If the change in treatment is for other reasons (e.g. intolerability), a Modified LoT is recorded and assigned the next sequential value to the right of the decimal point (e.g. following LoT 1.0, the Modified LoT will be LoT 1.1). EnLiST has been designed to serve the needs of a wide range of stakeholders while enhancing the quality of clinical care, clinical research and real-world data.
Janjigian YY, Shitara K, Ajani JA
… +23 more, Shen L, Garrido M, Gallardo C, Wyrwicz L, Yamaguchi K, Cleary JM, Elimova E, Bruges R, Karamouzis M, Skoczylas T, Bragagnoli A, Liu T, Tehfe M, Zander T, Kowalyszyn R, Pazo-Cid R, Schenker M, Feeny K, McCraith S, Hu N, Lei M, Zhang J, Moehler M
BACKGROUND: We report efficacy and safety results from the CheckMate 649 trial after 5 years of follow-up. PATIENTS AND METHODS: Adults with previously untreated, non-human epidermal growth factor receptor 2-positive, un...BACKGROUND: We report efficacy and safety results from the CheckMate 649 trial after 5 years of follow-up. PATIENTS AND METHODS: Adults with previously untreated, non-human epidermal growth factor receptor 2-positive, unresectable, advanced or metastatic gastroesophageal adenocarcinoma were randomized to receive nivolumab plus chemotherapy (n = 789) or chemotherapy (n = 792). Primary endpoints were met and reported previously, with nivolumab plus chemotherapy demonstrating superior overall survival (OS) and progression-free survival (PFS) versus chemotherapy in patients with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥5. RESULTS: With a minimum follow-up of 60.1 months, the OS benefit [hazard ratio (HR) 0.71, 95% confidence interval (CI) 0.61-0.81] and PFS benefit (HR 0.71, 95% CI 0.61-0.82) with nivolumab plus chemotherapy versus chemotherapy in patients with PD-L1 CPS ≥5 were sustained. Five-year OS and PFS rates were 16% versus 6% and 10% versus 6%, respectively. Objective response rate per blinded independent central review was 58% (95% CI 54% to 62%) versus 46% (95% CI 42% to 50%), and median duration of response was 8.5 months (95% CI 7.7-9.9 months) versus 6.9 months (95% CI 5.9-7.6 months), respectively. Survival and response benefits were also maintained in patients with PD-L1 CPS ≥1, patients with PD-L1 CPS ≥10, and all randomized patients. Grade 3/4 treatment-related adverse events occurred in 60% of patients receiving nivolumab plus chemotherapy and 45% of patients receiving chemotherapy. No new safety concerns were observed. CONCLUSIONS: To our knowledge, these are the first reported 5-year results of a programmed cell death protein 1 inhibitor plus chemotherapy in gastroesophageal adenocarcinoma. Nivolumab plus chemotherapy continued to demonstrate long-term survival benefit and acceptable safety after 5 years of follow-up, reinforcing its use as a standard first-line treatment for PD-L1-positive patients.
Deutsch JS, Cottrell TR, Chen KY
… +20 more, De Andrea CE, Baraban E, Fiset PO, Jedrych JJ, Orr CE, Real FX, Salgado R, Schürch CM, Scolyer RA, Seethala R, Sholl LM, Signoretti S, Tetzlaff M, Wang H, Wang T, Weissferdt A, Xu X, Ziai J, Cimino-Mathews A, Taube JM
BACKGROUND: Pathologic response is an emerging surrogate marker for therapeutic efficacy and long-term patient outcomes. Updated guidelines for pan-tumor pathologic response assessment have recently been adopted for ongo...BACKGROUND: Pathologic response is an emerging surrogate marker for therapeutic efficacy and long-term patient outcomes. Updated guidelines for pan-tumor pathologic response assessment have recently been adopted for ongoing clinical trials and routine clinical care. The goal of this study was to prospectively evaluate the interobserver variability among pathologists in assessments of treatment response across tumor types, anatomic locations, and specimen types. MATERIALS AND METHODS: A multi-institutional, international study led by the Society for Immunotherapy of Cancer was carried out to assess the concordance of pathologic response assessment using the pan-tumor criteria in neoadjuvant-treated resection specimens and on-treatment biopsies. Online lecture-based modules for scoring were developed, and 14 pathologists from multiple institutions were trained. The pathologists then assessed 42 specimens representing 12 different tumor types (total of n = 362 hematoxylin-eosin-stained slides) for the three tissue classes that are assessed: %residual viable tumor (RVT), %regression, and %necrosis. Pathologists were also surveyed regarding interest in and barriers related to pan-tumor pathologic response assessment, as well as quality and effectiveness of the training materials. RESULTS: Scoring of pathologic response using the pan-tumor system was highly reproducible, irrespective of disease location (primary tumor versus lymph node) or specimen type (resection versus biopsy), with intraclass correlation coefficients (ICCs) > 0.8 for %RVT, %regression, and %necrosis. Subset analyses also showed strong reproducibility of %RVT within almost all individual tumor types evaluated (ICC all ≥ 0.86). The poststudy survey completed by the participating pathologists was used to refine the training materials, and the revised modules are provided as a resource to the wider pathology and oncology communities. CONCLUSIONS: This highly reproducible scoring system enables quantitative assessment of treatment response in pathology specimens across multiple tumor types, anatomic sites, disease stages, and therapies, akin to RECIST for radiographic assessment. We identified potential barriers to implementation and highlight strategies to overcome these challenges.
Innovation in drug development is an evolving concept that can take many forms and is often confused with iteration, i.e. new versions of existing drug classes targeting familiar oncogenes. Yet meaningful innovation incr...Innovation in drug development is an evolving concept that can take many forms and is often confused with iteration, i.e. new versions of existing drug classes targeting familiar oncogenes. Yet meaningful innovation increasingly lies in translating approaches to historically 'untouchable' targets: transcription factors, tumor suppressors, and lineage-defining proteins, which have long resisted conventional pharmacologic approaches. At the European Society for Medical Oncology (ESMO) Targeted Anticancer Therapies (TAT) 2025 Congress, a growing body of early-phase trials has continued to test and refine this paradigm, showcasing first-in-human studies and novel modalities aimed at drugging long-deemed inaccessible sites. In this manuscript, we review key highlights from ESMO TAT and other pivotal drug development meetings and delve into targeting these so-called 'untouchable' targets. Organized by target class (KRAS, MYC, TP53, WNT) and modality [proteolysis-targeting chimeras (PROTACs), antibody-drug conjugates, bispecifics], we explore how translational frameworks, rational trial design, and platform-specific engineering are reshaping what is now clinically feasible in drug development. Finally, we present early-phase data from the most compelling trials and compounds and explore what remains to be achieved to move beyond proof of concept into clinically meaningful benefits for patients with cancer.