Annals of Oncology最新文献

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 amongst 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 performed 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 H&E-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 vs. lymph node) or specimen type (resection vs. 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 post-study 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 increasingly lies in translating approaches to historically 'untouchable' targets: transcription factors, tumor suppressors, and lineage-defining proteins, which have long resisted conventional pharmacological approaches. At the 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 (PROTACs, ADCs, 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.

Background: Therapeutic options after progression on EGFR tyrosine kinase inhibitors (TKIs) remain limited for patients with EGFR-mutated non-small cell lung cancer (NSCLC). Izalontamab brengitecan (Iza-bren; BL-B01D1) is a first-in-class bispecific antibody-drug conjugate targeting EGFR and HER3 with preclinical and early clinical activity.

Patients and methods: We pooled individual patient data from a phase 1a/1b dose-escalation/expansion trial (BL-B01D1-101; (NCT05194982) and a phase 2 multicohort trial (BL-B01D1-203; NCT05880706) in patients with advanced EGFR-mutated NSCLC who had disease progression on prior EGFR TKI therapy. Key endpoints were confirmed objective response rate (cORR), disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The recommended phase 2 dose (RP2D) was 2.5 mg/kg on days 1 and 8 every 3 weeks.

Results: 171 patients were included (data cutoff 30 June 2025; median follow-up 20.5 months). In the pooled population, cORR was 47.4% (95% CI, 39.7-55.1) and DCR was 81.3% (95% CI, 74.6-86.8); median DoR was 8.5 months (95% CI, 6.9-11.2), median PFS was 6.9 months (95% CI, 5.5-9.6), and median OS was 24.8 months (95% CI, 18.5-not reached). Efficacy at the RP2D (n = 121) was consistent (cORR, 48.8%; DCR, 81.0%; median PFS, 6.9 months; median OS, 24.8 months). In chemotherapy-naïve, post-TKI patients treated at the RP2D (n = 50), cORR was 56.0%, DCR was 90.0%, median DoR was 13.7 months, median PFS was 12.5 months, and median OS was not reached. Treatment-related adverse events (TRAEs) occurred in 98.8% (grade ≥3: 70.2%), predominantly hematologic; interstitial lung disease was rare (0.6%, all grade 1). Discontinuation for TRAEs was 1.2%; no treatment-related deaths were reported.

Conclusions: In this exploratory post hoc pooled analysis, Iza-bren demonstrated promising antitumor activity and a manageable safety profile in heavily pretreated EGFR-mutated NSCLC. These findings are hypothesis-generating and are being further evaluated in ongoing randomized trials.

Background: Gastric cancer after progression on trastuzumab treatment remains an unmet therapeutic challenge and is associated with suboptimal progression-free survival (PFS) and overall survival (OS).

Patients and methods: This multicentre, randomised, double-blind, phase 3 trial was conducted at 51 hospital sites in China. Patients with HER2-positive gastric cancer or gastro-oesophageal junction (GC/GEJ) adenocarcinoma whose previous therapy containing trastuzumab had failed were randomised (1:1) to receive anbenitamab 30 mg/kg or placebo every 3 weeks, in combination with chemotherapy (paclitaxel 175 mg/m² or docetaxel 75 mg/m² on day 1 of a 21-day cycle, or irinotecan 125 mg/m² on day 1 and 8 of a 21-day cycle), stratified by combined chemotherapy (taxane [paclitaxel or docetaxel] or irinotecan), HER2 expression (IHC 3+ or IHC 2+/FISH+), and previous lines of therapy (1 or ≥2). Primary endpoints were independent review committee-assessed PFS and OS in the intention-to-treat population. This interim analysis was planned when approximate 120 PFS events were observed.

Results: A total of 188 patients were enrolled and assigned to receive anbenitamab plus chemotherapy (anbenitamab group, n=95) or chemotherapy alone (control group, n=93). At the prespecified interim analysis, anbenitamab plus chemotherapy significantly improved PFS (median [95% confidence interval (CI)], 7.1 [5.5-10.3] vs 2.7 [1.5-3.0] months; hazard ratio [HR], 0.25; 95% CI, 0.17-0.39; p<0.0001) and OS (median [95% CI], 19.6 [15.0-not evaluable] vs 11.5 [6.5-14.4] months; HR, 0.29; 95% CI, 0.17-0.50; p<0.0001) compared with chemotherapy alone. Grade 3 or higher treatment-related adverse events occurred in 56 (60%) of 94 patients who received anbenitamab plus chemotherapy and 42 (45%) of 93 patients who received chemotherapy alone, with neutropenia (30% vs 22%) and leukopenia (21% vs 25%) being most common. Treatment-related deaths were reported in 0 and 5 patients in the anbenitamab and control groups, respectively.

Conclusions: Compared with chemotherapy alone, anbenitamab plus chemotherapy demonstrated clinically meaningful superior PFS and OS in patients with HER2-positive GC/GEJ adenocarcinoma whose previous therapy containing trastuzumab had failed. These findings warrant confirmation in the final analysis.

Background: Pan-FGFR inhibitors, targeting FGFR1-3 or FGFR1-4, are FDA-approved for FGFR2-driven cholangiocarcinoma. However, acquired resistance and dose-limiting toxicities from systemic FGFR inhibition constrain efficacy. Lirafugratinib (RLY-4008), a first-in-class FGFR2-selective inhibitor with activity against resistance-associated FGFR2 kinase domain mutations, shows promise in patients with FGFR2-altered solid tumors (ReFocus trial, NCT04526106). Defining acquired resistance mechanisms to selective FGFR2 targeting is essential for therapeutic development.

Methods: ctDNA samples from 28 patients treated with lirafugratinib (16 FGFR inhibitor-naïve, 12 FGFR inhibitor-refractory) were analyzed using targeted next-generation sequencing. Genomic alterations observed were compared to prior studies of pan-FGFR inhibitor resistance and validated in preclinical models.

Results: Polyclonal FGFR2 kinase domain mutations and RTK-MAPK bypass alterations emerged as common lirafugratinib resistance mechanisms in the FGFR inhibitor-naïve context (8/16 and 9/16 patients, respectively). Resistance profiles differed markedly from pan-FGFR inhibitors, with decreased FGFR2 V565F/L and N550H/K mutations, increased M538I and L618F mutations, and more frequent RTK-MAPK bypass alterations. The variant allele fraction was typically higher for FGFR2 kinase domain mutations, consistent with these alterations serving as primary resistance drivers. Preclinical studies confirmed differential sensitivity of these FGFR2 mutations to lirafugratinib. Importantly, lirafugratinib demonstrated clinical efficacy in the FGFR inhibitor-refractory setting, with ctDNA dynamics showing resolution of multiple FGFR2 mutations and persistence or emergence of others.

Conclusions: Lirafugratinib retains activity against multiple mutations that confer clinical resistance to pan-FGFR inhibitors. However, diverse resistance mechanisms, including various kinase domain mutations and RTK-MAPK bypass alterations, remain challenges in the treatment of FGFR2-altered tumors, even with selective FGFR2 kinase inhibition.

Background: The interim analysis of the JUPITER-06 study reveals significantly longer progression-free survival (PFS) and overall survival (OS) in advanced ESCC patients treated with toripalimab in combination with paclitaxel plus cisplatin (TP). Prior work proposed copy number alteration-corrected TMB (ccTMB) and an esophageal cancer genome-based immuno-oncology classification (EGIC) scheme as pre-specified biomarkers to predict treatment efficacy. Here, we present the final analysis of the JUPITER-06 study and further explore potential biomarkers associated with OS.

Patients and method: 514 patients with treatment-naïve advanced ESCC were randomized 1:1 to receive toripalimab or placebo in combination with paclitaxel plus cisplatin every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. The co-primary endpoints were OS and PFS assessed by blinded intendent central review. Whole-exome sequencing of 486 tumors enabled biomarker analyses.

Result: As of February 23, 2023, toripalimab plus TP significantly improved OS versus placebo plus TP (17.7 months [95% CI, 14.6-20.8] vs. 12.9 months [95% CI, 11.6-14.1]; HR, 0.72 [95% CI, 0.58-0.88]; P = 0.002). The 3-year OS rates were 29.7% and 19.9% in the two groups, respectively. Neither PD-L1 expression nor tumor mutation burden (TMB) significantly correlated with OS benefit. In contrast, pre-specified biomarkers, ccTMB and EGIC scheme, robustly stratified patients with different long-term OS benefits from immunochemotherapy. Further exploratory analysis discovered that loss-of-function alterations in the SWI/SNF chromatin remodeling complex were associated with improved OS, whereas gain-of-function alterations in cell cycle and WNT signaling pathways correlated with reduced survival benefits. Importantly, CDK4/6 and PORCN inhibitors were identified as potential partners to overcome resistance and enhance efficacy of immunochemotherapy.

Conclusion: This final OS analysis of JUPITER-06 confirms the sustained survival benefit of toripalimab plus chemotherapy in advanced ESCC. ccTMB and EGIC enable consistently precise patient stratification, while pathway-specific vulnerabilities highlight actionable targets for exploratory combination strategies.

Background: We provided updated cancer mortality estimates for 2026 in the European Union (EU) and its five most populous countries, with a focus on lung cancer.

Methods: Cancer death certifications and population data were obtained from the World Health Organization and United Nations databases. For the EU, France, Germany, Italy, Poland, Spain and the UK we derived data for all cancers combined and major cancer sites since 1970. Linear regression models, based on the most recent age-specific trends identified by Poisson joinpoint regression, were used to estimate deaths in 2026. The number of averted deaths between 1989 and 2026 was computed by applying the 1988 peak rate to subsequent populations.

Results: For 2026, we estimated about 1,230,000 EU cancer deaths, corresponding to age-standardised rates of 114.1/100,000 males (-7.8% vs 2020-2022) and 74.7/100,000 females (-5.9%). In the EU countries and the whole EU, favourable trends are predicted for most major cancers, except female pancreatic cancer. In the UK, predicted rates are also favourable, except female colorectal cancer. Lung cancer mortality continues to decrease markedly among males, while we predicted a levelling off of rates - around 12.5/100,000 - among females in all considered countries and the whole EU, except for Spain (+2.4%). Among females, lung cancer mortality declines are confined to those <65 years, while unfavourable trends continued in older age groups. Around 7.3 million total cancer deaths have been avoided in the EU since the peak observed in 1988. The corresponding figure for lung cancer is 1.8 million among males, while no averted deaths were recorded among females.

Conclusion: Lung cancer mortality predictions for 2026 indicate a levelling off among EU females, with age- and country-specific differences. Mortality trends in ASRs for most cancers remain favourable in the EU and the UK, though the absolute number of cancer deaths is not declining due to population ageing.