Hong SD, Wang YS, Zhao HY
… +35 more, Zhao YY, Wang QM, Ma YX, Li YS, Huang Y, Yang YP, Fu ZM, Chen LK, Zhou F, Yang J, Li XY, Hou X, Zhou NN, Sun LH, Zhang GF, Cui JW, Wu L, Chen G, Zhang YX, Wang HY, Lv DQ, Shi JH, Jiang B, Li C, Li XL, Tang KJ, Yu Y, Ji YH, He ZY, Zhu Y, Zhu H, Xiao S, Zhou CC, Zhang L, Fang WF
BACKGROUND: Therapeutic options after progression on epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) remain limited for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). Izalontamab...BACKGROUND: Therapeutic options after progression on epidermal growth factor receptor (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 human epidermal growth factor receptor 3 (HER3) with preclinical and early clinical activity. PATIENTS AND METHODS: We pooled individual patient data from a phase Ia/Ib dose-escalation/expansion trial (BL-B01D1-101; NCT05194982) and a phase II 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 II dose (RP2D) was 2.5 mg/kg on days 1 and 8 every 3 weeks. RESULTS: A total of 171 patients were included (data cut-off 30 June 2025; median follow-up 20.5 months). In the pooled population, cORR was 47.4% [95% confidence interval (CI) 39.7% to 55.1%] and DCR was 81.3% (95% CI 74.6% to 86.8%); median DoR was 8.5 months (95% CI 6.9-11.2 months), median PFS was 6.9 months (95% CI 5.5-9.6 months), and median OS was 24.8 months (95% CI 18.5 months to 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-naive, 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 occurred in 98.8% (grade ≥3: 70.2%), predominantly hematologic; interstitial lung disease was rare (0.6%, all grade 1). Discontinuation for treatment-related adverse events 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.
Ellis H, Balasooriya ER, Varkaris A
… +17 more, Hajian B, Wan J, Shekhar M, Gritti I, Vijay V, Albertelli L, Piot S, Lau K, Kehlmann A, Chevalier N, Nugent FW, Zhen Y, Silveira VS, Sellers WR, Corcoran RB, Juric D, Bardeesy N
BACKGROUND: Pan-fibroblast growth factor receptor (FGFR) inhibitors, targeting FGFR1-3 or FGFR1-4, are Food and Drug Administration-approved for FGFR2-driven cholangiocarcinoma. However, acquired resistance and dose-limi...BACKGROUND: Pan-fibroblast growth factor receptor (FGFR) inhibitors, targeting FGFR1-3 or FGFR1-4, are Food and Drug Administration-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. PATIENTS AND METHODS: Circulating tumor DNA (ctDNA) samples from 28 patients treated with lirafugratinib (16 FGFR inhibitor-naive, 12 FGFR inhibitor-refractory) were analyzed using targeted next-generation sequencing. Genomic alterations observed were compared with those reported in prior studies of pan-FGFR inhibitor resistance and validated in preclinical models. RESULTS: Polyclonal FGFR2 kinase domain mutations and receptor tyrosine kinase-mitogen activated protein kinase (RTK-MAPK) bypass alterations emerged as common lirafugratinib resistance mechanisms in the FGFR inhibitor-naive 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.
Liu R, Zhao J, Zhang R
… +25 more, Liu B, Liu Y, Li S, Chen Y, Yang H, Liu Z, Li Z, Qin Y, Huang M, Ba Y, Zhang H, Qu Y, Du Y, Deng T, Yang M, Hou X, Liu C, Ning F, Liu YP, Wu X, Xie Y, An Y, Zou K, She L, Xu J
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 METHO...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 multicenter, randomized, double-blind, phase III trial was conducted at 51 hospital sites in China. Patients with HER2-positive gastric cancer or gastroesophageal junction (GC/GEJ) adenocarcinoma whose previous therapy containing trastuzumab had failed were randomized (1 : 1) to receive anbenitamab 30 mg/kg or placebo every 3 weeks, in combination with chemotherapy (paclitaxel 175 mg/m or docetaxel 75 mg/m on day 1 of a 21-day cycle, or irinotecan 125 mg/m on day 1 and 8 of a 21-day cycle), stratified by combined chemotherapy [taxane (paclitaxel or docetaxel) or irinotecan], HER2 expression [immunohistochemistry (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 ∼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 7.1 months, 95% confidence interval (CI) 5.5-10.3 months versus 2.7 months, 95% CI 1.5-3.0 months; hazard ratio (HR), 0.25, 95% CI 0.17-0.39, P < 0.0001] and OS (median 19.6 months, 95% CI 15.0 months to not evaluable versus 11.5 months, 95% CI 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% versus 22%) and leukopenia (21% versus 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.
Chen YX, Jin Y, Chen YK
… +22 more, Cui C, Yao J, Zhang Y, Li M, Cao G, Yang S, Fan Y, Shi J, Zhang X, Shen L, Shu Y, Wang C, Dai T, Mao T, Luo X, Zhang X, Xie H, Zou J, Xu RH, Wang ZX, Wang F, JUPITER-06 investigators
BACKGROUND: The interim analysis of the JUPITER-06 study reveals significantly longer progression-free survival (PFS) and overall survival (OS) in advanced esophageal squamous-cell carcinoma (ESCC) patients treated with...BACKGROUND: The interim analysis of the JUPITER-06 study reveals significantly longer progression-free survival (PFS) and overall survival (OS) in advanced esophageal squamous-cell carcinoma (ESCC) patients treated with toripalimab in combination with paclitaxel (Taxol) plus cisplatin (TP). Prior work proposed copy number alteration-corrected tumor mutational burden (ccTMB) and an esophageal cancer genome-based immuno-oncology classification (EGIC) scheme as prespecified 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 METHODS: A total of 514 patients with treatment-naïve advanced ESCC were randomly assigned 1: 1 to receive toripalimab or placebo in combination with paclitaxel plus cisplatin every 3 weeks for up to six cycles, followed by toripalimab or placebo maintenance. The coprimary endpoints were OS and PFS assessed by blinded independent central review. Whole exome sequencing of 486 tumors enabled biomarker analyses. RESULT: As of 23 February 2023, toripalimab plus TP significantly improved OS versus placebo plus TP [17.7 months, 95% confidence interval (CI) 14.6-20.8 months versus 12.9 months, 95% CI 11.6-14.1 months; hazard ratio (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 programmed death-ligand 1 (PD-L1) expression nor TMB significantly correlated with OS benefit. In contrast, prespecified 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 the 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. MATERIALS AND METHODS: Cancer death certifications and pop...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. MATERIALS AND 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 ∼1 230 000 EU cancer deaths, corresponding to age-standardised rates of 114.1/100 000 males (-7.8% versus 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 of EU, except for Spain (+2.4%). Among females, lung cancer mortality declines are confined to those aged <65 years, while unfavourable trends continued in older age groups. Around 7.3 (5.0 in males, 2.3 in females) 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.
BACKGROUND: Standard treatment of localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), but ∼50% of patients relapse within 2 years. Adjuvant immunotherapy...BACKGROUND: Standard treatment of localized muscle-invasive bladder cancer (MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), but ∼50% of patients relapse within 2 years. Adjuvant immunotherapy is currently administered based on pathology and clinical assessment in high-risk patients only, potentially resulting in under- and overtreatment. PATIENTS AND METHODS: TOMBOLA is a Danish, multicenter, open-label, single-arm phase II trial evaluating serial circulating tumor DNA (ctDNA) testing to guide postoperative immunotherapy. Low- and high-risk patients with MIBC (cT2-4aN0-1M0) treated with NAC and RC were monitored postoperatively with tumor-informed ctDNA assays. ctDNA-positive patients initiated atezolizumab for up to 1 year, irrespective of imaging; ctDNA-negative patients received immunotherapy only upon radiographic detection of metastases. The primary endpoint was molecular and radiographic complete response. Key secondary endpoints included recurrence-free survival and overall survival. RESULTS: In total 192 patients were enrolled, and among 178 assessable patients in the intention-to-treat population (median follow-up 34 months), 104 (58%) were ctDNA-positive within 2 years after RC, 63% within 4 months. The median lead time from ctDNA detection to imaging-confirmed recurrence was 90 days (range -61 to 961 days). Of the ctDNA-positive patients, 84 completed atezolizumab and had scanning and ctDNA analyses available for primary endpoint assessment. Some 60% (50/84) of patients achieved the primary endpoint of complete response. One-year recurrence-free survival was 97% in ctDNA-negative patients and 76% in ctDNA-positive patients. Prespecified biomarker analyses showed that ctDNA status and levels, risk stratification, and immune-related gene expression signatures were associated with both recurrence risk and response to immunotherapy. Treatment was well tolerated with no new safety concerns. CONCLUSIONS: Tumor-informed ctDNA testing after NAC and RC predicts recurrence risk and enables personalized postoperative management in MIBC. TOMBOLA demonstrates that ctDNA-positive, low-risk patients may benefit from early immunotherapy, while ctDNA-negative high-risk patients may safely avoid adjuvant treatment without compromising outcomes.
BACKGROUND: Global inequities in access to cancer diagnostics and treatment contribute to wide variation in cancer mortality-to-incidence ratios (MIRs), a proxy for survival. We aimed to develop an interpretable machine...BACKGROUND: Global inequities in access to cancer diagnostics and treatment contribute to wide variation in cancer mortality-to-incidence ratios (MIRs), a proxy for survival. We aimed to develop an interpretable machine learning framework to quantify country-specific health system contributors to MIR and inform policy prioritization. MATERIALS AND METHODS: We assembled national MIRs from GLOBOCAN 2022 for 185 countries and health system indicators from multilateral sources, including gross domestic product (GDP) per capita, universal health coverage (UHC) index, radiotherapy centers per population, health spending (%GDP), out-of-pocket expenditure, work force densities (physicians; nurses/midwives; surgical work force), pathology availability, Human Development Index, and gender inequality index. A CatBoost gradient-boosting model was trained with repeated leave-one-country-out cross-validation (10 repeats; 1850 predictions). Nested hyperparameter optimization and strict leakage control were used. Model interpretability employed SHapley Additive exPlanations (SHAP; TreeExplainer) to generate global and country-level feature attributions. SHAP values, model-derived metrics quantifying each factor's contribution to cancer outcomes, were generated. Performance metrics included R, root mean squared error (RMSE), mean absolute error, and Pearson correlation; uncertainty was estimated by bootstrap resampling. RESULTS: The model showed strong out-of-sample performance [R = 0.852, 95% confidence interval (CI) 0.801-0.891; RMSE 0.057, 95% CI 0.050-0.064]; correlation between predicted and observed MIRs was r = 0.923 (P = 8.30 × 10). Global SHAP contributions ranked GDP per capita (22.5%), radiotherapy centers per population (15.4%), and UHC index (12.9%) as the leading determinants. Country-specific SHAP profiles revealed substantial heterogeneity in dominant drivers across settings, enabling tailored policy levers (e.g. infrastructure, coverage expansion, or financial protection). An accompanying web interface provides country-level SHAP summaries for decision support. CONCLUSIONS: An explainable machine learning approach accurately predicts national MIRs and decomposes predictions into country-specific health system attributions. While ecological and noncausal by design, the SHAP profiles translate population-level associations into actionable hypotheses for prioritizing investments-highlighting, across many contexts, radiotherapy capacity and UHC expansion as recurrent levers, and underscoring that higher total health spending alone may be insufficient without strategic allocation. Prospective, country-specific evaluations are warranted to test whether targeting model-identified drivers improve cancer outcomes.
Frost N, Joosten M, Franzen J
… +29 more, Wiesweg M, Rasokat A, Kulhavy J, Kollmeier J, Reinmuth N, Grohé C, Roeper J, Rittmeyer A, Heinzen S, Wermke M, Wesseler C, Christopoulos P, Kauffmann-Guerrero D, Althoff A, Bleckmann A, Collienne M, Berezucki E, Overbeck T, Kropf-Sanchen C, Griesinger F, Sebastian M, Schuler M, Braun S, Wenzel C, Furth C, Wolf J, Bischoff P, Reck M, National Network Genomic Medicine Lung Cancer Germany
BACKGROUND: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases health care burden, exposes patients to avoidable toxicities,...BACKGROUND: The optimal duration of immune checkpoint blockade (ICB) in lung cancer remains undefined. Indefinite treatment in long-term responders increases health care burden, exposes patients to avoidable toxicities, and is not supported by any clinical or biological rationale or translational data. Prospective strategies to determine the optimal duration of immunotherapy in lung cancer are urgently needed. PATIENTS AND METHODS: In this retrospective cohort study, 455 patients from 21 National Network Genomic Medicine Lung Cancer Germany (nNGM) centers with ≥2 years of disease control on first-line ICB-based therapy were grouped into PET/CT-guided discontinuation (cohort A, n = 126) or continued ICB without PET/CT (cohort B, n = 329), and assessed for overall survival (OS). Matched pre- and post-ICB tumor samples from cohort A patients with persistent or progressive disease were analyzed by comprehensive genomic profiling, histological tumor-infiltrating lymphocyte quantification, and spatial transcriptomics to explore mechanisms of late resistance. RESULTS: After a median follow-up of 55 months, cohort A showed significantly longer OS [median not reached versus 82 months, hazard ratio 0.35 (95% confidence interval 0.18-0.67), P = 0.002], despite substantially shorter treatment duration (27 versus 45 months, P < 0.001). Discontinuation was either PET-driven (A) or resulted from immune-related toxicity, progression, or patients' choice (B). Systematic re-biopsies in cohort A revealed a high incidence of second primary lung cancers (SPLC, 28%). All progression events were managed exclusively with local (ablative) treatments in 53% (A) versus 17% (B). Tumors that occurred after treatment exhibited features of acquired resistance, whereas SPLC displayed characteristics of primary resistance, including low programmed death ligand 1 expression, low tumor mutational burden, and immunologically cold tumor microenvironments. CONCLUSIONS: A structured discontinuation strategy appears to provide a safe approach for long-term ICB responders, enabling earlier detection of resistance before generalized progression. A confirmatory prospective non-inferiority randomized trial within the nNGM is underway.
BACKGROUND: Practice-changing clinical trials for novel therapeutic regimens administered in the neoadjuvant setting have been reported for multiple cancer types, bringing this treatment strategy to the forefront for pat...BACKGROUND: Practice-changing clinical trials for novel therapeutic regimens administered in the neoadjuvant setting have been reported for multiple cancer types, bringing this treatment strategy to the forefront for patients with high-risk surgically resectable disease. Previously, tumor-type- or therapy-type-specific scoring systems were used for pathologic response assessment. The goal of this effort is to update, harmonize, and standardize the emerging system(s) for pathologic response assessment and data capture. MATERIALS AND METHODS: Leaders in pathology, oncology, and surgery, including those from the Society for Immunotherapy of Cancer's Pan-tumor Harmonization of Pathologic Response Assessment (PATHdata) efforts and the International Neoadjuvant Melanoma Consortium (INMC), convened to develop updated consensus guidelines for pathologic response assessment, including specimen handling and tissue submission, scoring, and reporting. This paper builds upon previous recommendations, which are updated based on histologic features associated with patient outcomes. Specific attention was paid to commonalities across tumor types, as well as tumor-type-specific considerations. RESULTS: A revised and standardized approach to tissue submission is recommended, including total submission of tumors ≤3 cm in size for histologic analysis. Additional guidance is provided for larger tumors. Pathologic response is quantified through assessments of percentage of residual viable tumor (%RVT), necrosis, and regression. Descriptions of histologic features to be scored are provided together with a standardized reporting template. Recommendations regarding collecting additional key datapoints are also made, to allow continued, extended validation of this pan-tumor approach. CONCLUSIONS: As pathologic response emerges as a surrogate endpoint for long-term clinical outcomes and to help inform adaptive adjuvant therapy decisions in routine clinical care, standardization is critical to facilitate consistent and reliable application. This pan-tumor approach to scoring and reporting supports robust stratification of patient outcomes, facilitates comparisons across clinical trials and tumor types, enhances data collection, and establishes a foundation for identifying additional, clinically meaningful %RVT cut points.
Pistilli B, Jhaveri K, Im SA
… +18 more, Pernas S, De Laurentiis M, Wang S, Martínez Jañez N, Borges G, Cescon DW, Hattori M, Lu YS, Hamilton E, Tsurutani J, Kalinsky K, Rubini Liedke PE, Carroll D, Khan S, Rugo HS, Xu B, Bardia A, TROPION-Breast01 investigators
BACKGROUND: The TROPION-Breast01 study (NCT05104866) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) with the t...BACKGROUND: The TROPION-Breast01 study (NCT05104866) demonstrated statistically significant and clinically meaningful improvement in progression-free survival (PFS) by blinded independent central review (BICR) with the trophoblast cell-surface antigen 2-directed antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd) versus investigator's choice of chemotherapy (ICC) in patients with previously treated, inoperable/metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. In this article, we report results from the final overall survival (OS) analysis. PATIENTS AND METHODS: Patients with inoperable/metastatic HR-positive/HER2-negative breast cancer, who had disease progression on endocrine therapy and for whom endocrine therapy was unsuitable, and had received one to two prior lines of chemotherapy in the inoperable/metastatic setting were randomly assigned in a 1 : 1 ratio to Dato-DXd (6 mg/kg every 3 weeks) or ICC (eribulin/capecitabine/vinorelbine/gemcitabine). Dual primary endpoints were PFS by BICR and OS. RESULTS: At data cut-off, median follow-up was 22.8 months. OS for the Dato-DXd versus ICC arm did not reach statistical significance (hazard ratio 1.01, 95% confidence interval 0.83-1.22, P = 0.9445). Use of ADCs (trastuzumab deruxtecan and sacituzumab govitecan) as subsequent therapy was imbalanced: 12.3% in the Dato-DXd arm versus 24.0% in the ICC arm. Secondary efficacy endpoints (PFS by investigator assessment, objective response rate, duration of response, disease control rate at 12 weeks, time to first and second subsequent therapy or death, and time to second progression or death) continued to favor Dato-DXd at this final analysis. The overall safety profile of Dato-DXd remained favorable compared with ICC, and no new safety signals were observed with longer follow-up. CONCLUSIONS: TROPION-Breast01 met its dual primary endpoint of PFS by BICR. While there was no statistically significant improvement in the dual primary endpoint of OS with Dato-DXd versus ICC, subsequent ADC treatment may have affected OS results. The totality of efficacy and safety data supports Dato-DXd as a new treatment option for patients with previously treated, inoperable/metastatic HR-positive/HER2-negative breast cancer.
Ciardiello D, Martini G, Boscolo Bielo L
… +32 more, Pietrantonio F, Raimondi A, Manca P, Pisconti S, Nisi C, Tortora G, Salvatore L, Sartore-Bianchi A, Siena S, Blasi L, Ongaro E, Zaniboni A, Pinto C, Antonuzzo L, Avallone A, Normanno N, Santabarbara G, Zampino MG, Berardi R, Cogoni A, Lotesoriere C, Latiano TP, Maiello E, Fazio N, Curigliano G, Bordonaro R, Troiani T, De Vita F, Martinelli E, Ciardiello F, Napolitano S, CAVE-2 GOIM study group
BACKGROUND: Anti-epidermal growth factor receptor (EGFR) drug rechallenge could be of therapeutic value in a subgroup of refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The randomized phase II CAVE-...BACKGROUND: Anti-epidermal growth factor receptor (EGFR) drug rechallenge could be of therapeutic value in a subgroup of refractory metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The randomized phase II CAVE-2 GOIM trial compared two rechallenge regimens in RAS/BRAF wild-type mCRC (cetuximab monotherapy or in combination with avelumab). Patients were selected according to baseline plasma circulating tumor DNA (ctDNA) comprehensive genomic profiling (CGP) by FoundationOne Liquid CDx. Primary endpoint was overall survival (OS). RESULTS: From August 2022 to December 2024, 156 out of 328 screened patients were randomly assigned in a 2 : 1 ratio to cetuximab plus avelumab (arm A, 104 patients) or cetuximab (arm B, 52 patients). Median progression-free survival (mPFS) was 5.3 months [95% confidence interval (CI) 4.3-6 months] in arm A versus 4.3 months (95% CI 3.5-5.5 months) in arm B [hazard ratio (HR) 0.78, 95% CI 0.55-1.10, P = 0.158]. Median OS (mOS) was 14.8 months (95% CI 12.1-18.3 months) in arm A versus 12.9 months (95% CI 11 months-not evaluable) in arm B (HR 1.00, 95% CI 0.65-1.52, P = 0.983). A pre-planned exploratory analysis evaluated the impact of genomic pathogenic variants on therapeutic efficacy in the EGFR pathway. In the whole study population, 124/156 patients had tumors without any genomic alteration in KRAS, NRAS, BRAF, EGFR extracellular domain, PIK3CA exon 20, MAP2K1, AKT1, MET, PTEN, and ERBB2 ('negative hyperselection'). These patients had significantly improved mPFS [5.35 months (95% CI 4.4-5.9 months) versus 3.65 months (95% CI 2.8-4.8 months); HR 0.62, 95% CI 0.42-0.92, P = 0.017] and mOS [15.0 months (95% CI 12.6-19.9 months) versus 11.1 months (95% CI 8.6-15.6 months); HR 0.61, 95% CI 0.39-0.97, P = 0.037] compared with patients having at least one pathogenic variant ('positive hyperselection'). Similarly, improved objective response rate, mPFS, and OS were observed for each treatment arm in patients with 'negative hyperselection'. CONCLUSION: Addition of avelumab does not increase efficacy of cetuximab rechallenge. Liquid biopsy CGP identifies patients who benefit from anti-EGFR rechallenge supporting its implementation in the continuum of care of mCRC.
BACKGROUND: Addition of pembrolizumab to neoadjuvant chemotherapy (NACT) is a standard-of-care treatment in non-metastatic triple-negative breast cancer (TNBC). Trials employing reduced doses of immune checkpoint inhibit...BACKGROUND: Addition of pembrolizumab to neoadjuvant chemotherapy (NACT) is a standard-of-care treatment in non-metastatic triple-negative breast cancer (TNBC). Trials employing reduced doses of immune checkpoint inhibitors have yielded encouraging activity in several tumor types. Whether low-dose pembrolizumab enhances pathological complete response when added to NACT in TNBC remains uncertain. PATIENTS AND METHODS: A phase II, open-label, randomized controlled study was conducted at a tertiary cancer center in New Delhi, India. Eligible participants had previously untreated stage II-III TNBC and lacked access to standard-dose pembrolizumab. Patients were randomly assigned (1 : 1) to receive dose-dense NACT-four cycles of doxorubicin-cyclophosphamide followed by four cycles of paclitaxel with or without a low dose of pembrolizumab (50 mg every 6 weeks for three cycles). The primary endpoint was pathological complete response. RESULTS: Between February 2024 and February 2025, 157 patients were enrolled. Baseline characteristics were comparable between study arms. Surgery was completed in 152 patients. In the intention-to-treat population, pathological complete response was achieved in 53.8% [90% confidence interval (CI) 43.9% to 63.5%] of patients receiving low-dose pembrolizumab + NACT versus 40.5% (90% CI 31.1% to 50.4%) with NACT alone, corresponding to an absolute difference of 13.3% (90% CI 0.3% to 26.3%, one-sided P = 0.047). Among those who underwent surgery, the respective pathological complete response rates were 56.7% and 41.0% (absolute difference 15.7%, one-sided P = 0.031). Grade ≥3 toxicities occurred in 50% of patients in the low-dose pembrolizumab arm and in 59.5% in the control arm. CONCLUSIONS: Addition of low-dose immunotherapy to NACT led to a statistically significant increase in pathological complete response rates, and the benefit appears to be numerically similar to that seen in the KEYNOTE-522 trial. In settings where access to the standard regimen is restricted, a low-dose approach may offer a feasible and cost-effective treatment option for patients with TNBC.
BACKGROUND: Adding the pan-Akt serine/threonine kinase (AKT) inhibitor capivasertib to first-line paclitaxel in metastatic triple-negative breast cancer (TNBC) led to significantly longer progression-free survival (PFS)...BACKGROUND: Adding the pan-Akt serine/threonine kinase (AKT) inhibitor capivasertib to first-line paclitaxel in metastatic triple-negative breast cancer (TNBC) led to significantly longer progression-free survival (PFS) and overall survival (OS) versus placebo-paclitaxel in the phase II PAKT trial. CAPItello-290 was designed to further assess capivasertib-paclitaxel, including in patients with PIK3CA/AKT1/PTEN-altered tumours. PATIENTS AND METHODS: Patients with previously untreated metastatic TNBC were randomised 1 : 1 to paclitaxel 80 mg/m [day 1, weeks 1-3 (4-week cycle)] plus capivasertib 400 mg or placebo twice daily (days 2-5, weeks 1-3). PIK3CA/AKT1/PTEN alterations were analysed by retrospective central molecular testing. Dual primary endpoints were OS in the overall population and in patients with PIK3CA/AKT1/PTEN-altered tumours; investigator-assessed PFS was a key secondary endpoint. RESULTS: From July 2019 to February 2022, 812 patients were randomised; 30.7% of patients had PIK3CA/AKT1/PTEN tumour alterations. At final analysis [data cut-off (DCO) 18 March 2024], the median OS for the overall population was 17.7 and 18.0 months with capivasertib-paclitaxel and placebo-paclitaxel, respectively [hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.78-1.08, P = 0.3239] and for patients with PIK3CA/AKT1/PTEN-altered tumours, it was 20.4 months in both arms (HR 1.05, 95% CI 0.77-1.43, P = 0.7602). At PFS DCO (25 May 2022), the median PFS in the overall population numerically favoured capivasertib-paclitaxel (5.6 versus 5.1 months placebo-paclitaxel; HR 0.72, 95% CI 0.61-0.84); this was also the case in patients with PIK3CA/AKT1/PTEN-altered tumours (7.5 versus 5.6 months placebo-paclitaxel; HR 0.70, 95% CI 0.52-0.95). The most frequent adverse event (AE) of grade ≥3 was diarrhoea [12.7% versus 0.7% placebo-paclitaxel (overall population)]. Capivasertib was discontinued due to AEs in 8.5% of patients (4.9% placebo-paclitaxel; overall population); AEs led to death in 4.2% of all patients. CONCLUSIONS: Capivasertib-paclitaxel did not meet the prespecified boundary for improving OS in either population; PFS numerically favoured the combination, especially in PIK3CA/AKT1/PTEN-altered tumours. The safety of capivasertib-paclitaxel was generally manageable and consistent with prior studies.