Takahashi N, Funasaka C, Shimura M
… +14 more, Hirota A, Uematsu M, Fukuda M, Baba K, Mamishin K, Nakajima H, Kondoh C, Harano K, Matsubara N, Hosono A, Kawasaki T, Onishi T, Naito Y, Mukohara T
BACKGROUND: The KEYNOTE-522 (KN522) trial demonstrated significantly improved outcomes with neoadjuvant chemotherapy (NAC) combined with pembrolizumab in high-risk triple-negative breast cancer (TNBC). However, the effic...BACKGROUND: The KEYNOTE-522 (KN522) trial demonstrated significantly improved outcomes with neoadjuvant chemotherapy (NAC) combined with pembrolizumab in high-risk triple-negative breast cancer (TNBC). However, the efficacy of this chemoimmunotherapy for histologically uncommon TNBC subtypes, such as invasive ductal carcinoma (IDC) with apocrine feature (IDCapo) or metaplastic carcinoma, remains unclear. PATIENTS AND METHODS: This retrospective study examined clinicopathological characteristics and outcomes of patients with clinical stage II or III TNBC treated with either the KN522 regimen or conventional NAC without immunotherapy at the National Cancer Center Hospital East between August 2014 and December 2024. Patients pathologically diagnosed with IDC, IDCapo, or metaplastic carcinoma were included. We compared outcomes of the KN522 regimen among histologic subtypes and evaluated its efficacy versus conventional NAC in patients with IDCapo or metaplastic carcinoma. RESULTS: Seventy-two patients with TNBC received the KN522 regimen: 58 IDC, 10 IDCapo, and 4 metaplastic carcinoma. The pathological complete response (pCR) rate was significantly lower in IDCapo than in IDC (3/10 [30.0%] vs. 41/58 [70.7%], P = 0.027), and this difference remained after adjustment for clinical factors. There were no metaplastic carcinoma patients with pCR (0/4, 0%). Compared with conventional NAC, the KN522 regimen yielded a higher pCR rate in IDCapo (3/10 [30.0%] vs. 0/19 [0%], P = 0.033), but not in metaplastic carcinoma (0/4 [0%] vs. 1/10 [10.0%], P = 1.00). CONCLUSION: The pCR rate of NAC with pembrolizumab was significantly lower in IDCapo than in IDC but was improved compared with conventional NAC. No meaningful benefit was observed in metaplastic carcinoma. IMPLICATIONS FOR PRACTICE: This study suggests that neoadjuvant chemoimmunotherapy can improve pathological complete response rate in invasive ductal carcinoma with apocrine feature, known as therapeutically resistant uncommon histology of the breast cancer. Pathological complete response rates of the neoadjuvant chemoimmunotherapy is dismal in metaplastic breast carcinoma, which sheds light to highly unmet need of novel therapeutic strategies for such aggressive breast cancer.
Avancini A, Borsati A, Adamoli G
… +15 more, Toniolo L, Ciurnelli C, Trevisan A, Belluomini L, Trestini I, Tregnago D, Sposito M, Insolda J, Manduca S, Auriemma A, Fiorio E, Milella M, Lanza M, Schena F, Pilotto S
BACKGROUND: Despite strong evidence supporting exercise in oncology, real-world data on its feasibility and effectiveness across cancer types remain limited. The CHOiCE (Choose Health: Oncological patients Centered Exerc...BACKGROUND: Despite strong evidence supporting exercise in oncology, real-world data on its feasibility and effectiveness across cancer types remain limited. The CHOiCE (Choose Health: Oncological patients Centered Exercise) study aimed to evaluate a flexible, patient-centered exercise program in routine clinical practice. MATERIALS AND METHODS: This prospective cohort study enrolled 180 adult patients undergoing treatments. Participants completed a 12-week program combining aerobic and resistance training, delivered in person, at home, or hybrid. Primary outcomes were recruitment rate, adherence, dropout, and safety. Secondary outcomes included physical fitness, quality of life, and physical activity. Subgroup analyses explored responses by cancer type, stage, treatment, and delivery mode. RESULTS: Recruitment rate was 82%, with a median attendance of 88%. The dropout rate was 32%, mainly due to personal reasons or disease progression. No serious adverse events were reported. Significant improvements were observed in the six-minute walk test (+39 m, P < .001), leg press strength (+7.1 kg, P < .001), handgrip strength (+1.0 kg, P = .003), and flexibility tests (P < .05). Quality of life improved in physical, role, emotional, and social functioning. Fatigue, nausea, dyspnea, insomnia, and appetite loss were significantly reduced. Patients with gastrointestinal cancer, stage III-IV disease, or undergoing chemotherapy showed the largest gains. CONCLUSION: A patient-centered exercise program for patients with cancer is feasible and effective in a real-world setting. These findings support integrating tailored exercise into routine oncology care. TRIAL REGISTRATION: NCT04226508.
PURPOSE: To improve survival prediction in locally advanced cervical cancer (LACC) post-radiotherapy, we developed and compared a nomogram and machine learning (ML) models using immune-inflammatory markers. MATERIAL AND...PURPOSE: To improve survival prediction in locally advanced cervical cancer (LACC) post-radiotherapy, we developed and compared a nomogram and machine learning (ML) models using immune-inflammatory markers. MATERIAL AND METHODS: Clinical data from patients with LACC who received radical radiotherapy at our department between 2016 and 2019 were retrospectively analyzed. Key variables were selected using Spearman correlation and Boruta analysis. A Cox regression-based nomogram was developed and validated. ML models were also used to predict survival, with performance evaluated by accuracy, the area under the receiver operating characteristic curve (AUC), precision, recall, and the F1-score. The performance of the optimal ML model and the nomogram was compared using time-dependent predictive accuracy. RESULTS: A cohort of 300 patients with LACC was randomly allocated to training and validation cohorts at a 7:3 ratio. The nomogram and ML models incorporated immune-inflammatory markers and clinical variables. The nomogram demonstrated strong discriminative ability, calibration, and clinical utility, as evidenced by AUC, calibration plots, and decision curve analysis. Among ML models, logistic regression achieved superior performance (accuracy = 0.933, recall = 1.000, F1-score = 0.938). Time-dependent accuracy analysis revealed dynamic predictive performance over 12-60 months. The nomogram's predictive accuracy improved over time, reaching 0.611 at 53-59 months, while logistic regression peaked earlier (0.911 at 12-24 months) and consistently outperformed the nomogram. CONCLUSION: Both nomogram and ML models provide valuable prognostic insights for LACC. The logistic regression ML model showed superior predictive accuracy compared to the nomogram during 1-5 years of follow-up.
BACKGROUND: Triple therapy of transcatheter arterial chemoembolization (TACE) combined with lenvatinib and anti-PD-1 antibodies has demonstrated excellent efficacy in unresectable hepatocellular carcinoma (uHCC). However...BACKGROUND: Triple therapy of transcatheter arterial chemoembolization (TACE) combined with lenvatinib and anti-PD-1 antibodies has demonstrated excellent efficacy in unresectable hepatocellular carcinoma (uHCC). However, tumor drug resistance is still a major problem and the rate of complete response in uHCC following triple therapy is relatively low. This study aimed to investigate the efficacy and safety of sequential radiotherapy after triple therapy in patients with uHCC to improve tumor response rate. METHODS: This retrospective study included 29 patients with uHCC who received sequential radiotherapy after achieving partial response (PR) or stable disease (SD) in tumor response per the modified Response Evaluation Criteria in Solid Tumors (mRECIST) after triple therapy. The overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) were analyzed to evaluate the efficacy of this regimen. Treatment-related adverse events were assessed to determine the safety profile. RESULTS: Among the 29 patients, the median OS had not yet been reached, and the median PFS was 19.43 months. The 24-month OS and PFS rates were 72.8% and 46.5%, respectively. The lesions of 6 patients initially with tumor response of PR achieved complete response, and the lesions of 12 patients with SD achieved PR after sequential radiotherapy. All adverse events were manageable, and no treatment-related death occurred. CONCLUSION: Sequential radiotherapy after triple therapy enhanced tumor response and survival benefits for uHCC patients, with manageable adverse effects.
Rosnev S, Klein K, Heukamp L
… +14 more, Lenk J, Joosten M, Möbs M, Grob T, Benary M, Vecchione L, Ott CE, Modest DP, Knödler M, Keller U, Frost N, Keilholz U, Kiewe P, Rieke DT
Oncogenic alterations in MET represent therapeutically actionable driver alterations in non-small cell lung cancers (NSCLC). Among these, MET fusions are rare, occurring in approximately 0.1%-0.3% of NSCLC. We report the...Oncogenic alterations in MET represent therapeutically actionable driver alterations in non-small cell lung cancers (NSCLC). Among these, MET fusions are rare, occurring in approximately 0.1%-0.3% of NSCLC. We report the case of a 52-year-old woman with metastatic, TTF1-positive lung adenocarcinoma harboring a KIF5B::MET fusion. After progression on chemotherapy and immunotherapy, she achieved a durable response lasting nearly five years on third-line treatment with the type Ia MET inhibitor crizotinib. At the time of suspected disease progression, two tissue re-biopsies were non-diagnostic due of insufficient tumor cell content. Circulating tumor DNA (ctDNA) analysis identified two newly acquired on-target resistance mutations within the MET kinase domain (L1213V and Y1248C) in addition to the known KIF5B::MET fusion. After re-evaluation by the institutional molecular tumor board, both alterations were considered mediators of resistance to type I MET inhibitors, with available data indicating preserved sensitivity to type II inhibitors. Based on these findings, the patient was switched to cabozantinib, a multikinase type II MET inhibitor, resulting in a radiographic disease stabilization accompanied by a marked decline in tumor marker levels. This case illustrates the clinical utility of liquid biopsy for molecular resistance monitoring, particularly when tissue re-biopsy is not feasible, supports its integration into clinical decision-making, and underscores the therapeutic relevance of MET inhibitor class-switch strategies in MET fusion-positive disease.
Vernaci G, Griguolo G, Girardi F
… +12 more, Menichetti A, Ferrucci M, Marchet A, Bellu L, Faggioni G, Falci C, Landa G, La Commare M, Giarratano T, Giorgi CA, Guarneri V, Dieci MV
BACKGROUND: Isolated locoregional relapse (ILRR) after curative treatment for early breast cancer (BC) is associated with poor prognosis. Treatment strategies are poorly standardized. We aimed at exploring prognostic fac...BACKGROUND: Isolated locoregional relapse (ILRR) after curative treatment for early breast cancer (BC) is associated with poor prognosis. Treatment strategies are poorly standardized. We aimed at exploring prognostic factors and long-term outcomes of ILRR. PATIENTS AND METHODS: Overall, 1070 patients diagnosed with stage I-III BC between 2000 and 2007 were identified from a large mono-institutional dataset, with long follow up. Among these, 66 patients (6%) presented an ILRR as first BC event and 33% subsequently presented a distant recurrence (DR) (22/66). RESULTS: In the overall study cohort, patients with ILRR presented a significantly higher risk of DR compared to those without ILRR (P < .001). However, while being diagnosed with a DR was significantly associated with a worse overall survival (OS), ILRR was not. In the subgroup of patients with ILRR (N = 66), more advanced nodal status at initial diagnosis and HER2-positivity on the ILRR were significantly associated with worse distant relapse-free interval (DRFI) post-ILRR and worse OS post-ILRR. Moreover, switching from HR+ primary BC to HR- ILRR was associated with worse OS post-ILRR. In multivariate analyses, nodal involvement at primary diagnosis remained independently associated with both DRFI and OS post-ILRR, while HER2+ ILRR was independently associated with worse OS post-ILRR. CONCLUSION: Patients diagnosed with ILRR after curative treatment for primary BC are at higher risk of subsequent DR, highlighting the need for prompt diagnosis and treatment of ILRR. Moreover, biological recharacterization of ILRR provides potential key prognostic and predictive factors, such as HR loss, allowing personalization of treatment and follow-up after ILRR.
Patients with pancreatic cancer undergoing curative-intent surgery face incredible burdens, even long-term after surgery, but the amount of time spent in health care (ie, as health care contact days) was not hitherto qua...Patients with pancreatic cancer undergoing curative-intent surgery face incredible burdens, even long-term after surgery, but the amount of time spent in health care (ie, as health care contact days) was not hitherto quantified. In this cohort study of 649 patients with pancreatic cancer undergoing curative-intent surgery in the largest integrated health system in the United States, patients spent approximately 50% of days as contact days (and 50% as "home days"-without health care contact) in the first month after surgery. The percentage of home days only increased to approximately 60% even 1 year after surgery when including the approximate mortality 20% rate, and patients spent at least 20% of their days with health care contact even months/years after surgery. These data are important for counseling patients and caregivers (both to set expectations and to augment informed decision-making) and for health systems and policy makers to ensure appropriate supports.
BACKGROUND: Next generation sequencing (NGS) has driven the development of precision oncology. While adult cancer genomics has been extensively studied, pediatric cancer, particularly among Asian populations, has receive...BACKGROUND: Next generation sequencing (NGS) has driven the development of precision oncology. While adult cancer genomics has been extensively studied, pediatric cancer, particularly among Asian populations, has received less attention. METHODS: We screened gene alteration profiles of 99 pediatric cancer patients using the targeted NGS panel and compared the results with those from Western cohorts. The relationship between genes and clinical characteristics was also analyzed. RESULTS: The most frequently mutated gene was KMT2D (18.2%), followed by TP53 (11.1%) and DICER1 (9.1%). The frequency of KMT2D mutations in our cohort is significantly higher than in Western cohorts, whereas TP53 mutations showed no significant difference. Pathogenic or likely pathogenic (P/LP) germline mutations were identified in only 3.5% of the patients. Notably, 69%-75% of patients had at least one genomic alteration with potential clinical significance. In neuroblastoma (NB), the most commonly altered genes were MYCN (7/48), DICER1 (6/48), ARID1B, EGFR, KMT2D, and TCF3 (5/48). In a subset of intermediate-/high-risk NB patients (n = 33), MYCN amplification was associated with disease progression during induction chemotherapy, and gene alterations in the MAPK pathway were associated with poor survival. We also identified novel alterations in specific tumor types, including SFPQ-TACC1 fusion in NB. CONCLUSIONS: Our findings enhance understanding of the genomic landscape of Chinese pediatric cancer populations. Further research is required to validate these findings and fully explore the potential of genomic data to improve outcomes for pediatric cancer patients.
BACKGROUND: Anal cancer incidence is rising in the United States, now exceeding 10 000 cases annually. Chemoradiation (CRT) is the standard curative-intent treatment for non-metastatic squamous cell carcinoma of the anus...BACKGROUND: Anal cancer incidence is rising in the United States, now exceeding 10 000 cases annually. Chemoradiation (CRT) is the standard curative-intent treatment for non-metastatic squamous cell carcinoma of the anus (SCCA), with surgery generally reserved for non-responders with persistent or progressive disease. Recent trials have refined management, supporting the assessment of response at 26 weeks before considering surgery. However, contemporary population-level patterns of upfront primary surgery and associated survival trends remain incompletely described. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) registry (2004-2020), we identified adults with newly diagnosed non-metastatic anal squamous cell neoplasms (ICD-O-3 8050-8089). Outcomes were receipt of primary surgery as initial treatment and overall survival. We evaluated temporal trends (Cochran-Armitage), factors associated with primary surgery (multivariable logistic regression), and survival over time (Kaplan-Meier; multivariable Cox proportional hazards modeling). RESULTS: Among 16 718 patients with non-metastatic anal cancer, 33.1% (n = 5529) underwent primary surgery and 83.7% (n = 13 997) received radiation as part of initial management. Primary surgery declined from 46.0% in 2004 to 28.7% in 2020 (trend P < 0.001), while radiation utilization was relatively stable over time (trend P = 0.106). In adjusted analyses, younger age (<50 vs 60-69 years; OR 1.614), male sex (OR 1.508), and Non-Hispanic Black race (vs Non-Hispanic White; OR 1.178) were associated with higher odds of primary surgery. Tumor factors were strongly associated with surgical use (eg, T1 vs T2: OR 3.072; higher N stage associated with lower odds). Overall survival improved across diagnosis periods (log-rank P = 0.0002); in adjusted Cox models, diagnosis in 2016-2020 (vs 2004-2007) was associated with lower mortality risk (HR 0.77). CONCLUSIONS: From 2004 to 2020, primary surgery as initial management for non-metastatic anal cancer declined substantially, consistent with increasing adoption of CRT, while overall survival improved over time. Persistent use of upfront surgery in select subgroups warrants further study to clarify indications and ensure guideline-concordant care.
BACKGROUND: Without head-to-head trials comparing talazoparib plus enzalutamide (TALA+ENZA), olaparib plus abiraterone acetate and prednisone (OLAP+AAP), and niraparib plus abiraterone acetate and prednisone (NIRA+AAP) a...BACKGROUND: Without head-to-head trials comparing talazoparib plus enzalutamide (TALA+ENZA), olaparib plus abiraterone acetate and prednisone (OLAP+AAP), and niraparib plus abiraterone acetate and prednisone (NIRA+AAP) as first-line treatments for metastatic castration-resistant prostate cancer (mCRPC), treatment selection remains challenging. This study estimated the relative efficacy of TALA+ENZA vs OLAP+AAP and NIRA+AAP in unselected, homologous recombination repair (HRR)-deficient, and BRCA-mutated (BRCAm) populations. METHODS: Unanchored matching-adjusted indirect comparisons (MAICs) were conducted using individual patient data from TALAPRO-2 (TALA+ENZA) and published summary-level data from PROpel (OLAP+AAP) and MAGNITUDE (NIRA+AAP). TALAPRO-2 patients meeting PROpel/MAGNITUDE eligibility criteria were included; remaining patients were reweighted to align on key baseline characteristics. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for radiographic progression-free survival (rPFS) and overall survival (OS). RESULTS: In unselected patients, TALA+ENZA significantly prolonged rPFS vs OLAP+AAP (HR: 0.747; 95% CI, 0.583, 0.957), with no OS difference (HR: 0.821; 95% CI, 0.649, 1.039). In HRR-deficient patients, TALA+ENZA significantly prolonged rPFS vs OLAP+AAP (HR: 0.648; 95% CI, 0.423, 0.992), with no OS difference (HR: 0.834; 95% CI, 0.569, 1.223). Comparisons with OLAP+AAP in BRCAm were infeasible. Compared with NIRA+AAP, TALA+ENZA significantly prolonged rPFS and OS in HRR-deficient (HR: 0.406; 95% CI, 0.251, 0.655; HR: 0.554; 95% CI, 0.340, 0.902) and BRCAm patients (HR: 0.394; 95% CI, 0.222, 0.698; HR: 0.472; 95% CI, 0.247, 0.902). CONCLUSIONS: MAICs showed improved clinical benefit with TALA+ENZA vs OLAP+AAP and NIRA+AAP across multiple mCRPC populations and endpoints. Despite limitations of indirect comparisons, findings support TALA+ENZA as a first-line treatment option for mCRPC.
We explore how the COVID-19 pandemic amplified barriers across the lung cancer care continuum in Mexico. Drawing from a cross-sectional qualitative arm of a mixed-methods study (N = 46), interviews were conducted with lu...We explore how the COVID-19 pandemic amplified barriers across the lung cancer care continuum in Mexico. Drawing from a cross-sectional qualitative arm of a mixed-methods study (N = 46), interviews were conducted with lung cancer patients at the Mexican National Cancer Institute between 2020 and 2021. Using thematic analysis, patients reported care delays due to fear of infection, unclear communication, and service disruptions. Thematic patterns revealed that these challenges were compounded by financial hardship, emotional distress, and reluctance to seek care. Key policy and practice implications include the need for flexible healthcare delivery models, improved communication strategies, financial support mechanisms, tailored interventions for care-seeking behaviors, and integrated mental health and community support. These findings underscore the urgency for systemic adaptations to safeguard timely cancer care during future health crises, particularly in middle-income settings like Mexico. Ethical approval was obtained from the Mexican National Cancer Institute.
BACKGROUND: Regorafenib and trifluridine/tipiracil (FTD/TPI) are standard later-line treatments for patients with refractory metastatic colorectal cancer. However, these drugs show limited efficacy in some patients, and...BACKGROUND: Regorafenib and trifluridine/tipiracil (FTD/TPI) are standard later-line treatments for patients with refractory metastatic colorectal cancer. However, these drugs show limited efficacy in some patients, and inappropriate use may increase toxicity and reduce quality of life. This study aimed to identify clinical predictors of early mortality after regorafenib or FTD/TPI initiation. METHODS: We retrospectively analyzed patients enrolled in the multicenter REGOTAS study. Early mortality was defined as death within 12 weeks of treatment initiation. Variables with P < .05 in univariate analysis were entered into a multivariable Cox model for overall survival (OS). Patients alive at 15 weeks (a 3-week margin beyond 12 weeks) were censored. RESULTS: We analyzed 523 patients (regorafenib, N = 212; FTD/TPI, N = 311). Independent predictors of early mortality were Eastern Cooperative Oncology Group performance status (≥1), low albumin level (<3.5 g/dL), high C-reactive protein level (≥1.0 mg/dL), and short time from first-line chemotherapy initiation (<18 months). The high-risk group (patients with all four factors, N = 35) showed higher mortality and shorter OS than the low-risk group (others, N = 488): 12-week mortality rate 40% vs 14%, 14-week mortality rate 60% vs 18%, and median OS: 2.8 months vs 7.8 months (hazard ratio: 3.52; P-value < .0001). CONCLUSION: Our predictive model may help identify patients at high risk of early mortality after regorafenib or trifluridine/tipiracil initiation and support shared decision-making between clinicians and patients regarding further chemotherapy or best supportive care.
Scafetta R, Donato M, Gullotta C
… +75 more, Guarino A, Fiore C, Sisca L, Speziale E, Troiano R, Foderaro S, Venuti F, Vilardi FA, Ricozzi V, Iuliani M, Simonetti S, Cavaliere S, Cortellini A, La Cesa A, Botticelli A, Scagnoli S, Pisegna S, Criscitiello C, Chirco A, D'Alessandro S, Pedersini R, Sposetti C, Tiberi E, D'Auria G, Vergati M, Mazzotta M, Caputo R, Verrazzo A, Rossino MG, Domati F, Piombino C, Di Lisa FS, Filomeno L, Arcuri T, Puce F, Riva F, Palleschi M, Sirico M, Piras M, Stucci LS, De Lisi D, Orsaria P, Grasso A, Ippolito E, Ramella S, Visani L, Bertini N, Bonaparte I, Gori S, Rossi L, Meattini I, Tagliaferri B, Caffo O, Bonomo MV, Portarena I, Irelli A, Cretella E, Porta C, Bianchini G, Fabbri MA, De Giorgi U, Vici P, Toss A, Garrone O, De Laurentiis M, Villa F, Berardi R, Minelli M, Altomare V, Vernieri C, Curigliano G, Vincenzi B, Tonini G, Santini D, Pantano F
BACKGROUND: The introduction of CDK4/6 inhibitors (CDK4/6i) has improved outcomes in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC), including in patients with bone metastases. Assessing the...BACKGROUND: The introduction of CDK4/6 inhibitors (CDK4/6i) has improved outcomes in hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (mBC), including in patients with bone metastases. Assessing their comparative effectiveness in real-world settings is crucial. METHODS: This retrospective, multicenter cohort study (January 2019-December 2023; median follow-up 39 months) evaluated the real-world progression-free survival (rwPFS) of abemaciclib, ribociclib, and palbociclib combined with endocrine therapy (ET) in HR+/HER2- mBC patients with bone metastases. Overall survival (OS) was a secondary exploratory endpoint. A total of 1399 patients with ECOG PS 0-1 and at least 12 months of follow-up were included. Analyses used propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) to adjust for confounding. RESULTS: Palbociclib showed shorter rwPFS (22 months) compared to abemaciclib (32 months; HR = 1.47, p = 0.001) and ribociclib (35 months; HR = 1.49, p < 0.001). No significant difference was observed between abemaciclib and ribociclib. OS was also lower with palbociclib (47 months) versus abemaciclib (60 months; HR = 1.77, p < 0.001) and ribociclib (64 months; HR = 1.69, p = 0.001). Results were consistent after PSM and IPTW adjustment. CONCLUSION: Ribociclib and abemaciclib may provide superior rwPFS and OS compared to palbociclib in HR+/HER2- mBC patients with bone metastases.
Drilon A, Cho BC, Camidge DR
… +18 more, Nagasaka M, Besse B, Solomon B, Goto K, Wolf J, Popat S, Felip E, Yang N, de Langen AJ, Lu S, Velcheti V, Lin AL, Calvet CY, Li L, Tschaika M, Afsar S, Yang H, Lin JJ
BACKGROUND: Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety manageme...BACKGROUND: Repotrectinib, a next-generation ROS1/TRK tyrosine kinase inhibitor, is approved for ROS1 fusion-positive non-small cell lung cancer and NTRK fusion-positive solid tumors. Its side effects and safety management strategies require further characterization. PATIENTS AND METHODS: The safety profile of repotrectinib (treatment-emergent/related adverse events [TEAEs/TRAEs]) was established in patients who initiated treatment at the recommended dose (160 mg daily [QD] for 14 days, then 160 mg twice daily [BID]) across all cohorts of the global, multicenter phase 1/2 TRIDENT-1 study. AE management strategies were outlined. RESULTS: In 472 patients, the most common TRAEs (dizziness [58%] and dysgeusia [50%]) were likely TRK inhibition-related. Median relative dose intensity was 90%; 14% (n = 66/472) of patients did not increase their initial QD dose to BID (mostly due to CNS AEs). Rates of dizziness (median onset, 7 days) were similar in patients with/without baseline brain metastases. Dose modifications downgraded severity or resolved dizziness in 78% of patients; 58% of patients had pharmacologic intervention without dose modification. Dizziness was downgraded/resolved in 62% (n = 120/195) of patients who did not receive dose modification or pharmacologic intervention. Treatment-related cognitive impairment and weight gain occurred in 19% and 12% of patients, respectively. Treatment-emergent withdrawal pain occurred in 14% of patients (median resolution time, 2.1 weeks). Dose interruption and reduction from TRAEs occurred in 39% and 38% of patients, respectively; 10% reported later re-escalation back to 160 mg BID. CONCLUSION: Many repotrectinib AEs, including neurological AEs secondary to TRK inhibition, were mitigated with appropriate management, including dose modification and/or pharmacologic intervention.
Barrón-Hernández A, Ríos-Rodríguez JA, García-Pacheco JA
… +7 more, Cuevas-Estrada B, De-la-Rosa S, Castro-Hernández C, Jiménez-Ríos MA, Sobrevilla-Moreno N, Santibáñez-Andrade M, González-Barrios R
BACKGROUND: Testicular germ cell tumors (TGCT) are highly curable malignancies, yet the prognostic impact of host metabolic status remains underexplored, especially in non-Caucasian populations. METHODS: We analyzed 2755...BACKGROUND: Testicular germ cell tumors (TGCT) are highly curable malignancies, yet the prognostic impact of host metabolic status remains underexplored, especially in non-Caucasian populations. METHODS: We analyzed 2755 Mexican patients with TGCT treated at the Instituto Nacional de Cancerología (2007-2021). A Metabolic sub-cohort (n = 586) and an Imaging sub-cohort (n = 231) with baseline CT-derived lean mass index (LMI) were evaluated. Statistical analyses included multivariate Cox regression adjusted for IGCCCG risk, principal component analysis (PCA)-based clustering, and internal validation using bootstrapping. RESULTS: Multivariate Cox regression adjusted for IGCCCG risk identified LMI (HR 0.95, 95% CI 0.90-0.99, P = .047), serum albumin (HR 0.27, 95% CI 0.18-0.42, P < .001), and HDL cholesterol (HR 0.94, 95% CI 0.91-0.96, P < .001) as independently associated factors. PCA-based metabolic-nutritional risk profiles effectively stratified 5-year survival in patients with non-seminoma (from 16.1% in depleted profiles to 97.4% in preserved profiles) and seminoma (64.0% vs 100%). A reduced prognostic model (BMI, LMI, albumin) achieved a robust optimism-corrected AUC of 0.866. CONCLUSIONS: Metabolic and body composition profiling provides prognostic discrimination complementary to the IGCCCG classification, suggesting the potential utility of incorporating objective nutritional assessments. Early identification of patients with metabolic vulnerability-specifically hypoalbuminemia, skeletal muscle depletion, and altered lipid profiles-could help guide personalized supportive strategies prioritizing nutritional and medical optimization to improve outcomes in TGCT.
BACKGROUND: Metronomic cyclophosphamide is sometimes considered in older or frail patients with advanced cancer when disease-related symptoms affect quality of life and standard treatments are no longer suitable. While c...BACKGROUND: Metronomic cyclophosphamide is sometimes considered in older or frail patients with advanced cancer when disease-related symptoms affect quality of life and standard treatments are no longer suitable. While clinical feedback on its tolerance and efficacy is often positive, the evidence remains limited in geriatric, comorbid populations. PATIENTS AND METHODS: This retrospective, monocentric study evaluated the impact of patient-, tumour-, and treatment-related characteristics on the efficacy and safety of metronomic cyclophosphamide in patients aged ≥70 years with metastatic solid tumors. Baseline geriatric assessments were collected, and treatment exposure, tolerance, and outcomes were analyzed. An exploratory subgroup analysis focused on patients treated for ≥9 months. RESULTS: Thirty-seven patients (median age 84 years, range 70-96) were included: 15 had prostate cancer (40.5%), 8 breast cancer (21.6%), and 14 other primary tumors (37.8%). The median treatment duration was 4 months; the median progression-free survival was 4 months and 6 months in breast and prostate cancer subgroups. Overall dose intensity was 87%, with 62.2% of patients maintaining ≥90%. Treatment was generally well tolerated; only 5 grade ≥3 toxicities were reported, and 83.7% of patients remained at home during therapy. Notably, patients treated for ≥9 months had a poorer performance status and lower functional scores at baseline. No specific molecular alterations were associated with prolonged treatment benefit. CONCLUSION: Metronomic cyclophosphamide appears to be a safe and potentially effective option in older and frail patients with metastatic cancer, including those with limited functional reserve. These findings support its use as a pragmatic alternative to supportive care, even in late disease stages.
BACKGROUND: Mucinous phenotype has been associated with an immune-cold microenvironment in dMMR/MSI-H CRC. Here, we investigated the impact of mucinous histology on resistance to ICIs in patients with dMMR/MSI-H mCRC. PA...BACKGROUND: Mucinous phenotype has been associated with an immune-cold microenvironment in dMMR/MSI-H CRC. Here, we investigated the impact of mucinous histology on resistance to ICIs in patients with dMMR/MSI-H mCRC. PATIENTS AND METHODS: We collected data on patients with dMMR/MSI-H mCRC receiving anti-PD-1 alone or with anti-CTLA-4 agents in any line from a multinational dataset. Mucinous histology was defined locally as ≥50% mucinous component. The occurrence of progression or death of disease within or after 6 months from ICIs initiation were considered innate (IR) and acquired resistance (AR). Progression-free survival (PFS)-1 and overall survival (OS)-1 were calculated using the 6-month landmark from the start of ICIs in patients without IR. RESULTS: Among 929 patients, 316 (34%) had mucinous tumors and had inferior PFS and OS. At a median follow-up of 44.7 months, the 6-month PFS rate was similar in patients with mucinous and non-mucinous tumors (71.5% and 73.0%) and a subsequent divergence of the PFS and OS curves was observed beyond this timepoint. In patients without IR, mucinous histology was independently associated with shorter PFS-1 (multivariable model HR 2.10, 95%CI 1.56-2.82; p < 0.001), while OS-1 was non-significantly shorter (HR 1.36, 95%CI 0.91-2.02, p = 0.130). Dual anti-CTLA4/PD-1 blockade was associated with longer PFS and OS regardless of mucinous histotype, but the worst outcomes were observed in patients with mucinous histology receiving single-agent anti-PD-1 (3-year PFS and OS: 39.7% and 56.1%). CONCLUSION: Mucinous histology is associated with ICIs resistance, particularly AR, in dMMR/MSI-H mCRC. These findings may be useful to guide the management of this disease in practice.
BACKGROUND: Poorly differentiated neuroendocrine carcinomas (NECs) are aggressive malignancies with limited treatment options. The low activity of immune checkpoint inhibitors (ICI) is in part due to an immunosuppressive...BACKGROUND: Poorly differentiated neuroendocrine carcinomas (NECs) are aggressive malignancies with limited treatment options. The low activity of immune checkpoint inhibitors (ICI) is in part due to an immunosuppressive tumor microenvironment. We hypothesized that adding cabozantinib to dual ICIs may improve clinical outcomes for patients. METHODS: Patients with advanced or metastatic, poorly differentiated NECs, excluding small cell lung and Merkel cell carcinoma, who progressed on first-line systemic therapy enrolled on this Simon's two-stage trial. Patients received cabozantinib 40 mg daily, 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for four cycles, followed by maintenance cabozantinib nivolumab. The primary endpoint was ORR. RESULTS: Of 17 patients enrolled, 16 were evaluable. ORR was 12.5% (2/16; 95%CI: 1.6%-38.3%), with 2 durable (27 and 17 months). Median PFS was 2.7 months (95%CI: 1.8-5.6 months). Grade 3-4 treatment-related adverse events occurred in 9 patients (56%). The most frequent grade ≥3 toxicities were elevated liver enzymes, fatigue, and hypertension. Only one patient discontinued treatment due to toxicity. The study was terminated after the first stage, as it did not meet the threshold for proceeding to stage 2. CONCLUSION: Toxicities were consistent with the known safety profiles of cabozantinib and dual immune checkpoint blockade. Long-term responses were observed in a small subset of patients, but the study did not meet the prespecified efficacy threshold for continued accrual. CLINICALTRIALS.GOV IDENTIFIER: NCT04079712.