Journal of Thoracic Oncology最新文献

Introduction: The phase Ib two-part (dose escalation and expansion) six-cohort TROPION-Lung02 study evaluated datopotamab deruxtecan (Dato-DXd) plus pembrolizumab with or without platinum-based chemotherapy (Pt-CT) in patients with advanced or metastatic NSCLC (amNSCLC) without actionable genomic alterations.

Methods: Patients received Dato-DXd (4 or 6 mg/kg) plus pembrolizumab 200 mg alone (doublet) or with Pt-CT (triplet; carboplatin AUC 5 or cisplatin 75 mg/m²) once every 3 weeks. The primary objective was safety and tolerability; efficacy was a secondary objective. Exploratory biomarker analyses assessing trophoblast cell-surface antigen 2 (TROP2) normalized membrane ratio (NMR) by quantitative continuous scoring were performed in the treatment-naive patient subset.

Results: In total, 142 patients received doublet (n = 70) or triplet (n = 72) therapy; 96 were treatment-naive (doublet: n = 42; triplet: n = 54). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 37.1% (doublet) and 59.7% (triplet) of patients. No treatment-related deaths occurred. In treatment-naive patients receiving doublet therapy, confirmed objective response rate (ORR) was 54.8%, median duration of response (mDOR) was 20.1 months, and median progression-free survival (mPFS) was 11.2 months. With triplet therapy, confirmed ORR was 55.6%, mDOR was 13.7 months, and mPFS was 6.8 months. Tumor responses were observed across PD-L1 expression levels for both regimens. Exploratory TROP2 NMR biomarker analyses showed trends toward improved survival outcomes in patients who were biomarker positive compared with biomarker negative.

Conclusion: Dato-DXd plus pembrolizumab therapy (with and without Pt-CT) exhibited appreciable safety and durable antitumor activity across PD-L1 expression levels in patients with amNSCLC.

Clinical trial information: ClinicalTrials.gov Identifier: NCT04526691.

Introduction: Tarlatamab, a delta-like ligand 3-targeting bispecific T-cell engager, has demonstrated promising efficacy in relapsed SCLC. Data on immune effector cell-associated neurotoxicity syndrome (ICANS) in patients with central nervous system disease remain limited. In particular, tumor inflammation-associated neurotoxicity (TIAN), proposed in chimeric antigen receptor T-cell therapy as localized neurotoxicity linked to peritumoral inflammation, has not been characterized in this setting.

Case presentation: Here, we describe a single case of severe neurotoxicity in a young woman with SCLC and multiple brain metastases who had a history of symptomatic epilepsy and received tarlatamab as fourth-line therapy. She developed sudden loss of consciousness (immune effector cell-associated encephalopathy score: 0) and seizures 27 hours after the initial 1 mg dose of tarlatamab. The patient's presentation met the criteria for grade 4 neurotoxicity. Brain imaging revealed enlarged brain metastases with worsened peritumoral edema, and electroencephalography demonstrated focal epileptiform discharges at the tumor site. The symptoms resolved rapidly (within 36 h) after intensified corticosteroid therapy. Tarlatamab was cautiously continued without recurrence of severe neurotoxicity, and subsequent imaging revealed marked tumor regression. The event was interpreted as TIAN driven by local tumor inflammation rather than ICANS.

Conclusions: Severe acute neurotoxicity may indicate TIAN in patients with SCLC and brain metastases treated with tarlatamab. TIAN presents as severe but reversible symptoms that mimic high-grade ICANS. Differentiating TIAN from ICANS is crucial because TIAN may be manageable, and its recognition may inform individualized decisions regarding therapy continuation under careful monitoring.

Introduction: There is currently limited information on the prognostic association of molecular aberrations in pleural mesothelioma (PM). We examined the impact of common molecular alterations on overall survival (OS) in a 3-institution cohort from the IASLC 9^th edition Staging Project as a pilot study to guide future data collection.

Methods: Biomarker data included PD-L1 and BAP1 immunohistochemistry (IHC), and somatic genomic aberrations with putative functional impact (pathogenic) revealed by next generation sequencing (NGS). OS was calculated by Kaplan-Meier method and compared between groups by Cox proportional hazard regression. Models were compared using pseudo-R² and Harrell's C-statistic.

Results: Pathogenic alterations in BAP1 were most common (55.0%, 143/260), followed by CDKN2A (36.2%, 94/260), NF2 (23.8%, 62/260) and TP53 (18.1%, 47/260). Loss of BAP1 expression by IHC was detected in 260/452 (57.5%) cases. PD-L1 expression was positive (> 1% of tumor cells with membranous staining) in 89/200 (44.5%) cases. On univariate analysis, pathogenic alterations in CDKN2A, NF2 and TP53 were associated with worse OS (p<0.001); BAP1 alterations and loss of expression were associated with better OS (p=0.004 and <0.001, respectively); and PD-L1 expression was not associated with OS (p=0.645). Multivariable analyses confirmed OS associations (hazard ratios: CDKN2A, 2.12; NF2, 1.65; TP53, 1.74; BAP1 NGS, 0.58; BAP1 IHC, 0.58). While clinical covariates performed better than molecular alterations alone (C-statistic: 0.67 vs 0.65; R²: 25.3 vs 20.8), a model including BAP1 alterations plus any pathogenic alteration in CDKN2A, NF2, and TP53, along with clinical covariates best predicted survival (C-statistic: 0.70; R²: 37.0).

Conclusion: In this large PM cohort,CDKN2A, NF2, and TP53 alterations were associated with worse OS, while BAP1 alterations were associated with better prognosis, independent of clinical variables and histology. Modeling suggests that genomic alterations provide additional prognostic information beyond anatomic TNM and clinicopathologic features.

Introduction: In the final analysis of the randomized, phase 3 RATIONALE-312 trial (data cutoff: April 19, 2023), patients with extensive-stage SCLC (ES-SCLC) who received first-line tislelizumab plus chemotherapy experienced significant improvements in overall survival (OS) and tolerable toxicity versus placebo plus chemotherapy. We report long-term follow-up (LTFU; data cutoff: December 29, 2023) data.

Methods: Adults with previously untreated ES-SCLC were randomized 1:1 to four induction cycles of intravenous tislelizumab 200 mg or placebo once every 3 weeks plus investigator's choice of chemotherapy (intravenous carboplatin or cisplatin plus etoposide), followed by tislelizumab or placebo maintenance. The primary end point was OS.

Results: With a median survival follow-up of 39.8 and 36.4 months in the tislelizumab (n = 227) and placebo (n = 230) arms, respectively, OS benefit in the intent-to-treat (ITT) population was sustained relative to final analysis (median OS: 15.5 versus 13.5 months, respectively; hazard ratio = 0.78; 95% confidence interval: 0.63-0.95). Exploratory analyses showed a consistent OS improvement favoring tislelizumab versus placebo across programmed death-ligand 1(PD-L1) expression subgroups. The most frequently reported treatment-related adverse events in the tislelizumab and placebo arms were alopecia (78.4% versus 79.5%), anemia (76.7% versus 78.6%), and neutropenia (68.7% versus 70.3%).

Conclusions: LTFU data from RATIONALE-312 showed that patients with ES-SCLC treated with first-line tislelizumab plus chemotherapy had clinically meaningful and sustained improvements in OS versus placebo plus chemotherapy in the ITT and PD-L1-evaluable populations. Tislelizumab plus chemotherapy was tolerable, with no new safety signals identified.

Clinical trial information: ClinicalTrials.gov Identifier: NCT04005716.

Introduction: Novel treatment approaches are required for relapsed small cell lung cancer (SCLC). Previous studies showed promising activity for lurbinectedin combined with topoisomerase inhibitors in preclinical models of other solid tumors.

Methods: SCLC cell lines, patient-derived organoids and xenografts were used to evaluate the effects of lurbinectedin plus irinotecan. The underlying mechanism of interaction was elucidated using flow cytometry, immunofluorescence and western blotting. A phase I/II clinical trial assessed the efficacy and safety of the lurbinectedin/irinotecan combination in patients with advanced solid tumors.

Results: A synergistic antitumor effect was observed for the combination in vitro and in vivo, which resulted from impaired S-phase entry and progression, enhanced DNA damage, and induction of apoptosis. Based on the results of the dose escalation stage of the trial, a recommended dose (RD) of lurbinectedin 2.0 mg/m² on Day (D)1 plus irinotecan 75 mg/m² on D1,D8 every three weeks with primary growth factor prophylaxis was chosen for further evaluation. Of 47 patients with relapsed SCLC included in the trial, 21 with measurable disease treated at the RD showed overall response rate 61.9%, median progression-free survival 7.2 months, and median overall survival 12.3 months. Most common toxicities at the RD were myelosuppression, fatigue, gastrointestinal disorders and decreased appetite.

Conclusions: The lurbinectedin/irinotecan combination increased the induction of DNA damage and apoptosis, resulting in increased antitumor efficacy in vitro and in vivo. Early clinical data showed promising antitumor activity and a predictable safety profile for the combination in relapsed SCLC. Further development in this indication is ongoing.