Journal of Thoracic Oncology最新文献

Introduction: Effective therapies are needed for patients with NSCLC with HER2-mutant tumors who progress on the HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd), a standard-of-care treatment. A greater understanding of mechanisms mediating acquired T-DXd resistance and whether these tumors could benefit from HER2 tyrosine kinase inhibitors (TKIs) is needed.

Methods: Using preclinical models of acquired T-DXd resistance, LentiMutate scanning mutagenesis, and clinical analyses, we investigated mechanisms mediating acquired resistance to T-DXd and assessed the impact of each of these resistance mechanisms on cross-resistance to alternative HER2-targeting approaches.

Results: We determined that acquired resistance to T-DXd could occur through multiple mechanisms including payload resistance which could be mediated by SFLN11 loss and copy number gains in the efflux pump ABCC1/MRP1. Moreover, T-DXd resistance could be mediated by secondary HER2 extracellular mutations in domain IV, the trastuzumab binding site. Tumor cells with acquired payload resistance or domain IV mutations maintained HER2 signaling and remained sensitive to HER2 TKIs, including zongertinib or poziotinib. Likewise, patients with HER2-mutant NSCLC treated with poziotinib demonstrated similar response rates regardless of prior T-DXd.

Conclusions: In patients with HER2-mutant NSCLC, loss of HER2 is not a universal mechanism of T-DXd resistance. Collectively, these data highlight multiple mechanisms of resistance to T-DXd that do not result in loss of HER2 TKI responsiveness.

Introduction: Clinical guidelines recommend upfront osimertinib monotherapy for asymptomatic brain metastases (BM) in EGFR-mutant NSCLC, despite a lack of randomized trial evidence. We conducted two randomized phase II trials, OUTRUN and LUOSICNS, to evaluate the efficacy and safety of upfront stereotactic radiosurgery (SRS) plus osimertinib versus osimertinib in this patient population.

Methods: Participants with up to ten BM amenable to SRS were randomized 1:1 to SRS followed by osimertinib (80 mg daily) or osimertinib monotherapy. SRS was delivered as a single or multi-fraction regimen. The primary end point was 12-month intracranial progression-free survival (ic-PFS). Key secondary end points include overall survival (OS), patterns of intracranial progression, and safety. Data from both trials were prospectively pooled for a joint analysis.

Results: Overall, 79 participants were randomized. At a median follow-up of 39.0 months, 12-month ic-PFS was not significantly different between SRS plus osimertinib (n = 39) than osimertinib monotherapy (n = 40) (11%, 95% CI: -10% to 32%, p = 0.31; median ic-PFS 21.9 mo versus 17.2 mo). Median OS was 46.1 versus 29.1 months. Among those with intracranial progression, 35% in the SRS plus osimertinib group and 57% in the osimertinib monotherapy group underwent SRS at progression. Grade 3/4 radionecrosis occurred in 5% of participants treated with SRS plus osimertinib.

Conclusions: Adding upfront SRS to osimertinib did not significantly improve 12-month ic-PFS in EGFR-mutant NSCLC with BM. This represents the first randomized evidence supporting the use of osimertinib monotherapy as upfront therapy in minimally symptomatic patients with low-burden BM.

Clinicaltrials:

Gov identifier: OUTRUN: NCT03497767; LUOSICNS: NCT03769103.

Introduction: The cardiovascular toxicity of radiation therapy (RT) remains incompletely understood in patients with NSCLC. Our objective was to define changes in echocardiographic parameters of structure and function with RT and their associations with cardiac dose-volume metrics.

Methods: This multicenter, longitudinal, prospective cohort study included participants with NSCLC who received standard, curative-intent thoracic RT. Dose-volume metrics were extracted from centrally contoured cardiac substructures. Echocardiograms at baseline, end of RT, 6 months post-RT, and 12 months post-RT were core laboratory-quantified. Repeated-measures multivariable linear regression via generalized estimating equations estimated changes in echocardiographic measures and associations with dose-volume metrics.

Results: Across 125 participants, there was a modest worsening in left ventricular ejection fraction (LVEF) (p = 0.019), global longitudinal strain (p < 0.001), circumferential strain (p < 0.001), and Ea/Ees (p = 0.011) post-RT that largely recovered by 12 months. Cardiac dysfunction, defined as LVEF declines of at least 10% from baseline to a threshold value of less than 50%, occurred in 7.2% of participants at a median of 1.7 months after RT initiation. Mean heart dose was associated with LVEF declines (-1.1%, 95% confidence interval: -2.2 to 0.0 per interquartile range increase, p = 0.044), as was whole heart V30 (-1.4%, 95% confidence interval: -2.5 to -0.3 per interquartile range increase, p = 0.015); with multiple comparison adjustment, whole heart V30 remained significant (p = 0.030).

Conclusions: On average, there were modest changes in cardiac function immediately after RT in patients with NSCLC, with a subset experiencing clinically relevant cardiac dysfunction. Although whole heart V30 was associated with LVEF declines, suggesting its relevance in RT planning, there is also a need for newer dose-volume measures.