Journal of Thoracic Oncology最新文献

Introduction: Patients with ALK-positive NSCLC developing resistance to second-generation inhibitors have limited treatment options. Deulorlatinib is a highly brain-penetrant, new-generation ALK/ROS1 inhibitor. We evaluated the safety, efficacy and pharmacokinetics of deulorlatinib in ALK-positive NSCLC.

Methods: This 3-part (dose-escalation/dose-expansion/cohort-expansion), open-label, phase 1/1b trial was conducted at 22 sites in China (ClinicalTrials.gov, NCT05441956). Eligible patients had advanced ALK/ROS1-positive NSCLC. Patients enrolled into dose-escalation/dose-expansion parts were previously treated with ≥1 second-generation ALK inhibitors (ALK-positive) or crizotinib (ROS1-positive); received deulorlatinib 5-125mg once daily. Patients enrolled into cohort-expansion parts were either crizotinib-treated, second-generation TKI-treated or TKI-naïve; received deulorlatinib at recommended phase 2 dose (RP2D). Primary outcomes were safety and tolerability. Here, we report safety analysis in all patients and efficacy analysis in ALK-positive patients.

Results: Between April 2021 and March 2023, 198 patients were enrolled (ALK-positive=171, ROS1-positive=27). Most common treatment-related adverse events (TRAEs) were hypercholesterolemia (79.3%), hypertriglyceridemia (77.3%) and weight gain (53.0%). 40.4% of patients had grade≥3 TRAEs. TRAE-associated dose interruptions, reduction and discontinuation occurred in 11.1%, 3.0% and 1.5% of patients, respectively. The RP2D was set at 60mg once daily. A total of 144 ALK-positive patients were treated at RP2D. For crizotinib-treated (n=14), second-generation TKI-treated (n=97) and TKI-naïve (n=33) patients, ORR to deulorlatinib at RP2D was 71.4%, 38.1%, and 87.9%, respectively. Intracranial ORR was 50%, 70.4%, and 75%. Median duration of response was 18.0 months for second-generation TKI-treated patients, and not reached for crizotinib-treated and TKI-naïve patients. Biomarker analyses identified undetectable ALK alterations at baseline and ALK ctDNA clearance at week 6 as potential predictive biomarkers.

Conclusions: Deulorlatinib showed desirable tolerability and efficacy in ALK-positive NSCLC, demonstrating the potential to become a new treatment option in this population.

Prophylactic cranial irradiation (PCI) has long been used for small-cell lung cancer (SCLC) to reduce the risk of brain metastases and potentially improve overall survival. However, recent immunotherapy trials have provided limited data on its impact, as few patients were treated with PCI. The ADRIATIC trial demonstrated improved outcomes with consolidation immunotherapy in limited-stage SCLC, and PCI was a stratification factor. Notably, patients receiving PCI in both arms had better outcomes compared to those who did not. Ongoing studies, such as EORTC-1901 PRIMALung (NCT04790253) and SWOG 1827-MAVERICK (NCT04155034), are further investigating PCI's role in the era of immunotherapy, highlighting its potential importance in evolving treatment strategies.

Introduction: Despite the reduction in mortality shown by Low dose computer tomography (LDCT) lung cancer screening, the uptake is still low. Patients undergo chest imaging for several other medical reasons, and this is a unique opportunity to detect lung nodules.

Methods: In a cohort of NSCLC patients from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked data, tumor size at previous imaging was calculated as: VDT = [(T₂-T₁)·ln2]/ln(V₂/V₁), solving for diameter of V₁. V₁ and V₂ are tumor volume at times T₁ (previous imaging) and T₂ (diagnostic procedure) according to three different growth models. 10-year lung cancer-specific mortality was calculated as: lung cancer survival rate = (-0.0098 × maximum tumor diameter) + 1.

Results: 1,007 patients who had a chest imaging performed up to one year prior to lung cancer diagnosis. The median size of the tumor at diagnosis was 25 mm, the predicted median tumor size at previous imaging was 12.16 mm, 17.3 mm, and 20.42 mm under the fast, medium and slow growth model. Under the fast growth model, a detection of the nodule at previous imaging would have yield a decrease in mortality of 7.79%; the corresponding values for the medium growth model is 4.5%, for the slow growth model 2.45%.

Conclusions: Identifying malignant lung nodules in imaging performed for other clinical reasons can help decreasing the burden of NSCLC, especially for non-LDCT eligible patients and the medically vulnerable. We show here that clinical benefits, especially among patients with aggressive disease, can be considerable.

Chemotherapy continues to be the standard treatment for patients non-eligible to targeted or immune-based therapies; however, treatment resistance remains a major clinical challenge. We previously found that expression levels of DSTYK, a poorly explored dual serine/threonine and tyrosine kinase frequently amplified in cancer, identifies lung cancer patients exhibiting poor response to immune checkpoint inhibitors and showed that its inhibition sensitizes to immunotherapy. Seeking to explore the potential of DSTYK targeting in additional indications, we investigated the functional relevance and actionability of DSTYK in lung cancer chemoresistance. We show that DSTYK depletion specifically sensitizes lung cancer cells to taxane-based chemotherapy, particularly in combination with carboplatin. Mechanistically, DSTYK ablation remodels the cytoskeleton and impairs distant invasion and metastatic outgrowth in vivo. DSTYK downregulation sensitizes both primary and metastatic lung tumors to chemoimmunotherapy treatment leading to tumor regression in mouse models. Consistently, clinical data of early - in the neoadjuvant and adjuvant settings- and advanced lung cancer patients show a strong correlation between DSTYK amplification and taxane resistance, underscoring the clinical significance of our findings to inform treatment decision-making. Collectively, our data indicates that DSTYK amplification may be a predictor of resistance to taxane-based treatments and represents an actionable target for these patients.

Introduction: PEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic non-small cell lung cancer (mNSCLC [EGFR/ALK wild type]) with PD-L1 tumor cell (TC) membrane expression status ≥25%. We report the final analysis of PEARL.

Methods: Adults (N=669) with previously untreated Stage IV mNSCLC were randomized (1:1) to durvalumab 20mg/kg every 4 weeks or chemotherapy every 3 weeks for 4 to 6 cycles. Dual primary endpoints were overall survival (OS) in the PD-L1 TC ≥25% and the PD-L1 TC ≥25% low risk of early mortality (LREM) populations.

Results: Durvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the PD-L1 TC ≥25% population (OS hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.71, 0.99, p = 0.037; median OS 14.6 months [95% CI: 12.2, 16.9] versus 12.8 months [95% CI: 10.1, 14.7], respectively). In the PD-L1 TC ≥25% LREM population the OS HR for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79, 1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6, 17.2) versus 15.0 months (95% CI: 13.1, 16.8), respectively. In the safety population, the incidence of grade 3/4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy).

Conclusions: Durvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and PD-L1 TC ≥25%. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC.

Background: Poly (ADP-ribose) inhibitors, including olaparib, upregulate programmed cell death ligand 1 (PD-L1), which may increase efficacy of anti-PD-(L)1 therapies.

Methods: In the phase 3 KEYLYNK-006 trial (NCT03976323), eligible adults with previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations who had complete response (CR), partial response (PR), or stable disease (SD) following induction therapy with 4 cycles of pembrolizumab 200 mg Q3W, pemetrexed 500 mg/m² , and carboplatin AUC5 or cisplatin 75 mg/m² were randomized 1:1 to olaparib 300 mg orally twice daily or pemetrexed Q3W, both given with ≤31 cycles of pembrolizumab Q3W. Dual primary endpoints were progression-free survival (PFS) and overall survival (OS). PFS was tested at interim analysis 2 (IA2; ie, final PFS analysis), OS at final analysis (FA).

Results: Of 1003 patients who received induction therapy, 672 (67.0%) were randomized to pembrolizumab plus olaparib (n=337) or pembrolizumab plus pemetrexed (n=335) in the intention-to-treat population. Median follow-up at FA was 39.9 (range, 28.1-51.5) months. At IA2, median (95% CI) PFS was 7.1 (5.6-8.7) months versus 8.3 (6.9-11.5) months in the olaparib versus pemetrexed groups (HR, 1.12; 95% CI, 0.92-1.36; P=0.87). At FA, median (95% CI) OS was 20.7 (18.0-24.8) months versus 23.0 (19.0-26.4) months (HR, 1.04; 95% CI, 0.87-1.25; P=0.6649). Grade 3-5 maintenance treatment-related AEs occurred in 26.1% versus 30.1% patients.

Conclusion: Pembrolizumab plus maintenance olaparib did not improve PFS or OS versus pembrolizumab plus pemetrexed in previously untreated metastatic nonsquamous NSCLC without targetable genetic alterations.

Introduction: An increasing number of early-stage lung adenocarcinomas (LUAD) are detected as lung nodules. The radiological features related to LUAD progression warrant further investigation. Exploration is required to bridge the gap between radiomics-based features and molecular characteristics of lung nodules.

Methods: Consensus clustering was applied to the radiomic features of 1212 patients to establish stable clustering. Clusters were illustrated using clinicopathological and next-generation sequencing. A classifier was constructed to further investigate the molecular characteristics in patients with paired computed tomography and RNA sequencing data.

Results: Patients were clustered into four clusters. Cluster 1 was associated with a low consolidation-to-tumor ratio, preinvasion, grade I disease, and good prognosis. Clusters 2 and 3 reported increasing malignancy with a higher consolidation-to-tumor ratio, higher pathologic grade, and poor prognosis. Cluster 2 possessed more spread through air spaces and cluster 3 reported a higher proportion of pleural invasion. Cluster 4 had similar clinicopathological features as cluster 1 except but a proportion of grade II disease. RNA sequencing indicated that cluster 1 represented nodules with indolent growth and good differentiation, whereas cluster 4 reported progression in cell development but still had low proliferative activity. Nodules with high proliferation were classified into clusters 2 and 3. In addition, the radiomics classifier distinguished cluster 2 as nodules harboring an activated immune environment, whereas cluster 3 represented nodules with a suppressive immune environment. Furthermore, signatures associated with the prognosis of early-stage LUAD were validated in external datasets.

Conclusions: Radiomics features can manifest molecular events driving the progression of LUAD. Our study provides molecular insight into radiomics features and assists in the diagnosis and treatment of early-stage LUAD.