Journal of Thoracic Oncology最新文献

Background: The efficacy and safety of sotorasib plus platinum-doublet chemotherapy in KRAS G12C-mutated non-squamous non-small cell lung cancer (non-Sq NSCLC) were previously reported with limited follow-up period.

Method: SCARLET was a single-arm phase II study of chemotherapy-naïve patients with KRAS G12C-mutated non-Sq NSCLC. Participants received sotorasib 960 mg daily plus four cycles of carboplatin (area under the curve, 5)/pemetrexed 500 mg/m², followed by sotorasib/pemetrexed until disease progression. The primary endpoint was the overall response rate (ORR); secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Using plasma samples, next-generation sequencing was performed at baseline, 3 weeks, and disease progression (jRCT2051210086).

Results: Thirty patients were enrolled between Oct 2021 and Jul 2022, with a median follow-up of 14.8 months. ORR was 88.9% (80% confidence interval [CI], 78.5-94.8%; 95% CI, 70.8-97.6%), median PFS was 6.6 months (95% CI, 5.3-16.7 months), and median OS was 20.6 months (95% CI, 8.1 months-not estimated). Among patients with programmed death ligand 1 expression levels ≥ 1% and < 1%, ORRs were 82.3 and 100% and median PFS was 7.6 and 9.7 months, respectively. Using plasma samples, patients without KRAS G12C at baseline, without KRAS-related pathway co-alterations, or who cleared KRAS G12C at 3 weeks had better median PFS (16.7, 13.9, 8.7 months, respectively). TP53 mutation and epidermal growth factor receptor (EGFR) and MET amplification were detected acquired resistances.

Conclusion: In patients with KRAS G12C-mutated non-Sq NSCLC, sotorasib plus carboplatin/pemetrexed demonstrated favorable efficacy especially in PD-L1 <1%, with manageable toxicity.

Hypothesis: To evaluate how comorbidities affect mortality benefits of lung cancer screening (LCS) with low-dose computed-tomography (LDCT).

Methods: We developed a comorbidity index (PLCO-ci) using LCS-eligible participants' data from the Prostate Lung Colorectal and Ovarian (PLCO) trial (training set) and the National Lung Screening Trial (NLST) (validation set). PLCO-ci predicts 5-year non-lung cancer (LC) mortality using a regularized Cox model; with performance evaluated by the area under the ROC curve (ROC_AUC). In NLST, LC mortality (per original publication) was compared between LDCT and chest X-ray arms across PLCO-ci quintile (Q1-5) using cause-specific hazard ratio (csHR) with 95% confidence intervals [95%CI].

Results: Analyses included 34,690 PLCO and 53,452 NLST participants (mean age: 62 (±5) and 61 (±5) years old, 58% and 59% males, 39% and 41% active smokers, respectively). PLCO-ci predicted 5-year non-LC mortality with ROC_AUC [95%CI] of 0.72 [0.71-0.74] in PLCO and 0.69 [0.67-0.70] in NLST. In NLST, at median follow-up of 6.5 years, LC mortality was significantly reduced for participants with intermediate comorbidity (Q2-Q3-Q4): csHR [95% CI] 0.62 [0.41-0.95], 0.68 [0.48-0.96] and 0.72 [0.54-0.96] respectively, with a non-statistically significant reduction for Q1 (csHR=0.72 [0.45-1.17]) and no reduction for Q5 participants (csHR=0.99 [0.79-1.23]). Participants in Q2-Q3-Q4 (60%) accounted for 89% of LC deaths averted among all NLST participants. Q1 participants had low LC incidence, while Q5 had higher localized LC lethality, more squamous cell carcinomas, and untreated LC.

Conclusion: The PLCO-ci developed in this work shows that individuals with intermediate comorbidity benefited the most from LCS, highlighting the need of addressing comorbidities to achieve LC mortality benefits.

Introduction: Osimertinib is the first-line treatment for patients with non-small cell lung cancer (NSCLC) who have EGFR mutations and favorable performance status (PS). Despite increasing clinical data on osimertinib, evidence in patients with an impaired PS remains limited. Therefore, a multicenter phase II trial (OPEN/TORG2040) was conducted to evaluate the efficacy and safety of first-line osimertinib for patients with EGFR mutation-positive NSCLC and poor PS.

Methods: Patients with previously untreated, advanced NSCLC harboring EGFR-sensitizing mutations and a PS of 2-4 were enrolled. Osimertinib, 80 mg once daily, was orally administered to eligible patients. The primary endpoint was the objective response rate. The secondary endpoints were the disease control rate, PS improvement rate, patient-reported outcomes, and safety.

Results: Between February 2021 and February 2022, 30 patients with poor PS (22 with PS of 2, 6 with PS of 3, and 2 with PS of 4) were enrolled. The median age was 75 years (range: 41-92), and 18 patients had brain metastases. The objective response rate was 63.3% (90% confidence interval, 46.7-77.9%; one-sided, p = 0.033). Disease control and PS improvement rates were 93.3% and 63.3%, respectively. Global health status/quality of life also improved. Median progression-free and overall survival were 8.0 and 25.4 months, respectively. Eight patients (26.7%) experienced serious adverse events leading to discontinuation, and six (20.0%) experienced interstitial lung disease (ILD).

Conclusions: This prospective study confirmed the efficacy of first-line osimertinib in patients with EGFR mutation-positive NSCLC and poor PS, highlighting the need for ILD risk management.

Introduction: Treatment options for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) with disease progression on/after osimertinib and platinum-based chemotherapy are limited.

Methods: CHRYSALIS-2 Cohort A evaluated amivantamab+lazertinib in patients with EGFR exon 19 deletion- or L858R-mutated NSCLC with disease progression on/after osimertinib and platinum-based chemotherapy. Primary endpoint was investigator-assessed objective response rate (ORR). Patients received intravenous amivantamab 1050 mg (1400 mg if ≥80 kg) plus oral lazertinib 240 mg.

Results: In Cohort A (n=162), investigator-assessed ORR was 28% (95% CI, 22-36). Blinded independent central review (BICR)-assessed ORR was 35% (95% CI, 27-42), with median duration of response (DoR) of 8.3 months (95% CI, 6.7-10.9) and clinical benefit rate of 58% (95% CI, 50-66). At a median follow-up of 12 months, 32/56 responders (57%) achieved a DoR ≥6 months. Median progression-free survival by BICR was 4.5 months (95% CI, 4.1-5.8); median overall survival was 14.8 months (95% CI, 12.2-18.0). Preliminary evidence of central nervous system-anti-tumor activity was reported among 7 patients with baseline brain lesions and no prior brain radiation/surgery. Exploratory biomarker analyses using circulating tumor DNA next-generation sequencing showed responses in patients with and without identified EGFR/MET-dependent resistance. Most frequent adverse events were rash (grouped term; 81%), infusion-related reaction (68%), and paronychia (52%). Most common grade ≥3 treatment-related adverse events were rash (grouped term; 10%), infusion-related reaction (9%), and hypoalbuminemia (6%).

Conclusions: For patients with limited treatment options, amivantamab+lazertinib demonstrated anti-tumor activity with a safety profile characterized by EGFR/MET-realated adverse events, which were generally manageable.

Introduction: The phase 2 TROPiCS-03 study evaluated the efficacy/safety of sacituzumab govitecan (SG) as second-line treatment in patients with previously treated extensive-stage small cell lung cancer (ES-SCLC).

Methods: TROPiCS-03 (NCT03964727) is a multicohort, open-label, phase 2 basket study in solid tumors, including ES-SCLC. Adults with ES-SCLC that progressed after one prior line of platinum-based chemotherapy and anti-programmed death-(ligand) 1 (PD-[L]1) therapy received SG 10 mg/kg on days 1 and 8 of a 21-day cycle. The primary endpoint was investigator-assessed objective response rate (ORR), per RECIST v1.1. Key secondary endpoints included investigator-assessed duration of response (DOR) and progression-free survival (PFS); blinded independent central review (BICR)-assessed ORR, DOR, and PFS; overall survival (OS); and safety. Efficacy was evaluated in patients with platinum-resistant and platinum-sensitive disease.

Results: Among 43 patients (median follow-up, 12.3 [range, 8.1-20.1] months), investigator-assessed ORR was 41.9% (95% CI: 27.0%-57.9%), with 18 confirmed partial responses; median (95% CI) DOR, PFS, and OS were 4.73 (3.52-6.70), 4.40 (3.81-6.11), and 13.60 (6.57-14.78) months, respectively. Efficacy results by BICR assessment were similar. Investigator-assessed ORR (95% CI) was 35.0% (15.4%-59.2%) in patients with platinum-resistant disease (n=20) and 47.8% (26.8%-69.4%) with platinum-sensitive disease (n=23). Thirty-two (74.4%) patients experienced grade ≥3 treatment-emergent adverse events (TEAEs). No TEAE led to SG discontinuation; one treatment-related TEAE (neutropenic sepsis) led to death.

Conclusions: SG demonstrated promising efficacy in the second-line treatment of ES-SCLC, irrespective of platinum sensitivity. Safety was manageable and consistent with that observed in other SG studies.

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.