JTO Clinical and Research Reports最新文献

Introduction

Anti-programmed cell death 1 (PD-1) immunotherapy is the standard of care for metastatic NSCLC but many tumors develop resistance. We hypothesized that combining a T-cell agonist such as varlilumab (anti-CD27 antibody) with checkpoint inhibition may be synergistic and this synergy may be potentiated further by using targeted radiation (RT).

Methods

We conducted an open-label, single-center, phase I trial (NCT04081688) to determine the safety and clinical benefit of the atezolizumab and varlilumab in combination with palliative RT in patients with advanced or metastatic NSCLC with progression on prior programmed cell death ligand 1therapy. On day 1 of each 21-day cycle, patients received varlilumab followed by atezolizumab on day 2. RT to a lung lesion was administered between cycle 1 and cycle 2.

Results

A total of 15 patients were enrolled (one patient did not start treatment). The median age was 64 years; 10 patients were female. Eight patients (57%) had at least one treatment-related adverse event (AE) and 7 (50%) had at least one grade III or worse treatment-related AE. There was only one grade III immune-related AE requiring steroids (1 diarrhea and colitis); there were no treatment-related deaths. Of the 12 patients evaluable for efficacy, three patients had stable disease (2 with stable disease > 4 mo) and the clinical benefit rate was 25%. The median progression-free survival was two months and the median overall survival was 6.4 months.

Conclusions

Varlilumab in combination with atezolizumab and RT was safe and well tolerated; no additional signal was identified for toxicity. Clinical activity for the combination was modest with 25% of patients with stable disease as the best response.

Non-small cell lung cancer recurrence after curative-intent surgery remains a challenge despite advancements in treatment. We review postoperative surveillance strategies and their impact on overall survival, highlighting recommendations from clinical guidelines and controversies. Studies suggest no clear benefit from more intensive imaging, whereas computed tomography scans reveal promise in detecting recurrence. For early-stage disease, including ground-glass opacities and adenocarcinoma in situ or minimally invasive adenocarcinoma, less frequent surveillance may suffice owing to favorable prognosis. Liquid biopsy, especially circulating tumor deoxyribonucleic acid, holds potential for detecting minimal residual disease. Clinicopathologic factors and genomic profiles can also provide information about site-specific metastases. Machine learning may enable personalized surveillance plans on the basis of multi-omics data. Although precision medicine transforms non-small cell lung cancer treatment, optimizing surveillance strategies remains essential. Tailored surveillance strategies and emerging technologies may enhance early detection and improve patients’ survival, necessitating further research for evidence-based protocols.

Introduction

ALK–rearranged advanced NSCLC (aNSCLC) represents 4% of all NSCLCs, and multiple ALK-targeted therapies (ALK-inhibitors) are now available for use. Little is known about changes in treatment patterns, or how prognostic factors and sequence of therapy may impact overall survival in the real-world setting. We aim to describe initial and subsequent treatments used, survival outcomes, prognostic factors, and the impact of treatment on overall survival in the largest (N = 739) real-world cohort of patients with ALK+ aNSCLC reported in the literature.

Methods

Retrospective observational cohort study with data drawn from a U.S.-based electronic health record–derived, deidentified database. Eligible patients were diagnosed with ALK+ aNSCLC between 2011-2020 and were treated in multiple different cancer clinics and across multiple geographic regions throughout the United States.

Results

From a cohort of 63,667 patients with aNSCLC, 739 patients with ALK+ NSCLC were eligible for analysis, median age was 63 years, 54% patients were female, and 85% were managed in community setting. More than 168 different treatment sequences were observed, and treatment utilization changed over time. Cohort median overall survival was 37 months (95% confidence interval: 33–45). Positive prognostic factors were as follows: never-smoking history, younger age, treatment in an academic setting, and initial early stage at diagnosis. Initial treatment with a second-generation ALK-inhibitor was associated with improved survival compared with chemotherapy.

Conclusions

For people with ALK+ aNSCLC, this study has identified several important clinical prognostic factors and is practice affirming; first-line treatment with a second-generation ALK-inhibitor improves survival compared with chemotherapy.

Introduction

Lung cancer screening (LCS) reduces lung cancer mortality, yet uptake pre– and post–coronavirus disease 2019 (COVID-19) remains low. The impact of COVID-19 on LCS programs across the United States is unknown. Ours is the first multi-institutional study to identify barriers to LCS experienced during the pandemic. Our work will hopefully inform the development of targeted resources to facilitate increased uptake of LCS.

Methods

A nationwide survey of Centers of Excellence (SCOE) in LCS was conducted by GO2 for Lung Cancer Foundation. In 2021, survey items included questions regarding program structure, screening rates, and systemic barriers to LCS delivery experienced amid COVID-19.

Results

A total of 99 programs representing 1112 screening sites responded. A median of 868 patients were screened during the year of 2020. Patient recruitment, patient education, and in-person service access were negatively affected by COVID-19, whereas the use of telemedicine was positively affected. Coordination of care and timely reporting of results were largely unaffected by the pandemic.

Conclusions

Our findings provide a real-world snapshot of how COVID-19 affected LCS from a program perspective. These findings highlight ongoing challenges with educating and engaging those at high risk for lung cancer in LCS. Program resources should be directed toward increasing adherence to LCS among eligible patients.

Introduction

Methods

Results

Conclusions

IRB approval number

A 20-year-old man with metastatic large cell neuroendocrine carcinoma of the lung was treated with the delta-like ligand 3–targeting bispecific T cell engager, tarlatamab. Treatment was complicated by transient cytokine release syndrome but resulted in a partial response. Bispecific T cell engagers may offer a novel treatment approach for large cell neuroendocrine carcinoma of the lung.

Introduction

EGFR-mutated NSCLC is minimally responsive to programmed cell death protein 1 or programmed death-ligand 1 blockade. We evaluated the safety, tolerability, and immunomodulatory effects of the EGFR tyrosine kinase inhibitor (TKI) afatinib in combination with the programmed cell death protein 1 antibody pembrolizumab in patients with EGFR-mutant NSCLC.

Methods

Patients with advanced EGFR-mutant NSCLC with progression (PD) on previous EGFR TKI(s), aged above or equal to 18 years, Eastern Cooperative Oncology Group performance status less than or equal to 1, acceptable organ function, no significant autoimmune disease, measurable disease, and controlled brain metastases were eligible. Primary end point was determination of the maximum tolerated dose and recommended phase 2 dose. Serial specimens were collected to assess for alterations in cytokines and immune cell subsets by quantitative immunofluorescence in tissue and Luminex and flow cytometry in the blood.

Results

A total of 11 patients were enrolled, six in dose finding and five in dose expansion. No dose-limiting toxicities were observed. The maximum tolerated dose was determined to be afatinib 40 mg orally daily and pembrolizumab 200 mg intravenously every 21 days. Four (36%) patients had immune-related adverse events (irAEs). Ten patients were assessable for response: two partial response, seven stable disease, and one PD. Peripheral natural killer and natural killer T-cells (p = 0.027, p = 0.01) increased and exhausted CD8+ T-cells decreased on treatment (p = 0.0035). Peripheral CD4/CD8 T-cells (area under the curve = 0.96, p = 0.042) and central memory T-cells (CD4/CD8) (area under the curve = 1.0, p = 0.0006) increased in patients who had disease control more than 6 months or partial response to afatinib/pembrolizumab as did CD3+ T-cells in a patient with progression-free survival more than 6 months after afatinib/pembrolizumab treatment.

Conclusions

Afatinib and pembrolizumab were found to have modest activity associated with irAEs after PD on previous EGFR TKI setting. Proinflammatory changes in immune cell subsets in tissue and blood were detected and associated with antitumor activity and irAEs.

Introduction

Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce.

Methods

We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing.

Results

Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFR exon 21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0–17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2–29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0–5.9 mo).

Conclusions

SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.

Introduction

Lepidic growth is considered noninvasive in lung nonmucinous adenocarcinoma, whereas other patterns are invasive. Considerable interobserver variability in assessing “invasion” has been reported. We assessed the utility of cytokeratin 7 (CK7) stain and recently proposed International Association for the Study of Lung Cancer criteria to improve assessment of noninvasion in lung adenocarcinoma.

Methods

Four pathologists (two staff, two trainees) assessed 158 hematoxylin and eosin (HE)- and CK7-stained slides of 108 pT1N0-2 nonmucinous lung adenocarcinoma cases. Scoring took place in four rounds. First, sections were independently scored for percentage of noninvasive or probable noninvasive and invasive or probable invasive patterns. Second, after a consensus scoring algorithm for CK7 was formulated, the slides were rescored. Subsequent third-round scoring was conducted only on HE slides using the 2023 International Association for the Study of Lung Cancer proposed criteria, and fourth-round scoring on both HE and CK7 slides simultaneously. Intraclass correlation coefficient (ICC) was calculated for each round. Recurrence-free survival was assessed using Cox proportional hazards regression methods.

Results

In the first two rounds, interobserver concordance was consistently higher with CK7 (ICC range = 0.44–0.6) than HE (range = 0.24–0.49) scores. The IASLC proposed algorithm improved ICC of HE scores to 0.60 (95% confidence interval: 0.52–0.67), and round 4 HE and CK7 combined improved ICC to 0.75 (95% confidence interval: 0.70–0.80). Continuous measures of averaged noninvasive and probable noninvasive scores on HE were associated with improved recurrence-free survival (hazard ratio: 0.83–0.86).

Conclusions

CK7 staining consistently increased interobserver concordance in assessment of invasive versus noninvasive patterns than HE. Combining CK7 with the 2023 IASLC criteria for morphologic features of invasion may further improve the interobservers’ concordance for the recognition of lepidic growth in nonmucinous lung adenocarcinoma.

Neurocognitive adverse events (NAEs) have been reported in up to 60% of patients on lorlatinib, a potent central nervous system–active ALK inhibitor. Manifestations may include psychotic, mood, speech, and cognitive symptoms. Current guidance recommends permanent discontinuation of lorlatinib in cases of grade IV NAEs. Here, we report a case of successful rechallenge of dose-reduced lorlatinib after recovery of grade IV psychosis in a patient with ALK-positive NSCLC.