HLA-I Evolutionary Divergence Confers Response to PD-1 Blockade plus Chemotherapy in Untreated Advanced Non-Small Cell Lung Cancer.

PURPOSE: PD-1 blockade plus chemotherapy has become the new standard of care in patients with untreated advanced non-small cell lung cancer (NSCLC), whereas predictive biomarkers remain undetermined. EXPERIMENTAL DESIGN: We integrated clinical, genomic, and survival data of 427 NSCLC patients treated with first-line PD-1 blockade plus chemotherapy or chemotherapy from two phase III trials (CameL and CameL-sq) and investigated the predictive and prognostic value of HLA class I evolutionary divergence (HED). RESULTS: High HED could predict significantly improved objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) in those who received PD-1 blockade plus chemotherapy [in the CameL trial, ORR: 81.8% vs. 53.2%; P = 0.032; PFS: hazard ratio (HR), 0.47; P = 0.012; OS: HR, 0.40; P = 0.014; in the CameL-sq trial, ORR: 89.2% vs. 62.3%; P = 0.007; PFS: HR, 0.49; P = 0.005; OS: HR, 0.38; P = 0.002], but not chemotherapy. In multivariate analysis adjusted for PD-L1 expression and tumor mutation burden, high HED was independently associated with markedly better ORR, PFS, and OS in both trials. Moreover, the joint utility of HED and PD-L1 expression showed better performance than either alone in predicting treatment benefit from PD-1 blockade plus chemotherapy. Single-cell RNA sequencing of 58,977 cells collected from 11 patients revealed that tumors with high HED had improved antigen presentation and T cell-mediated antitumor immunity, indicating an inflamed tumor microenvironment phenotype. CONCLUSIONS: These findings suggest that high HED could portend survival benefit in advanced NSCLC treated with first-line PD-1 blockade plus chemotherapy. See related commentary by Dimou, p. 4706.

Advanced lung adenocarcinoma patient with EGFR exon 20 insertion benefits from high-dose furmonertinib for nine months after progression from mobocertinib: a case report.

Background: The treatment landscape of non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation has significantly changed in the past decade. However, EGFR exon 20 insertion (20ins), which accounts for at least 9% of all EGFR mutated cases, has been generally associated with resistance to common EGFR tyrosine kinase inhibitors (TKIs). In recent years, major progress has been made in the precision treatment of NSCLC harboring EGFR exon 20ins, thanks to the development of TKIs and mAb-based agents specifically targeting EGFR 20ins. However, the efficacy of these novel agents, such as mobocertinib and amivantamab, is not quite satisfactory. Therefore, there is an urgent need to identify other effective targeted drugs. Case Description: Herein, we describe a case with EGFR 20ins diagnosed by amplification refractory mutation system polymerase chain reaction (ARMS-PCR) who benefited from high-dose (160 mg/d comparing with Phase II recommended dose 80 mg/d) furmonertinib, a novel third-generation EGFR TKI, after progression from mobocertinib. A 58-year-old male was referred to our clinic with multiple lung lesions detected in computed tomography (CT) scanning. The patient participated in a phase I/II trial (NCT02716116) receiving TAK-788 and was confirmed with partial response at follow-up. Intriguingly, after progression from 9 months of TAK-788 treatment, the patient still showed response to furmonertinib. The progression free survival was 10 months with no complications or adverse events observed. The overall survival was 34 months till last follow-up in March, 2022. The patient is still in follow-up. Conclusions: Supported by this case and data from other studies, the potency of furmonertinib warrants further evaluation in patients with EGFR 20ins, especially those pretreated with TKIs.

Systematic Pan-Cancer Population-Based Analysis Reveals the Incidence and Prognosis of Lung Metastases at Diagnosis.

BACKGROUND: Metastasis is one of the most prevalent causes of death in cancer patients and the lungs are among the organs most commonly affected by metastasis. However, analysis of the incidence and prognosis of lung metastasis (LM) based on primary cancer sites is lacking. METHODS: We enrolled cancer patients with LM from the Surveillance, Epidemiology, and End Results (SEER) database. The risk factors for LM were determined using multivariate logistics regression. Forest plots were used to compare the impact of with LM versus without LM alone among different primary caner site subgroups. RESULTS: Among 1,525,441 cases, 47,537 presented with LM at initial diagnosis. Multivariate logistics regression revealed that male sex, older age, later T/N stage, unmarried status, and lack of insurance were risk factors for LM. The incidence of LM was 11.91% in bone cancer and 11.19% in pancreatic cancer. In terms of the distribution of primary cancers, 19.22% of LMs originated from the colon and rectum, with 11.63% from the kidneys. The median survival for LM cases was 6 months, with the best survival in testicular cancer (19 months) and bone cancer (12 months). Patients with LM had higher hazard ratio (HR) for mortality compared to those without LM, except for those with primary cancer in the brain (P=0.09). We stratified patients by primary cancer site, and subgroup analyses showed that LM had a significant negative impact on survival. The most significant was in thyroid cancer (HR = 44.79), followed by melanoma (HR = 24.26), prostate (HR = 16.0), breast (HR = 13.46), endometrial (HR = 12.64), testicular (HR = 12.31), and kidney (HR = 11.33) cancer (all P < 0.001). CONCLUSION: Patients presenting with LM had higher HR for mortality compared to those without LM, except for those with brain tumor. Clinicians should pay more attention to the occurrence of LM, especially in patients with a significantly increased HR for mortality, such as those with thyroid cancer, melanoma, and prostate cancer.

Clinical, pathological and treatment factors associated with the survival of patients with pulmonary sarcomatoid carcinoma.

Pulmonary sarcomatoid carcinoma (PSC) is a group of five rare non-small cell lung cancer subtypes. In the present study, the clinical characteristics and outcomes of patients with PSC registered in the Surveillance, Epidemiology and End Results (SEER) database were investigated. For this purpose, data for patients with PSC (n=1,723) who received their initial diagnosis between 1988 and 2016 were collected from the SEER database. Survival analysis was performed using the Kaplan-Meier curves and the log-rank test. Subsequently, multivariate analyses with the Cox proportional hazards model were used to identify significant independent predictors. A nomogram model was established to predict survival performance using the concordance index (C-index). From the total cohort, patients with pulmonary blastoma demonstrated improved 1-year overall survival (OS) rate compared with other pathological types (P<0.001). The 2-year overall survival rates of the 'only radiotherapy' cohort and the 'no specific treatment' cohort were 9.1 and 5.4% (P<0.001), respectively. Radiotherapy significantly improved the OS rate in stage I-III patients with PSC (P<0.001) when stratified by stage. After matching the propensity scores, the 'surgery combined with radiotherapy' group comprised 156 patients and the 'surgery-only' group had 247 patients (1:1.6). However, no significant differences in prognosis were found between the 2 subgroups (P=0.052). The multivariate Cox analysis demonstrated that older age (≥76 years old), male, unmarried, pathological type, larger tumor size (≥56 mm), later tumor node metastasis stages and treatment modalities were independent prognostic factors. A nomogram model was established to predict the survival of patients with PSC. This model incorporated the seven aforementioned independent prognostic factors (C-index for survival, 0.75; 95% confidence interval, 0.74-0.76). Radiotherapy needs to considered for stage I-III patients with PSC who undergo radiation therapy without surgical resection.

Chinese Herbal Medicine Combined With EGFR-TKI in EGFR Mutation-Positive Advanced Pulmonary Adenocarcinoma (CATLA): A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

Background: To determine the clinical activity and safety of Chinese herbal medicine (CHM) combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) in patients with advanced pulmonary adenocarcinoma (ADC) and the ability of CHM combined with EGFR-TKI to activate EGFR mutations. Methods: Three hundred and fifty-four patients were randomly assigned to EGFR-TKI (erlotinib 150 mg/d, gefitinib 250 mg/d, or icotinib 125 mg tid/d) plus CHM (TKI+CHM, N = 185) or EGFR-TKI plus placebo (TKI+placebo, N = 169). Progression-free survival (PFS) was the primary end point; the secondary end points were overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life [Functional Assessment of Cancer Therapy-Lung (FACT-L) and Lung Cancer Symptom Scale (LCSS)], and safety. Results: The median PFS was significantly longer for the TKI+CHM group (13.50 months; 95% CI, 11.20-16.46 months) than with the EGFR-TKI group (10.94 months; 95% CI, 8.97-12.45 months; hazard ratio, 0.68; 95% CI, 0.51-0.90; P = 0.0064). The subgroup analyses favored TKI+CHM as a first-line treatment (15.97 vs. 10.97 months, P = 0.0447) rather than as a second-line treatment (11.43 vs. 9.23 months, P = 0.0530). Patients with exon 19 deletion had a significantly longer PFS than with 21 L858R. The addition of CHM to TKI significantly improved the ORR (64.32% vs. 52.66%, P = 0.026) and QoL. Drug-related grade 1-2 adverse events were less common with TKI+CHM. Conclusions: TKI+CHM improved PFS when compared with TKI alone in patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). Clinical Trial Registration: www.ClinicalTrials.gov, identifier NCT01745302.

Exploratory analysis of introducing next-generation sequencing-based method to treatment-naive lung cancer patients.

BACKGROUND: The utilization of cancer-linked genetic alterations for categorizing patients against optimal treatment is becoming increasingly popular, especially in non-small cell lung cancer (NSCLC). However, disadvantages of the conventional techniques, such as the low throughput and limited detectable alteration types, lead to the demand of large-scale parallel sequencing for different forms of genetic variants. METHODS: We evaluated the potential of performing next-generation sequencing (NGS)-based methods in a cohort of 61 treatment-naive NSCLC patients to profile their driver mutations, using a panel consisting of 8 well-established driver genes of lung cancer. RESULTS: Our data revealed that 80% of patients harbored driver mutations. Moreover, our data revealed a few rare mutations, such as BRAF K601E and EGFR exon 20 insertion, which cannot be detected using commercially available single gene testing kits of conventional methods. We detected one patient with dual driver mutations. Next, correlations between driver mutations and clinical characteristics were interrogated in this cohort. Our results revealed that EGFR alterations were positively correlated with early stage, adenocarcinoma, alveolar and papillary component, TTF1 expression, and negatively correlated with P40 and Ki67 expression. ERBB2 alterations were associated with younger age and micro-invasive feature of tumor. Rearrangements of ALK indicated tumor relapse. CONCLUSIONS: Our study highlights the potential of NGS-based methods in treatment-naive patients, thus paving its way for routine clinical use. Investigation of clinical correlation of driver mutations might be helpful for clinicians in cancer diagnosis and has implications for seeking patients with specific gene alteration in clinical studies.

Multicenter study of diagnostic procedures, genetic aberration analysis, and first-line treatment of lung cancer in Jiangsu Province, China.

BACKGROUND: Jiangsu Province, China, is highly developed economically and culturally, and has a high prevalence of lung cancer. We aimed to evaluate the diagnostic procedures, genetic aberration analysis status, and first-line treatment models of lung cancer in Jiangsu Province. METHODS: Lung cancer patients diagnosed in 2016 at 22 tertiary care hospitals were evaluated. Demographic characteristics, tumor histology, staging, family history of lung cancer, auxiliary examinations, genetic testing, and first-line treatment were collected on discharge. Diagnostic and treatment data were analyzed by descriptive statistics. RESULTS: A total of 928 patients were enrolled. Chest computed tomography was the most frequently used diagnostic method; pathology diagnosis was carried out by transbronchial lung biopsy and transthoracic needle aspiration. Stage T1-2N0M0 small-cell lung cancer patients experienced surgical resection, and others received cisplatin and etoposide chemotherapy. Stage I and stage II non-small cell lung cancer patients experienced surgical resection; stage III and stage IV patients received cisplatin and pemetrexed chemotherapy as first-line treatment. Detection of epidermal growth factor receptor (EGFR) mutations occurred in 29.9% of non-selective, 36.5% of locally advanced or metastatic, and 42.1% of advanced non-squamous non-small cell lung cancer. The overall EGFR-positive rates were 49.0%, 52.5%, and 53.9%. A total 72.0% of patients with EGFR mutations were treated with tyrosine kinase inhibitors. CONCLUSION: Chest computed tomography was the most commonly performed diagnostic method for lung cancer. First-line treatment was primarily determined by disease stages and EGFR mutation status, with few expectations.