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Background ROS1-rearranged lung cancers benefit from first-line crizotinib therapy; however, clinical and molecular factors that could affect crizotinib efficacy in ROS1-rearranged lung cancers are not yet well-elucidated. Our retrospective study aimed to compare the efficacy of chemotherapy and crizotinib in the first-line treatment of ROS1-rearranged advanced lung cancer and evaluate various clinical and molecular factors that might impact crizotinib efficacy in real-world practice. Methods Treatment responses, survival outcomes, and patterns of disease progression were analyzed for 235 patients with locally advanced to advanced disease who received first-line chemotherapy (n = 67) or crizotinib (n = 168). Results The overall response rate was 85.7% (144/168) for first-line crizotinib and 41.8% (28/67) for chemotherapy. Patients treated with first-line crizotinib (n = 168) had significantly longer median progression-free survival (PFS) than chemotherapy (n = 67) (18.0 months vs. 7.0 months, p < 0.001). Patients harboring single CD74-ROS1 (n = 90) had significantly shorter median PFS with crizotinib than those harboring non-CD74 ROS1 fusions (n = 69) (17.0 months vs. 21.0 months; p = 0.008). Patients with baseline brain metastasis (n = 45) had a significantly shorter PFS on first-line crizotinib than those without brain metastasis (n = 123) (16.0 months vs. 22.0 months; p = 0.03). At progression, intracranial-only progression (n = 40), with or without baseline CNS metastasis, was associated with longer median PFS than those with extracranial-only progression (n = 64) (19.0 months vs. 13.0 months, p < 0.001). TP53 mutations were the most common concomitant mutation, detected in 13.1% (7/54) of patients with CD74-ROS1 fusions, and 18.8% (6/32) with non-CD74 ROS1 fusions. Patients with concomitant TP53 mutations (n=13) had significantly shorter PFS than those who had wild-type TP53 (n = 81) (6.5 months vs. 21.0 months; p < 0.001). PFS was significantly shorter for the patients who harbored concomitant driver mutations (n = 9) (11.0 months vs 24.0 months; p = 0.0167) or concomitant tumor suppressor genes (i.e., TP53, RB1, or PTEN) (n = 25) (9.5 months vs 24.0 months; p < 0.001) as compared to patients without concomitant mutations (n = 58). Conclusion Our results demonstrate that baseline brain metastatic status and various molecular factors could contribute to distinct clinical outcomes from first-line crizotinib therapy of patients with ROS1-rearranged lung cancer. Clinical trials registration CORE, NCT03646994

Background The combination of bevacizumab and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could prolong progression-free survival (PFS) in patients with EGFR-mutant advanced non-small-cell lung cancer (NSCLC). Our study investigated the clinical and molecular factors that affect the efficacy of first-generation EGFR-TKI with or without bevacizumab and identify the subset of patients who can benefit from combination therapy. Methods Our study included 318 patients with EGFR-mutant locally advanced/advanced NSCLC treated with either first-generation EGFR-TKI combined with bevacizumab (A+T; n = 159) or EGFR-TKI monotherapy (T; n = 159). Two nomogram models to predict PFS and overall survival (OS), respectively, were constructed using two factors that impact EGFR-TKI efficacy: metastatic site and presence of concurrent mutations. The study cohort was stratified into 2 cohorts for training (n = 176) and validation (n = 142) of the nomogram model. Using the median score from the nomogram, the patients were stratified into two groups to analyze their survival outcome. Results The A+T group had significantly longer PFS (14.0 vs. 10.5 months; p < 0.001) and OS (37.0 vs. 26.0 months; p = 0.042) than the T group. Among the patients with concurrent mutations in tumor suppressor genes, those in the A+T group had significantly longer PFS and OS than the T group (PFS 14.5 vs. 8.0 months, p < 0.001; OS 39.0 vs. 20.0 months, p = 0.003). The higher scores from the nomograms were associated with the presence of brain/liver/pleural metastasis or concomitant gene mutations, which indicated a higher likelihood of shorter PFS and OS. The validation of the nomogram revealed that patients with lower scores had significantly longer PFS for the T group than those with higher scores (15.0 vs. 9.0 months, p = 0.002), but not for the A+T group (15.9 vs. 13.9 months, p = 0.256). Conclusions Using a nomogram, our study demonstrated that the addition of bevacizumab may enhance the therapeutic effectiveness of EGFR-TKI by overcoming the negative impact of certain clinical and molecular factors on the efficacy of EGFR-TKI.

Lung adenocarcinoma (LUAD) is a heterogeneous disease. Our study aimed to understand the unique molecular features of preinvasive to invasive LUAD subtypes. We retrospectively analyzed the clinical, histopathological, and molecular data of 3,254 Chinese patients with preinvasive lesions (n = 252), minimally invasive adenocarcinomas (n = 479), and invasive LUAD (n = 2,523). Molecular data were elucidated using a targeted 68-gene next-generation sequencing panel. Our findings revealed four preinvasive lesion-predominant gene mutations, including MAP2K1 insertion-deletions (indels), BRAF non-V600E kinase mutations, and exon 20 insertions (20ins) in both EGFR and ERBB2, which we referred to as mutations enriched in AIS (MEA). The detection rate of MEA in invasive tumors was relatively lower. MAP2K1 missense mutations, which were likely passenger mutations, co-occurred with oncogenic driver mutations, while small indels were mutually exclusive from other genes regardless of the invasion level. BRAF non-V600E kinase-mutant invasive adenocarcinomas (IAC) had significantly higher mutation rates in tumor suppressor genes but lower frequency of co-occurring oncogenic driver mutations than non-kinase-mutant IAC, suggesting the potential oncogenic activity of BRAF non-V600E kinase mutations albeit weaker than BRAF V600E. Moreover, similar to the extremely low frequency of MAP2K1 indels in IAC, BRAF non-V600E kinase domain mutations co-occurring with TSC1 mutations were exclusively found in preinvasive lesions. Compared with EGFR L858R and exon 19 deletion, patients with preinvasive lesions harboring 20ins in either EGFR or ERBB2 were significantly younger, while those with IAC had similar age. Furthermore, our study demonstrated distinct mutational features for subtypes of oncogene mutations favored by different invasion patterns in adenocarcinomas. In conclusion, our data demonstrate distinct mutational features between preinvasive lesions and invasive tumors with MEA, suggesting the involvement of MEA in the early stages of tumorigenesis. Further pre-clinical studies are required to establish the role of these genes in the malignant transformation of LUAD.

Background: Patient-specific flexible gene panels designed based on whole-exome sequencing (WES) of resected tumor tissues is a promising strategy for ctDNA-based detection of molecular residual disease (MRD) in early-stage NSCLC. Flexible gene panels could potentially overcome the limitations of fixed panels by incorporating more unique genomic regions that might be absent in fixed panels; however, no study has reported a head-to-head comparison of these two approaches in postoperative disease monitoring. In this study, we investigated the clinical utility of a novel Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) tumor-informed ctDNA assay. Using the same set of longitudinal blood samples, we further compared the performance of PROPHET assay with tumor-informed (TI) and tumor-naïve (TN) fixed panels for predicting MRD and prognosis in surgical NSCLC patients. Methods: Fifty-three patients with stage I-III resected NSCLC from the MEDAL study (NCT03634826) with adequate samples and median follow-up of 647 days were analyzed. Matched surgical tumor tissue and blood samples collected at various time points, including before surgery (baseline), 3-days (B) and 1-month (C) postoperative time points before any adjuvant therapy and subsequent follow-up time points (F) were analyzed. PROPHET assay involved four major steps: identify somatic mutations using WES, customized design of a patient-specific panel consisting of 50 single nucleotide variants, ultra-deep unique molecular-identifier-based next-generation sequencing (UMI-NGS) of serial blood samples using the patient-specific panel, and MRD risk prediction. Fixed panel assay of serial blood samples was performed using UMI-NGS with 168 gene panel spanning 273 kb of human genome. Results: At 1-month post-surgery, PROPHET assay accurately predicted MRD-positive cases among relapsed patients (50%, 13/26), whereas all disease-free patients were MRD-negative (100%, 21/21). Three-year prognostication with PROPHET assay at B+C yielded higher sensitivity (59% vs 26% vs 22%), negative predictive value (66% vs 51% vs 50%), and hazard ratio (7.15, 95%CI [3.2-15.9] vs 4.48 [1.9-10.9] vs 5.58 [2.1-14.7]) as compared with TI and TN fixed panel assays. Disease monitoring using PROPHET assay at B/C/F accurately predicted the MRD risk in 70% (21/30) of relapsed patients at a median lead time of 318 days (range: 20-751), whereas TI assay predicted 43% (13/30) at 282 days (range 20-716) and TN assay predicted 37% (11/30) at 282 days (range: 20-634). Conclusion: Patient-specific tumor-informed ctDNA-based postoperative monitoring enables risk stratification at early postoperative settings better than fixed panel, which paves an alternative strategy in the individualized management of surgical NSCLC patients. Citation Format: Kezhong Chen, Haifeng Shen, Shuailai Wu, Pengfei Zhu, Chenyang Wang, Analyn Lizaso, Guannan Kang, Yang Wang, Juan Lv, Shuai Fang, Wenjun Wu, Fujun Qiu, Yuan Sun, Qiang Lu, Heng Zhao, Shannon Chuai, Fan Yang, Zhihong Zhang. Tumor-informed patient-specific panel outperforms tumor-naïve and tumor-informed fixed panel for circulating tumor DNA (ctDNA)-based postoperative monitoring of non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5916.