Clinicopathologic Characteristics, Treatment Outcomes, and Acquired Resistance Patterns of Atypical EGFR Mutations and HER2 Alterations in Stage IV Non-Small-Cell Lung Cancer.

The clinicopathologic characteristics, acquired resistance patterns, and outcomes among patients with atypical EGFR mutations and HER2 alterations remain underexplored. A single-center retrospective review was conducted. Oncogenes assessed include typical EGFR (t-EGFR; exon 19 del and L858R), atypical EGFR (a-EGFR; G719X, exon 20, L861Q), HER2 (exon 19, exon 20, amplifications), gene fusions (ALK, ROS1, RET), RAS (KRAS, NRAS), and RAF (BRAF V600E). Progression-free survival (PFS), overall survival (OS), disease control rate, and objective response rate (Response Evaluation Criteria in Solid Tumors 1.1) were collected. Among 570 patients, we found 55 a-EGFR mutations (13 G719X, 38 exon 20, 4 L861Q) and 31 HER2 alterations (2 exon 19 mutations, 27 exon 20 insertions, 2 amplifications). Patients with EGFR and HER2 alterations had increased lung and bone metastases relative to patients with gene fusions, RAS/RAF mutations, and no identified driver oncogenes (P < .001). Patients with EGFR exon 20 insertions had a median PFS to EGFR tyrosine kinase inhibitors (TKIs) of 5 months and an OS of 16 months-significantly worse than exon 19 del and L858R (Bonferroni correction; P < .001), but not G719X or L861Q. Relative to t-EGFR mutations, T790M and MET amplification occurred less frequently as acquired resistance mechanisms among a-EGFR samples (P < .001). Ten patients with a-EGFR mutations and HER2 alterations received single-agent immune checkpoint inhibitors (ICIs) with no radiographic responses and a median PFS of 2 months. EGFR and HER2-mutated NSCLC have a high rate of synchronous lung and bone metastases. Patients with a-EGFR mutations have inferior responses to EGFR-directed therapies with lower rates of acquired T790M and MET amplification. Responses to ICIs are uniformly poor. Novel therapeutic approaches are needed.

Patil T ，Mushtaq R ，Marsh S ，Azelby C ，Pujara M ，Davies KD ，Aisner DL ，Purcell WT ，Schenk EL ，Pacheco JM ，Bunn PA ，Camidge DR ，Doebele RC ... -  《-》

Benefit of Targeted DNA Sequencing in Advanced Non-Small-Cell Lung Cancer Patients Without EGFR and ALK Alterations on Conventional Tests.

Genetic sequencing testing has become widely used to inform treatment decisions for advanced non-small-cell lung cancer (NSCLC) patients. We analyzed benefits of genetic sequencing testing in real practice. We retrospectively reviewed 209 NSCLC patients who had no EGFR and ALK alterations on routine molecular tests and underwent next-generation targeted DNA sequencing of 380 cancer-related genes between November 2013 and October 2016. Median patient age was 59 years. A total of 96 patients (46%) were never smokers, and 195 patients (93%) had adenocarcinoma. Among 209 total patients, 64 (31%) demonstrated actionable genetic alterations; 20 had EGFR mutations (6 L858R, 8 exon 19 deletions, 1 L861Q, 1 G719S, 4 exon 20 duplications), 4 ALK fusions, 9 ROS1 fusions, 6 BRAF V600E mutations, 15 RET fusions, 1 MET high-level amplification, 6 MET exon 14 skipping mutations, and 3 ERBB2 exon 20 insertion mutations. Of the 64 patients harboring actionable alterations, 28 patients received therapy targeted to their own actionable alterations (15 EGFR, 3 ALK, 1 ROS1, 8 RET, 1 BRAF). There were significant differences in overall survival between individuals with no actionable alterations, those with actionable alterations but no targeted therapy, and those with actionable alterations and targeted therapy (20.1 vs. 17.1 vs. 66.2 months, P < .001). The results of targeted DNA sequencing testing could provide improved treatment options for some NSCLC patients and result in a survival benefit to NSCLC patients with no EGFR and ALK alterations on routine tests who are treated with targeted therapy.

Byeon S ，Lee B ，Park WY ，Choi YL ，Jung HA ，Sun JM ，Ahn JS ，Ahn MJ ，Park K ，Lee SH ... -  《-》

Treatment outcome and clinical characteristics of HER2 mutated advanced non-small cell lung cancer patients in China.

HER2 mutation is found in 1%-2% of lung cancer patients. Studies comparing chemotherapy to HER2-TKIs are limited. This study aimed to investigate the molecular and clinical patterns of HER2 mutations in advanced non-small cell lung cancer (NSCLC), and compare the different outcomes between chemotherapy and HER2-TKIs. Advanced or recurrent non-small cell lung cancer patients with de novo HER2 mutations (N = 75) were included in this study. Molecular information, clinical features, and treatment outcomes were retrospectively collected from a web-based patient registry and hospital chart review. Between October 2012 and December 2018, 65 patients with in-frame insertion mutations, eight with point mutations and two with gene amplification were found. The most common subtypes of insertion mutations were A775_G776insYVMA, G776delinsVC, and V777_G778insGSP. HER2 mutated patients were mostly young-aged, females, never or light smokers, with adenocarcinoma. Chemotherapy achieved better outcomes than HER2-TKIs (median PFS: 5.5 vs. 3.7 months in the first-line setting and 4.2 vs. 2.0 months in the second-line setting, P = 0.001 and 0.031, respectively). In particular for the most common subtype, YVMA insertions, PFS was significantly longer in chemotherapy than HER2-TKIs both in the first-line (6.0 vs. 2.6 months, P = 0.008) and the second-line (4.2 vs. 2.6 months P < 0.001). HER2 mutated lung cancer patients were younger, mostly females, never or light smokers, with histologically diagnosed adenocarcinomas. Compared with afatinib, chemotherapy might bring more benefit to HER2 mutated advanced lung cancer patients, especially the most common type of HER2 exon 20 insertions, A775_G776insYVMA subtype. Chemotherapy achieved better outcomes than afatinib for Chinese HER2 mutated advanced NSCLC patients, especially for the most common subtype, YVMA insertions.

Xu F ，Yang G ，Xu H ，Yang L ，Qiu W ，Wang Y ... -  《-》

Investigation of efficacy and acquired resistance for EGFR-TKI plus bevacizumab as first-line treatment in patients with EGFR sensitive mutant non-small cell lung cancer in a Real world population.

We aimed to investigate the clinical efficacy of EGFR tyrosine kinase inhibitor (TKI, T) plus bevacizumab (an antiangiogenic therapy, A) in a real-world population and to provide insights into their mechanism of resistance. This study included 256 NSCLC patients harboring EGFR sensitizing mutations (EGFR 19del and L858R) who underwent nextgeneration sequencing (NGS) with 168-gene panel prior to treatment between Jan 2015 to Aug 2018. Cohort A included 60 patients treated with A + T; while cohort B consisted of 120 patients treated with EGFR-TKI monotherapy with the patients identified using Propensity Score Matching (Ratio of 1:2). Clinical outcomes and potential resistance mechanism were evaluated. Baseline clinical characteristics were not significantly different between Cohort A and B. Compared with cohort B, cohort A had significantly better overall response rate (95% vs 74.2%, p = 0.001) and longer median progression-free survival (PFS, 16.5m vs.12.0 m, HR = 0.7, p = 0.001). Until Jan 2019, 31 and 103 patients in cohort A and B, respectively, were evaluated with progressive disease and underwent tissue re-biopsy and NGS profiling with 168-gene panel. In cohort B, T790M was the predominant acquired resistance mechanism, detected in 51.5% (53/103) of progressive tumors, followed by amplifications in EGFR (15.5%, 16/103) and MET (6.8%, 7/103). Contrastingly, cohort A had a significantly lower rate of T790 M mutation (35.5%, 11/31, p = 0.0003), followed by mutations in TP53 (29.0%, 9/31), RB1 (9.7%, 3/31), SMAD4 (3.2%, 1/31) and EGFR V834 L (3.2%, 1/31) and amplifications in EGFR (9.7%, 3/31), and MET(6.5%, 2/31). Treatment with first-line A + T significantly extends the time to progression and increases the response rate with acceptable safety profile. T790 M was the most common acquired resistance mechanism but it was less common in patients who received A + T.

Zeng L ，Xiao L ，Jiang W ，Yang H ，Hu D ，Xia C ，Li Y ，Zhou C ，Xiong Y ，Liu L ，Liao D ，Guan R ，Li K ，Wang J ，Zhang Y ，Yang N ，Mansfield AS ... -  《-》

Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma.

Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations. We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan-Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS). Median age was 58.9 years (range 42.8-81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0-1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2-3 previous treatment lines. Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h. With a median follow-up of 11.4 months (1-38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9-7.3] and the median OS 10.1 months (95% CI 5.9-14.3). The objective response rate (ORR) was 44.4% (23.7-66.8%) and the disease control rate (DCR) 72.2% (49.4-88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1-10.5) versus (vs.) 4.8 (95% CI 3.5-6.1) and a median OS of 12.3 months (95% CI 8.6-16.0) vs. 6.7 months (95% CI 3.9-9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively). Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0-6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported. Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC.

Riudavets M ，Bosch-Barrera J ，Cabezón-Gutiérrez L ，Diz Taín P ，Hernández A ，Alonso M ，Blanco R ，Gálvez E ，Insa A ，Mielgo X ，Morán T ，Ponce S ，Roa D ，Sánchez JM ，Majem M ... -  《-》