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JCES01.19 Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma
January 2017
to evaluate the efficacy and safety of epitinib in EGFRmutant NSCLC patients with brain metastasis. Methods: This is an ongoing open label, multi-center Phase I dose expansion study. EGFR-mutant NSCLC patients with confirmed brain metastasis, either prior EGFR TKI treated or EGFR TKI treatment naïve, were enrolled to receive oral epitinib 160 mg per day. Patients with extra-cranial disease progression while on treatment with an EGFR TKI were excluded. Tumor response was assessed per RECIST 1.1. Results: As of 31 May, 2016, 27 patients (13 EGFR TKI pretreated, 14 EGFR TKI treatment naïve) have been enrolled and treated with epitinib. The most frequent adverse events (AEs) were skin rash (89%), elevated ALT (41%)/AST (37%), hyper-pigmentation (41%) and diarrhea (30%). The most frequent Grade 3/4 AEs were elevations in ALT (19%), gamma-GGT (11%), AST (7%), hyperbilirubinemia (7%) and skin rash (4%). There have been no Grade 5 AEs to date. Among the 24 efficacy evaluable patients (11 TKI pretreated, 13 TKI naïve), 7 (7/24, 29%) achieved a partial response (PR), including 1 unconfirmed PR. All PRs occurred in EGFR TKI treatment naïve patients (7/13, 53.8%). Of the 24 evaluable patients, 8 (5 EGFR TKI treatment naïve, 3 EGFR TKI pretreated) had measurable brain metastasis (lesion diameter>10 mm per RECIST 1.1) with 2 PRs (both EGFR TKI treatment naïve patients, 2/5, 40%). Conclusion: Epitinib 160mg per day treatment in EGFRmutant NSCLC patients with brain metastasis demonstrated clinical activity both extra- and intra-cranial. Epitinib was well tolerated. The data to date appears encouraging and warrants further development of epitinib.
JCES01.18 Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity Si-Yang Liu,1 Zhong-Yi Dong,2 Wen-Zhao Zhong,3 Si-Pei Wu,1 Zhi Xie,2 Hai-Yan Tu,4 Yi Long Wu 1 Guangdong Lung Cancer Institute; Guangdong General Hospita & Guangdong Academy of Medical Sciences, Guangzhou/China, 2Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou/China, 3 Department of Pulmonary Oncology, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou/China, 4Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou/China
Abstracts
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Background: Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8+ TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well. Methods: Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The KaplaneMeier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures. Results: 288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p¼0.031) and OS (p¼0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups. Conclusion: Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.
JCES01.19 Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma Zhengbo Song,1 Xinmin Yu,2 Yiping Zhang2 1Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China, 2 Zhejiang Cancer Hospital, Hangzhou/China Background: RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer
S238
(NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients. Methods: For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test. Results: Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET arrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods, including six females and five males with a median age of 54 years. The presence of RET rearrangement was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5BeRET and two CCDC6eRET fusions. Four patients had concurrent gene variability by NGS detection, including EGFR (n¼1), MAP2K1 (n¼1), CTNNB1 (n¼1) and AKT1 (n¼1). No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P¼0.504). The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases, and longer than RET-negative patients (7.5 vs. 5.0 months, P¼0.026). The level of TS mRNA was lower in RET-positive patients than that in those RETnegative counterparts (239±18810-4 vs. 394±45710-4, P¼0.019). Conclusion: The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET arrangement is characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.
JCES01.20 Patients with ROS1 Rearrangement Positive Non-Small Cell Lung Cancer Benefit from Pemetrexed-Based Chemotherapy Zhengbo Song,1 Yiping Zhang,2 Xinmin Yu2 1Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China, 2 Zhejiang Cancer Hospital, Hangzhou/China Background: ROS1 gene-rearrangement in non-small cell lung cancer (NSCLC) patients has recently been
Journal of Thoracic Oncology
Vol. 12 No. 1S
identified as a driver gene and benefited from crizotinib treatment. However, no data is available for ROS1-positivity NSCLC about chemotherapeutic options and prognostic data. We investigated pemetrexed-based treatment efficacy in ROS1 translocation NSCLC patients and determined the expression of thymidylate synthetase (TS) to provide a rationale for the efficacy results. Methods: We determined the ROS1 status of 1750 patients with lung adenocarcinoma. Patients’ clinical and therapeutic profile were assessed. In positive cases, thymidylate synthetase (TS) mRNA level was performed by RT-PCR. For comparison, we evaluated the TS mRNA status and pemetrexed-based treatment efficacy from 170 NSCLC patients with anaplastic lymphoma kinase (ALK) translocation(n¼46), EGFR mutation (n¼50), KRAS mutation (n¼32) and wild-type of EGFR/ALK/ ROS1/KRAS (n ¼ 42). Results: Thirty-four ROS1 translocation patients were identified at two institutions. Among the 34 patients, twelve with advanced stage or recurrence were treated with pemetrexed-based first-line chemotherapy. The median progression-free survivals of pemetrexed-based first-line chemotherapy in ROS1 translocation, ALK translocation, EGFR mutation, KRAS mutation and EGFR/ ALK/ROS1/KRAS wild-type patients were 6.8, 6.7, 5.2, 4.2 and 4.5 months, respectively (P¼0.003). The TS mRNA level was lower in patients with ROS1-positive than ROS1-negative patients (264±46910-4 vs. 469 ± 61510-4, P¼0.03), but similar with ALK-positive patients (264±46910-4 vs. 317±52410-4, P¼0.64). Conclusion: Patients diagnosed with ROS1 translocation lung adenocarcinoma may benefit from pemetrexedbased chemotherapy. TS mRNA level enables the selection of therapeutic options for ROS1 translocation patients.
JCES01.21 Molecular Profiling and Survival of Primary Pulmonary Neuroendocrine Carcinoma with Completely Resection Guangyuan Lou,1 Zhengbo Song,2 Yiping Zhang1 Zhejiang Cancer Hospital, Hangzhou/China, 2Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China
1
Background: According to the 2015 World Health Organization classification of lung tumors, pulmonary large cell neuroendocrine carcinoma (PLCNC) is grouped with the small cell lung cancer (SCLC) and carcinoid as pulmonary neuroendocrine carcinoma (PNC) for the common features of neuroendocrine characteristics. Molecular profiles and prognosis of primary pulmonary
to evaluate the efficacy and safety of epitinib in EGFRmutant NSCLC patients with brain metastasis. Methods: This is an ongoing open label, multi-center Phase I dose expansion study. EGFR-mutant NSCLC patients with confirmed brain metastasis, either prior EGFR TKI treated or EGFR TKI treatment naïve, were enrolled to receive oral epitinib 160 mg per day. Patients with extra-cranial disease progression while on treatment with an EGFR TKI were excluded. Tumor response was assessed per RECIST 1.1. Results: As of 31 May, 2016, 27 patients (13 EGFR TKI pretreated, 14 EGFR TKI treatment naïve) have been enrolled and treated with epitinib. The most frequent adverse events (AEs) were skin rash (89%), elevated ALT (41%)/AST (37%), hyper-pigmentation (41%) and diarrhea (30%). The most frequent Grade 3/4 AEs were elevations in ALT (19%), gamma-GGT (11%), AST (7%), hyperbilirubinemia (7%) and skin rash (4%). There have been no Grade 5 AEs to date. Among the 24 efficacy evaluable patients (11 TKI pretreated, 13 TKI naïve), 7 (7/24, 29%) achieved a partial response (PR), including 1 unconfirmed PR. All PRs occurred in EGFR TKI treatment naïve patients (7/13, 53.8%). Of the 24 evaluable patients, 8 (5 EGFR TKI treatment naïve, 3 EGFR TKI pretreated) had measurable brain metastasis (lesion diameter>10 mm per RECIST 1.1) with 2 PRs (both EGFR TKI treatment naïve patients, 2/5, 40%). Conclusion: Epitinib 160mg per day treatment in EGFRmutant NSCLC patients with brain metastasis demonstrated clinical activity both extra- and intra-cranial. Epitinib was well tolerated. The data to date appears encouraging and warrants further development of epitinib.
JCES01.18 Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity Si-Yang Liu,1 Zhong-Yi Dong,2 Wen-Zhao Zhong,3 Si-Pei Wu,1 Zhi Xie,2 Hai-Yan Tu,4 Yi Long Wu 1 Guangdong Lung Cancer Institute; Guangdong General Hospita & Guangdong Academy of Medical Sciences, Guangzhou/China, 2Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou/China, 3 Department of Pulmonary Oncology, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou/China, 4Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou/China
Abstracts
S237
Background: Recent studies have identified that the degree of tumor infiltrating lymphocyte (TIL) infiltration and PD-L1 expression in the tumor microenvironment (TME) are significantly correlated with the clinical outcomes of anti-PD-1/PD-L1 therapies. Here we conducted this study to verify the distribution of PD-L1/CD8+ TIL expression and its clinical significance in non-small cell carcinoma (NSCLC). Potential mechanism predicted for PD-1 blockade was explored in depth as well. Methods: Immunohistochemistry was performed to detect PD-L1 and CD8 expression in NSCLC. The KaplaneMeier (KM) survival curve was used to estimate disease free survival (DFS) and overall survival (OS). Gene Set Enrichment Analysis (GSEA) was used to determine potentially relevant gene expression signatures. Results: 288 cases with stage I-IIIA NSCLC were evaluated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant subtype in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p¼0.031) and OS (p¼0.002) showed a significant difference between four subgroups. Furthermore, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups. Conclusion: Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.
JCES01.19 Clinicopathologic Characteristics, Genetic Variability and Therapeutic Options of RET Rearrangement Patients in Lung Adenocarcinoma Zhengbo Song,1 Xinmin Yu,2 Yiping Zhang2 1Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China, 2 Zhejiang Cancer Hospital, Hangzhou/China Background: RET fusion gene is identified as a novel oncogene in a subset of non-small cell lung cancer
S238
(NSCLC). However, few data are available about the prevalence, clinicopathologic characteristics, genetic variability and therapeutic options in RET-positive lung adenocarcinoma patients. Methods: For 615 patients with lung adenocarcinoma, RET status was detected by reverse transcription-polymerase chain reaction (RT-PCR). Next-generation sequencing (NGS) and FISH were performed in positive cases. Thymidylate synthetase (TS) mRNA level was assayed by RT-PCR. Overall survival (OS) was evaluated by Kaplan-Meier method and compared with log-rank test. Results: Twelve RET-positive patients were identified by RT-PCR. However, one patient failed the detection of RET arrangement by FISH and NGS. Totally, 11 patients (1.8%) confirmed with RET rearrangements by three methods, including six females and five males with a median age of 54 years. The presence of RET rearrangement was associated with lepidic predominant lung adenocarcinoma subtype in five of 11 patients. RET rearrangements comprised of nine KIF5BeRET and two CCDC6eRET fusions. Four patients had concurrent gene variability by NGS detection, including EGFR (n¼1), MAP2K1 (n¼1), CTNNB1 (n¼1) and AKT1 (n¼1). No survival difference existed between RET-positive and negative patients (58.1 vs. 52.0 months, P¼0.504). The median progression-free survival of first-line pemetrexed/platinum regimen was 7.5 months for four recurrent cases, and longer than RET-negative patients (7.5 vs. 5.0 months, P¼0.026). The level of TS mRNA was lower in RET-positive patients than that in those RETnegative counterparts (239±18810-4 vs. 394±45710-4, P¼0.019). Conclusion: The prevalence of RET fusion is approximately 1.8% in Chinese patients with lung adenocarcinoma. RET arrangement is characterized by lepidic predominance and a lower TS level. RET-rearranged patients may benefit more from pemetrexed-based regimen.
JCES01.20 Patients with ROS1 Rearrangement Positive Non-Small Cell Lung Cancer Benefit from Pemetrexed-Based Chemotherapy Zhengbo Song,1 Yiping Zhang,2 Xinmin Yu2 1Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China, 2 Zhejiang Cancer Hospital, Hangzhou/China Background: ROS1 gene-rearrangement in non-small cell lung cancer (NSCLC) patients has recently been
Journal of Thoracic Oncology
Vol. 12 No. 1S
identified as a driver gene and benefited from crizotinib treatment. However, no data is available for ROS1-positivity NSCLC about chemotherapeutic options and prognostic data. We investigated pemetrexed-based treatment efficacy in ROS1 translocation NSCLC patients and determined the expression of thymidylate synthetase (TS) to provide a rationale for the efficacy results. Methods: We determined the ROS1 status of 1750 patients with lung adenocarcinoma. Patients’ clinical and therapeutic profile were assessed. In positive cases, thymidylate synthetase (TS) mRNA level was performed by RT-PCR. For comparison, we evaluated the TS mRNA status and pemetrexed-based treatment efficacy from 170 NSCLC patients with anaplastic lymphoma kinase (ALK) translocation(n¼46), EGFR mutation (n¼50), KRAS mutation (n¼32) and wild-type of EGFR/ALK/ ROS1/KRAS (n ¼ 42). Results: Thirty-four ROS1 translocation patients were identified at two institutions. Among the 34 patients, twelve with advanced stage or recurrence were treated with pemetrexed-based first-line chemotherapy. The median progression-free survivals of pemetrexed-based first-line chemotherapy in ROS1 translocation, ALK translocation, EGFR mutation, KRAS mutation and EGFR/ ALK/ROS1/KRAS wild-type patients were 6.8, 6.7, 5.2, 4.2 and 4.5 months, respectively (P¼0.003). The TS mRNA level was lower in patients with ROS1-positive than ROS1-negative patients (264±46910-4 vs. 469 ± 61510-4, P¼0.03), but similar with ALK-positive patients (264±46910-4 vs. 317±52410-4, P¼0.64). Conclusion: Patients diagnosed with ROS1 translocation lung adenocarcinoma may benefit from pemetrexedbased chemotherapy. TS mRNA level enables the selection of therapeutic options for ROS1 translocation patients.
JCES01.21 Molecular Profiling and Survival of Primary Pulmonary Neuroendocrine Carcinoma with Completely Resection Guangyuan Lou,1 Zhengbo Song,2 Yiping Zhang1 Zhejiang Cancer Hospital, Hangzhou/China, 2Medical Oncology, Zhejiang Cancer Hospital, Hangzhou/China
1
Background: According to the 2015 World Health Organization classification of lung tumors, pulmonary large cell neuroendocrine carcinoma (PLCNC) is grouped with the small cell lung cancer (SCLC) and carcinoid as pulmonary neuroendocrine carcinoma (PNC) for the common features of neuroendocrine characteristics. Molecular profiles and prognosis of primary pulmonary