- Email: [email protected]
P1.01-018 Acquired Resistance to Crizotinib in Advanced NSCLC with De Novo MET Overexpression
November 2017 gene panel of next-generation sequencing (NGS). Method: Archival tumor tissue used to screen patients for enrollment was analyzed using the FoundationOne NGS panel (Cambridge, MA). Results of the analyses from tumor tissue positive by ALK FISH were compared for a subgroup of progressors (N¼22) with a randomly selected subgroup of responders (N¼25). Result: There was a higher proportion of patients who were ALK-negative by NGS in progressors (8 of 22; 36%) as compared to responders (3 of 25; 12%) (p¼0.083), including 5 patients with oncogenic driver mutations in KRAS (G12S, Q61H, amp), EGFR (L858R) and BRAF (G469A). Among responders, 4 patients (16%) had non-EML4 ALK fusions (KIDINS220, EDC4, DTWD2, AFF2) while no such case was detected in progressors. TP53 mutations were detected in 10 progressors (45%) and 5 responders (20%) (p¼0.115). Excluding NGS-negative patients, TP53 mutations were detected in 7 of 14 progressors (50%) and 3 of 22 responders (13%) (p¼0.026). Conclusion: In the small percentage of patients with ALK-positive NSCLC with a best response of progression upon treatment with crizotinib, a higher proportion are ALK-negative by NGS, representing either a technical false-positive or an accurate FISH result reflecting a non-activating gene rearrangement that is not detected by NGS. TP53 mutations were observed at a higher frequency in progressors than in responders in patients with ALK-positive NSCLC by both FISH and NGS. Both technical and biologic factors thus may contribute to apparent intrinsic resistance in patients with ALK-positive NSCLC treated with crizotinib. Keywords: crizotinib, Intrinsic resistance
P1.01-017 ALK-Rearranged May Promote VTE by Increasing the Expression of TF in Advanced Lung Adenocarcinoma Y. Sen,1 H. Tang,2 Q. Wang1 1Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou/CN, 2Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou/CN Background: Patients with lung cancer are at increased risk for venous thromboembolism (VTE).About 8% to 15% of patients with advanced none small-cell lung cancer(NSCLC) experience a VTE in the course of their disease. However, the incidences of VTE in different molecular subtypes of NSCLC are rarely reported though they have big differentiation in clinical feature and therapeutic effect. Tissue Factor (TF) expressed in many solid tumors could bind and activate coagulation factor FVII and trigger the downstream coagulation cascade leading to thrombin generation and clot formation. Method: Here we extracted retrospective data from electronic medical records at Henan Cancer Hospital in China between January 2015 and January 2016. Lung adenocarcinomas with ALK-rearranged, EGFR mutation and both negative were classified. The incidence rate of VTE after diagnosed with lung adenocarcinoma was calculated and analyzed. Then we randomly selected ALK-rearranged and ALK-rearranged negative lung adenocarcinoma tissues and detected TF expression in them with immunohistochemistry. Result: At a median follow-up of 19 months, 5.85% (30 in 513) patients with advanced lung adenocarcinoma experienced VTE. Patients with different molecular subtypes put up different rate of VTE (P¼0.0021). Among them ALK-rearranged were more likely to experience VTE (6 in 29, 20.69%). EGFR and both negative had lower rate of VTE and had no big difference between them (11 in 218, 5.05%; 13 in 266, 4.89% respectively).The expression of TF performed similar feature. TF high expression in ALK-rearranged tissues is 41.67% (10 in 24) dramatically higher than that in ALK-rearranged negative tissues (11.54%, 3 in 26, P¼0.0152). Conclusion: The rate of VTE in ALKrearranged advanced lung adenocarcinoma cohorts was about 4 fold higher than that in EGFR mutation and both negative patients. ALKrearranged may promote that by increasing TF expression. The mechanism warrants further research. Keywords: venous thromboembolism, lung adenocarcinoma, ALK-rearranged
Abstracts
S1899
P1.01-018 Acquired Resistance to Crizotinib in Advanced NSCLC with De Novo MET Overexpression A. Li,1 J. Yang,1 X. Zhang,2 J. Su,2 Q. Zhou,2 H. Chen,1 Z. Xie,2 H. Tu,1 W. Zhong,1 Z. Wang,1 C. Xu,1 Z. Chen,2 H. Yan,2 Y. Wu3 1Divison 1 Tumor Center, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou/CN, 2 Guangdong Lung Cancer Institute, Guangzhou/CN, 3Guangdong General Hospital, Guangzhou/CN Background: MET exon14 skipping mutation has been regarded the driver mutation for MET activation, but with relatively low frequency of occurrence. MET overexpression can be a promising biomarker to predict the response to crizotinib. However, little is known about acquired resistance to treatments in tumors with de novo MET overexpression. Method: This prospective observational study included 33 NSCLC patients with MET IHC overexpression received crizotinib treatment From January 2013 to June 2017, 23 eligible patients evaluable for response. MET expression level were detected by immunohistochemistry (IHC) with antibody SP44, and 50% tumor cells with moderate to high intensity staining were defined as positive. Gene copy numbers were detected by FISH (Met probes from KREATECHTM.), and referring to Cappuzzo scoring system or MET/CEP7 ratio, 5 copies were positive or MET/CEP7 ratio 1.8 (low 1.82.2, Intermediate >2.2-<5 and High 5) was defined as MET amplification;. The status of EGFR, ALK, KRAS and ROS1 were also tested at baseline. Biopsy specimens obtained both at baseline and at the time of progression using targeted next-generation sequencing to assess for mechanisms of resistance. Result: Response were evaluable for 23 NSCLC patients with MET overexpression (4 female, 19 male). Fifteen of them achieved partial response (PR, 65.2%), 2 were stable disease (SD) and 6 were progressive disease (PD). All responders had high MET expression, and 12(52.2%) with FISH positive. The PFS and OS in the ITT population were 3.2 and 13.2 month respectively. Median PFS was 7.4m(95% CI,4.5-10.4) for MET IHC (100%+++) patients vs. MET IHC (50%++w100%+++) 1.9m (95% CI 0.9-2.9,P¼0.053), For FISH positive patients, mPFS was 8.2 m(95% CI,5.2-11.1) m v.s. FISH negative 1.3m(95% CI,0.2-1.7,p¼0.002). Two acquired resistance mechanisms were found after resistance, a 64 male patient with MET IHC 100%3,FISH (+),crizotinib first line and the best response PR, rebiopsy after resistance showed the MET D1228N mutation by NGS, and the second patient was 50 years old male with MET IHC 100% 3,FISH (+),crizotinib first line and the best response was PR, EGFR amplification were found upon progression when rebiopsy after resistance. The patient achieved PR with subsequent treatment of cetuximab plus Taxel. Conclusion: Multiple mechanisms of acquired resistance to crizotinib were found in de novo MET overexpressed patients. A secondary mutation in the MET gene and EGFR amplification may be the two main mechanisms. MET overexpression could be as a biomarker for de novo MET positive NSCLC. FISH seems better in predicting efficacy for MET inhibitor. Keywords: MET resistance, nonsmall cell lung cancer, crizotinib
P1.01-019 ALK+ Non-Small Cell Lung Cancer Treated with First Line Crizotinib: Patient Characteristics, Treatment Patterns, and Survival C. Martín,1 A. Cardona,2 O. Arrieta,3 O. Castillo-Fernandez,4 G. Oblitas,5 L. Corrales,6 L. Lupinacci,7 M.A. Pérez,8 L. Rojas,9 L. González,5 L. Chirinos,10 C. Ortíz,11 M. Lema,12 C. Vargas,11 C. Puparelli,13 H. Carranza,11 J. Otero,11 L. Ramirez-Tirado3 1 Medical Oncology Group, Fleming Institute, Buenos Aires/AR, 2Clinical and Translational Oncology Group, Foundation for Clinical and Applied
P1.01-017 ALK-Rearranged May Promote VTE by Increasing the Expression of TF in Advanced Lung Adenocarcinoma Y. Sen,1 H. Tang,2 Q. Wang1 1Department of Internal Medicine, Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou/CN, 2Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou/CN Background: Patients with lung cancer are at increased risk for venous thromboembolism (VTE).About 8% to 15% of patients with advanced none small-cell lung cancer(NSCLC) experience a VTE in the course of their disease. However, the incidences of VTE in different molecular subtypes of NSCLC are rarely reported though they have big differentiation in clinical feature and therapeutic effect. Tissue Factor (TF) expressed in many solid tumors could bind and activate coagulation factor FVII and trigger the downstream coagulation cascade leading to thrombin generation and clot formation. Method: Here we extracted retrospective data from electronic medical records at Henan Cancer Hospital in China between January 2015 and January 2016. Lung adenocarcinomas with ALK-rearranged, EGFR mutation and both negative were classified. The incidence rate of VTE after diagnosed with lung adenocarcinoma was calculated and analyzed. Then we randomly selected ALK-rearranged and ALK-rearranged negative lung adenocarcinoma tissues and detected TF expression in them with immunohistochemistry. Result: At a median follow-up of 19 months, 5.85% (30 in 513) patients with advanced lung adenocarcinoma experienced VTE. Patients with different molecular subtypes put up different rate of VTE (P¼0.0021). Among them ALK-rearranged were more likely to experience VTE (6 in 29, 20.69%). EGFR and both negative had lower rate of VTE and had no big difference between them (11 in 218, 5.05%; 13 in 266, 4.89% respectively).The expression of TF performed similar feature. TF high expression in ALK-rearranged tissues is 41.67% (10 in 24) dramatically higher than that in ALK-rearranged negative tissues (11.54%, 3 in 26, P¼0.0152). Conclusion: The rate of VTE in ALKrearranged advanced lung adenocarcinoma cohorts was about 4 fold higher than that in EGFR mutation and both negative patients. ALKrearranged may promote that by increasing TF expression. The mechanism warrants further research. Keywords: venous thromboembolism, lung adenocarcinoma, ALK-rearranged
Abstracts
S1899
P1.01-018 Acquired Resistance to Crizotinib in Advanced NSCLC with De Novo MET Overexpression A. Li,1 J. Yang,1 X. Zhang,2 J. Su,2 Q. Zhou,2 H. Chen,1 Z. Xie,2 H. Tu,1 W. Zhong,1 Z. Wang,1 C. Xu,1 Z. Chen,2 H. Yan,2 Y. Wu3 1Divison 1 Tumor Center, Guangdong Lung Cancer Institute, Guangdong General Hospital & Guangdong Academy of Medical Sciences, Guangzhou/CN, 2 Guangdong Lung Cancer Institute, Guangzhou/CN, 3Guangdong General Hospital, Guangzhou/CN Background: MET exon14 skipping mutation has been regarded the driver mutation for MET activation, but with relatively low frequency of occurrence. MET overexpression can be a promising biomarker to predict the response to crizotinib. However, little is known about acquired resistance to treatments in tumors with de novo MET overexpression. Method: This prospective observational study included 33 NSCLC patients with MET IHC overexpression received crizotinib treatment From January 2013 to June 2017, 23 eligible patients evaluable for response. MET expression level were detected by immunohistochemistry (IHC) with antibody SP44, and 50% tumor cells with moderate to high intensity staining were defined as positive. Gene copy numbers were detected by FISH (Met probes from KREATECHTM.), and referring to Cappuzzo scoring system or MET/CEP7 ratio, 5 copies were positive or MET/CEP7 ratio 1.8 (low 1.82.2, Intermediate >2.2-<5 and High 5) was defined as MET amplification;. The status of EGFR, ALK, KRAS and ROS1 were also tested at baseline. Biopsy specimens obtained both at baseline and at the time of progression using targeted next-generation sequencing to assess for mechanisms of resistance. Result: Response were evaluable for 23 NSCLC patients with MET overexpression (4 female, 19 male). Fifteen of them achieved partial response (PR, 65.2%), 2 were stable disease (SD) and 6 were progressive disease (PD). All responders had high MET expression, and 12(52.2%) with FISH positive. The PFS and OS in the ITT population were 3.2 and 13.2 month respectively. Median PFS was 7.4m(95% CI,4.5-10.4) for MET IHC (100%+++) patients vs. MET IHC (50%++w100%+++) 1.9m (95% CI 0.9-2.9,P¼0.053), For FISH positive patients, mPFS was 8.2 m(95% CI,5.2-11.1) m v.s. FISH negative 1.3m(95% CI,0.2-1.7,p¼0.002). Two acquired resistance mechanisms were found after resistance, a 64 male patient with MET IHC 100%3,FISH (+),crizotinib first line and the best response PR, rebiopsy after resistance showed the MET D1228N mutation by NGS, and the second patient was 50 years old male with MET IHC 100% 3,FISH (+),crizotinib first line and the best response was PR, EGFR amplification were found upon progression when rebiopsy after resistance. The patient achieved PR with subsequent treatment of cetuximab plus Taxel. Conclusion: Multiple mechanisms of acquired resistance to crizotinib were found in de novo MET overexpressed patients. A secondary mutation in the MET gene and EGFR amplification may be the two main mechanisms. MET overexpression could be as a biomarker for de novo MET positive NSCLC. FISH seems better in predicting efficacy for MET inhibitor. Keywords: MET resistance, nonsmall cell lung cancer, crizotinib
P1.01-019 ALK+ Non-Small Cell Lung Cancer Treated with First Line Crizotinib: Patient Characteristics, Treatment Patterns, and Survival C. Martín,1 A. Cardona,2 O. Arrieta,3 O. Castillo-Fernandez,4 G. Oblitas,5 L. Corrales,6 L. Lupinacci,7 M.A. Pérez,8 L. Rojas,9 L. González,5 L. Chirinos,10 C. Ortíz,11 M. Lema,12 C. Vargas,11 C. Puparelli,13 H. Carranza,11 J. Otero,11 L. Ramirez-Tirado3 1 Medical Oncology Group, Fleming Institute, Buenos Aires/AR, 2Clinical and Translational Oncology Group, Foundation for Clinical and Applied