- Email: [email protected]
Antitumor activity of TAK-788 in NSCLC With EGFR exon 20 insertions
abstracts
Annals of Oncology 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr 3 TEAEs (5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant. Conclusions: In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs.
MO2 15 4 MO2 14 6
Were the more examined lymph nodes the better for stage IA NSCLC patients? A Population Study of the US SEER Database
Liu Huang, Vanisha Chummun, Qian Chu, Yuan Chen Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China Background: To find out the optimal number of examined lymph nodes (ELNs) in stage IA non-small cell lung cancer (NSCLC). To figure out whether there was a turning point beyond which ELNs might have adverse effects on survival. Methods: Using the Surveillance, Epidemiology, and End Results registry (SEER) database, we selected all NSCLC patients diagnosed with stage IA (T1N0M0) from 1995 to 2015. Cases from 1995 to 2005 were as analytical data set (group 1) and from 2006 to 2015 were as Validation data set (group 2). The overall survival (OS) of patients with different ELNs was compared statistically by SPSS. The optimal cut point of ELNs was calculated by X-Tile and verified by univariable and multivariable analyses. Propensity score matching (PSM) was did by R software 3.5.2. Results: In total, we extracted 57481 stage IA NSCLC patients (group 1, n ¼ 20814; group 2, n ¼ 36667). The PSM of Group 1 and Group 2 were balanced based on sex, age and race. In both group 1 and group 2, when divided patients into 3 subgroups, recording as ELN ¼ 0, 1 ELNs < n and ELNs n. ELN ¼ 0 has the highest risk of death in each subgroup (all p < 0.001). From n ¼ 6 to 16, OS was significantly different between 1 ELNs < n, and ELNs n. But From n ¼ 17 to 30, OS was of no difference between 1 ELNs < n and ELNs n. When divided patients into ELNs ¼ 0, 1 to 2, 3 to 5, 6 to 9, 10 to 29 and 30, serial improvement in OS with increasing ELNs, up to ELNs were 6 to 9, beyond which there was little further incremental survival benefit. The survival curve of ELNs 30 even had an obvious trend to drop down. Conclusion: For stage IA NSCLC, we suggested that to resect 6 to 9 LNs were enough, and no more than 16 LNs were accepted. More than 16 ELNs did not improve survival and more than 30 ELNs may have bad effect on survival.
MO2 15 1½Encore 1
Antitumor activity of TAK-788 in NSCLC With EGFR exon 20 insertions 2
3
4
Jin Kang, Jun Hua Chen, Ji Jin Yang, Long Yi Wu Division of Pulmonary Oncology, Cancer Center, Guangdong Lung Cancer Institute (GLCI), Guangdong Provincial People’s Hospital (GDPH), China Background: The EGFR-mutant adenocarcinomas with histologic transformation usually had poor prognosis. However, few studies have focused on the different frequencies and molecular mechanism after the treatment of different tyrosine kinase inhibitors(TKIs). Methods: Pathology was confirmed in 296 EGFR-mutant patients at baseline and recurrence. Among these patients, 190 patients were treated with gefitinib/erlotinib, 51 with afatinib and 55 with osimertinib. The sufficient tumor specimens from 9 patients were detected by next-generation sequencing. Demographics, disease features, and outcomes of these patients were analyzed. Results: The frequencies of EGFR-mutant adenocarcinomas with histologic transformation after different EGFR-TKIs were quite different. The frequency of gefitinib/erlotinib group was 7.9% (15/190), while the others were 5.8% (3/51, afatinib group) and 14.5% (8/55, osimertinib group). The progression free survival (PFS) to different EGFR-TKIs were 10.7 months (gefitinib/erlotinib group), 9 months (afatinib group) and 7.7 months (osimertinib group), respectively. Four adenocarcinomas treated with gefitinib/erlotinib all harbored TP53 mutations at baseline. One adenocarcinoma after the treatment of afatinib had acquired MET amplification and transformed to smallcell lung cancer meanwhile. There were 2 patients treated with osimertinib transformed from adenocarcinomas to adenosquamous carcinoma and they were characterized by KRAS amplification and EGFR amplification. The others transformed to small-cell cancers were harboring with TP53, Rb1 and PIK3CA mutations. Conclusion: The EGFR-mutant adenocarcinomas treated with osimertinib had the highest rate of histologic transformation. The genetic profiles vary greatly between transformation to squamous carcinomas and transformation to small-cell cancers in EGFR-mutant adenocarcinomas treated with osimertinib. Further verification is needed.
MO2 15 5
Tepotinib in NSCLC patients with METex14 mutations: interim results from the phase II VISION study
5
Pasi A. J€anne , Joel W Neal , D R Camidge , Alexander Spira , Zofia Piotrowska , Leora Horn6, Daniel B Costa7, Anne Tsao8, Jyoti Patel9, Shirish Gadgeel10, Lyudmila Bazhenova11, Viola W Zhu12, Howard West13, Sylvie Vincent14, Jian Zhu14, Shuanglian Li14, Gregory J Riely15 1 Dana-Farber Cancer Institute, Boston, MA, United States, 2Stanford Cancer Institute, Stanford University, Stanford, CA, USA, 3University of Colorado Cancer Center, Aurora, CO, USA, 4Virginia Cancer Specialists, Fairfax, VA, USA, 5Massachusetts General Hospital, Boston, MA, USA, 6Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, 7Beth Israel Deaconess Medical Center, Boston, MA, USA, 8MD Anderson Cancer Center, Houston, TX, USA, 9University of Chicago, Chicago, IL, USA, 10University of Michigan, Ann Arbor, MI, USA, 11UCSD Moores Cancer Center, La Jolla, CA, USA, 12University of California, Irvine School of Medicine, Orange, CA, USA, 13Swedish Cancer Institute, Seattle, WA, USA, 14Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, 15Memorial Sloan Kettering Cancer Center, New York, NY, USA Background: We report results of a phase 1/2 open-label, multicenter study of TAK788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor. Methods: Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results: As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; 2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with 1 disease assessment was PR, n ¼ 14; SD, n ¼ 9; and PD, n ¼ 1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control.
vi108 | Oral Session : Mini-Oral Abstracts Session
The different frequencies of histologic transformation after different EGFR-TKIs in EGFR-mutant adenocarcinomas
Hiroshi Sakai1, Remi Veillon2, Alexis B Cortot3, Enriqueta Felip4, Julien Mazieres5, Masahiro Morise6, Tomohiro Sakamoto7, Takaaki Tokito8, Shinji Atagi9, Terufumi Kato10, Toru Kumagai11, Hiroshi Tanaka12, Rolf Bruns13, Josef Straub13, Juergen Scheele13, Xiuning Le14, Paul K Paik15 1 Saitama Cancer Center, Japan, 2CHU Bordeaux, service des maladies respiratoires, Bordeaux, France, 3Thoracic Oncology Dept, Lille University Hospital, Univ. Lille, Lille, France, 4Oncology Department, Vall d Hebron University Hospital, Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain, 5CHU de Toulouse-Hopital Larrey, IUCT Oncopole, Quai de livraison Pharmacie, Toulouse, France, 6Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan, 7Tottori University Hospital, Department of Respiratory Medicine, Yonago, Tottori, Japan, 8 Kurume University Hospital, Kurume-shi, Japan, 9Kinki-chuo Chest Medical Center, Osaka, Japan, 10Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan, 11Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan, 12Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan, 13Merck KGaA, Darmstadt, Germany, 14MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA, 15Memorial Sloan Kettering Cancer Center, New York, USA Background: Activating MET exon 14 skipping (METex14) mutations can be detected by liquid biopsy (LBx) or tumor biopsy (TBx) and are sensitive to MET inhibition. We report interim data from the phase II VISION study of tepotinib, a highly selective MET inhibitor, in NSCLC patients with METex14 mutations (NCT02864992). Methods: Patients (pts) with advanced EGFR/ALK wild-type NSCLC harboring METex14 mutation identified by RNA-based testing with LBx or TBx (both 60 pts; overlap of LBx/TBx anticipated), enrolled at 113 sites in 8 countries (13 sites in Japan), receive tepotinib 500mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint is ORR by independent review committee (IRC); secondary endpoints include investigator assessed ORR (INV) and safety.
Volume 30 | Supplement 6 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.077/5582924 by Stockholm University Library user on 30 October 2019
(8%); ALK fusion, n ¼ 2 (4%)/n¼3 (6%). A total of 72 PFS events were observed at the data cut-off (28 November 2018). After a median follow-up of 32.1 months, median PFS was 12.7/13.8 months (HR ¼ 1.16, 95% CI, 0.73-1.84, p ¼ 0.538), and 2-year PFS rate was 36.5% (95% CI, 23.5-49.6)/32.1% (95%CI, 18.9-45.4). After a median followup of 34.6 months, 44 OS events were observed. Median OS was 48.3/59.1 months (HR ¼ 1.05, 95%CI, 0.58-1.90, p ¼ 0.883), and 2-year OS rate was 69.2% (95%CI, 56.781.8)/66.4% (95%CI, 53.0-79.9). 27 patients in each arm received post-study chemotherapy including EGFR-TKIs (n ¼ 7/n¼5), ALK-TKIs (n ¼ 0/n¼3), and immunocheckpoint inhibitors (n ¼ 6/n¼10). Conclusions: 2-year PFS rate in the CDDPþS-1 arm was better than that in the CDDPþPEM arm. We will select the CDDPþS-1 arm as the investigational arm in a future phase III study.
Annals of Oncology 23/24 evaluable pts with EGFR exon 20 insertions treated at 160 mg qd had decreased target lesion measurements (median best percent change, -32.6% [-79.1%, 3.8%]). Most common TEAEs (20%) in pts treated with 160 mg qd: diarrhea (85%), rash (43%), nausea (41%), vomiting (30%), decreased appetite (28%), and stomatitis (22%); gr 3 TEAEs (5%): diarrhea (26%); hypokalemia, nausea, and stomatitis (7% each). Among pts treated with 160 mg qd, median dose intensity was 93%, and the rate of treatment discontinuation due to AEs was 10.7%. There is no clear trend that response to TAK-788 is enriched in any single EGFR exon 20 insertion variant. Conclusions: In NSCLC pts with EGFR exon 20 insertions, TAK-788 demonstrated antitumor activity and an AE profile consistent with other EGFR TKIs.
MO2 15 4 MO2 14 6
Were the more examined lymph nodes the better for stage IA NSCLC patients? A Population Study of the US SEER Database
Liu Huang, Vanisha Chummun, Qian Chu, Yuan Chen Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, China Background: To find out the optimal number of examined lymph nodes (ELNs) in stage IA non-small cell lung cancer (NSCLC). To figure out whether there was a turning point beyond which ELNs might have adverse effects on survival. Methods: Using the Surveillance, Epidemiology, and End Results registry (SEER) database, we selected all NSCLC patients diagnosed with stage IA (T1N0M0) from 1995 to 2015. Cases from 1995 to 2005 were as analytical data set (group 1) and from 2006 to 2015 were as Validation data set (group 2). The overall survival (OS) of patients with different ELNs was compared statistically by SPSS. The optimal cut point of ELNs was calculated by X-Tile and verified by univariable and multivariable analyses. Propensity score matching (PSM) was did by R software 3.5.2. Results: In total, we extracted 57481 stage IA NSCLC patients (group 1, n ¼ 20814; group 2, n ¼ 36667). The PSM of Group 1 and Group 2 were balanced based on sex, age and race. In both group 1 and group 2, when divided patients into 3 subgroups, recording as ELN ¼ 0, 1 ELNs < n and ELNs n. ELN ¼ 0 has the highest risk of death in each subgroup (all p < 0.001). From n ¼ 6 to 16, OS was significantly different between 1 ELNs < n, and ELNs n. But From n ¼ 17 to 30, OS was of no difference between 1 ELNs < n and ELNs n. When divided patients into ELNs ¼ 0, 1 to 2, 3 to 5, 6 to 9, 10 to 29 and 30, serial improvement in OS with increasing ELNs, up to ELNs were 6 to 9, beyond which there was little further incremental survival benefit. The survival curve of ELNs 30 even had an obvious trend to drop down. Conclusion: For stage IA NSCLC, we suggested that to resect 6 to 9 LNs were enough, and no more than 16 LNs were accepted. More than 16 ELNs did not improve survival and more than 30 ELNs may have bad effect on survival.
MO2 15 1½Encore 1
Antitumor activity of TAK-788 in NSCLC With EGFR exon 20 insertions 2
3
4
Jin Kang, Jun Hua Chen, Ji Jin Yang, Long Yi Wu Division of Pulmonary Oncology, Cancer Center, Guangdong Lung Cancer Institute (GLCI), Guangdong Provincial People’s Hospital (GDPH), China Background: The EGFR-mutant adenocarcinomas with histologic transformation usually had poor prognosis. However, few studies have focused on the different frequencies and molecular mechanism after the treatment of different tyrosine kinase inhibitors(TKIs). Methods: Pathology was confirmed in 296 EGFR-mutant patients at baseline and recurrence. Among these patients, 190 patients were treated with gefitinib/erlotinib, 51 with afatinib and 55 with osimertinib. The sufficient tumor specimens from 9 patients were detected by next-generation sequencing. Demographics, disease features, and outcomes of these patients were analyzed. Results: The frequencies of EGFR-mutant adenocarcinomas with histologic transformation after different EGFR-TKIs were quite different. The frequency of gefitinib/erlotinib group was 7.9% (15/190), while the others were 5.8% (3/51, afatinib group) and 14.5% (8/55, osimertinib group). The progression free survival (PFS) to different EGFR-TKIs were 10.7 months (gefitinib/erlotinib group), 9 months (afatinib group) and 7.7 months (osimertinib group), respectively. Four adenocarcinomas treated with gefitinib/erlotinib all harbored TP53 mutations at baseline. One adenocarcinoma after the treatment of afatinib had acquired MET amplification and transformed to smallcell lung cancer meanwhile. There were 2 patients treated with osimertinib transformed from adenocarcinomas to adenosquamous carcinoma and they were characterized by KRAS amplification and EGFR amplification. The others transformed to small-cell cancers were harboring with TP53, Rb1 and PIK3CA mutations. Conclusion: The EGFR-mutant adenocarcinomas treated with osimertinib had the highest rate of histologic transformation. The genetic profiles vary greatly between transformation to squamous carcinomas and transformation to small-cell cancers in EGFR-mutant adenocarcinomas treated with osimertinib. Further verification is needed.
MO2 15 5
Tepotinib in NSCLC patients with METex14 mutations: interim results from the phase II VISION study
5
Pasi A. J€anne , Joel W Neal , D R Camidge , Alexander Spira , Zofia Piotrowska , Leora Horn6, Daniel B Costa7, Anne Tsao8, Jyoti Patel9, Shirish Gadgeel10, Lyudmila Bazhenova11, Viola W Zhu12, Howard West13, Sylvie Vincent14, Jian Zhu14, Shuanglian Li14, Gregory J Riely15 1 Dana-Farber Cancer Institute, Boston, MA, United States, 2Stanford Cancer Institute, Stanford University, Stanford, CA, USA, 3University of Colorado Cancer Center, Aurora, CO, USA, 4Virginia Cancer Specialists, Fairfax, VA, USA, 5Massachusetts General Hospital, Boston, MA, USA, 6Vanderbilt-Ingram Cancer Center, Nashville, TN, USA, 7Beth Israel Deaconess Medical Center, Boston, MA, USA, 8MD Anderson Cancer Center, Houston, TX, USA, 9University of Chicago, Chicago, IL, USA, 10University of Michigan, Ann Arbor, MI, USA, 11UCSD Moores Cancer Center, La Jolla, CA, USA, 12University of California, Irvine School of Medicine, Orange, CA, USA, 13Swedish Cancer Institute, Seattle, WA, USA, 14Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, Cambridge, MA, USA, 15Memorial Sloan Kettering Cancer Center, New York, NY, USA Background: We report results of a phase 1/2 open-label, multicenter study of TAK788 (NCT02716116), an oral investigational EGFR/HER2 inhibitor. Methods: Pts with advanced, previously treated NSCLC received daily TAK-788 in dose escalation and expansion cohorts based on tumor genotype. Antitumor activity was determined for pts with EGFR exon 20 insertions who received TAK-788 at the RP2D. Safety is reported for all pts across all doses and at 160 mg. Results: As of 14 Sep 2018, 101 pts (median age, 61 y; female, 70%; 2 prior anticancer therapies, 76%; brain metastases, 53%) were treated with TAK-788 at 5-180 mg qd. RP2D was determined to be 160 mg. 28 pts with EGFR exon 20 insertions were treated with 160 mg qd during dose escalation or in expansion cohort 1 (3.6 mo on treatment; 3.8 treatment cycles [medians]); 24 pts remain on treatment. At data cutoff, best response (by RECIST v1.1) among 26 pts with 1 disease assessment was PR, n ¼ 14; SD, n ¼ 9; and PD, n ¼ 1; 2 pts were not evaluable. 7/14 objective responses (all PR) were confirmed, with 6 awaiting confirmation and 1 unconfirmed PR at 160 mg qd; median time to response in these 14 pts was 56 days. 23/26 pts achieved disease control.
vi108 | Oral Session : Mini-Oral Abstracts Session
The different frequencies of histologic transformation after different EGFR-TKIs in EGFR-mutant adenocarcinomas
Hiroshi Sakai1, Remi Veillon2, Alexis B Cortot3, Enriqueta Felip4, Julien Mazieres5, Masahiro Morise6, Tomohiro Sakamoto7, Takaaki Tokito8, Shinji Atagi9, Terufumi Kato10, Toru Kumagai11, Hiroshi Tanaka12, Rolf Bruns13, Josef Straub13, Juergen Scheele13, Xiuning Le14, Paul K Paik15 1 Saitama Cancer Center, Japan, 2CHU Bordeaux, service des maladies respiratoires, Bordeaux, France, 3Thoracic Oncology Dept, Lille University Hospital, Univ. Lille, Lille, France, 4Oncology Department, Vall d Hebron University Hospital, Vall d Hebron Institute of Oncology (VHIO), Barcelona, Spain, 5CHU de Toulouse-Hopital Larrey, IUCT Oncopole, Quai de livraison Pharmacie, Toulouse, France, 6Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, Nagoya, Japan, 7Tottori University Hospital, Department of Respiratory Medicine, Yonago, Tottori, Japan, 8 Kurume University Hospital, Kurume-shi, Japan, 9Kinki-chuo Chest Medical Center, Osaka, Japan, 10Department of Thoracic Oncology, Kanagawa Cancer Center, Yokohama, Japan, 11Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan, 12Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, Japan, 13Merck KGaA, Darmstadt, Germany, 14MD Anderson Cancer Center, The University of Texas, Houston, Texas, USA, 15Memorial Sloan Kettering Cancer Center, New York, USA Background: Activating MET exon 14 skipping (METex14) mutations can be detected by liquid biopsy (LBx) or tumor biopsy (TBx) and are sensitive to MET inhibition. We report interim data from the phase II VISION study of tepotinib, a highly selective MET inhibitor, in NSCLC patients with METex14 mutations (NCT02864992). Methods: Patients (pts) with advanced EGFR/ALK wild-type NSCLC harboring METex14 mutation identified by RNA-based testing with LBx or TBx (both 60 pts; overlap of LBx/TBx anticipated), enrolled at 113 sites in 8 countries (13 sites in Japan), receive tepotinib 500mg QD until progression, intolerable toxicity or withdrawal. Primary endpoint is ORR by independent review committee (IRC); secondary endpoints include investigator assessed ORR (INV) and safety.
Volume 30 | Supplement 6 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz338.077/5582924 by Stockholm University Library user on 30 October 2019
(8%); ALK fusion, n ¼ 2 (4%)/n¼3 (6%). A total of 72 PFS events were observed at the data cut-off (28 November 2018). After a median follow-up of 32.1 months, median PFS was 12.7/13.8 months (HR ¼ 1.16, 95% CI, 0.73-1.84, p ¼ 0.538), and 2-year PFS rate was 36.5% (95% CI, 23.5-49.6)/32.1% (95%CI, 18.9-45.4). After a median followup of 34.6 months, 44 OS events were observed. Median OS was 48.3/59.1 months (HR ¼ 1.05, 95%CI, 0.58-1.90, p ¼ 0.883), and 2-year OS rate was 69.2% (95%CI, 56.781.8)/66.4% (95%CI, 53.0-79.9). 27 patients in each arm received post-study chemotherapy including EGFR-TKIs (n ¼ 7/n¼5), ALK-TKIs (n ¼ 0/n¼3), and immunocheckpoint inhibitors (n ¼ 6/n¼10). Conclusions: 2-year PFS rate in the CDDPþS-1 arm was better than that in the CDDPþPEM arm. We will select the CDDPþS-1 arm as the investigational arm in a future phase III study.