1490PDA phase Ia/IIa trial of Sym015, a MET antibody mixture, in patients with advanced solid tumours
Abstract Background MET gene amplification/mutation is implicated in oncogenesis of many tumor types. Sym015 is a recombinant antibody (Ab) mixture containing 2 humanized Abs binding non-overlapping epitopes on MET which has superior preclinical activity compared to other MET Abs. Here we present in...
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| creator | Camidge, D R Janku, F Bueno, A Martinez Catenacci, D V Lee, J Lee, S-H Chung, H C Dowlati, A Rohrberg, K S Felip Font, E Garralda, E Kang, Y-K Moon, Y W López Criado, M Chiu, C-F Poulsen, T T Rudbæk, H Alifrangis, L Dalal, R P Patnaik, A |
| description | Abstract
Background
MET gene amplification/mutation is implicated in oncogenesis of many tumor types. Sym015 is a recombinant antibody (Ab) mixture containing 2 humanized Abs binding non-overlapping epitopes on MET which has superior preclinical activity compared to other MET Abs. Here we present interim results from the First in Human study of Sym015.
Methods
In part 1 dose escalation, Sym015 was evaluated on every 2-week (q2w) schedule at 6/12/18/24 mg/kg doses in late line advanced solid tumor patients (pts). Based on PK/PD assessment, 18 mg/kg loading dose followed by 12 mg/kg q2w was selected as RP2D. The on-going Part 2 Dose expansion enrolls pts with MET amplification (METAmp >5 MET copies by Next Generation Sequencing (NGS) or FISH MET/CEP7 ratio >2.2 updated to ≥ 3.0) and/or MET exon 14 deletion (METEx14Δ) positive tumors. Central FISH confirmation of tumor MET status and longitudinal circulating tumor (ct)DNA profiling is performed.
Results
By April 2019, 51 pts (median age 61 yrs) have been treated, 12 pts in Part 1 and 39 pts in Part 2, the majority are non small cell lung cancer (NSCLC; 14 pts; 6 METAmp,7 METEx14Δ, 1 both) and gastric cancer (GC; 12 METAmp pts). Treatment-related adverse events (TRAE) occurred overall in 41,2%; TRAE ≥ gr3 in 9,8% (edema, colitis, septic shock, hypoalbuminemia, hypophosphatemia, increased amylase). No pts discontinued or died due to TRAE. The most common TRAE of ≥ 5% were fatigue 15.7%, peripheral edema 7,8%, nausea, decreased appetite, pruritus and abdominal pain reported by 5.9% of pts each. The table shows preliminary efficacy in NSCLC patients. Sym015 PK was slightly non-linear, with a dose-dependent t½ of 7-10 days for the first dose. 83% METAmp concordance (10/12 samples) between tumor and blood was observed.
Table:1490PDNSCLC PtMET Status (Local Assessment)Best Response (Best % Change From Baseline)Previous MET TKI therapyDuration of Response (weeks)1METAmp NGS 6.8 CopiesPR (-53%)No802METAmp NGS >5 CopiesSD (-29%)No9, Ongoing3METAmp NGS >5 CopiesSD (+3%)No9, Ongoing4METEx14ΔSD (-28%)No7, Ongoing5METAmp FISH MET/ CEP7:4.9SD (+6%)No116METEx14ΔSD (-4%)Yes87METEx14ΔSD (-21%)Yes158METEx14ΔSD (-20%)Yes89METAmp SISH MET/ CEP7: 15.2PendingNoOngoing10METEx14ΔPendingYesOngoing11METEx14Δ + METAmpPendingPendingOngoing12METEx14ΔPendingNoOngoing13METEx14ΔPendingNoOngoing14METEx14ΔNot EvaluableYesNot Evaluable
Conclusions
Sym015 was well tolerated with early evidence of antitumor activity. Predictive biomarker analysis |
| doi_str_mv | 10.1093/annonc/mdz260.012 |
| format | Article |
| fullrecord | <record><control><sourceid>oup</sourceid><recordid>TN_cdi_oup_primary_10_1093_annonc_mdz260_012</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/annonc/mdz260.012</oup_id><sourcerecordid>10.1093/annonc/mdz260.012</sourcerecordid><originalsourceid>FETCH-oup_primary_10_1093_annonc_mdz260_0123</originalsourceid><addsrcrecordid>eNqVz0tOwzAUQFELgUT4LIDZW0DSPOcHHiIoIoNKSHRuPWpXNYrtyHaAdPUFlQ10dCd3chi747jgKOqSnPNuU1q1rzpcIK_OWMbbThQP2PBzlqGo6uK-rZtLdhXjJyJ2ohIZ07wR-Pb8COOOooaeyr4nSMHQAH4L77NF3uZAsFqugVwyH17NYM1PmoLOwTgYKRntUoRvk3ZA6ovcRiuIfjAK0mT9FOINu9jSEPXtf69Z_rJcP70WfhrlGIylMEuO8o8ijxR5pMhfSn3ifgDDnlIX</addsrcrecordid><sourcetype>Publisher</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>1490PDA phase Ia/IIa trial of Sym015, a MET antibody mixture, in patients with advanced solid tumours</title><source>Alma/SFX Local Collection</source><source>EZB Electronic Journals Library</source><creator>Camidge, D R ; Janku, F ; Bueno, A Martinez ; Catenacci, D V ; Lee, J ; Lee, S-H ; Chung, H C ; Dowlati, A ; Rohrberg, K S ; Felip Font, E ; Garralda, E ; Kang, Y-K ; Moon, Y W ; López Criado, M ; Chiu, C-F ; Poulsen, T T ; Rudbæk, H ; Alifrangis, L ; Dalal, R P ; Patnaik, A</creator><creatorcontrib>Camidge, D R ; Janku, F ; Bueno, A Martinez ; Catenacci, D V ; Lee, J ; Lee, S-H ; Chung, H C ; Dowlati, A ; Rohrberg, K S ; Felip Font, E ; Garralda, E ; Kang, Y-K ; Moon, Y W ; López Criado, M ; Chiu, C-F ; Poulsen, T T ; Rudbæk, H ; Alifrangis, L ; Dalal, R P ; Patnaik, A</creatorcontrib><description>Abstract
Background
MET gene amplification/mutation is implicated in oncogenesis of many tumor types. Sym015 is a recombinant antibody (Ab) mixture containing 2 humanized Abs binding non-overlapping epitopes on MET which has superior preclinical activity compared to other MET Abs. Here we present interim results from the First in Human study of Sym015.
Methods
In part 1 dose escalation, Sym015 was evaluated on every 2-week (q2w) schedule at 6/12/18/24 mg/kg doses in late line advanced solid tumor patients (pts). Based on PK/PD assessment, 18 mg/kg loading dose followed by 12 mg/kg q2w was selected as RP2D. The on-going Part 2 Dose expansion enrolls pts with MET amplification (METAmp >5 MET copies by Next Generation Sequencing (NGS) or FISH MET/CEP7 ratio >2.2 updated to ≥ 3.0) and/or MET exon 14 deletion (METEx14Δ) positive tumors. Central FISH confirmation of tumor MET status and longitudinal circulating tumor (ct)DNA profiling is performed.
Results
By April 2019, 51 pts (median age 61 yrs) have been treated, 12 pts in Part 1 and 39 pts in Part 2, the majority are non small cell lung cancer (NSCLC; 14 pts; 6 METAmp,7 METEx14Δ, 1 both) and gastric cancer (GC; 12 METAmp pts). Treatment-related adverse events (TRAE) occurred overall in 41,2%; TRAE ≥ gr3 in 9,8% (edema, colitis, septic shock, hypoalbuminemia, hypophosphatemia, increased amylase). No pts discontinued or died due to TRAE. The most common TRAE of ≥ 5% were fatigue 15.7%, peripheral edema 7,8%, nausea, decreased appetite, pruritus and abdominal pain reported by 5.9% of pts each. The table shows preliminary efficacy in NSCLC patients. Sym015 PK was slightly non-linear, with a dose-dependent t½ of 7-10 days for the first dose. 83% METAmp concordance (10/12 samples) between tumor and blood was observed.
Table:1490PDNSCLC PtMET Status (Local Assessment)Best Response (Best % Change From Baseline)Previous MET TKI therapyDuration of Response (weeks)1METAmp NGS 6.8 CopiesPR (-53%)No802METAmp NGS >5 CopiesSD (-29%)No9, Ongoing3METAmp NGS >5 CopiesSD (+3%)No9, Ongoing4METEx14ΔSD (-28%)No7, Ongoing5METAmp FISH MET/ CEP7:4.9SD (+6%)No116METEx14ΔSD (-4%)Yes87METEx14ΔSD (-21%)Yes158METEx14ΔSD (-20%)Yes89METAmp SISH MET/ CEP7: 15.2PendingNoOngoing10METEx14ΔPendingYesOngoing11METEx14Δ + METAmpPendingPendingOngoing12METEx14ΔPendingNoOngoing13METEx14ΔPendingNoOngoing14METEx14ΔNot EvaluableYesNot Evaluable
Conclusions
Sym015 was well tolerated with early evidence of antitumor activity. Predictive biomarker analysis is underway. The study continues to enroll NSCLC patients with METAmp and/or METEx14Δ. MET screening in blood seems feasible and may be included in future trials.
Clinical trial identification
NCT02648724.
Legal entity responsible for the study
Symphogen A/S.
Funding
Symphogen A/S.
Disclosure
D.R. Camidge: Advisory / Consultancy: 2019: Takeda, CBT Pharmaceuticals, Daiichi-Sankyo (ILD adjudication committee), G1 Therapeutics (DSMB), Bio-Thera (DSMB), Blueprint; Advisory / Consultancy: 2018: AstraZeneca, Takeda, Arrys/Kyn, Regeneron, Hengrui, G1 Therapeutics (DSMB), Daiichi Sankyo (ILD adjudication committee), Hansoh (SRC), Bio-Thera (DSMB), Ribon, BMS, Blueprint, Roche/Genentech, Inivata; Advisory / Consultancy: 2017: Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Takeda, Ignyta, Daiichi Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med; Research grant / Funding (self), Research grant / Funding (institution): 2017: Takeda Investigator-initiated Trial; Research grant / Funding (self), Research grant / Funding (institution), Company Sponsored Trials at Institution: 2018/9: AbbVie, AstraZeneca, BMS, Hansoh, Lycera, MedImmune, Merck, Pfizer, Phosplatin, Roche/Genentech, Seattle Genetics, Symphogen, Takeda. F. Janku: Research grant / Funding (self): Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Upsher-Smith Laboratories; Advisory / Consultancy: Guardant Health, IFM Therapeutics, Synlogic, Deciphera; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Trovagene; Advisory / Consultancy: Immunomet. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Merck, BMS, Lilly, Astellas, Gritstone, Taiho, Five Prime, Genentech Roche, Foundation Medicine, Guardant Health, Tempus. H.C. Chung: Honoraria (self): Merck-Serono, Lilly, Foundation Medicine; Advisory / Consultancy: Taiho, Celltrion, MSD, Lilly,Quintiles, BMS, Merck-Serono; Research grant / Funding (institution): Lilly, GSK, MSD, Merck-Serono, BMS-ONO, Taiho. A. Dowlati: Advisory / Consultancy: Seattle genetics, Takeda, AbbVie; Research grant / Funding (institution): Takeda, Taiho, Roche, EMD Serono, Bayer, Tesaro, Regeneron, Amgen, Mirati, BMS. K.S. Rohrberg: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Loxo Oncology, Orion Pharma, Pfizer, PUMA, Cantargia, Genmab, Novartis, Incyte, Bayer, AstraZeneca, Alligator, Merck, BMS; Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (institution): Symphogen. T.T. Poulsen: Full / Part-time employment: Symphogen A/S. H. Rudbæk: Full / Part-time employment: Symphogen A/S. L. Alifrangis: Full / Part-time employment: Symphogen A/S. R.P. Dalal: Full / Part-time employment: Symphogen A/S. All other authors have declared no conflicts of interest.</description><identifier>ISSN: 0923-7534</identifier><identifier>EISSN: 1569-8041</identifier><identifier>DOI: 10.1093/annonc/mdz260.012</identifier><language>eng</language><publisher>Oxford University Press</publisher><ispartof>Annals of oncology, 2019-10, Vol.30 (Supplement_5)</ispartof><rights>European Society for Medical Oncology 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com. 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids></links><search><creatorcontrib>Camidge, D R</creatorcontrib><creatorcontrib>Janku, F</creatorcontrib><creatorcontrib>Bueno, A Martinez</creatorcontrib><creatorcontrib>Catenacci, D V</creatorcontrib><creatorcontrib>Lee, J</creatorcontrib><creatorcontrib>Lee, S-H</creatorcontrib><creatorcontrib>Chung, H C</creatorcontrib><creatorcontrib>Dowlati, A</creatorcontrib><creatorcontrib>Rohrberg, K S</creatorcontrib><creatorcontrib>Felip Font, E</creatorcontrib><creatorcontrib>Garralda, E</creatorcontrib><creatorcontrib>Kang, Y-K</creatorcontrib><creatorcontrib>Moon, Y W</creatorcontrib><creatorcontrib>López Criado, M</creatorcontrib><creatorcontrib>Chiu, C-F</creatorcontrib><creatorcontrib>Poulsen, T T</creatorcontrib><creatorcontrib>Rudbæk, H</creatorcontrib><creatorcontrib>Alifrangis, L</creatorcontrib><creatorcontrib>Dalal, R P</creatorcontrib><creatorcontrib>Patnaik, A</creatorcontrib><title>1490PDA phase Ia/IIa trial of Sym015, a MET antibody mixture, in patients with advanced solid tumours</title><title>Annals of oncology</title><description>Abstract
Background
MET gene amplification/mutation is implicated in oncogenesis of many tumor types. Sym015 is a recombinant antibody (Ab) mixture containing 2 humanized Abs binding non-overlapping epitopes on MET which has superior preclinical activity compared to other MET Abs. Here we present interim results from the First in Human study of Sym015.
Methods
In part 1 dose escalation, Sym015 was evaluated on every 2-week (q2w) schedule at 6/12/18/24 mg/kg doses in late line advanced solid tumor patients (pts). Based on PK/PD assessment, 18 mg/kg loading dose followed by 12 mg/kg q2w was selected as RP2D. The on-going Part 2 Dose expansion enrolls pts with MET amplification (METAmp >5 MET copies by Next Generation Sequencing (NGS) or FISH MET/CEP7 ratio >2.2 updated to ≥ 3.0) and/or MET exon 14 deletion (METEx14Δ) positive tumors. Central FISH confirmation of tumor MET status and longitudinal circulating tumor (ct)DNA profiling is performed.
Results
By April 2019, 51 pts (median age 61 yrs) have been treated, 12 pts in Part 1 and 39 pts in Part 2, the majority are non small cell lung cancer (NSCLC; 14 pts; 6 METAmp,7 METEx14Δ, 1 both) and gastric cancer (GC; 12 METAmp pts). Treatment-related adverse events (TRAE) occurred overall in 41,2%; TRAE ≥ gr3 in 9,8% (edema, colitis, septic shock, hypoalbuminemia, hypophosphatemia, increased amylase). No pts discontinued or died due to TRAE. The most common TRAE of ≥ 5% were fatigue 15.7%, peripheral edema 7,8%, nausea, decreased appetite, pruritus and abdominal pain reported by 5.9% of pts each. The table shows preliminary efficacy in NSCLC patients. Sym015 PK was slightly non-linear, with a dose-dependent t½ of 7-10 days for the first dose. 83% METAmp concordance (10/12 samples) between tumor and blood was observed.
Table:1490PDNSCLC PtMET Status (Local Assessment)Best Response (Best % Change From Baseline)Previous MET TKI therapyDuration of Response (weeks)1METAmp NGS 6.8 CopiesPR (-53%)No802METAmp NGS >5 CopiesSD (-29%)No9, Ongoing3METAmp NGS >5 CopiesSD (+3%)No9, Ongoing4METEx14ΔSD (-28%)No7, Ongoing5METAmp FISH MET/ CEP7:4.9SD (+6%)No116METEx14ΔSD (-4%)Yes87METEx14ΔSD (-21%)Yes158METEx14ΔSD (-20%)Yes89METAmp SISH MET/ CEP7: 15.2PendingNoOngoing10METEx14ΔPendingYesOngoing11METEx14Δ + METAmpPendingPendingOngoing12METEx14ΔPendingNoOngoing13METEx14ΔPendingNoOngoing14METEx14ΔNot EvaluableYesNot Evaluable
Conclusions
Sym015 was well tolerated with early evidence of antitumor activity. Predictive biomarker analysis is underway. The study continues to enroll NSCLC patients with METAmp and/or METEx14Δ. MET screening in blood seems feasible and may be included in future trials.
Clinical trial identification
NCT02648724.
Legal entity responsible for the study
Symphogen A/S.
Funding
Symphogen A/S.
Disclosure
D.R. Camidge: Advisory / Consultancy: 2019: Takeda, CBT Pharmaceuticals, Daiichi-Sankyo (ILD adjudication committee), G1 Therapeutics (DSMB), Bio-Thera (DSMB), Blueprint; Advisory / Consultancy: 2018: AstraZeneca, Takeda, Arrys/Kyn, Regeneron, Hengrui, G1 Therapeutics (DSMB), Daiichi Sankyo (ILD adjudication committee), Hansoh (SRC), Bio-Thera (DSMB), Ribon, BMS, Blueprint, Roche/Genentech, Inivata; Advisory / Consultancy: 2017: Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Takeda, Ignyta, Daiichi Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med; Research grant / Funding (self), Research grant / Funding (institution): 2017: Takeda Investigator-initiated Trial; Research grant / Funding (self), Research grant / Funding (institution), Company Sponsored Trials at Institution: 2018/9: AbbVie, AstraZeneca, BMS, Hansoh, Lycera, MedImmune, Merck, Pfizer, Phosplatin, Roche/Genentech, Seattle Genetics, Symphogen, Takeda. F. Janku: Research grant / Funding (self): Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Upsher-Smith Laboratories; Advisory / Consultancy: Guardant Health, IFM Therapeutics, Synlogic, Deciphera; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Trovagene; Advisory / Consultancy: Immunomet. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Merck, BMS, Lilly, Astellas, Gritstone, Taiho, Five Prime, Genentech Roche, Foundation Medicine, Guardant Health, Tempus. H.C. Chung: Honoraria (self): Merck-Serono, Lilly, Foundation Medicine; Advisory / Consultancy: Taiho, Celltrion, MSD, Lilly,Quintiles, BMS, Merck-Serono; Research grant / Funding (institution): Lilly, GSK, MSD, Merck-Serono, BMS-ONO, Taiho. A. Dowlati: Advisory / Consultancy: Seattle genetics, Takeda, AbbVie; Research grant / Funding (institution): Takeda, Taiho, Roche, EMD Serono, Bayer, Tesaro, Regeneron, Amgen, Mirati, BMS. K.S. Rohrberg: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Loxo Oncology, Orion Pharma, Pfizer, PUMA, Cantargia, Genmab, Novartis, Incyte, Bayer, AstraZeneca, Alligator, Merck, BMS; Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (institution): Symphogen. T.T. Poulsen: Full / Part-time employment: Symphogen A/S. H. Rudbæk: Full / Part-time employment: Symphogen A/S. L. Alifrangis: Full / Part-time employment: Symphogen A/S. R.P. Dalal: Full / Part-time employment: Symphogen A/S. All other authors have declared no conflicts of interest.</description><issn>0923-7534</issn><issn>1569-8041</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid/><recordid>eNqVz0tOwzAUQFELgUT4LIDZW0DSPOcHHiIoIoNKSHRuPWpXNYrtyHaAdPUFlQ10dCd3chi747jgKOqSnPNuU1q1rzpcIK_OWMbbThQP2PBzlqGo6uK-rZtLdhXjJyJ2ohIZ07wR-Pb8COOOooaeyr4nSMHQAH4L77NF3uZAsFqugVwyH17NYM1PmoLOwTgYKRntUoRvk3ZA6ovcRiuIfjAK0mT9FOINu9jSEPXtf69Z_rJcP70WfhrlGIylMEuO8o8ijxR5pMhfSn3ifgDDnlIX</recordid><startdate>20191001</startdate><enddate>20191001</enddate><creator>Camidge, D R</creator><creator>Janku, F</creator><creator>Bueno, A Martinez</creator><creator>Catenacci, D V</creator><creator>Lee, J</creator><creator>Lee, S-H</creator><creator>Chung, H C</creator><creator>Dowlati, A</creator><creator>Rohrberg, K S</creator><creator>Felip Font, E</creator><creator>Garralda, E</creator><creator>Kang, Y-K</creator><creator>Moon, Y W</creator><creator>López Criado, M</creator><creator>Chiu, C-F</creator><creator>Poulsen, T T</creator><creator>Rudbæk, H</creator><creator>Alifrangis, L</creator><creator>Dalal, R P</creator><creator>Patnaik, A</creator><general>Oxford University Press</general><scope/></search><sort><creationdate>20191001</creationdate><title>1490PDA phase Ia/IIa trial of Sym015, a MET antibody mixture, in patients with advanced solid tumours</title><author>Camidge, D R ; Janku, F ; Bueno, A Martinez ; Catenacci, D V ; Lee, J ; Lee, S-H ; Chung, H C ; Dowlati, A ; Rohrberg, K S ; Felip Font, E ; Garralda, E ; Kang, Y-K ; Moon, Y W ; López Criado, M ; Chiu, C-F ; Poulsen, T T ; Rudbæk, H ; Alifrangis, L ; Dalal, R P ; Patnaik, A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-oup_primary_10_1093_annonc_mdz260_0123</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Camidge, D R</creatorcontrib><creatorcontrib>Janku, F</creatorcontrib><creatorcontrib>Bueno, A Martinez</creatorcontrib><creatorcontrib>Catenacci, D V</creatorcontrib><creatorcontrib>Lee, J</creatorcontrib><creatorcontrib>Lee, S-H</creatorcontrib><creatorcontrib>Chung, H C</creatorcontrib><creatorcontrib>Dowlati, A</creatorcontrib><creatorcontrib>Rohrberg, K S</creatorcontrib><creatorcontrib>Felip Font, E</creatorcontrib><creatorcontrib>Garralda, E</creatorcontrib><creatorcontrib>Kang, Y-K</creatorcontrib><creatorcontrib>Moon, Y W</creatorcontrib><creatorcontrib>López Criado, M</creatorcontrib><creatorcontrib>Chiu, C-F</creatorcontrib><creatorcontrib>Poulsen, T T</creatorcontrib><creatorcontrib>Rudbæk, H</creatorcontrib><creatorcontrib>Alifrangis, L</creatorcontrib><creatorcontrib>Dalal, R P</creatorcontrib><creatorcontrib>Patnaik, A</creatorcontrib><jtitle>Annals of oncology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Camidge, D R</au><au>Janku, F</au><au>Bueno, A Martinez</au><au>Catenacci, D V</au><au>Lee, J</au><au>Lee, S-H</au><au>Chung, H C</au><au>Dowlati, A</au><au>Rohrberg, K S</au><au>Felip Font, E</au><au>Garralda, E</au><au>Kang, Y-K</au><au>Moon, Y W</au><au>López Criado, M</au><au>Chiu, C-F</au><au>Poulsen, T T</au><au>Rudbæk, H</au><au>Alifrangis, L</au><au>Dalal, R P</au><au>Patnaik, A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>1490PDA phase Ia/IIa trial of Sym015, a MET antibody mixture, in patients with advanced solid tumours</atitle><jtitle>Annals of oncology</jtitle><date>2019-10-01</date><risdate>2019</risdate><volume>30</volume><issue>Supplement_5</issue><issn>0923-7534</issn><eissn>1569-8041</eissn><abstract>Abstract
Background
MET gene amplification/mutation is implicated in oncogenesis of many tumor types. Sym015 is a recombinant antibody (Ab) mixture containing 2 humanized Abs binding non-overlapping epitopes on MET which has superior preclinical activity compared to other MET Abs. Here we present interim results from the First in Human study of Sym015.
Methods
In part 1 dose escalation, Sym015 was evaluated on every 2-week (q2w) schedule at 6/12/18/24 mg/kg doses in late line advanced solid tumor patients (pts). Based on PK/PD assessment, 18 mg/kg loading dose followed by 12 mg/kg q2w was selected as RP2D. The on-going Part 2 Dose expansion enrolls pts with MET amplification (METAmp >5 MET copies by Next Generation Sequencing (NGS) or FISH MET/CEP7 ratio >2.2 updated to ≥ 3.0) and/or MET exon 14 deletion (METEx14Δ) positive tumors. Central FISH confirmation of tumor MET status and longitudinal circulating tumor (ct)DNA profiling is performed.
Results
By April 2019, 51 pts (median age 61 yrs) have been treated, 12 pts in Part 1 and 39 pts in Part 2, the majority are non small cell lung cancer (NSCLC; 14 pts; 6 METAmp,7 METEx14Δ, 1 both) and gastric cancer (GC; 12 METAmp pts). Treatment-related adverse events (TRAE) occurred overall in 41,2%; TRAE ≥ gr3 in 9,8% (edema, colitis, septic shock, hypoalbuminemia, hypophosphatemia, increased amylase). No pts discontinued or died due to TRAE. The most common TRAE of ≥ 5% were fatigue 15.7%, peripheral edema 7,8%, nausea, decreased appetite, pruritus and abdominal pain reported by 5.9% of pts each. The table shows preliminary efficacy in NSCLC patients. Sym015 PK was slightly non-linear, with a dose-dependent t½ of 7-10 days for the first dose. 83% METAmp concordance (10/12 samples) between tumor and blood was observed.
Table:1490PDNSCLC PtMET Status (Local Assessment)Best Response (Best % Change From Baseline)Previous MET TKI therapyDuration of Response (weeks)1METAmp NGS 6.8 CopiesPR (-53%)No802METAmp NGS >5 CopiesSD (-29%)No9, Ongoing3METAmp NGS >5 CopiesSD (+3%)No9, Ongoing4METEx14ΔSD (-28%)No7, Ongoing5METAmp FISH MET/ CEP7:4.9SD (+6%)No116METEx14ΔSD (-4%)Yes87METEx14ΔSD (-21%)Yes158METEx14ΔSD (-20%)Yes89METAmp SISH MET/ CEP7: 15.2PendingNoOngoing10METEx14ΔPendingYesOngoing11METEx14Δ + METAmpPendingPendingOngoing12METEx14ΔPendingNoOngoing13METEx14ΔPendingNoOngoing14METEx14ΔNot EvaluableYesNot Evaluable
Conclusions
Sym015 was well tolerated with early evidence of antitumor activity. Predictive biomarker analysis is underway. The study continues to enroll NSCLC patients with METAmp and/or METEx14Δ. MET screening in blood seems feasible and may be included in future trials.
Clinical trial identification
NCT02648724.
Legal entity responsible for the study
Symphogen A/S.
Funding
Symphogen A/S.
Disclosure
D.R. Camidge: Advisory / Consultancy: 2019: Takeda, CBT Pharmaceuticals, Daiichi-Sankyo (ILD adjudication committee), G1 Therapeutics (DSMB), Bio-Thera (DSMB), Blueprint; Advisory / Consultancy: 2018: AstraZeneca, Takeda, Arrys/Kyn, Regeneron, Hengrui, G1 Therapeutics (DSMB), Daiichi Sankyo (ILD adjudication committee), Hansoh (SRC), Bio-Thera (DSMB), Ribon, BMS, Blueprint, Roche/Genentech, Inivata; Advisory / Consultancy: 2017: Genoptix, G1 Therapeutics (DSMB), Mersana Therapeutics, Roche/Genentech, Takeda, Ignyta, Daiichi Sankyo (ILD adjudication committee), Hansoh SRC, Bio-Thera DSMB, Lycera, Revolution Med; Research grant / Funding (self), Research grant / Funding (institution): 2017: Takeda Investigator-initiated Trial; Research grant / Funding (self), Research grant / Funding (institution), Company Sponsored Trials at Institution: 2018/9: AbbVie, AstraZeneca, BMS, Hansoh, Lycera, MedImmune, Merck, Pfizer, Phosplatin, Roche/Genentech, Seattle Genetics, Symphogen, Takeda. F. Janku: Research grant / Funding (self): Novartis, Genentech, BioMed Valley Discoveries, Astellas, Agios, Plexxikon, Deciphera, Piqur, Symphogen, Bristol-Myers Squibb, Asana, Upsher-Smith Laboratories; Advisory / Consultancy: Guardant Health, IFM Therapeutics, Synlogic, Deciphera; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Trovagene; Advisory / Consultancy: Immunomet. D.V. Catenacci: Honoraria (self), Advisory / Consultancy: Merck, BMS, Lilly, Astellas, Gritstone, Taiho, Five Prime, Genentech Roche, Foundation Medicine, Guardant Health, Tempus. H.C. Chung: Honoraria (self): Merck-Serono, Lilly, Foundation Medicine; Advisory / Consultancy: Taiho, Celltrion, MSD, Lilly,Quintiles, BMS, Merck-Serono; Research grant / Funding (institution): Lilly, GSK, MSD, Merck-Serono, BMS-ONO, Taiho. A. Dowlati: Advisory / Consultancy: Seattle genetics, Takeda, AbbVie; Research grant / Funding (institution): Takeda, Taiho, Roche, EMD Serono, Bayer, Tesaro, Regeneron, Amgen, Mirati, BMS. K.S. Rohrberg: Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Loxo Oncology, Orion Pharma, Pfizer, PUMA, Cantargia, Genmab, Novartis, Incyte, Bayer, AstraZeneca, Alligator, Merck, BMS; Travel / Accommodation / Expenses: Sanofi; Research grant / Funding (institution): Symphogen. T.T. Poulsen: Full / Part-time employment: Symphogen A/S. H. Rudbæk: Full / Part-time employment: Symphogen A/S. L. Alifrangis: Full / Part-time employment: Symphogen A/S. R.P. Dalal: Full / Part-time employment: Symphogen A/S. All other authors have declared no conflicts of interest.</abstract><pub>Oxford University Press</pub><doi>10.1093/annonc/mdz260.012</doi></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0923-7534 |
| ispartof | Annals of oncology, 2019-10, Vol.30 (Supplement_5) |
| issn | 0923-7534 1569-8041 |
| language | eng |
| recordid | cdi_oup_primary_10_1093_annonc_mdz260_012 |
| source | Alma/SFX Local Collection; EZB Electronic Journals Library |
| title | 1490PDA phase Ia/IIa trial of Sym015, a MET antibody mixture, in patients with advanced solid tumours |
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