A PHASE IIA STUDY OF TISOTUMAB VEDOTIN (HUMAX -TF-ADC) IN PATIENTS WITH RELAPSED, RECURRENT AND/OR METASTATIC CERVICAL CANCER

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1 A PHASE IIA STUDY OF TISOTUMAB VEDOTIN (HUMAX -TF-ADC) IN PATIENTS WITH RELAPSED, RECURRENT AND/OR METASTATIC CERVICAL CANCER Vergote I, Concin N, Den E, Lssen U, Drew Y, Mchiels JP, Nielsen D, Arkenu T, Forster M, Jones R, Slomovitz B, Spicer J, Johnson M, Cornez N, Gennigens C, Fulton B, Bsse L, Lisby S, Colemn RL, Hong DS 1

2 DISCLOSURES Disclosures include Disclosures Lind Bsse Is former employee of Genmb Robert Colemn Served on the scientific dvisory committee for Genmb Emm Den Hs subsequently tken up employment with AstrZenec Dvid Hong Reserch/Grnt Funding: Byer, Lilly, Genentech, LOXO, Pfizer, Amgen, Mirti, Ignyt, Merck, Diichi-Snkyo, Eisi Trvel, Accommodtions, Expenses: MiRNA, LOXO Consulting or Advisory Role: Byer, Bxter, Guidepoint Globl Other ownership interests: Oncoresponse (founder) Steen Lisby Is former employee of Genmb Jen-Pscl Mchiels Advisory bord: MSD, AstrZenec, Debio, Nnobiotix, Innte Ignce Vergote Grnts: Novrtis, Roche, Jnssen Reserch/Grnt Funding: Genmb Consulting or Advisory Role: Genmb The remining uthors hd no conflicts of interest to disclose This study ws sponsored by Genmb A/S 2

3 CURRENT TREATMENT PARADIGM IN RECURRENT/ADVANCED CERVICAL CANCER First-line stndrd of cre is pclitxel-pltinum in combintion with bevcizumb 1-3 Second-line therpies hve limited response rtes 1 Agent Overll Response Rte (%) 1 Agent Overll Response Rte (%) 1 Bevcizumb 11% Pemetrexed 14%-15% Topotecn 13%-19% Irinotecn 21% Vinorelbine 14% Lptinib 5% Gemcitbine 5% Pzopnib 9% Albumin-bound pclitxel 29% Pegylted liposoml Docetxel 9% doxorubicin 11% There is no stndrd of cre in second-line cervicl cncer, creting n unmet medicl need for new tretments 1 Dose dense regimen. 1. Mrth C et l. Ann Oncol. 2017;28(suppl 4):iv72-iv Tewri KS et l. N Engl J Med. 2014;370(8): Koh WJ et l. J Ntl Compr Cnc Netw. 2015;13(4):

4 TISOTUMAB VEDOTIN MECHANISM OF ACTION Mechnism of ction 1,2 Tisotumb vedotin is n Antibody-Drug Conjugte (ADC) composed of humn mab specific for Tissue Fctor (TF), proteseclevble linker, nd the microtubule disrupting gent MMAE 1,,b TF is trnsmembrne protein tht is the min physiologicl inititor of cogultion nd is involved in ngiogenesis, cell dhesion, motility, nd cell survivl 3 TF is berrntly expressed in brod rnge of solid tumours, including cervicl cncer, nd is ssocited with poor prognosis 4,5 1. Binding to TF 2. Internliztion of tisotumb vedotin 3. Intrcellulr trfficking to the lysosomes 4. Enzymtic degrdtion of tisotumb vedotin, intrcellulr relese of MMAE 5. MMAE induces cell deth by microtubule disruption 6. Relese of MMAE in tumour ADC=ntibody-drug conjugte; mab=monoclonl ntibody; MMAE=monomethyl uristtin E. microenvironment induces bystnder Tissue fctor is known s TF, CD142, nd thromboplstin. killing of neighbouring cncer cells b MMAE-bsed ADC technology ws licensed from Settle Genetics, Inc., in license nd collbortion greement. 1. Breij EC et l. Cncer Res. 2014;74(4): De Goeij BE et l. Mol Cncer Ther. 2015;14(5): Chu AJ. Int J Inflm. 2011;2011. doi: /2011/ Förster Y et l. Clin Chim Act. 2006;364(1-2): Cocco E et l. BMC Cncer. 2011;11:263. 4

5 ANTI-TUMOUR ACTIVITY IN A CERVICAL SQUAMOUS CELL CARCINOMA PDX MODEL: EFFICACY IN A TAXANE-RELAPSED SETTING TF expression in PDX model of cervicl squmous cell crcinom α-tf α-cytokertin Tumour size (mm 3 ) Primry tretment b Dys fter first tretment Tisotumb vedotin Isotype ctrl ADC Isotype ctrl lgg1 Pclitxel Tretment pclitxel 20 mg/kg Tretment ADC/lgG 4 mg/kg Re-tretment fter pclitxel (individul mice) c Curves represent individul mice treted with tisotumb vedotin Despite heterogeneous TF expression, tisotumb vedotin induced robust tumour regression, event fter pclitxel, in cervicl cncer PDX models ADC=ntibody-drug conjugte; IgG=immunoglobulin G; PDX=ptient-derived xenogrft; TF=tissue fctor. A cervicl squmous cell crcinom PDX model ws estblished by subcutneous implnttion of ptient tumour frgments into mice. Immunohistochemistry nlysis of PDX model using the TF humn monoclonl ntibody nd humn cytokertin, which identifies humn tumour cells. b Dtpoints re the verge tumour size per group, with 8 mice per group. c Curves nd dt points represent tumour size in individul mice. Ptient-derived cervicl squmous cell crcinom cells were implnted in mice, nd when the tumours reched size of mm 3, mice were treted with 20 mg/kg of pclitxel t the indicted time points. Upon tumour outgrowth following pclitxel discontinution, mice were treted with 2 doses of tisotumb vedotin 4 mg/kg t the indicted time points. Breij EC et l. Cncer Res. 2014;74(4): Tumour size (mm 3 ) Dys fter first tretment 5

6 GEN701 IS THE FIRST-IN-HUMAN STUDY OF TISOTUMAB VEDOTIN Key inclusion criteri: Ptients with relpsed, dvnced, nd/or metsttic cncer who hve filed vilble stndrd therpy Mesurble disese Key exclusion criteri: Abnorml cogultion prmeters t bseline Ongoing mjor bleeding Presence of CTCAE grde 2 peripherl neuropthy Prt 1: Dose escltion 3+3 dose-escltion design Dose rnge tested: mg/kg IV q3w Ptients enrolled included those with the following tumour types (N=27): Gynecologic (ovrin, cervicl, nd endometril) Prostte Bldder Oesophgel NSCLC SCCHN c Primry endpoint: Sfety nd tolerbility Key secondry endpoints: Anti-tumour ctivity Prt 2: Expnsion cohort Ongoing expnsion cohort Dose selected: 2.0 mg/kg IV q3w Cervicl (n=34) b Ovrin (n=36) b Prostte (n=18) Bldder (n=15) Oesophgel (n=15) Endometril (n=14) NSCLC (n=15) CTCAE=Common Terminology Criteri for Adverse Events; IV=intrvenous; NSCLC=non smll cell lung cncer; SCCHN=squmous cell crcinom of the hed nd neck. Subjects were enrolled into cohorts t incresing dose levels of tisotumb vedotin in 21-dy tretment cycles. b In phse 2, ovrin nd cervicl cohorts were expnded to pproximtely 30 ptients bsed on preliminry efficcy observed in the first 14 ptients enrolled. c The SCCHN cohort ws closed by protocol mendment 4 due to n event of phryngel tumour hemorrhge with ftl outcome. The event ws deemed to be most likely relted to the disese itself. Clinicltrils.gov. Accessed August 7,

7 PATIENT DISPOSITION IN THE CERVICAL CANCER COHORT Treted N=34 Ongoing on tretment 7 Withdrwn from tril 27 Due to dverse event 5 Due to progressive disese 16 Other b 6 Died 0 Including ptients who experienced peripherl neuropthy (n=2), peripherl neuropthy nd rthrlgi (n=1), peripherl neuropthy nd reduced visul cuity (n=1), nd conjunctivitis (n=1). b Including ptients who withdrew due to ptient choice (n=1), investigtor judgement (n=1), non-rdiogrphic clinicl progression (n=1), nd other resons (n=3). Dt cutoff dte July 24,

8 BASELINE PATIENT CHARACTERISTICS IN CERVICAL CANCER COHORT Cervicl (N=34) Age (medin, rnge), y 43 (21-73) ECOG score, no (%) 0 7 (21%) 1 26 (76%) Missing 1 (3%) Cncer type, no (%) Adenocrcinom 15 (44%) Adeno-squmous 3 (9%) Squmous 15 (44%) Missing/TBD 1 (3%) Previous lines of systemic tretments, no (%) 0 3 (9%) 1 13 (38%) 2 11 (32%) 3 4 (12%) Cervicl (N=34) Prior tretments, % b Pltinum 91% Txne 91% Bevcizumb c 71% GOG 240 regimen d 68% 1 pltinum doublet 17% Prior rdiotherpy e 74% 4 3 (9%) ECOG=Estern Coopertive Oncology Group; TBD=to be determined. Ptients progressed on therpy dministered for tretment of loclly dvnced disese. b Missing dt from 1 ptient. c Including bevcizumb dministered s combintion therpy s either pltinum/bevcizumb/pclitxel or topotecn/bevcizumb/pclitxel. d Combintion therpy with cispltin, pclitxel, nd bevcizumb. e Externl bem rdiotherpy dministered to the cervix or surrounding tissues. Dt cutoff dte July 24,

9 ADVERSE EVENTS ( 15% OF PATIENTS) IN CERVICAL CANCER COHORT 100 N=34 Ptients, % % 47% 47% 47% 44% 35% 35% 32% 32% 29% 29% Any grde Grde % 9% 9% 3% 15% 3% 21% 21% 18% 18% 18% 18% 18% 15% 15% 9% 6% 6% 6% 6% ALT=lnine minotrnsferse. Adverse events with events of ny grde occurring in 15% of ptients or of grde 3 in 2 or more ptients. b Grde 2 conjunctivitis ws reported in 32% of ptients. Dt cutoff dte July 24,

10 ADVERSE EVENTS OF SPECIAL INTEREST IN CERVICAL CANCER COHORT AEOSI Term N=34 Any Grde, n (%) Grde 3, n (%) Oculr (ny) 18 (53%) 1 (3%) Conjunctivitis 17 (50%) 1 (3%) Conjunctivitis scr 1 (3%) 0 Conjunctivitis virl 1 (3%) 0 Conjunctivl ulcertion 0 0 Kertitis 1 (3%) 0 Ulcertive kertitis 2 (6%) 0 Symblephron 0 0 Neuropthy (ny) 12 (35%) 2 (6%) AESOI=dverse events of specil interest. Most ptients who experienced other events thn conjunctivitis lso experienced conjunctivitis. Dt cutoff dte July 24,

11 Ptients, % MITIGATION MEASURES SUBSTANTIALLY REDUCED CONJUNCTIVAL TOXICITY IN CERVICAL CANCER COHORT 73% Ptients experiencing conjunctivitis 50% 32% 3% 5% Any grde Grde 3 Prior to Mitigtion (n=15) All Ptients (N=34) After Mitigtion (n=19) Risk mitigtion mesures involved prophylctic steroid, lubricting eye drops, nd cooling eye msks worn during tretment infusion, s well s stricter dose djustment guidnce Mitigtion mesures substntilly reduced the rtes of conjunctivl toxicity Dt cutoff dte July 24,

12 32% OF PATIENTS WITH RECURRENT/ADVANCED CERVICAL CANCER ACHIEVED RESPONSE WITH TISOTUMAB VEDOTIN Best Percent Chnge From Bseline, % PR N=34 b b b b Chnge t first scn Mximum reduction Confirmed response 50% (17 of 34 ptients; 95% CI, 35%-65%) chieved clinicl benefit fter 12 weeks (DCR) c,d 32% (11 of 34 ptients; 95% CI, 17%-50%) chieved response (ORR) d 8 PR, confirmed 3 PR, unconfirmed e CI=confidence intervl; CR=complete response; CT=computed tomogrphy; DCR=disese control rte; ORR=overll response rte; PD=progressive disese; PR=prtil response; RECIST=Response Evlution Criteri in Solid Tumors; SD=stble disese. Two ptients were withdrwn prior to CT scn, nd so re not represented in the grph. b PD due to new lesion t sme scn. c Clinicl benefit ws defined s the DCR rte, the proportion of ptients who chieved CR, PR, or SD fter 12 weeks. d Response ws s ssessed by investigtors using stndrd RECIST 1.1 criteri. e One of which is still ongoing. Dt cutoff dte July 24,

13 RESPONSES WITH TISOTUMAB VEDOTIN BY PRIOR LINES IN CERVICAL CANCER COHORT Ptients Achieving Response, % N=34 46% 33% 36% 0% b (n=3) (n=13) (n=11) (n=7) c Prior Systemic Therpies, no. Including confirmed nd unconfirmed responses. b Ptients were refrctory to therpy dministered for erly stge disese. c Ptients received either 3 (n=4) or 4 (n=3) prior systemic therpies. Dt cutoff dte July 24,

14 DURATION OF RESPONSE WITH TISOTUMAB VEDOTIN IN CERVICAL CANCER COHORT Individul Ptients N=34 NE SD PR PD Ongoing PD Discontinution, no PD Medin DoR of confirmed response is 8.3 months (95% CI; 2.1, -) nd 5.3 months for confirmed nd unconfirmed responses (95% CI; 1.5, 10.0) b 7 ptients re ongoing c DoR=durtion of response; NE=not evluted; PD=progressive disese; PFS=progression-free survivl; PR=prtil response; SD=stble disese. Ptient withdrwn. b 4 responders hve progressed s of the dt cutoff of July 24, 2017 nd 4 hve been withdrwn becuse of other resons nd re thus censored for DoR. c Estimted medin PFS ws 6.4 months. Dt cutoff dte July 24, Months 14

15 TISOTUMAB VEDOTIN DEMONSTRATED ROBUST EFFICACY AND A MANAGEABLE SAFETY PROFILE IN THE CERVICAL CANCER EXPANSION COHORT Tisotumb vedotin is n ADC composed of humn mab specific for TF, protese clevble linker, nd the microtubule disrupting gent MMAE The sfety profile of tisotumb vedotin in recurrent cervicl cncer ws generlly consistent with other MMAE-bsed ADCs Conjunctivitis ws the most common TEAE The mitigtion mesures substntilly reduced conjunctivl toxicity ORR (confirmed + unconfirmed responders) is 32% nd medin DoR (confirmed responders) is 8.3 months The substntil efficcy nd the mngeble sfety wrrnts further development of tisotumb vedotin in previously treted recurrent/dvnced cervicl cncer ptients ADC=ntibody-drug conjugte; DoR=durtion of response; mab=monoclonl ntibody; MMAE=monomethyl uristtin E; ORR=overll response rte; TEAE=tretment-emergent dverse event; TF=tissue fctor. Dt cutoff dte July 24,

16 ACKNOWLEDGEMENTS The uthors would like to thnk the ptients, investigtors, nd study tems who were involved in the GEN701 study This presenttion ws drfted by Cindy Puente, PhD, Dvid Bonnyy, PhD, nd Sndi Lusk on behlf of Ogilvy CommonHelth, funded by Genmb A/S, with the ongoing guidnce of the primry uthor, Dr Vergote. The finl presenttion ws pproved by ll the uthors. 16