Why was HOPE 205 a Positive After Years of Negative Studies?

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2 Why was HOPE 205 a Positive After Years of Negative Studies? Prof. Dr. med. Viktor Grünwald Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation

3 Why do we pursue combinations? PRO: Better response rate/efficacy Better survival CON: Needs to balance toxicity Needs to beat sequential treatment

4 More of the same or is there a splendid TKI? Activity as biochemical assays (IC50 [nmol/l]) FGF- R1 PDGF- R PDGF- R VEGF- R1 (Flt-1) VEGF-R2 (Flk-1, Kdr) VEGF-R3 (Flt-4) Sunitinib Sorafenib Pazopanib Axitinib Nintedanib Dovitinib Tivozanib Lenvatinib Mendel DB, et al. Clin Cancer Res Jan;9(1): LaMontagne, et al. Angiogenis. 2009;12(3): Kumar R, Mol Cancer Ther Jul;6(7): Gilbert JA, Pancreas Apr;42(3): Kitigawa D, et al. Genes Cells Feb;18(2): Eisen T et al, ASCO 2013, #4506. Grünwald & Merseburger. (2013). EJC, 49(11),

5 Nintedanib also inhibits FGFR, but no additional clinical benefit Eisen et al. BJC. DOI: /bjc

6 Combinations in 1 st line no winning team in sight Flaherty et al. JCO 2015, 33 (21):

7 Sunitinib + sirolimus require dose-compromise in phase I 40% DR: dose reduction. ED: early discontinuation Li et al. (2016). Cancer Chemother Pharmacol,

8 N=4 1 toxic death PR: 1/4 N=27 ORR: 23% Full dose possible 74% after prior TKI

9 What made lenvatinib a target for combinations? Phase Ib (NCT ) Randomized Phase II (NCT )

10 MTD Cohort 1 LEN 12 mg + EVE 5 mg (n = 7) Cohort 2 LEN 18 mg + EVE 5 mg (n = 11) Cohort 3 LEN 24 mg + EVE 5 mg (n = 2) Total (N=20) Prior Rx, median 3 (1-4) 1 (0-4) 0.5 (0-1) 1.5 (0-4) Prior TKI, n (%) 7 (100) 11 (100) 2 (100) 20 (100) Prior TKI + mtori 4 (57) 3 (27) 0 (0) 7 (35) PR, n (%) 2 (29) 4 (36) 0 (0) 6 (30) SD, n (%) 4 (57) 5 (46) 1 (50) 10 (50) PD, n (%) 0 (0) 1 (9) 0 (0) 1 (5) NE, n (%) 1 (14) 1 (9) 1 (50) 3 (15) DLTs: abdominal pain III Nausea/vomitinig III Failure to receive 75% of planned dose (multiple AEs) LEN: lenvatinib. EVE: everolimus Molina et al. (2014). Cancer Chemother Pharmacol, 73(1),

11 Tumor shrinkage Phase 1b PFS: 10.9 mo. Molina et al. (2014). Cancer Chemother Pharmacol, 73(1),

12 Tolerability Lenvatinib: Reduction 10/20 (50%). Interruption: 14/20 (70%) Everolimus: no reduction. Interruption: 9/20 (45%) Molina et al. (2014). Cancer Chemother Pharmacol, 73(1),

13 Randomized Phase II N=153 Everolimus 10 mg OD n=50 ccrcc PD on VEGFi (or within 9 mo. of last Rx) 1 prior line ECOG: 0-1 no CNS mets. Strata: Hb, Ca Lenvatinib 24 mg OD Lenvatinib 18 mg + Everolimus 5 mg OD n=52 n=51 70% power for 50% improvement in PFS (HR 0.67; 5 vs 7.5 mo.; =0.15) between everolimus and experimental arm(s) 90 events in 150 pts events for arms of interest Motzer et al. (2015) Lancet Oncology, 16(15),

14 Better efficacy with the combination 14.6 mo. ( ) 5.5 mo. ( ) 7.4 mo. ( ) PFS events, n (%) 26 (51) 38 (73) 37 (74) Motzer et al. (2015) Lancet Oncology, 16(15),

15 Similar pattern with post-hoc central imaging review PFS events, n (%) 24 (47) 33 (63) 29 (58) Motzer et al. (2016). Lancet Oncol, 17(1), e4 5.

16 Response rate LEN 18 mg + EVE 5 mg (n = 51) LEN 24 mg (n = 52) EVE 10 mg (n = 50) Site IRR Site IRR Site IRR Poor risk, n (%) 10 (20) - 23 (44) - 19 (38) - DOR, mo CR, n (%) 1 (2) 1 (2) 0 1 (2) 0 0 PR, n (%) 21 (41) 17 (33) 14 (27) 19 (37) 3 (6) 0 SD, n (%) 21 (41) 24 (47) 27 (52) 22 (42) 31 (62) 40 (80) PD, n (%) 2 (4) 2 (4) 3 (6) 4 (8) 12 (24) 4 (8) NE, n (%) 6 (12) 7 (14) 8 (15) 6 (12) 4 (8) 6 (12) DOR: duration of response. IRR: independentreview of response. LEN: lenvatinib. EVE: everolimus Motzer et al. (2015) Lancet Oncology, 16(15), Motzer et al. (2015) Lancet Oncology, 16(15),

17 Derosa et al. ECC 2015 N=316, included: 222. OS: 16,8 Mo. EVE: 27%. SU: 24%. SOR : 22%. AXI: 8%. others: 19%. IMDC 2 nd line score Factor estimate (±SE) HR 95%CI P Hb <ULN 0,43 (0,18) 1,54 1,08-2,20 0,015 Thrombocyte >ULN 0,48 (0,21) 1,62 1,06-2,47 0,025 ANC >ULN 0,89 (0,22) 2,45 1,57-3,82 <0,0001 KPS <80 0,74 (0,20) 2,10 1,41-3,14 0,0003 T to Rx <1year 0,31 (0,17) 0,73 0,52-1,04 0,085 Tumorburden >9.5cm 0,24 (0,17) 1,27 0,91-1,78 0,152 TS >30% in 1 st line 0,66 (0,19) 0, ,74 0,0004 New mets. 0,03 (0,18) 1,03 0,72-1,46 0,870

18 Some imbalances in prior treatment response Motzer et al. (2015) Lancet Oncology, 16(15),

19 Criticism Only modest size - prone to imbalances Not stratified according to prior response/pfs Not blinded Looses power by central review (fewer events counted)

20 Improvement of OS with the combination 25.5 mo. (16.4-NE) 15.4 mo. ( ) 19.1 mo. ( ) Motzer et al. (2015) Lancet Oncology, 16(15),

21 Escudier et al. ECC 2015 # Motzer et al. (2015) Lancet Oncology, 16(15), Motzer et al. NEJM Studies comparing to everolimus in later lines LEN-EVE vs. EVE Phase II CABO vs. EVE Phase III NIVO vs. EVE Phase III Line 2 nd 2 nd - 4 th 2 nd -3 rd Primary endpoint PFS PFS (OS) OS PFS (HR; CI95%) 0.40 ( ) 0.52 ( ) 0.88 ( ) ORR (%) 35 vs vs vs. 6* OS (HR; CI95%) 0.55 ( ) 0.66 ( ) 0.73 ( ) Median OS (mo) 25.5 vs vs vs *investigator-based assessment. LEN: lenvatinib. EVE: everolimus. CABO: cabozantinib. NIVO: nivolumab

22 Conclusion Combination therapies have failed in the past Dose-compromise due to toxicity was limiting its usability Success of lenvatinib + everolimus was unexpected 1 st study to show OS benefit of a combination Unknown whether off-targets contribute to the treatment effect Optimal dose/schedule may be still not found How good is the activity in poor risk patients? Future phase III studies are warranted

Sequencing of therapies in mrcc. Ari Hakimi MD Assistant Professor Urology Service, Department of Surgery MSKCC

Sequencing of therapies in mrcc Ari Hakimi MD Assistant Professor Urology Service, Department of Surgery MSKCC Old Paradigm Sequencing approved agents VEGF TKI Sunitinib Pazopanib Axitinib TKI TKI MTORi