Why was HOPE 205 a Positive After Years of Negative Studies? Prof. Dr. med. Viktor Grünwald Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation
Why do we pursue combinations? PRO: Better response rate/efficacy Better survival CON: Needs to balance toxicity Needs to beat sequential treatment
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 830 69 8 2 9 50 Sorafenib 580-57 - 15-90 20 Pazopanib 140 71 84 10 30 47 Axitinib - 5 1.6 1.2 0.2 0.3 Nintedanib 69 59 65 34 21 13 Dovitinib 8 150 12 10 13 8 Tivozanib - - 1.7 0.2 0.2 0.2 Lenvatinib 46 51 39 22 4 5 Mendel DB, et al. Clin Cancer Res. 2003 Jan;9(1):327-37. LaMontagne, et al. Angiogenis. 2009;12(3):287-96. Kumar R, Mol Cancer Ther. 2007 Jul;6(7):2012-21. Gilbert JA, Pancreas. 2013 Apr;42(3):411-21. Kitigawa D, et al. Genes Cells. 2013 Feb;18(2):110-22 Eisen T et al, ASCO 2013, #4506. Grünwald & Merseburger. (2013). EJC, 49(11), 2504 2511.
Nintedanib also inhibits FGFR, but no additional clinical benefit Eisen et al. BJC. DOI:10.1038/bjc.2015.313
Combinations in 1 st line no winning team in sight Flaherty et al. JCO 2015, 33 (21): 2384-2391
Sunitinib + sirolimus require dose-compromise in phase I 40% DR: dose reduction. ED: early discontinuation Li et al. (2016). Cancer Chemother Pharmacol, 1 8. http://doi.org/10.1007/s00280-016-3033-7
N=4 1 toxic death PR: 1/4 N=27 ORR: 23% Full dose possible 74% after prior TKI
What made lenvatinib a target for combinations? Phase Ib (NCT00563147) Randomized Phase II (NCT01136733)
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), 181 189. http://doi.org/10.1007/s00280-013-2339-y
Tumor shrinkage Phase 1b PFS: 10.9 mo. Molina et al. (2014). Cancer Chemother Pharmacol, 73(1), 181 189. http://doi.org/10.1007/s00280-013-2339-y
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), 181 189. http://doi.org/10.1007/s00280-013-2339-y
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. + 60 events for arms of interest Motzer et al. (2015) Lancet Oncology, 16(15), 1473 1482. http://doi.org/10.1016/s1470-2045(15)00290-9
Better efficacy with the combination 14.6 mo. (5.9-20.1) 5.5 mo. (3.5-7.1) 7.4 mo. (5.6-10.2) PFS events, n (%) 26 (51) 38 (73) 37 (74) Motzer et al. (2015) Lancet Oncology, 16(15), 1473 1482. http://doi.org/10.1016/s1470-2045(15)00290-9
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. http://doi.org/10.1016/s1470-2045(15)00543-4
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 13.0-7.5-8.5 - 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), 1473 1482. http://doi.org/10.1016/s1470-2045(15)00290-9. Motzer et al. (2015) Lancet Oncology, 16(15), 1473 1482. http://doi.org/10.1016/s1470-2045(15)00290-9
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) 0,51 0.35-0,74 0,0004 New mets. 0,03 (0,18) 1,03 0,72-1,46 0,870
Some imbalances in prior treatment response Motzer et al. (2015) Lancet Oncology, 16(15), 1473 1482. http://doi.org/10.1016/s1470-2045(15)00290-9
Criticism Only modest size - prone to imbalances Not stratified according to prior response/pfs Not blinded Looses power by central review (fewer events counted)
Improvement of OS with the combination 25.5 mo. (16.4-NE) 15.4 mo. (11.8-19.6) 19.1 mo. (13.6-26.2) Motzer et al. (2015) Lancet Oncology, 16(15), 1473 1482. http://doi.org/10.1016/s1470-2045(15)00290-9
Escudier et al. ECC 2015 #3657. www.fda.gov. Motzer et al. (2015) Lancet Oncology, 16(15), 1473 1482. Motzer et al. NEJM 2015. 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 (0.24-0.68) 0.52 (0.43-0.64) 0.88 (0.75-1.03) ORR (%) 35 vs. 0 17 vs. 3 25 vs. 6* OS (HR; CI95%) 0.55 (0.30-1.01) 0.66 (0.53-0.83) 0.73 (0.57-0.93) Median OS (mo) 25.5 vs. 15.4 21.4 vs. 16.5 25.0 vs. 19.6 *investigator-based assessment. LEN: lenvatinib. EVE: everolimus. CABO: cabozantinib. NIVO: nivolumab
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