The Current Champion: Angiogenesis inhibitors

Transcription

1 The Current Champion: Angiogenesis inhibitors Baek-Yeol RYOO University of Ulsan College of Medicine ASAN Medical Center Dept. of Oncology Seoul, Korea

2 Survival probability Sorafenib: Overall Survival SHARP Asia-Pacific 1.00 Sorafenib (n=299) = 10.7 months Placebo (n=303) = 7.9 months HR = 0.69 (95% CI: ) p< Time from randomisation (months) - approved by FDA (Dec. 2007), EMEA (Oct. 2007) and KFDA (Mar. 2008) Llovet et al. N Engl J Med 2008 Cheng et al. Lancet Oncol 2009

3 Sorafenib: Targets Tumor Cell Proliferation and Angiogenesis Wilhelm et al. Mol Cancer Ther 2008

4 Sorafenib in the Tx of HCC Sorafenib is the first systemic therapy to significantly prolong survival in HCC patients. Sorafenib established a proof of concept for the use of a multi-kinase inhibitor strategy for the treatment of HCC. Sorafenib is the new reference standard for systemic therapy for HCC patients.

5 Systemic Therapy for HCC : 1 drug : 4 drugs (3 TKIs, 1 ICI)

6 Clinical Trials of 1st-line Therapy for HCC Trial Drug Targets Design n OS (mo) HR P SHARP Asia-Pacific SUN Sorafenib vs placebo Sorafenib vs placebo Sunitinib vs sorafenib Raf-1, VEGFR, PDGFR Raf-1, VEGFR, PDGFR c-kit, VEGFR, PDGFR Superiority DB 299 vs vs <0.001 Superiority DB 150 vs vs Superiority OL 530 vs vs LIGHT Linifanib vs sorafenib VEGFR, PDGFR Non-inferiority OL 514 vs vs NS BRISK-FL Brivanib vs sorafenib FGFR, VEGFR Non-inferiority DB 577 vs vs Nintedanib SEARCH CALGB REFLECT Nintetanib vs sorafenib Erlotinib+sorafenib vs sorafenib Doxorubicin+sorafenib vs sorafenib Lenvatinib vs sorafenib VEGFR, PDGFR, FGFR R-PII (PE: TTP) OL 63 vs vs NS EGFR Superiority DB 362 vs vs cytotoxic agent Superiority OL 180 vs vs VEGFR, FGFR, PDGFR *PE, Primary endpoint; DB, double-blinded; OL, open-label Non-inferiority OL 478 vs vs Non-inferior

7 Clinical Trials of 2nd-line Therapy for HCC Trial Drug Targets Design n OS (mo) HR P Axitinib Axitinib vs placebo VEGFR, PDGFR R-PII (PE: OS) 134 vs vs REACH Ramucirumab vs placebo VEGFR-2 (mab) Superiority 283 vs vs BRISK-PS Brivanib vs placebo FGFR, VEGFR Superiority 263 vs vs EVOLVE-1 Everolimus vs placebo mtor Superiority 362 vs vs ADI-PEG20 ADI-PEG20 vs placebo arginine auxotrophy Superiority 424 vs vs METIV-HCC Tivantinib vs placebo c-met (high) Superiority 226 vs vs JET-HCC Tivantinib vs placebo c-met (high) Superiority 134 vs vs REACH-2 Ramucirumab vs placebo VEGFR-2 (mab) Superiority Ongoing (AFP 400 ng/ml) RESORCE Regorafenib vs placebo VEGFR, PDGFR, Raf-1 Superiority 379 vs vs < CELESTIAL Cabozantinib vs placebo VEGFR, c-met Superiority 470 vs vs Checkmate 040 Nivolumab PD-1 (mab) Ph II *PE, Primary endpoint

8 Inhibits Regorafenib - VEGFR-1-3, PDGFR-β, Raf-1, c-kit, RET IC 50 (nm) Target Sorafenib Lenvatinib Regorafenib VEGFR VEGFR VEGFR PDGFR PDGFR-β c-kit 68-7 FGFR Flt c-raf Wilhelm et al. Cancer Res 2004 Selleckchem.com

9 RESORCE Trial RP III (2:1), 2nd-line, Regorafenib vs. Placebo Trial Design Bruix et al. Lancet 2017

10 Regorafenib Bruix et al. Lancet 2017

11 Regorafenib Bruix et al. Lancet 2017

12 Regorafenib Bruix et al. Lancet 2017

13 Regorafenib Bruix et al. Lancet 2017

14 Regorafenib Bruix et al. Lancet 2017

15 Regorafenib Finn et al. ASCO GI 2017

16 Regorafenib Is the First Treatment That Demonstrated Prolonged OS in Second-line Setting for HCC Patients Regorafenib demonstrated a statistically significant and clinically meaningful improvement in OS for patients with HCC who progressed on prior sorafenib Regorafenib significantly improved PFS Patients treated with regorafenib had significantly better ORR and DCR AEs were manageable and consistent with the regorafenib safety profile Bruix et al. Lancet 2017

17 Inhibits Lenvatinib (E7080) - VEGFR-1~3, FGFR-1~4, RET, PDGFR-β, c-kit IC 50 (nm) Target Sorafenib Regorafenib Lenvatinib VEGFR VEGFR VEGFR PDGFR PDGFR-β c-kit FGFR Flt c-raf *IC 50 represents the concentration of a drug that is required to achieve 50% inhibition of the enzyme in a biochemical assay Wilhelm et al. Cancer Res 2004 Selleckchem.com

18 Phase II Trial: Lenvatinib Sorafenib Lenvatinib N Line 1st 1st or 2nd Author Abou-Alfa Ikeda CR or PR (%) SD (%) PFS (median, mo) TTP (median, mo) OS (median, mo) Abou-Alfa et al. J Clin Oncol 2006 Ikeda et al. ESMO 2012

19 REFLECT Study RP III, 1st-line, Lenvatinib vs. Sorafenib Study Schema Cheng et al. ASCO 2017

20 Lenvatinib Lenvatinib demonstrated non-inferiority in overall survival compared to sorafenib in patients with previously untreated advanced HCC Cheng et al. ASCO 2017

21 Lenvatinib Cheng et al. ASCO 2017

22 Lenvatinib Cheng et al. ASCO 2017

23 Lenvatinib Cheng et al. ASCO 2017

24 Lenvatinib Cheng et al. ASCO 2017

25 Lenvatinib Lenvatinib has demonstrated noninferiority versus sorafenib in OS in patients with unresectable HCC (13.6 months for lenvatinib versus 12.3 months for sorafenib) Lenvatinib has achieved statistically significant and clinically meaningful improvement in PFS, TTP, and ORR versus sorafenib in this population The safety profiles of lenvatinib and sorafenib in this study appear consistent with those previously reported in patients with HCC Cheng et al. ASCO 2017

26 inhibit VEGFR, MET, AXL, RET Cabozantinib Kelley et al. Ann Oncol 2017

27 CELESTIAL Trial RP III (2:1), 2nd/3rd-line, Cabozantinib vs. Placebo Abou-Alfa et al. ASCO-GI 2018

28 Cabozantinib Abou-Alfa et al. ASCO-GI 2018

29 Cabozantinib Abou-Alfa et al. ASCO-GI 2018

30 Cabozantinib Abou-Alfa et al. ASCO-GI 2018

31 Cabozantinib Abou-Alfa et al. ASCO-GI 2018

32 Cabozantinib Abou-Alfa et al. ASCO-GI 2018

33 Cabozantinib Abou-Alfa et al. ASCO-GI 2018

34 Cabozantinib Cabozantinib significantly improves overall survival in advanced HCC patients after prior systemic anticancer therapy Progression-free survival and objective response rate were also significantly improved The safety profile is acceptable with a low rate of discontinuation (16%) due to treatment-related adverse events Abou-Alfa et al. ASCO-GI 2018

35 Summary 1L TKI for HCC Sorafenib Levatinib Mechanism VEGFR + Raf? VEGFR + FGFR? Evidence Ph III (vs placebo) Ph III (vs sorafenib) Efficacy (OS) superior to placebo non-inferior to sorafenib Toxicity HFSR Hypertension Comments poor-px Pts excluded modified from Cheng AL. ASCO-GI 2018

36 Summary 2L TKI for HCC Regorafenib Cabozantinib Mechanism VEGFR + Raf? VEGFR + MET? AXL? Evidence Ph III (vs placebo) Ph III (vs placebo) Pt characteristics Efficacy OS RR sorafenib-tolerant (radiologic progression) mo 4 11% sorafenib experienced (11.3) mo 0.4 4% Toxicity HTN, HFSR HFSR, HTN modified from Cheng AL. ASCO-GI 2018

37 Conclusion Perspective of Systemic Therapy for HCC L: Sorafenib, Lenvatinib 2L: Regorafenib, Cabozantinib, Nivolumab

38 감사합니다.

39 Back-up

40 1st-line Agent Trial Yr TTP (mo) OS (mo) Sorafenib SHARP Asia-Pacific SUN LIGHT BRISK-FL Nintedanib REFLECT Lenvatinib REFLECT

41 Why Not TTP? Trial Drug n TTP or PFS (mo) HR P OS (mo) HR P First-line SHARP Sorafenib vs placebo 299 vs vs < vs <0.001 Asia-Pacific Sorafenib vs placebo 150 vs vs vs SUN Sunitinib vs sorafenib 530 vs vs vs LIGHT Linifanib vs sorafenib 514 vs vs < vs NS BRISK-FL Brivanib vs sorafenib 577 vs vs vs Nintedanib Nintetanib vs sorafenib 63 vs vs NS 10.2 vs NS REFLECT Lenvatinib vs sorafenib 478 vs vs < vs Non-inferior First-line in Combination with Sorafenib SEARCH Erlotinib with sorafenib 358 vs vs vs CALGB80802 Doxorubicin with sorafenib 173 vs vs vs Second-line Axitinib Axitinib vs placebo 134 vs vs vs REACH Ramucirumab vs placebo 283 vs vs < vs BRISK-PS Brivanib vs placebo 263 vs vs < vs RESORCE Regorafenib vs placebo 379 vs vs < vs < REACH-2 Ramucirumab vs placebo (AFP 400 ng/ml) Ongoing EVOLVE-1 Everolimus vs placebo 362 vs vs ADI-PEG20 ADI-PEG20 vs placebo 424 vs vs METIV-HCC Tivantinib vs placebo 226 vs vs vs CELESTITIAL Cabozantinib vs placebo 773 (2:1)