The Current Champion: Angiogenesis inhibitors Baek-Yeol RYOO University of Ulsan College of Medicine ASAN Medical Center Dept. of Oncology Seoul, Korea
Survival probability Sorafenib: Overall Survival SHARP Asia-Pacific 1.00 Sorafenib (n=299) = 10.7 months Placebo (n=303) = 7.9 months 0.75 0.50 0.25 0 HR = 0.69 (95% CI: 0.55 0.87) p<0.001 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 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
Sorafenib: Targets Tumor Cell Proliferation and Angiogenesis Wilhelm et al. Mol Cancer Ther 2008
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.
Systemic Therapy for HCC 2007-2016 : 1 drug 2016-2018 : 4 drugs (3 TKIs, 1 ICI)
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 303 10.7 vs 7.9 0.69 <0.001 Superiority DB 150 vs 76 6.5 vs 4.2 0.68 0.014 Superiority OL 530 vs 544 7.9 vs 10.2 1.30 0.001 LIGHT Linifanib vs sorafenib VEGFR, PDGFR Non-inferiority OL 514 vs 521 9.1 vs 9.8 1.046 NS BRISK-FL Brivanib vs sorafenib FGFR, VEGFR Non-inferiority DB 577 vs 578 9.5 vs 9.9 1.01 0.3116 Nintedanib SEARCH CALGB 80802 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 32 10.2 vs 10.7 0.94 NS EGFR Superiority DB 362 vs 358 9.5 vs 8.5 0.929 0.408 cytotoxic agent Superiority OL 180 vs 176 8.9 vs 10.5 1.06 0.31 VEGFR, FGFR, PDGFR *PE, Primary endpoint; DB, double-blinded; OL, open-label Non-inferiority OL 478 vs 476 13.6 vs 12.3 0.92 Non-inferior
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 68 12.7 vs 9.7 0.870 0.211 REACH Ramucirumab vs placebo VEGFR-2 (mab) Superiority 283 vs 282 9.2 vs 7.6 0.866 0.1391 BRISK-PS Brivanib vs placebo FGFR, VEGFR Superiority 263 vs 132 9.4 vs 8.2 0.89 0.3307 EVOLVE-1 Everolimus vs placebo mtor Superiority 362 vs 184 7.6 vs 7.3 1.05 0.68 ADI-PEG20 ADI-PEG20 vs placebo arginine auxotrophy Superiority 424 vs 211 7.8 vs 7.4-0.884 METIV-HCC Tivantinib vs placebo c-met (high) Superiority 226 vs 114 8.4 vs 9.1 0.97 0.81 JET-HCC Tivantinib vs placebo c-met (high) Superiority 134 vs 61 9.9 vs 8.5 0.85 - 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 194 10.6 vs 7.8 0.63 <0.0001 CELESTIAL Cabozantinib vs placebo VEGFR, c-met Superiority 470 vs 237 10.2 vs 8.0 0.76 0.0049 Checkmate 040 Nivolumab PD-1 (mab) Ph II 145 15.6 *PE, Primary endpoint
Inhibits Regorafenib - VEGFR-1-3, PDGFR-β, Raf-1, c-kit, RET IC 50 (nm) Target Sorafenib Lenvatinib Regorafenib VEGFR-1-22 13 VEGFR-2 90 4 4.2 VEGFR-3 20 5.2 46 PDGFR- - 51 PDGFR-β 57 39 22 c-kit 68-7 FGFR-1 580 46 Flt-3 58 - c-raf 6-2.5 Wilhelm et al. Cancer Res 2004 Selleckchem.com
RESORCE Trial RP III (2:1), 2nd-line, Regorafenib vs. Placebo Trial Design Bruix et al. Lancet 2017
Regorafenib Bruix et al. Lancet 2017
Regorafenib Bruix et al. Lancet 2017
Regorafenib Bruix et al. Lancet 2017
Regorafenib Bruix et al. Lancet 2017
Regorafenib Bruix et al. Lancet 2017
Regorafenib Finn et al. ASCO GI 2017
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
Inhibits Lenvatinib (E7080) - VEGFR-1~3, FGFR-1~4, RET, PDGFR-β, c-kit IC 50 (nm) Target Sorafenib Regorafenib Lenvatinib VEGFR-1-13 22 VEGFR-2 90 4.2 4 VEGFR-3 20 46 5.2 PDGFR- - 51 PDGFR-β 57 22 39 c-kit 68 7 - FGFR-1 580 46 Flt-3 58 - c-raf 6 2.5 - *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
Phase II Trial: Lenvatinib Sorafenib Lenvatinib N 137 46 Line 1st 1st or 2nd Author Abou-Alfa Ikeda CR or PR (%) 2.2 23.9 SD (%) 39.4 54.3 PFS (median, mo) TTP (median, mo) 5.5 7.5 OS (median, mo) 9.2 18.3 Abou-Alfa et al. J Clin Oncol 2006 Ikeda et al. ESMO 2012
REFLECT Study RP III, 1st-line, Lenvatinib vs. Sorafenib Study Schema Cheng et al. ASCO 2017
Lenvatinib Lenvatinib demonstrated non-inferiority in overall survival compared to sorafenib in patients with previously untreated advanced HCC Cheng et al. ASCO 2017
Lenvatinib Cheng et al. ASCO 2017
Lenvatinib Cheng et al. ASCO 2017
Lenvatinib Cheng et al. ASCO 2017
Lenvatinib Cheng et al. ASCO 2017
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
inhibit VEGFR, MET, AXL, RET Cabozantinib Kelley et al. Ann Oncol 2017
CELESTIAL Trial RP III (2:1), 2nd/3rd-line, Cabozantinib vs. Placebo Abou-Alfa et al. ASCO-GI 2018
Cabozantinib Abou-Alfa et al. ASCO-GI 2018
Cabozantinib Abou-Alfa et al. ASCO-GI 2018
Cabozantinib Abou-Alfa et al. ASCO-GI 2018
Cabozantinib Abou-Alfa et al. ASCO-GI 2018
Cabozantinib Abou-Alfa et al. ASCO-GI 2018
Cabozantinib Abou-Alfa et al. ASCO-GI 2018
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
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
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) 7.8 10.6 mo 4 11% sorafenib experienced 8.0 10.2 (11.3) mo 0.4 4% Toxicity HTN, HFSR HFSR, HTN modified from Cheng AL. ASCO-GI 2018
Conclusion Perspective of Systemic Therapy for HCC 2018 1L: Sorafenib, Lenvatinib 2L: Regorafenib, Cabozantinib, Nivolumab
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Back-up
1st-line Agent Trial Yr TTP (mo) OS (mo) Sorafenib SHARP 2008 5.5 10.7 Asia-Pacific 2009 2.8 6.5 SUN 2011 4.1 10.2 LIGHT 2013 4.0 9.8 BRISK-FL 2013 4.1 9.9 Nintedanib 2015 3.7 10.7 REFLECT 2017 3.7 12.3 Lenvatinib REFLECT 2017 8.9 13.6
Why Not TTP? Trial Drug n TTP or PFS (mo) HR P OS (mo) HR P First-line SHARP Sorafenib vs placebo 299 vs 303 5.5 vs 2.8 0.58 <0.001 10.7 vs 7.9 0.69 <0.001 Asia-Pacific Sorafenib vs placebo 150 vs 76 2.8 vs 1.4 0.57 0.0005 6.5 vs 4.2 0.68 0.014 SUN Sunitinib vs sorafenib 530 vs 544 3.8 vs 4.1 1.13 0.16 7.9 vs 10.2 1.30 0.001 LIGHT Linifanib vs sorafenib 514 vs 521 5.4 vs 4.0 0.759 <0.001 9.1 vs 9.8 1.046 NS BRISK-FL Brivanib vs sorafenib 577 vs 578 4.2 vs 4.1 1.01 0.8532 9.5 vs 9.9 1.01 0.3116 Nintedanib Nintetanib vs sorafenib 63 vs 32 2.8 vs 3.7 1.21 NS 10.2 vs 10.7 0.94 NS REFLECT Lenvatinib vs sorafenib 478 vs 476 8.9 vs 3.7 0.63 <0.00001 13.6 vs 12.3 0.92 Non-inferior First-line in Combination with Sorafenib SEARCH Erlotinib with sorafenib 358 vs 362 3.2 vs 4.0 1.135 0.18 9.5 vs 8.5 0.929 0.408 CALGB80802 Doxorubicin with sorafenib 173 vs 173 3.6 vs 3.2 0.90-9.3 vs 10.5 1.06 0.31 Second-line Axitinib Axitinib vs placebo 134 vs 68 3.6 vs 1.9 0.618 0.004 12.7 vs 9.7 0.870 0.211 REACH Ramucirumab vs placebo 283 vs 282 2.8 vs 2.1 0.625 <0.0001 9.2 vs 7.6 0.866 0.1391 BRISK-PS Brivanib vs placebo 263 vs 132 4.2 vs 2.7 0.56 <0.001 9.4 vs 8.2 0.89 0.3307 RESORCE Regorafenib vs placebo 379 vs 194 3.2 vs 1.4 0.46 <0.001 10.6 vs 7.8 0.63 <0.0001 REACH-2 Ramucirumab vs placebo (AFP 400 ng/ml) Ongoing EVOLVE-1 Everolimus vs placebo 362 vs 184 0.93 7.6 vs 7.3 1.05 0.68 ADI-PEG20 ADI-PEG20 vs placebo 424 vs 211 7.8 vs 7.4-0.884 METIV-HCC Tivantinib vs placebo 226 vs 114 2.1 vs 2.0 0.96 0.72 8.4 vs 9.1 0.97 0.81 CELESTITIAL Cabozantinib vs placebo 773 (2:1) - - - - 0.76 -