When patients fail on molecular targeted therapy: what to do in 2013
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- Samuel Reed
- 5 years ago
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1 When patients fail on molecular targeted therapy: what to do in 2013 For 3 rd APASAL HCC conference on 23 Nov 2013 Dr. Stephen L. Chan Department of Clinical Oncology The Chinese University of Hong Kong
2 Sorafenib for advanced HCC The issue of what to do next occurs at a median of ~3-month duration after commencement of treatment. OS TTP TTSP Sorafenib 6.5m Placebo 4.2m Cheng AL et al. Lancet Oncology 2009
3 Simple answer to the question: No, we don t have standard second line agent
4 Existing weapons Novel treatment approach End of the talk
5 In the absence of alternative therapies with proven efficacy.continuing sorafenib treatment after disease progression may be beneficial European Journal of Gastro & Hepatol. 2010: 22:
6 Case-control study Tumor size Decision to continue sorafenib beyond progression relies on physicians decision Predominantly HCV infection Total sample size 23 continued sorafenib beyond progression 13 stopped sorafenib upon progression Overall survival
7 Phase II randomized study on dose escalated sorafenib versus best supportive care after PD to sorafenib: Abstract results Child s A/B PD (RECIST) not suitable for any locoregional therapy R Sorafenib 600mg BD (S-arm) Best supportive care (BSC arm) , 300 sorafenib-treated patients were registered; 101 (34%) randomized 93% Child s A, 58% without extrahepatic spread S arm: 46% (full dose); others required dose reduction End point S-arm BSC-arm p HR Median PFS (months) Median OS (months) ( ) ( ) Pressiani T et al. ASCO 2011 abstract 4115
8 Use of sorafenib beyond progression Lack of evidence One small scaled non-controlled study One phase II randomized study (abstract only) The benefit is likely negligible to small, even if present Reimbursement program/funding policy may also be a limiting factor
9 Back to basic: use the old weapon
10 Cytotoxic chemotherapy Before chemo AFP: ng/ml After 3 chemo AFP: 450 ng/ml
11 Phase III data on chemotherapy Doxorubicin arm PIAF arm p Median no. of cycles Overall responses 10.5% (95% CI %) 20.9% (95% CI %) Median Survival: - Dox months (95%CI ) - PIAF months (95%CI ) p= Yeo W et al, J Natl Cancer Inst 2005
12 Partial response rate ~8%
13 From: Doxorubicin Plus Sorafenib vs Doxorubicin Alone in Patients With Advanced Hepatocellular Carcinoma: A Randomized Trial JAMA. 2010;304(19): doi: /jama Doxorubicin + sorafenib Doxorubirin Arm Doxorubicin Arm: 4% meets PR criteria (RECIST) 29% has shrinkage of tumor
14 Limitation: Toxicity Phase III trial FOFLOX 4 vs. DOX Phase III trial PIAF vs. doxorubicin Child s A Child s B Child s A Child s B P value No. of cycle Relatively young (and likely more fit patients) G3/4 Hyperbilirubinemia (%) GI Bleeding (%) Qin S et al. J Clini Oncol 2013 Yeo W Chan SL. Contemp Clin Trials 2009
15 Use of chemotherapy in sorafenib-refractory HCC Clinical data extrapolated from non-sorafenib era/population Radiologic response seen in 8-10% of population Tolerability; suitable for young patients with good ECOG and Child s A liver function
16 Molecular targeted agents: Current status
17 List of Phase III clinical trials on novel agents as the second-line treatment (vs. Placebo) FGFR: Brivanib mtor: Everolimus C-met inhibitor: Tivanitinb Multi-targeted TKI: Carbozanitib Regorafenib Negative Negative (pending full data) Ongoing Ongoing Ongoing Anti-VEGF Mab: Ramacirumab Others: ADI-PEG20 Completed Ongoing
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19 Hypothesis: Only a small number (few %) of patients respond to the new drug in the clinical trial New Drug R Old drug
20 Biomarker enriched trial Selected population (biomarker enriched clinical trial)
21 Cases of significant response with targeted agent Pre-treatment Post-treatment Pre-treatment Post-treatment
22 HR23B as predictive biomarker for HDAC inhibitor IHC staining (histoscore) of HR23B is associated with disease control rate (CR+PR+SD) (p<0.05) Before Treatment After treatment Low (histoscore 30/300) High (histoscore 255/300) Yeo W et al. J Clin Oncol 2012
23 Biomarker driven drug testing c-met FISH/IHC for c-met inhibitor: under clinical testing in phase II setting HR23B for HDAC inhibitor: Phase II data More to come.
24 Genomic profile of druggable targets for HCC Mutation A A treatment Mutation B B treatment Advanced HCC Genomic Profile Mutation C C treatment Biopsy Mutation D D treatment Others Conventional treatment
25 Note on second line targeted therapy for HCC No standard second-line agent of proven benefit at present Phase III clinical trial results are awaited Predictive biomarker may be important for drug development. Tissue biopsy is indicated (not for diagnosis but for genomic profiling of tumor)
26 Thank you
12 AISF Special Conference Sorafenib: magnitude of benefit, side effects and stopping rules 9 years after approval
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