When patients fail on molecular targeted therapy: what to do in 2013

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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

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 2.8 3.5 Placebo 4.2m 1.4 3.4 Cheng AL et al. Lancet Oncology 2009

Simple answer to the question: No, we don t have standard second line agent

Existing weapons Novel treatment approach End of the talk

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: 391-98

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

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) 2007-2008, 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) 3.9 2.6 0.07 0.66 (0.41-1.04) 6.1 6.0 0.14 0.73 (0.47-1.11) Pressiani T et al. ASCO 2011 abstract 4115

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

Back to basic: use the old weapon

Cytotoxic chemotherapy Before chemo AFP: 120000 ng/ml After 3 chemo AFP: 450 ng/ml

Phase III data on chemotherapy Doxorubicin arm PIAF arm p Median no. of cycles 4 3 0.076 Overall responses 10.5% (95% CI 3.9-16.9%) 20.9% (95% CI 12.5-29.2%) 0.0578 Median Survival: - Dox- 6.83 months (95%CI 4.80-9.56) - PIAF- 8.67 months (95%CI 6.36-12.00) p= 0.830 Yeo W et al, J Natl Cancer Inst 2005

Partial response rate ~8%

From: Doxorubicin Plus Sorafenib vs Doxorubicin Alone in Patients With Advanced Hepatocellular Carcinoma: A Randomized Trial JAMA. 2010;304(19):2154-2160. doi:10.1001/jama.2010.1672 Doxorubicin + sorafenib Doxorubirin Arm Doxorubicin Arm: 4% meets PR criteria (RECIST) 29% has shrinkage of tumor

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 4 2.5 0.01 Relatively young (and likely more fit patients) G3/4 Hyperbilirubinemia (%) 11.9 28.6 0.02 GI Bleeding (%) 3.1 17.9 0.001 Qin S et al. J Clini Oncol 2013 Yeo W Chan SL. Contemp Clin Trials 2009

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

Molecular targeted agents: Current status

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

Gene RET Description p.thr76ser/c.226a>t p.leu574pro/c.1721t>c p.ser45pro/c.133t>c p.asn51his/c.151a>c p.thr371ala/c.1111a>g p.lys435glu/c.1303a>g p.met731val/c.2191a>g p.ser437phe/c.1310g>a p.ile381thr/c.1142a>g p.glu29gly/c.86t>c p.gly388arg/c.1162g>a p.pro494his/c.1481c>a p.phe407leu/c.1219a>g p.lys282arg/c.845t>c p.ile237thr/c.710a>g p.ile8val/c.22t>c p.val249ala/c.746a>g p.ile185val/c.553t>c p.leu174pro/c.521a>g p.thr284ala/c.850t>c p.ser18pro/c.52a>g p.phe17tyr/c.50a>t p.phe17leu/c.49a>g p.cys828arg/c.2482a>g p.asn337asp/c.1009t>c p.arg120cys/c.358g>a p.leu906pro/c.2717a>g p.arg902gly/c.2704t>c p.leu898pro/c.2693a>g p.his712pro/c.2135t>g p.his709tyr/c.2125g>a p.gly707glu/c.2120c>t p.his484arg/c.1451t>c p.ile15thr/c.44t>c p.ile156val/c.466a>g p.lys572arg/c.1715a>g p.phe722ser/c.2165t>c p.his727arg/c.2180a>g p.ile999thr/c.2996t>c p.leu1163pro/c.3488a>g p.thr940ala/c.2818t>c p.lys406arg/c.1217t>c p.pro328his/c.983g>t p.lys287glu/c.859t>c p.thr279ala/c.835t>c p.phe195leu/c.583t>c p.lys303arg/c.908a>g p.lys306arg/c.917a>g p.val427leu/c.1279g>c p.gln433his/c.1299a>t p.leu455pro/c.1364t>c p.thr75ala/c.223a>g p.gln152arg/c.455a>g p.ser124gly/c.370a>g p.val141glu/c.422t>a p.arg318lys/c.953c>t p.gly230glu/c.689c>t p.tyr904cys/c.2711t>c p.leu648pro/c.1943a>g p.thr294ser/c.880t>a p.val221met/c.661c>t p.glu487gly/c.1460t>c p.ser49pro/c.145a>g p.phe276ser/c.827a>g p.asp251gly/c.752t>c p.val174ala/c.521a>g p.ser127cys/c.379a>t p.val190met/c.568g>a p.ser359gly/c.1075t>c p.tyr232his/c.694a>g p.pro197ala/c.589g>c p.thr461ala/c.1381a>g p.phe512val/c.1534a>c p.ser330gly/c.988t>c p.lys271arg/c.812t>c p.cys44arg/c.130t>c p.lys288arg/c.863a>g p.gln349arg/c.1046a>g p.lys543glu/c.1627a>g p.lys543arg/c.1628a>g BT-1A 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/1 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 u 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 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0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 BT-80A 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 u u 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 u 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 0/0 TEK PSMD9 MET KDR HDAC7 CTNNB1 FGFR2 FLT1 RXRB PDGFC PDGFRB RAF1 GPC3 IGF1R ARAF FLT3 FGFR4 FLT4 PSMD5 0/1 Tolerated Mutation 1/1 Deleterious Mutation u Mutation Located in Conserved Domain MiSeq Data HCC is a heterogeneous disease in terms of actionable targets.

Hypothesis: Only a small number (few %) of patients respond to the new drug in the clinical trial New Drug R Old drug

Biomarker enriched trial Selected population (biomarker enriched clinical trial)

Cases of significant response with targeted agent Pre-treatment Post-treatment Pre-treatment Post-treatment

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

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.

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

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)

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