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Abstracts 4005-8 Jordan Berlin, MD Ingram Professor of Clinical Research Co-Director, GI Oncology Program Vanderbilt-Ingram Cancer Center Disclosures • With regards to these presentations: – I have done an advisory board and have had multiple trials with Amgen, – Vanderbilt has trials open from Daiichi and Arqule The obvious groupings •Abstracts 4005-7 –These abstracts address the use of Cmet inhibition as a therapeutic target in GI cancers •I will be reversing the order of these abstracts •Abstract 4008 –This abstract addresses the oft ignored issue of trying to reduce the discomforts caused by one of our therapeutic options First, and Foremost • All 4 abstracts represent excellent work from dedicated individuals who want to make a difference in the lives of our patients – All the authors should be congratulated for their efforts. – This does not mean I won’t be critical cMet • You have seen the pathway • Key factor: Expression has been a prognostic marker • Frequently dysregulated in a number of tumor types including HCC and gastric cancers – Gene amplification in the primary has been reported in a limited number of diseases including colon and gastric primaries • Overexpression has been found to be a potential resistance mechanism to HER pathway inhibition, VEGF inhibition and possibly IGF1R inhibition • It does bad things: proliferation, survival, etc, etc – We have all seen most of this rationale for almost any targeted agent Activity of Cabozantinib (XL184) in Hepatocellular Carcinoma: Results From a Phase 2 Randomized Discontinuation Trial (RDT) Chris Verslype1, Allen Lee Cohn2, Robin Katie Kelley3, Tsai-Shen Yang4, Wu-Chou Su5, David A. Ramies6, Yihua Lee6, Xiaodong Shen6, Eric Van Cutsem1 University Hospitals Gasthuisberg, Leuven, Belgium1; Rocky Mountain Cancer Center, LLP, Denver, CO2; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA3; Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan4; National Cheng Kung University Hospital, Tainan, Taiwan5; Exelixis, South San Francisco, CA6 Tivantinib (ARQ 197) vs Placebo in Patients (Pts) with Hepatocellular Carcinoma (HCC) Who Failed One Systemic Therapy:Results of a Randomized Controlled Phase 2 Trial (RCT) L Rimassa, C Porta, I Borbath, B Daniele, S Salvagni, JL Van Laethem, H Van Vlierberghe,J Trojan, F Kolligs, A Weiss, N Barahona, A Gasbarrini, M Lencioni, A Pande, M Lamar, Y Chen, G Abbadessa, B Schwartz, A Santoro Similarities • Both are randomized phase II studies of -nibs that are primarily cMet inhibitors studied in patients with HCC • Both study groups clearly understood the difficulties of this disease and incorporated it into study design – Frequent stable disease, heterogeneous etiologies, etc • Both studies had designs that encouraged enrollment • Both groups felt further study is warranted based on their results Significant differences • Cabozantinib – Has inhibitory effects on two key pathways: cMet and VEGFR2 – Had a novel trial design (randomized discontinuation) • Recognized the frequent stability of this disease in Child’s A patients and low platelets despite good PS – Focused on PFS as well as tumor shrinkage and AFP reduction – Had a more heterogeneous patient population • Number and type of prior therapies Significant Differences • Tivantinib – Selective for cMet pathway inhibition – Had a predefined biomarker analysis incorporated into the design – Clearly defined prior therapies • (1 systemic therapy taken for at least 21 days) – Primary endpoint was TTP, but looked at OS and PFS – Had two different doses of drug due to toxicities in the first 57 patients randomized Best Target Lesion Regression of Patients with ≥1 Post-Baseline Tumor Assessment (N=36)* 50 % Change from Baseline Prior sorafenib 30 10 -10 -30 -50 -70 *per Original RECIST 1.0 ‡ Confirmed PRs No prior sorafenib ‡ ‡ Best AFP Time Point Response of Patients with ≥1 Post-Baseline Measurement (N=26)* % Change from Baseline 100 + + + Prior sorafenib No prior sorafenib 80 60 40 20 0 -20 -40 -60 -80 -100 + Increase >100% from Baseline * Only Patients with AFP ≥ 20ng/mL at baseline are shown. Cabozantinib Results • There is reduction in AFP, change in tumor measurements • PFS over 4 months suggests some effect and while 15 month survival is encouraging, this is a highly selected patient group in a small study • Does it warrant further study? – Further phase II planned is appropriate. – Biomarkers should be considered based on the other two abstracts I am discussing Tivantinib Results • First, cMet expression was prognostic – OS 9 months for cMet low and 3.8 months for cMet high (based on 28 patients) • While tivantinib had no apparent effect in cMet low patients, • cMet high patients appeared to get benefit Primary Endpoint: TTP (ITT Population) Median TTP Patients Events Tivantinib 6.9 wks 71 46 Placebo 6.0 wks 36 30 HR: 0.64 (90% CI: 0.43-0.94) Log Rank: P=0.04 • • • • Study powered to detect a treatment difference with a 1-sided type I error α = 0.05 PFS consistent with TTP: HR 0.67 (95% CI: 0.44-1.04) Log Rank: P=0.06 1 PR was observed in the 240mg BID group. Disease control rate: 44% on tivantinib (32-56) vs 31% (16-48) Of 23 crossed-over patients, 11 showed best response of SD (3 ongoing at time of data cut-off), 8 PD, 4 non evaluable ARQ 197-215 PRESENTED BY: LORENZA RIMASSA Improved TTP in MET Diagnostic High Group Median TTP Patients Events Tivantinib 11.7 wks 22 14 Placebo 6.1 wks 15 13 HR: 0.43 (95% CI: 0.19-0.97) Log Rank: P=0.03 PFS: HR 0.45 (95% CI: 0.21-0.95) Log Rank: P=0.02 DCR: 50% on tivantinib (28-72) vs 20% (4-48) ARQ 197-215 PRESENTED BY: LORENZA RIMASSA Improved OS in MET Diagnostic High Group Median OS Patients Events Tivantinib 7.2 mos 22 17 Placebo* 3.8 mos 15 15 HR: 0.38 (95% CI: 0.18-0.81) Log Rank: P=0.01 *8 MET Dx High patients crossed-over, 5 remained on open-label tivantinib for at least 6 weeks (1 non-evaluable at cut-off date) ARQ 197-215 PRESENTED BY: LORENZA RIMASSA cMet in HCC: Conclusions • Both studies demonstrated some benefit • Both studies warrant further analysis • A randomized phase II study for crizontanib is appropriate • A randomized phase III study for tivantinib seems appropriate, and I laud the conviction to follow the biomarker hypothesis, but – A large, randomized trial is now being built on a subset analysis of 37 patients out of a 107 patient study – This scenario has been repeated multiple times in pancreatic cancer and look where it has gotten us – Do the randomized phase II in cMet high patients first INTRIGUINGLY, SUPPORT FOR A BIOMARKER APPROACH COMES FROM ANOTHER DISEASE SITE Evaluation of MET Pathway Biomarkers in a Phase 2 Study of Rilotumumab or Placebo in Combination With Epirubicin/Cisplatin/Capecitabine in Patients With Locally Advanced or Metastatic Gastric or Esophagogastric Junction Cancer Kelly S. Oliner,1 Rui Tang,1 Abraham Anderson,1 Yun Lan,1 Timothy Iveson,2 Ross C. Donehower,3 Yizhou Jiang,1 Sarita Dubey,4 Elwyn Loh4 1Amgen Inc., Thousand Oaks, CA, USA; 2Southampton General Hospital, Southampton, UK; 3Johns Hopkins Cancer Center, Baltimore, MD, USA; 4Amgen Inc., South San Francisco, CA, USA Progression-Free Survival (%) Clinical Efficacy in the Intent-to-Treat Population* 100 Progression-Free Survival 60 40 20 HR† (80% CI) P Value Rilotumumab + ECX (n = 82) 5.6 (4.9–6.9) 0.64 (0.48–0.85) 0.045 Placebo + ECX (n = 39) 4.2 (3.7–4.6) Median Months (80% CI) HR† (80% CI) P Value Rilotumumab + ECX (n = 82) 11.1 (9.5–12.1) 0.73 (0.53–1.01) 0.215 Placebo + ECX (n = 39) 8.9 (5.7–10.6) HR 0.64 0 0 1 2 3 4 5 6 100 Overall Survival (%) Median Months (80% CI) 80 7 8 9 10 11 12 13 14 15 16 Time (months) Overall Survival 80 60 40 HR 0.73 20 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Time (months) *Results based on the updated analysis with data cutoff of April 1, 2011. †Adjusted for baseline randomization stratification variables (ECOG status [0 or 1] and disease extent [locally advanced or metastatic]). Iveson T, et al. European Multidisciplinary Cancer Congress, September 23-27, 2011, Stockholm, Sweden; abstract #6504. Selected Biomarkers to find a better population for further study – Biomarkers selected – Tumor MET protein expression HER2 status MET gene copy number – Circulating plasma total HGF/SF and soluble MET – For Met protein expression, used similar methods to the Brivantinib study – Criteria chosen for clinical trial assay performed by a central lab: – METHigh: > 50% of tumor cells with ≥ 1+ cytoplasmic staining – METLow: ≤ 50% of tumor cells with ≥ 1+ cytoplasmic staining – For Met expression ~75% of patients in each arm had samples Improved PFS and OS in METHigh Patients Progression-Free Survival Progression-Free Survival (%) 100 80 Median Months (80% CI) HR* (95% CI) P Value Rilotumumab + ECX (n = 27) 6.9 (5.1–7.5) 0.51 (0.24–1.10) 0.085 Placebo + ECX (n = 11) 4.6 (3.7–5.2) Median Months (80% CI) HR+ (95% CI) P Value Rilotumumab + ECX (n = 27) 11.1 (9.2–13.3) 0.29 (0.11–0.76) 0.012 Placebo + ECX (n = 11) 5.7 (4.5–10.4) 60 40 20 0 HR 0.51 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Time (Months) Overall Survival Overall Survival (%) 100 80 60 40 20 HR 0.29 0 0 1 2 3 4 5 6 • MET-evaluable OS HR, 0.95 7 8 9 10 11 12 13 14 15 16 17 Time (Months) *HR adjusted for baseline disease extent and ECOG PS. • ITT OS HR, 0.73 High Levels of Tumor MET May Be Predictive and Prognostic 100 Overall Survival (%) 90 80 70 60 Median Months (80% CI) 50 40 30 Placebo + ECX (METLow, n = 17) NE (8.5–NE) 20 Placebo + ECX (METHigh, n = 11) 5.7 (4.5–10.4) Logrank P value 0.023 10 0 0 1 2 3 4 5 6 7 8 9 10 11 Time (Months) 12 13 14 15 16 17 • Patients with gastric tumors with high MET expression may have a poorer prognosis but may receive more benefit from rilotumumab Rilotumumab in Gastric Cancer Conclusions • Once again, Met expression was prognostic • And predictive of drug effect • It is good when these things are consistent across tumor types • Once again, the company is moving forward with a phase III trial based on the data from a subset analysis • Once again, I would urge caution, and prefer a less dramatic step Last thing on cMet trials • Thank you to the authors for calling the toxicity profiles manageable. • The most common phrase concluding ASCO abstracts – “This (drug, regimen, etc) was well-tolerated and further study is warranted” • Often, neither is true Symptom Management • We have spent millions of dollars, man/woman-hours, and gigabytes of memory on global quality of life – This has been of limited utility • Difficult to interpret – Worsening disease negatively affects QOL, as can side effects of drug • Heterogeneity as to how we as individuals define QOL • We mostly use it to justify that it is okay to use borderline effective agents – Desperation will make patients “tolerate” a lot more side effect Safety events from first SHARP presentation Sorafenib (n=297) Placebo (n=302) • Treatment-emergent serious adverse events (SAE, %) 52 54 • Drug-related adverse events (%) 13 9 • Drug-related adverse events (%) Diarrhea Pain (abdomen) Weight loss Anorexia Nausea Hand-foot skin reaction Vomiting Alpecia Liver dysfunction Bleeding All 39 8 9 14 11 21 5 14 <1 7 Grade 3/4 8 2 2 <1 <1 8 1 0 <1 <1 All Grade 3/4 11 3 <1 3 8 3 3 2 0 4 2 <1 0 <1 1 <1 <1 0 0 <1/<1 CTC Version 3.0: – Grade 2: Skin changes (e.g., peeling, blisters, bleeding, edema) or pain, not interfering with function – Grade 3: Ulcerative dermatitis or skin changes with pain interfering with function – While we might not know how to measure global quality of life in a meaningful way, we can choose a symptom/side effect and address it A Randomized Controlled Phase II Study of the Prophylactic Effect of Urea-Based Cream on the Hand-Foot Skin Reaction Associated with Sorafenib in Advanced Hepatocellular Carcinoma Zhenggang Ren1,Kangshun Zhu2, Haiyan Kang3, Minqiang Lu2, Zengqiang Qu4, Ligong Lu5, Tianqiang Song6, Weiping Zhou4, Hui Wang7, Weizhu Yang8, Xuan Wang9, Yongping Yang10, Lehua Shi4, Yuxian Bai11, Sheng-Long Ye1* 1 Zhongshan Hospital, Fudan University, Shanghai, China; 2 The Third Affiliated Hospital of Sun Yatsen University, Guangdong, China; 3 301 Military Hospital, Beijing, China; 4 Eastern Hepatobiliary Surgery Hospital of the Second Military Medical University, Shanghai, China; 5 Guangdong Provincial People's Hospital, Guangdong, China; 6 Tianjin Cancer Hospital , Tianjin, China; 7 Jilin Provincial Tumor Hospital, Jilin, China; 8 Union Hospital of Fujian Medical University, Fujian, China; 9 The 81 Hospital of the Chinese People's Liberation Army, Nanjing, China; 10 302 Military Hospital, Beijing, China; 11 Heilongjiang Provincial Cancer Hospital, Heilongjiang, China Incidence of Worst-grade HFSR Prophylactic Ureabased Cream + BSC Grade of HFSR* (Arm A) N=439 (%) BSC (Arm B) N=432 (%) Total N=871 (%) 193(44.0) 114(26.4) 307(35.3) 246(56.0%) 318(73.6%) 564(64.8%) 1 155(35.3) 192(44.4) 347(39.8) 2 72(16.4) 98(22.7) 170(19.5) 3 19(4.3) 28(6.5) 47(5.4) 2/3 91 (20.7) 126(29.2) 217(24.9) 0 All Grade (%) P Value <.0001 0.004 • Primary Endpoint: The incidence of all-grade HFSR was significantly lower in Arm A (p<0.0001) • Secondary Endpoint: The incidence of grade ≥ 2 HFSR was significantly lower in Arm A (p=0.004) • The incidence of HFSR by grade was lower in Arm A • More patients in Arm A did not develop HFSR Prevalence of All-grade HFSR at Each Visit 60 50 Arm A Arm B % 40 30 20 10 0 Week 0 Arm A 1.16 Arm B 1.18 Week 2 31.4 36.1 Week 4 40.8 49.8 *EOS: 2 weeks after end of study Week 6 36.2 52.1 Week 8 Week 10 Week 12 28.9 23.2 18.5 47.2 33.8 28.2 EOS* 13 17.8 % Time to the first HFSR event Secondary Endpoint • The median time to the first HFSR event was 2.5 fold longer in Arm A compared to Arm B (84 days vs. 34 days, p<0.0001) HFSR Conclusions • Urea-based hand creams helped – Less severity – Delay of onset • This reduces the number of people who will not get benefit from sorafenib who have to endure this side effect • It is worth a consideration for your patients • More studies like this should be done to alleviate the suffering brought on by our treatments Overall Conclusions • We all have little tricks we do to help ameliorate side effects of our drugs – But Ren, et al showed that we can systematically analyze what we are doing – I would argue these types of studies that focus on a symptom or side effect are more valuable than all the QOL analyses we have ever done • I cannot name one incidence where we changed our therapies based on global QOL • We have solely used it to justify what we wanted to do anyhow