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Abstracts 4005-8

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,

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Abstracts 4005-8

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  1. Abstracts 4005-8 Jordan Berlin, MD Ingram Professor of Clinical Research Co-Director, GI Oncology Program Vanderbilt-Ingram Cancer Center

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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

  11. Best Target Lesion Regression of Patients with ≥1 Post-Baseline Tumor Assessment (N=36)* ‡ Prior sorafenib Confirmed PRs No prior sorafenib ‡ ‡ *per Original RECIST 1.0

  12. Best AFP Time Point Response of Patients with ≥1 Post-Baseline Measurement (N=26)* + + + Prior sorafenib No prior sorafenib + Increase >100% from Baseline * Only Patients with AFP ≥ 20ng/mL at baseline are shown.

  13. 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

  14. 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

  15. Primary Endpoint: TTP (ITT Population) HR: 0.64 (90% CI: 0.43-0.94) Log Rank: P=0.04 ARQ 197-215 PRESENTED BY: LORENZA RIMASSA 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

  16. Improved TTP in MET Diagnostic High Group 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

  17. Improved OS in MET Diagnostic High Group 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

  18. 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

  19. INTRIGUINGLY, SUPPORT FOR A BIOMARKER APPROACH COMES FROM ANOTHER DISEASE SITE

  20. 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

  21. Clinical Efficacy in the Intent-to-Treat Population* Progression-Free Survival HR 0.64 Overall Survival HR 0.73 • *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.

  22. 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

  23. Improved PFS and OS in METHigh Patients Progression-Free Survival HR 0.51 Overall Survival HR 0.29 • MET-evaluable OS HR, 0.95 • ITT OS HR, 0.73 *HR adjusted for baseline disease extent and ECOG PS.

  24. High Levels of Tumor MET May Be Predictive and Prognostic • Patients with gastric tumors with high MET expression may have a poorer prognosis but may receive more benefit from rilotumumab

  25. 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

  26. 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

  27. 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

  28. Safety events from first SHARP presentation

  29. 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

  30. 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 Yat-sen 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

  31. Incidence of Worst-grade HFSR • 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

  32. Prevalence of All-grade HFSR at Each Visit % *EOS: 2 weeks after end of study

  33. Time to the first HFSR eventSecondary 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)

  34. 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

  35. 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

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