2015 Eugene P. Schonfeld Award

Transcription

1 2015 Eugene P. Schonfeld Award

2 Eugene P. Schonfeld

3 Schonfeld Award Past Winners David Swanson Michael Atkins Ronald Bukowski Nicholas Vogelzang Robert Motzer William Kaelin Robert Figlin Bernard Escudier

4 Lesson #1 Good mentorship and collaborations are required

5 Mentors University of Chicago Residency and Fellowship UCSF Cleveland Clinic

6 Collaborators Lab collaborators Jim Finke, Dan Lindner Nursing colleagues Laura Wood, Beth Zanick Clinical collaborators Jorge Garcia, Steve Campbell

7 RESULTS: Of the 39 assessable patients, there were no complete responses but seven partial responses (objective response rate = 17%; 95% confidence interval, 8% to 34%). Five minor responses (25% to 50% decreased tumor size) were also observed. Median progression-free survival for the gemcitabine/5-fu group was 28.7 weeks. J Clin Oncol Jun;18(12): Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer. Rini BI, Vogelzang NJ, Dumas MC, Wade JL 3rd, Taber DA, Stadler WM. Section of Hematology/Oncology, University of Chicago Hospitals, IL PURPOSE: To determine the clinical response rate of the combination of weekly intravenous (IV) gemcitabine with continuous infusion fluorouracil (5-FU) in patients with metastatic renal cell carcinoma (RCC) PATIENTS AND METHODS: Between June 1998 and February 1999, 41 patients with metastatic RCC were enrolled onto this multi-institutional phase II study of gemcitabine 600 mg/m(2) over 30 minutes on days 1, 8, and 15 and 5-FU 150 mg/m(2)/d via continuous IV infusion through a permanent catheter on days 1 to 21 of a 28-day cycle.

8 You mean that s all you ve got?

9 Lesson #2 RCC is susceptible to attack by the immune system

10 Non-Myeloablative Allogeneic Transplantation in Renal Cell Carcinoma Author Pts. Response Rate GVHD TRM Childs 19 53% 74% 12% Rini 18 22% 55% 28% Ueno 15 20% 60% 22% Hentschke 10 0% 70% 20% Bregni 7 57% 86% 14% Nakagawa 9 11% 56% 0% Massenkeil 7 14% 71% 14% Pedrazolli 7 0% NR 17%

11 CALGB Adoptive Immunotherapy with Allogeneic Stem Cell Transplantation for Metastatic Renal Cell Carcinoma An Intergroup Phase II Study Brian I. Rini, MD University of California San Francisco

12 Efficacy No objective response was observed in 20 evaluable pts. Median progression-free survival: 4.2 months Median overall survival: 7.2 months

13 Lesson #3 Kidney Cancer is addicted to VEGF

14 Vascular endothelial growth factor (VEGF) receptor binding and intracellular signalling Brian I. Rini and Eric J. Small JCO 2005; 23:

15 Mechanism of activity of vascular endothelial growth factor (VEGF) -directed agents in renal cell carcinoma

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17 Change in Tumor Burden During Bevacizumab Therapy 200 Placebo 200 Low Dose 200 High Dose Tumor Burden Compared to Baseline (%) Weeks of Treatment Yang et al. N Engl J Med. 2003

18 Bevacizumab plus Interferon-alpha versus Interferon-alpha Monotherapy in Patients with Metastatic Renal Cell Carcinoma: Results of CALGB Brian I. Rini 1, Susan Halabi 2,3, Jonathan E. Rosenberg 4, Walter M. Stadler 5, Daniel A.Vaena 6, James N. Atkins 7, Joel Picus 8, Piotr Czaykowski 9, Janice Dutcher 10 and Eric J. Small 4 1. Cleveland Clinic Taussig Cancer Institute, Cleveland, OH 2. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC 3. CALGB Statistical Center, Durham, NC 4. University of California San Francisco, San Francisco, CA 5. University of Chicago Medical Center, Chicago, IL 6. University of Iowa, Iowa City, IA 7. Southeast Cancer Control Consortium Inc. 8. Washington University, St. Louis, MO 9. McGill University, Montreal, Quebec and the NCI Canada, Toronto, ON, Canada 10. New York Medical College, NY, NY and ECOG, Boston, MA

19 Progression-free Survival Progression-Free Survival Probability Bevacizumab plus IFN IFN, p< Time(months) Number of Patients at Risk IFN Bevacizumab plus IFN The median PFS was 8.5 months in patients receiving bevacizumab plus IFNA (95% CI= ) compared with 5.2 months (95% CI= ) in patients receiving IFNA monotherapy (p<0.0001). The estimate of HR adjusting for stratification factors is 0.71 (95% CI = , p<0.0001).

20 AG , a VEGFR/PDGFR Inhibitor, Demonstrates Anti-Tumor Activity in Cytokine-Refractory, Metastatic Renal Cell Carcinoma (RCC) B. Rini 1, O. Rixe 2, R. Bukowski 3, D. Michaelson 4, G. Wilding 5, G. Hudes 6, O. Bolte 7, H. Steinfeldt 8, S.D. Reich 8, R. Motzer 9 1 UCSF Comprehensive Cancer Center 2 Hosp. Pitie-Salpetriere 3 Cleveland Clinic Foundation 4 Massachusetts General Hospital 5 University of Wisconsin 6 Fox Chase Cancer Center 7 Medizinische Hochschule Hannover, Abt 8 Pfizer Inc 9 Memorial Sloan-Kettering Cancer Center San Francisco, CA Paris, France Cleveland, OH Boston, MA Madison, WI Philadelphia, PA Hannover, Germany La Jolla, CA New York, NY

21 Best Response by RECIST (N=52) No. % Partial Response 24 46% Stable Disease 21 40% No. with Tumor Shrinkage 20 38% No Response 7 14% Progression 4 8% Indeterminate 3 6% 21

22 Abstract No Axitinib vs Sorafenib as Second-line Therapy for Metastatic Renal Cell Carcinoma: Results of the Phase 3 AXIS Trial Brian I. Rini, 1 Bernard Escudier, 2 Piotr Tomczak, 3 Andrei Kaprin, 4 Thomas E. Hutson, 5 Cezary Szczylik, 6 Jamal Tarazi, 7 Brad Rosbrook, 7 Sinil Kim, 7 Robert J. Motzer 8 1 The Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; 2 Institut Gustave Roussy, Villejuif, France; 3 Klinika Onkologii, Oddzial Chemioterapii, Poznań, Poland; 4 Russian Scientific Center of Roentgen-Radiology of Rosmedtechnology, Moscow, Russia; 5 Baylor- Sammons/Texas Oncology Physician's Association, Dallas, TX, USA; 6 Central Clinical Hospital of Military Medical Academy, Warsaw, Poland; 7 Pfizer Oncology, La Jolla, CA, USA; 8 Memorial Sloan-Kettering Cancer Center, New York, NY, USA

23 Progression-Free Survival (probability) Progression-free Survival Subjects at risk, n Axitinib Sorafenib Time (months) Axitinib Sorafenib mpfs, mo % CI P< (log-rank) Stratified HR (95% CI ) Rini BI, et al. Lancet. 2011;378(9807):

24 Outcome to Sunitinib Rechallenge Characteristic (n=23) N (%) Median (range) duration of treatment (months) 6.8 ( ) Best Objective Response PR SD PD 5 (22%) 17 (74%) 2 (9%) Median PFS (months, range) 7.2 ( )

25 Lesson #4 The method in which VEGF TKIs are administered is intimately tied to their efficacy (i.e. dose and schedule matter)

26 AUC 12 (ng hr/ml) Progression-free Survival vs Exposure: Retrospective Analysis of Phase II RCC Data Fraction of Patients 900 Pts with AUC ng hr/ml before titration Pts with AUC 12 < 150 ng hr/ml before titration Pooled RCC Patients AUC 12 after Dose Titration AUC 12 AUC 12 < 150 ng hr/ml 150 ng hr/ml PFS (weeks) ALL patients before titration No titration Before titration After titration Before titration After titration 5 mg BID 7 mg BID 10 mg BID mpfs, wks (95% CI) AUC 12 < 150 ng hr/ml 32 (24, 48) n=36, 26 AUC ng hr/ml 52 (43, 69) n=139, 83 HR (95% CI) 0.56 (0.359, 0.874) n=number of patients meeting AUC criterion, number of PFS events assessed by investigator AUC 12 = area under the plasma concentration-time curve from 0 to 12 hr

27 Front-line Axitinib Dose Titration Study Lead-in period (Cycle 1) Axitinib 5 mg BID (4 wks) During Cycle 1 (subset of patients) Randomization criteria a BP 150/90 mmhg and 2 concurrent anti-htn medications and No grade 3 or 4 axitinib-related toxicities and No dose reduction Yes No R A N D O M I Z E 1:1 Arm A Axitinib 5 mg BID + Axitinib dose titration b (blinded therapy) Arm B Axitinib 5 mg BID + Placebo dose titration b (blinded therapy) ABPM c 6-h PK sampling d a For at least 2 consecutive weeks b Titrated stepwise to 7 mg BID and then to a maximum of 10 mg BID if criteria for randomization to dose titration were met Arm C Axitinib 5 mg BID (no dose titration) C Ambulatory blood pressure monitoring performed at baseline and on Cycle 1 Days 4 and 15 d 6-hr PK sampling performed on Cycle 1 Day 15 Rini et al. Lancet Oncology 2013

28 Clinical Effect of Axitinib Dose Titration ORR (95% CI) P PFS from first dose Median, mo (95% CI) Total* (N=213) Active Titration (n=56) Placebo Titration (n=56) Nonrandomized (n=91) 48% 54% 34% 59% P= HR (95% CI) 0.85 (0.54, 1.35) P P=0.244 * Includes 10 patients who withdrew during lead-in period. P value is from a 1-sided Cochran-Mantel-Haenszel test stratified by ECOG PS from randomization system. Assuming proportional hazards, HR <1 indicates a reduction in favor of active titration; HR >1 indicates a reduction in favor of placebo titration. P value is from a 1-sided log-rank test stratified by ECOG PS from randomization system. CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; HR = hazard ratio; ORR = objective response rate; PFS = progression-free survival

29 Kaplan-Meier Estimates of PFS From First Dose in Randomized Arms There may be a higher tail of the curve in titrated patients Going from 10mg/day to 14 mg/day causes early drop off for either toxicity or pts who progress before an optimal dose is reached * P value is from a 1-sided log-rank test stratified by ECOG PS from randomization system. CI = confidence interval; ECOG PS = Eastern Cooperative Oncology Group performance status; HR = hazard ratio; mpfs = median progression-free survival

30 Kaplan-Meier Estimates of OS From First Dose in Randomized Arms Rini et al. ACSO 2015

31 AUC study by best observed RECIST response (or, why you can t guide axitinib dosing by measuring PK)

32 Initial and Escalated TKI Treatment Durations Of pts with evaluable tumor measurements 82% had a decrease in tumor burden after dose escalation at PD Ornstein et al. KCA 2015

33 Lesson #5 There are subsets of patients who benefit wildly from TKIs, and we have done a miserable job of identifying them prior to treatment

34 Preliminary Data: Axitinib Front-line mrcc Treatment Duration (n=402)

35 ORR 66% and mpfs 27.6 months!

36 Survival distribution function OS in patients with or without dbp 90 mmhg pooled axitinib mrcc studies dbp <90 mmhg (n=49) median OS 9.7 months dbp 90 mmhg (n=63) median OS 30.1 months Months Rini B et al. Clin Cancer Res Jun 1;17(11):3841-9

37 End of Cycle 2 Landmark OS Analysis Rini B et al. J Natl Cancer Inst May 4;103(9):763-73

38 Final multivariate models of associations between adverse events and survival endpoints for mrcc patients receiving sunitinib on schedule 4/2 Adverse event at any time point Adverse event by the 12-week landmark HR 95% CI P value* HR 95% CI P value* Neutropenia PFS OS Hypertension PFS OS < < Hand-foot syndrome PFS OS Asthenia/fatigue PFS OS < Thrombocytopenia PFS OS Donskov et al. Br J Cancer 2015

39 Lesson #6 Kidney cancer is extremely biologically diverse, and strategies to capitalize on that feature for select patients can best balance risk and benefit

40 RCC is an Inherently Diverse Disease Months

41 Prospective RCC Observation Study Clinically-evident metastatic RCC of any histologic subtype First documentation (radiographic or histologic) of metastatic RCC up to 12 months prior to registration on study No prior systemic therapy for RCC in the metastatic or neo/adjuvant setting. Prior XRT (including for CNS metastases) and prior nephrectomy/metastasectomy permitted but not required No disease-related symptoms Measurable / evaluable disease per RECIST v 1.0 CTs q 3 months year 1; q4m year 2, then q 6 months FKSI-DRS (QOL) and HADS (anxiety/depression) administered at baseline and every CT scan timepoint. Peripheral blood for immune cell quantification drawn at baseline and every CT scan timepoint. Initiation of systemic treatment per MD / pt discretion Rini et al. ACSO 2014

42 Results The median time on observation (from study registration to start of systemic therapy) was 14.9 months 21 patients (44%) have been under observation for >18 months 3 patients on observation over 5 years

43 Other lessons.... Don t debate an English-speaking Professor from Cambridge on European soil Don t ever follow either of these men into a bar for a quick pint

44 Conclusions Kidney cancer is a biologically diverse disease, with fundamental reliance on the VEGF pathway, and susceptibility to immune attack Every patient decision is a balance of risk and benefit

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