Comparing Immunotherapy with High Dose IL-2 and Ipilimumab

Transcription

1 Comparing Immunotherapy with High Dose IL-2 and Ipilimumab Michael K Wong MD PhD FRCPC mike.wong@med.usc.edu

2 Disclosures Speaker s Bureau, Advisory Boards, Consultant: Prometheus Bristol Myers Squibb Novartis Merck

3 Why is this important? The ability to deliver cures to patients is at stake (patient stories) accessed April 9th, 2012

4 Why is this important? Both HD IL-2 and Ipilimumab individually give rise to long term durable responses.

5 Agenda Compare and Contrast IL-2 and Ipilimumab Composition Mechanism of Action Administration Efficacy Toxicity Profile Special, Specific Situations Construct an approach to make decisions about melanoma patients

6 IL-2 and ipilimumab differ in their composition 133 amino acids, MW: 16 kd ½ life: 7 minutes 2 nd phase: 2 hours ½ life: 359 hours 1400 amino acids, MW: kD

7 Waldmann TA. Nature Rev. Immun. 6 (8): (2006) ;

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9 IL-2 use in melanoma Various Dose, Schedules, Routes tested Subcutaneous, Intralesional, etc. Low Dose, High Dose, Decrescendo, In combination with cytotoxic chemotherapy Units/kg IV Q8hours X 14 REST Units/kg IV Q8hours X 14

10 CTLA-4 Blockade Enhances Tumor-Specific Immune Responses Inhibit the Inhibitor Antibodies to CTLA-4 Antibodies binds to CTLA-4 on the cell surface CTLA-4 cannot bind B7

11 Unfair Comparisons

12 Ground Rules for Comparison There are no head to head comparisons between IL-2 and Ipilimumab Therefore each have to be interpreted within its own context Patient population Other therapies, supportive care options Viewer s viewpoint is colored by their own experience and perception of toxicity and efficacy.

13 Deaths from therapy Trend to improvement Interleukin -2 % Deaths on IL-2 Therapy (n=155) Kammula US et al. Cancer 1998;83: Ipilimumab Hodi Trial: 9/2004 8/2008 (ipi vs. ipi +GP100 vs. GP100) 14 study related deaths (2.1%), 7 deaths associated with immune-related adverse events Robert Trial: 8/2006 1/2008 (DTIC + ipi vs. DTIC + placebo) No GI perforations No deaths due to study drug on DTIC + ipi arm.

14 Timing of Toxicity Ipilimumab Outside of your vision Immune related toxicities can be moderate, severe, or life-threatening. Multiple organ systems. May be slow onset, insiduous, and mimic disease progression. May mimic common ailments (diarrhea). IL-2 Right in front of you Major life threatening issue is capillary leak syndrome (CLS) and its downstream effects. Occurs and resolves within hours of an IL-2 dose. Patient are usually discharged free of permanent sequelae of CLS. Prescribing Information: Vervoy, 2011

15 Yervoy Yervoy Yervoy Prescribing Information, 2011

16 Timing of Toxicity Onset is Variable Lebbé C, O Day SJ, Sileni VC, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma. Presented at the Perspectives in Melanoma XII. New York City, NY; 2008 Oct 2-4. Abstract O-015

17 Time to Resolution maybe prolonged Lebbé C, O Day SJ, Sileni VC, et al. Analysis of the onset and resolution of immune-related adverse events during treatment with ipilimumab in patients with metastatic melanoma. Presented at the Perspectives in Melanoma XII. New York City, NY; 2008 Oct 2-4. Abstract O-015

18 IL-2 Toxicity is predictable Mantra: If you know what you are doing, you can get in front of the toxicity

19 Capillary Leak and Vasodilation is the Primary Problem Adapted from: Lee RE et al, J Clin Oncol 1989;7:7-20.

20 Mean serum creatinine for 199 HD IL-2 patients. Significant impairment of Return renal to function baseline at within the end days of IL-2 therapy. Baseline Schwartzentruber DJ Principles of Administration and Management of Side Effects. In: Biologic Therapy of Cancer, Ed DeVita, Jr. et al, 1991

21 Interleukin-2 induces profound reversible cholestasis Fisher B et al. J Clin Oncol 1989;7:

22 Logistical issues with immunotherapy sequencing Failure of Primary Therapy at first evaluation IL-2 3 weeks Ipi Ipi 9 weeks IL-2 Steroids Steroids Steroids Endocrinopathy Adrenal failure Steroids

23 Evidence based issues with immunotherapy sequencing Hodi FS et al, N Eng J Med 2010

24 Impression: Complete Response Remains in CR at Year 3. Pre Anti-CTLA4 Therapy 12 weeks weeks 36 weeks 3 4

25 Special Specific Situations Brain Metastases Combination with Vaccines

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27 Brain Metastases: Suggestion of efficacy for ipilimumab Data from: anecdotal, case reports (1), expanded access trial. Phase II brain metastases (2) Asymptomatic : OS - 31% at 1 year ; 26% at 2 years Symptomatic : OS - 9% at 1 year ; 10% at 2 years No new safety signals, no increase CNS-related events (1) Schartz NEC, Farges C, Madelaine I, et al. Complete Regression of a previously untreated melanoma brain metastasis with ipilimumab. Mel. Res. 2010, 20: 247, 250 (2) Margolin K, et al. Safety and efficacy of ipilimumab-treated patients with melanoma and brain metastases. Presented at the European Multidisciplinary Cancer Congress. Stockholm; 2011 Sep 24. Abstract 9306.

28 The combination of IL-2 + GP100 shows benefit over IL-2 alone Median OS IL-2: 11.1 months IL-2+ gp100: 17.8 months Median PFS IL-2: 1.6 months IL-2+ gp100: 2.2 months *Schwartzentruber D et al. gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma. NEJM 364: 2119 (2011), Central Reviewed

29 Combining Ipilimumab + GP100 does not provide addition benefit to Ipi alone Median OS IPI: 10.1 months * IPI+gp100: 10.0 months Gp100: 6.4 months * p=.003 Median PFS IPI: IPI+gp100: Gp100: 2.86 months 2.76 months 2.76 months Hodi FS et al. N Engl J Med Aug 19;363(8):711-23

30 Practical Conclusions Patients who are suitable for immunotherapy should be considered for IL-2 and ipilimumab Selection of the therapeutic strategy requires careful evaluation of the risks:benefits of each approach by a knowledgeable practitioner with the full participation of the patient and their support team. Brain metastases are a special situation where ipilimumab maybe the immunotherapy option of choice.

31 If you have the runway Give (Braf) IL-2 then Ipi So What are you doing on Monday?

32 Comparing Immunotherapy with High Dose IL-2 and Ipilimumab Michael K Wong MD PhD FRCPC mike.wong@med.usc.edu