Interleukin-2 Single Agent and Combinations

Transcription

1 Interleukin-2 Single Agent and Combinations Michael K Wong MD PhD Norris Cancer Center University of Southern California mike.wong@med.usc.edu

2 Disclosures Advisory Board Attendance Merck Bristol Myers Squibb

3 Reframe the discussion IL-2 is a viable first option in selected patients with metastatic melanoma IL-2 is a viable combination agent with other immunorx and Targeted Therapies Single Agent Sequencing Combination

4 Interleukin : T cell growth factor cdna 1983 recombinant Soluble "hormone-like" mediator of the immune system. Cytokine: Immune system signaling molecule, leukocytotrophic hormone Stimulate B-cells, monocytes, Lymphokine-activated killer cells, natural killer cells, dendritic cells Function: Mediates natural response to microbial infection, Self: Non-self Waldmann TA. Nature Rev. Immun. 6 (8): (2006) ; Rosenberg, S. A. Cancer J. Sci. Am. 6, S2 S7 (2000).

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

6 Why is this a relevant discussion? IL-2 consistently delivers durable complete responses

7 Before IL-2 8 weeks after IL-2

8 Melanoma Case: IL-2 responses

9 Melanoma Case: IL-2 responses

10 IL-2 responses (270 patients) No progression in those responding for 30 mo. Six deaths (2%) all due to sepsis. CR: 17 (6%) (1 %) (1.5 %) PR: 26 (10%) (5 %) (9.5 %) RR: 16% (6%) (10.9 %) SD: (27 %) (17.5 %) Disease Control: (31 %) (28.5%) *Schwartzentruber D et al. gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma. NEJM 364: 2119 (2011), Central Reviewed (**) Best response group Table 2 from: Hodi FS et al. N Engl J Med. Aug 19;363(8): * 3 deaths (1.7%) ** 14 deaths (2.1%)

11 Durable responses with HD IL-2 Eight Phase II clinical studies conducted at 22 institutions Atkins M et al., High-Dose Recombinant Interleukin 2 Therapy for Patients with Metastatic Melanoma: Analysis of 270 Patients Treated Between 1985 and 1993., J Clin Onc 17: 2105 (1999).

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14 Safety 12 year study of consecutive patients on HD IL-2 no treatment-related deaths in the last 809 study patients

15 PROCLAIM Registry Data 267 patients from 13 sites in the US The adverse events associated with HD IL-2 administration are predictable, manageable and transient. Despite substantial excursions, lab values and AE returned to baseline prior to the next cycle of dosing Wong MK et al. The transient nature of significant toxicities associated with high dose interleukin-2: Preliminary data from the PROCLAIM Study SITC

16 Ipi Onset and Resolution of Toxicities Conclusions Ipilimumab toxicity onset is variable (3 weeks to > 3 months) Resolution takes on the orders of weeks to months Some toxicities are long term (but may not matter) Management of Immune-Related Adverse Events and Kinetics of Response With Ipilimumab.Weber JS et al. J Clin Oncol 30: 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 Timing of Therapy IL-2 ipilimumab

18 Timing of Therapy ipilimumab IL-2 Steroid taper First Evaluation

19 Subgroup Analyses of Overall Survival Hodi FS et al, Improved Survival with Ipilimumab in Patients with Metastatic Melanoma. N Engl J Med, 2010

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21 How might IL-2 + ipi work in synergy IL-2 T-cell expansion Augments T-cell cytolytic activity Augments the synthesis of secondary cytokines TNF-a, TNF-b, IFN-g Increases the number of circulating CD4 + CD25 hi FoxP3 + immunosuppressive Ipilimumab regulatory T cells. Constitutively expresses CTLA4

22 Combination: Ipi + IL-2 Long term follow up : the NCI experience. Patients with metastatic melanoma treated in three trials from 2002 to 2005 Protocol 1: 56 pt - ipilimumab + gp100 peptides. Protocol 2: 36 pt - ipilimumab + interleukin-2. Protocol 3: 85 pt - ipilimumab + gp100 peptides. dose escalation CTLA-4 Blockade with Ipilimumab: Long-term Follow-up of 177 Patients with Metastatic Melanoma. Prieto, PA et. al. Clin Cancer Res 2012;18:

23 Response Rate and Duration of Response (1) (*) (2) (*) It took an average of 30 months for patients to attain a CR status (1) There is [not] evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 (2) The combination of ipilimumab and interleukin-2 seems to have an increased CR rate Table 2 from: CTLA-4 Blockade with Ipilimumab: Long-term Follow-up of 177 Patients with Metastatic Melanoma. Prieto, PA et. al. Clin Cancer Res 2012;18: Tumor Regression and Autoimmunity in Patients Treated With Cytototic T Lymphocyte-Associated Antigen 4 Blockade and Interleukin 2: A Phase I/II Study. Maker AV et al. Annals Surg Oncol 2005; 12:

24 Overall Survival by Protocol Figure 1 from: CTLA-4 Blockade with Ipilimumab: Long-term Follow-up of 177 Patients with Metastatic Melanoma. Prieto, PA et. al. Clin Cancer Res 2012;18:

25 Incidence of Grade III / IV IRAEs there was a trend toward a decreased rate of grade III/IV IRAEs in protocol 2 P 2 = 0.14

26 Rationale IL-2 + XRT TIL TIL HMGB1 Tumor Antigens Inflam. Cytokines Fas/CD95 B7.1 MHC Type 1 Tumor Antigens TIL TIL

27 Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2 Tumor and Immunological Responses. Seung SK et al., Sci Transl Med 6 June 2012: Vol. 4, Issue 137, 137ra74 Treatment Naive 1 3 doses SBRT (20 Gy/fraction) 3 days IL 2 600,000 IU per kilogram

28 Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2 Tumor and Immunological Responses. Seung SK et al., Sci Transl Med 6 June 2012: Vol. 4, Issue 137, 137ra74 Stereotactic body radiation therapy (SBRT) X 3 Doses and IL-2 (6 cycles) PRE POST

29 Best tumor response by RECIST criteria of all target lesions not treated with SBRT Phase 1 Study of Stereotactic Body Radiotherapy and Interleukin-2 Tumor and Immunological Responses. Seung SK et al., Sci Transl Med 6 June 2012: Vol. 4, Issue 137, 137ra74

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31 PD1 :::::::::: PD1L IL - 2 IL - 2 IL - 2 IL - 2 IL - 2 IL - 2 IL - 2

32 Interaction between IL-2 and PD-1 PD-1 inhibits IL-2 production by Activated Lymphocytes Exogenous IL-2 overcomes PD-1 inhibitory signals at all time points Carter LL, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur J Immunology Volume 32, Issue 3, pages , 2002

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34 Targeted Rx + IL-2 Inhibitors possess high response rates but low cure rates (if any) Immunotherapy can cure but have low response rates Control MEK i BRAF i 100 Melanoma Differentiation Antigen Lymphocyte recognition within tumor Biopsy Study Increased T4 infiltration of BRAF i tissues. Boni A, et al Selective BRAF V600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Research 70:

35 BRAF i and IL-2: Considerations Pace of V600E (+) disease may preclude the ability to deliver immunotherapy (IL-2) Effect of BRAF inhibition on the intact immune systems is poorly understood. BRAF inhibition failures may not be amenable to be treated subsequently on immunorx. Combination vs Sequential therapy.

36 IL-2 has awaken from its dormancy IL-2 trials under Clinical Trials.gov Open trials Investigator Initiated Trials Preclinical Sequencing, combination, GI, GU, Ovarian..

37 Give If you IL-2 have as primary the runway therapy (in the absence of trials) What are you doing on Monday?

38 Interleukin-2 Single Agent and Combinations Michael K Wong MD PhD Norris Cancer Center University of Southern California mike.wong@med.usc.edu