Perspectives on defining ruxolitinib resistance/suboptimal response and therapeutic decision-making in this setting Claire Harrison, MD

Burden of Myelofibrosis MF Associated Symptoms Splenomegaly Premature death Anemia/ Cytopenias

Assessing Ruxolitinib in MF Patients Anemia PLTS Therapy Symptoms Anemia PLTS Spleen Symptoms NET Spleen

Ruxolitinib Therapy Scenarios Clear benefit spleen, symptoms, no heme toxicity Clear benefit spleen/ symptoms, heme tox Clear benefit symptoms, suboptimal spleen, no heme tox Clear benefit symptoms, suboptimal spleen, heme tox Suboptimal symptoms/ Spleen, no heme tox Suboptimal symptoms/Spleen, heme tox Minimal symptoms +/- Spleen, no heme tox Minimal symptoms +/- Spleen, heme tox No response, no heme tox No response, heme tox ? Change Change

Definitions………………… Primary resistance an inability to achieve landmark response, eg fail to achieve major or complete cytogenetic response in CML ie optimal vs suboptimal response Secondary resistance those who achieve but subsequently lose relevant response Relapse ? more appropriate here progression Intolerance usually heme toxicity for ruxolitinib

In addition Requires a facet – eg measure of symptoms or spleen size Requires definition of appropriate response AND Definition of sufficient “lack of” or “loss of” response or progression

Spleen Definition of “optimal response” Definition of progression? Comfort I – 25% beyond baseline Comfort II – 25% above nadir eg, patient with a starting spleen volume of 2000cm3 and study nadir of 500cm3 would have progressed with a spleen volume of 625cm3 on Comfort –II, but 2500cm3 on Comfort-I.

Symptoms Optimal response ……..? Progression could be loss of that response but by how much?.......and what about durability?

Molecular resistance We do not understand this aspect well! At present patients are poorly characterised Potential mechanisms eg specific mutations or overexpression of JAK1 have been described in vitro but not in vivo

Other aspects of resistance/progression Other disease progression? Anemia or thrombocytopenia Blasts Leucocytosis Event eg thrombosis?

CASE 63 year ♂, MF diagnosed 2008, presented with pancytopenia and splenomegaly, JAK2 V617F neg HC but dose limited by cytopenias Enrolled COMFORT II trial Oct 2009 commenced 15mg bd Dose reduction Jan 2010 for thrombocytopenia, 10 mg and then further to 5 mg Ongoing bone pain Stopped trial at week 72 due to lack of effect on symptoms and splenomegaly and thrombocytopenia.

Thrombocytopenia Start of study Dose reduction Dose reduction Stop

Week 12 Week 60

Primary refractory disease +/- intolerance Stopped ruxolitnib Managed with small doses of HC Enrolled in ARD12181 with JAK inhibitor SAR302503 Currently cycle 12 on study Reduction in spleen and symptom improvement

SAR302503 Phase II Study Design: ARD12181 JAKARTA 2 Phase 2, single arm, multicenter, open-label study Subjects who previously received Ruxolitinib treatment for PMF or Post-PV MF or Post-ET MF or PV or ET for at least 14 days and discontinued the treatment for at least 14 days prior to study entry Intermediate or High risk Primary MF Post-Polycythemia Vera Myelofibrosis Post-Essential Thrombocythemia Myelofibrosis according to the 2008 World Health Organization (WHO) criteria Recent amendment changing discontinuation period from 30 days to 14 days 70 pts Dose regimen SAR302503 once daily, Starting dose: 400mg/day Continuously in 28-day cycles Titration allowed: 200mg, 300mg, 400mg, 500mg or 600mg Primary endpoint: % of patients who achieve ≥35% reduction in spleen volume from baseline at C6 EOC by MRI/CT. Secondary endpoint: - % of subjects with a ≥50% reduction from baseline to the end of Cycle 6 in the total symptom score using the modified MFSAF Safety, PK/PD, JAK2V617F allele burden, JAK-STAT and other signaling pathways, OS 15

Study population Key inclusion criteria Diagnosis of PMF or Post-PV MF or Post-ET MF, according to the 2008 World Health Organization (Appendix B) and IWG-MRT criteria Subjects who previously received Ruxolitinib treatment for PMF or Post-PV MF or Post-ET MF or PV or ET for at least 14 days and discontinued the treatment for at least 14 days prior to study entry. Myelofibrosis classified as high-risk or intermediate-risk (IWG-MRT response criteria DIPSS assess MF score (Passamonti). Spleen ≥5 cm below costal margin as measured by palpation. Key exclusion criteria Absolute Neutrophil Count (ANC) <1.0 x 109/L Platelet count <50 x 109/L

Platelet count while on ARD12181

Haemoglobin on ARD12181

Leucocyte count on ARD12181

Current status Spleen MRI 20/11/2012

Current status Bone marrow

Why do patients respond differently to different agents? Heterogeneity of disease Molecular Cytokine Stage Hemopoietic reserve Individual target of patient/physician Ability to withstand different toxicities

Binding Specificity of JAK2 Inhibitors In Clinical Development Fold-increase in concentration in comparison to that needed to inhibit JAK2 JAK2 (nM) JAK1 JAK3 TYK2 FLT3 JAK2 V617F Other† Ruxolitinib1 2.8 1X 153X 7X - SAR3025032 3 35X 334X 135X 5x CYT3873 18 9X JNK1, CDK2 AZD14804 <3 16X TrkA, Aurora A, FGFR SB15185 23 56X 23X 2X Yes LY27845447 2260 0.024X (55) Lestaurtinib8 1 NA 3X JAK2 inhibitors have different binding specificities and several of the JAK2 inhibitors have additional kinase targets SAR302503, SB1518 and AZD1480 exhibit selective binding specificity for JAK2. Ruxolitinib and CYT387 are dual JAK1 and JAK2 inhibitors, which may potentially cause more off-target effects. LY2784544 is unique amongst the JAK2 inhibitors, as it is highly specific for the JAK2V617F mutant allele. References 1. Quintás-Cardama A, et al. Blood 2010; 115:3109–3117. 2. Wernig G, et al. Cancer Cell 2008; 13:311–320. 3. Tyner JW, et al. Blood 2010; 115:5232–5240. 4. Ioannidis S, et al. J Med Chem 2011; 54:262–276. 5. Hart S, et al. Leukemia 2011;25:1751–1759. 6. Paquette R, et al. Blood 2008; 112: Abstr 2810. 7. Ma L, et al. ASH Annual Meeting 2010; Poster 2014087. 8. Hexner EO, et al. Blood 2008; 111:5663–5671. Data are taken from separate studies and are not comparative. †Includes other kinases of note. Extensive lists of kinases tested and IC50 values are available in the literature.CDK2, cyclin-dependent kinase 2; FGFR, fibroblast growth factor-receptor; FLT3, Fms-like tyrosine kinase 3; JNK1, Mitogen-activated protein kinase 8; TrkA, neurotrophic tyrosine kinase receptor type 1. A full list of references is provided in the slide notes.

SUMMARY JAK inhibitors deliver meaningful effects upon splenomegaly, symptoms and survival BUT optimal response is not yet defined Resistance, progression and intolerance need to be defined but are being identified in some patients Switching to alternative JAK inhibitors may be a successful strategy for these patients