NOYCIA Validation of the Princess Margaret Immune Oncology Prognostic Index (PM-IPI) for patients treated in immune oncology early phase trials

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Anissa Garrett
5 years ago
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Razak 1,2, Aaron R. Hansen 1,2, Lisa Wang 1,2, Marcus O. Butler 1,2, Lillian L. Siu 1,2 and Philippe L.

1 Validation of the Princess Margaret Immune Oncology Prognostic Index (PM-IPI) for patients treated in immune oncology early phase trials Daphne Day 1,2, Anna Spreafico 1,2, Stephanie Lheureux 1,2, Albiruni R. Razak 1,2, Aaron R. Hansen 1,2, Lisa Wang 1,2, Marcus O. Butler 1,2, Lillian L. Siu 1,2 and Philippe L. Bedard 1,2 1 Princess Margaret Cancer Centre, Toronto, Canada 2 Department of Medicine, University of Toronto, Canada NOYCIA 2017

2 Background and Study Objective Over the next decade, numerous immune oncology (IO) agents will enter early drug development. Phase I trials are the first clinical studies to evaluate the safety and efficacy of novel therapies, and typically involve patients with advanced refractory malignancies. Thus, the appropriate selection of patients who will derive benefit and survive long enough to evaluate the causality of adverse events is vital. Previously published P1 prognostic scoring systems were developed in patients treated in cytotoxic and molecularly targeted trials 1-4. Of these, only the Royal Marsden Hospital Prognostic Index (RMI: albumin <35g/L, LDH >upper limit of normal and >2 metastatic sites) has been independently validated 5. 1.Arkenau et al, Br J Cancer 98: , Chau et al, BMC Cancer 11:426, Fussenich et al, Eur J Cancer 47: , Stavraka et al, Cancer 120:262-70, Garrido-Laguna et al, Cancer 118:1422-8, 2012

3 Development of the Princess Margaret Immune Oncology Prognostic Index (PM-IPI) We previously developed the PM-IPI (ECOG performance status [PS] 1, albumin <lower limit of normal [LLN] and >2 metastatic sites) from a retrospective cohort of 192 pts treated in phase I IO trials (development cohort). Other baseline clinical variables analyzed were: albumin, hemoglobin, sodium, age, number of prior systemic treatments, neutrophil-to-lymphocyte ratio and platelet count. The PM-IPI prognosticated for overall survival (OS), 90-day mortality (90DM) and was associated with improved overall response rate (ORR) and progression free survival (PFS). Our aim was to prospectively validate the PM-IPI in an independent cohort of pts treated on IO trials.

4 Methods We identified consecutive patients treated in early phase IO trials at PM from an institutional electronic database. A study was included if it is an early phase trial and at least one of the investigational agents is an immune checkpoint inhibitor or co-stimulatory agonist. Patients from the development cohort were excluded. The ability of the PM-IPI to prognosticate OS and 90DM, and predict PFS and ORR was compared with the RMI using the C-index and AUC (0.5 = no discrimination, 1 = perfect discrimination).

Results Baseline patient characteristics Number % Median (range) Gender Male 80 53% Female 72 47% Age 60.0 (20.0-84.

Neuroendocrine 3 2% Other 17 11% Time from diagnosis 68.4 (1.6-621.

5 Results Baseline patient characteristics Number % Median (range) Gender Male 80 53% Female 72 47% Age 60.0 ( ) years ECOG ECOG % ECOG % Primary tumor site Gastrointestinal 35 23% Gynecology 25 16% Head and nec 23 15% GU 15 10% Melanoma 9 6% Sarcoma 9 6% Breast 8 5% Thoracic 8 5% Neuroendocrine 3 2% Other 17 11% Time from diagnosis 68.4 ( ) weeks Numbers of prior systemic therapies 1 (0-7) < % % Number of metastatic sites 3 (1-7) 2 sites 75 >2 sites 77 Sites of metastasis Lung 91 60% Liver 62 41% Bone 39 26% Brain 5 3% Drug target(s) IO trials: Drug targets No. of patients Drug target(s) No. of patients PD-1 35 PD-1 3 GITR +/- PD-1 22 OX40 2 PD-1 19 PD-L1, CTLA-4 or both 2 LAG-3 +/- PD BB + PD-L1 2 OX40 + PD-L1 +/- VEGF 9 CD40 + PD-L1 2 IDO + PD-1 8 CD40 + Ang-2/VEGF 2 CSF-1R + PD-1 6 CD73 + PD-1 1 VEGF + PD-1 6 PD-1 + CTLA-4 1 TIM-3 +/- PD-1 5 PD-L1 + CTLA-2 1 PD-L1 5 TIGIT +/- PD-L1 1 PD-L1 5 MEK + PD-L1 1 PD-1 3 ICOS +/- PD-1 1 Total 152 Combination 54% Single agent 46%

6 Results - PM-IPI is validated in an internal cohort Patient outcomes (n=152) Median PFS: 9.0 weeks 90DM: 14% OS: 39.7 weeks ORR: 7% by RECIST 1.1/ irecist/irrc Multivariable analysis ECOG PS 1 (HR 2.7, p=0.01), albumin <LLN (HR 2.09, p=0.01) and metastatic sites >2 (HR 1.8, p=0.04) remain independently prognostic for OS. Comparison with the RMI The prognostic performance of PM-IPI was superior to the RMI for OS and 90DM, but not PFS and ORR. OS PFS 90DM ORR C-index AUC PM-IPI RMI

7 OS Results PFS PM-IPI N Events Median OS (weeks) PM-IPI N Events Median PFS (weeks) Patients with a PM-IPI score of 2-3 compared to 0-1 had significantly shorter OS (HR 3.3, p<0.0001) shorter PFS (HR 1.7, p=0.005) higher 90DM (OR 12.2, p=0.019) trend towards lower ORR (OR 0.4, p=0.15)

8 Conclusions In this independent validation cohort, the PM-IPI prognosticated for OS and 90DM and was associated with PFS. Validation in a large external cohort is ongoing. Assessment of tumor-infiltrating lymphocytes and immune-related gene expression in pre-treatment archival tumor samples is also underway, to determine if factors in the tumor immune microenvironment are independently prognostic and may be integrated in the PM-IPI. PM-IPI may be used as an eligibility criterion or a stratification factor in future IO trials. This may assist in improving patient selection for IO phase I trials and accelerating the development of IO therapies.

9 Acknowledgements Drs. Philippe Bedard Lillian Siu Anna Spreafico Stephanie Lheureux Albiruni R. Razak Aaron R. Hansen Marcus O. Butler Anthony Joshua Natasha Leighl Amy Prawira Jeremy Lewin Kyaw Aung Daniel Shepshelovich Yada Kanjanapan Neda Stjepanovic Rossanna Pezo Biostatistics support: Ms Lisa Wang TIP and DDP Nursing Staff Study and Data Coordinators Patients

Understanding Checkpoint Inhibitors: Approved Agents, Drugs in Development and Combination Strategies. Michael A. Curran, Ph.D.

Understanding Checkpoint Inhibitors: Approved Agents, Drugs in Development and Combination Strategies Michael A. Curran, Ph.D. MD Anderson Cancer Center Department of Immunology Disclosures I have research