Revisiting the Role of Radiation Therapy in Advanced Disease Abigail T. Berman, MD, MSCE Dept. of Radiation Oncology Perelman School of Medicine of University of Pennsylvania 6/21/18 2018 New Advances in Lung Cancer Rittenhouse Hotel
Disclosures NIH R01 PQ10 Microbiome and Radiotherapy (pending) NIH SBIR Lignamed 2
PENN Thoracic Radiation Oncology Steven Feigenberg, MD Abigail T. Berman, MD William P. Levin, MD 3
Radiation in the setting of metastatic NSCLC (beyond the role of palliation): 1) Oligometastatic disease 2) Oligoprogressive disease 3) Potentiating an immune response 4
Gomez et al. Lancet Oncology 2017 5
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Using irradiated tumor as in situ tumor vaccine By its nature, RT is a local form of therapy However, can it be used to potentiate a systemic response? Pre-clinical studies: RT can augment immune response TLR4 on dendritic cells (DCs) T cell migration and effector T cell function vascular permeability: influx of leukocytes Endothelial cell adhesion molecules priming of T cells in draining lymph nodes (VCAM-1, E-selectin,..) tumor Ag presentation by DCs T cell chemokines MHC molecules on tumor cells FAS death receptor on tumor cells CXCL16 (recruits activated effector T cells) 10
9.5 Gy x 3 Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma Postow et al. NEJM 2012 11
PD-1/PD-L1 Ab can also augment immune response Effector Phase stimulates immune response brakes immune response 12
Clinical Evidence: Radiation + anti-pd-1 Phase I Trials: University of Chicago: Phase I trial of pembrolizumab + radiation for metastatic cancers (27 tumor types) N=79 with a median of 5 prior therapies 13.2% objective response Overall, safe, but unclear how much radiation adds Luke JJ et al. JCO, 2018 13
PD-1-RADVAX: A stratified phase I trial of pembrolizumab (PD-1 mab) with hypofractionated radiotherapy in patients with advanced and metastatic cancers 2.1 Trial Design Phase I cohort study of a fixed dose of Pembrolizumab in combination with 2 distinct regimens of hypofractionated RT. There will be 5 groups of patient diagnoses: Stratum 1 Metastatic melanoma patients who progressed while on PD-1 or PD-L1 therapy Metastatic NSCLC patients who progressed while on PD-1 or PD-L1 therapy Metastatic & locally advanced pancreatic Ca patients Metastatic breast Ca patients Other metastatic sites Stratum 2 PI: Maity 14
Stratum 1 PI: Maity 15
Hypofractionated RT in Patients with Advanced/Metastatic Cancers UPCC 40914 Clinicaltrials.gov NCT02303990 PI: Maity 16
Results of Safety Phase 12 patients in each stratum 20 of 24 patients (83%) had treatment-related AEs (all grade 1 or 2) 9 grade 3 AEs, none treatment related 2 immune-related AEs, both grade 2 (in same patient) Hypothyroidism Pneumonitis Stratum 1: 2 partial responses (by RECIST) Stratum 2: 1 complete response (RCC), 2 prolonged stable disease PI: Maity 17
Stratum 1: Patient 15 9/2013: Dx w/metastatic NSCLC (R hilar mass with bone mets) carbo/taxol x 6 cycles palliative RT to R lung mass (37.5 Gy) 9/2014 5/2015: nivolumab 1/2015 5/2015: progression PI: Maity 18
5/2015: taken off nivolumab and enrolled on RADVAX study started on pembrolizumab and given 8 Gy x 3 to paraaortic mass (6/2015) Continued on pembro after 6 cycles PI: Maity 19
no RT 5/2015 (pre-radvax) 12/2015 8 Gy x 3 20
Conclusions Radiation can be a key component of management of oligoprogressive or oligometastatic patients There is evidence in patients that radiation can reinvigorate immune system in patients progressing on prior ICB Pembro + HFRT trial NSCLC: 1 out of 7 had PR Melanoma: 1 out of 5 had PR Unanswered questions How to predict responders Optimal ICB, RT dose, site to irradiate, sequencing 21
RADVAX Collaborators RadOnc Amit Maity Stephen Hahn (MDACC) Andy Minn Abigail Berman Charles Simone Lilie Lin John Lukens Edgar Ben-Josef John Christodouleas Dana Patsch Ramesh Rengan (U. Wash) Pathology George Xu Radiology Dan Pryma Statistics Rosemarie Mick 22
RADVAX Collaborators RADVAX pre-clinical team Minn lab Vonderheide Lab Wherry Lab Christina Twyman- Andrew Rech Alex Huang Saint Victor Lee Richman Erietta Stelekati Hannah Dada Joseph Benci Pamela Odorizzi Ramin Herati Kathleen Mansfield Kristen Pauken 23