NRG Oncology Lung Cancer Portfolio 2016

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1 NRG Oncology Lung Cancer Portfolio 2016 Roy Decker, MD PhD Yale Cancer Center Walter J Curran, Jr, MD Winship Cancer Institute of Emory University

2 NRG Oncology Lung Cancer Selected Discussion Stage III NSCLC Technology Trials Stereotactic Radiation Trials RT and Immuno-Oncology Concepts RTOG Foundation Lung Cancer Trial

3 SUMMARY NRG Oncology Lung Cancer Research Robust Portfolio Recent Major Observations Participatory in Basket and Bucket Trials Portfolio Complementary to Other Groups

4 Good PS Stage III NSCLC Pts: Selected Research Questions in 2016 Can Radiotherapy Be Further Improved? Better Use of Functional Imaging? Testing of Proton Therapy? Can New Systemic Therapies Help? Targeted to a Mutation Defined Subgroup? Not Targeted to a Specific NSCLC Subgroup?

5 NRG 1106: Stage III NSCLC Adaptive RT Based on Mid-Course PET Response REGISTRATION PRE-TX FDG-PET/CT (FMISO-PET/CT) IMAGING STRATIFIED RANDOMIZATION (TUMOR SIZE, NODAL DISEASE, HISTOLOGY) ARM 1: CONCURRENT CHEMO-RT RT to 50 Gy (2 Gy/Fx) Carboplatin/Paclitaxel Weekly ARM 2: CONCURRENT CHEMO-RT RT to 48.3 Gy (2.3 Gy/Fx) Carboplatin/Paclitaxel Weekly DURING-TX FDG-PET/CT IMAGING (AFTER FX BOTH ARMS) ARM 1: CONTINUE RT Same RT plan to 60 Gy total (30 Fx) ARM 2: ADAPTIVE RT Based on during-tx FDG-PET RT Gy/Fx up to 74 Gy individualized by MLD CONSOLIDATIVE CHEMOTHERAPY

6 PET-Adapted Radiation Initial PET/CT Therapy Mid-Tx PET/CT RTOG 1106 ~3 wks

7 PET-Adapted Radiation Therapy RTOG 1106 ~3 wks (47.5 Gy/ Gy/fx)

8 Good PS Stage III NSCLC Pts: Selected Research Questions in 2015 Can Radiotherapy Be Further Improved? Better Use of Functional Imaging? Testing of Proton Therapy? Can New Systemic Therapies Help? Targeted to a Mutation Defined Subgroup? Not Targeted to a Specific NSCLC Subgroup?

9 Promise of Proton Therapy in Lung Cancer? No grade 5 toxicities (treatment deaths) Two grade 4 protocol specified toxicity (decline in PFTs to <25% predicted & hypocalcemia) Same as initial report at 2-3 years 15 grade 3 protocol related toxicities Mostly pulmonary Two more patients since initial report

10 NRG1308: Protons vs IMRT Sample size = 560 patients Xing Liao, MD: PI

11 Multivariate Cox Model: RTOG 0617 Covariate Comparison (RL) HR (95% CI) p-value Radiation dose 60 Gy v 74 Gy 1.51 (1.12, 2.04) Histology Non-squam v Squam 1.31 (0.99, 1.75) Max esophagitis grade <3 vs (1.06, 2.20) Heart Contour Per Protocol vs. Not per protocol 0.67 (0.47, 0.96) GTV Continuous (1.000, 1.002) Heart V50(%) Continuous (1.004, 1.030) Backwards Selection: Exit criteria p>0.10 Two-sided p-values Removed from model: Age (continuous), overall RT review (per protocol vs. not per protocol), and lung V5 (continuous)

12 Proton Therapy Reduces Heart Dose Tucker and Liao, UTMDACC

13 3D Radiation vs Proton for NSCLC Proton Photon 3-DCRT JOE Y. CHANG, IJROBP Vol. 65, No. 4, pp , 2006I

14 Good PS Stage III NSCLC Pts: Selected Research Questions in 2015 Can Radiotherapy Be Further Improved? Better Use of Functional Imaging? Biomarkers for RT-Responsiveness? Better Education of Low Volume Centers? Testing of Proton Therapy? Can New Systemic Therapies Help? Targeted to a Mutation Defined Subgroup? Not Targeted to a Specific NSCLC Subgroup?

15 NRG/Alliance 1306 Current Design Eligibility: -Stage III -Good PS EGFRm or ALKm at CLIA Lab R E G I S T E R Stratify: -Wt. Loss -IIIA vs. IIIB -Chemo (EP vs. CboTax) EGFR m ALK m R A N D O M I Z E R A N D O M I Z E Standard Concurrent ChemoRT Erlotinib x 12 weeks Standard Concurrent ChemoRT Crizotinib x 12 weeks Standard Concurrent ChemoRT Standard Concurrent ChemoRT

16 Stratify: Wt. Loss NRG/Alliance 1306: Proposed Re-Design IIIA vs. IIIB Chemo choice Known vs. unknown molecular status at Step 1 R E G I S T E R S T E P 1 Pts with Unknown Molecular Status Testing at Central Facility (similar to MATCH) Pt. with Known EGFR/AL K Status R E R E G I S T E R S T E P 2 EGFRm ALKm Wild Type R R R Standard Concurrent ChemoRT Erlotinib x 12 weeks Standard Concurrent ChemoRT Crizotinib x 12 weeks Standard Concurrent ChemoRT Standard ChemoRT Standard ChemoRT Standard Concurrent ChemoRT + anti-

17 Non-Specific Stage III NSCLC Group Targeting Survival Signaling Networks M-Tor Bax Immunomodulary Approaches: Stage III Pts RTOG Foundation trial Pacific Trial Pilot NRG Trials

18 RTOG Foundation 3505 Phase III Trial of Chemo-RT +/- Adj Nivolumab: Activated in July 2016!

19 RTOG Foundation 3505 Chemo/RT +/- Nivolumab Lead-In Tolerability Arm (Phase I/III Design) Co-Primary Endpoints of Survival and PFS 660 Patients to be Enrolled International Enrollment MST Improvement from 24 to 34 Months MPFST Improvement from 12 to 18 Months

20 NRG Pilot: Re-RT + anti-pd1 for Recurrent NSCLC Phase I: Safety Assessment Phase II: Randomization/Efficacy Assessment Locally Recurrent NSCLC 1) Received prior RT for lung cancer 2) Received prior platinumchemotherapy 3) Recurrence within 50% isodose line 4) Not a candidate for surgery or SABR 5) Candidate for systemic therapy 6) Patients who have received prior systemic therapy for recurrence are eligible Primary endpoint - PFS Overall sample size = 72 Gomez: PI Pilot Safety Arm Radiation (60 Gy in 2 Gy fractions) with IMRT + PBT + Adjuvant anti-pd-1 Radiation (60 Gy in 2 Gy fractions) with IMRT or PBT+ Adjuvant Anti PD-1 Anti-PD-1 Primary Endpoint: PFS Secondary Endpoints: 1) OS 2) LFFS 3) DMFS Phase II Stratification: 1) Histology (SCC vs. non- SCC) 2) Prior Systemic Therapy for Recurrence (yes vs. no)

21 NRG Oncology Concept ARCHON-1: A Phase I Study of Accelerated Hypofractionated Radiotherapy Combined with ImmunotHerapy in LOcally Advanced NSCLC PI: Steven H. Lin, M.D., Ph.D. Statistician: Hu Chen, Ph.D.

22 Objectives Primary Safety of ACRT + immunotherapy based on incidence of grade 3+ Thoracic Radiation Pneumonitis (TRP) at 12 weeks after completion of ACRT Secondary Incidence of grade 3 TRP within 15 weeks of start of ACRT (12 weeks after completion of RT) Overall Survival Biomarker correlates (tissue and blood-based) to PFS and OS

23 Inclusion Criteria Age > 18 years Non-metastatic, unresectable NSCLC, either newly diagnosed or recurrent locally advanced NSCLC after prior surgery Patients who will not receive concurrent chemoradiation Induction chemotherapy allowed PS 0-1 No liver or renal end organ damage Lung function FEV 1.0 1L, FEV 1.0 > 40% and DLCO > 40% Must have measurable or evaluable disease

24 ARCHON-1 Trial Schema A Phase IB concept (N=80 max) Cohort 1: no induction chemo (IndCT) Cohort 2: +induction chemo +/- IndCT +/- IndCT +/- IndCT

25 Localized Lung Ca & Stereotactic Body RT

26 Primary Study Endpoint Analysis for NRG Oncology/RTOG 0813 Trial of SBRT for centrally located NSCLC A Bezjak, R Paulus, LE Gaspar, RD Timmerman, WL Straube, WF Ryan, YI Garces, AT Pu, AK Singh, GMM Videtic, RC McGarry, P Iyengar, JR Pantarotto, JJ Urbanic, AY Sun, ME Daly, IS Grills, DP Normolle, JD Bradley, H Choy ASTRO 2015 San Antonio Oct 21 st 2015

27 Centrally-located lung cancers

28 0813 SBRT Dose Levels Level 1 8 Gy x 5 fr 40 Gy total Level Gy x Gy Level 3 9 Gy x 5 45 Gy Level Gy x Gy Level 5 10 Gy x 5 50 Gy Level Gy x Gy Level 7 11 Gy x 5 55 Gy Level Gy x Gy Level 9 12 Gy x 5 60 Gy

29 Results Worst treatment related AE at any time SBRT Dose # pts Grade 2 n (%) Grade 3 n (%) Grade 4 n (%) Grade 5* n (%) 10X5 8 5 (62.5) X5 7 1 (14.3) (14.3) 11X (28.6) 1 (7.1) X (28.9) 4 (10.5) 0 2 (5.3) 12X (12.1) 5 (15.2) 1 (3.0) 1 (3.0) *grade 5 AEs = hemoptysis at a mean 13 mo postsbrt (range mo)

30 Central Lesion SBRT Conclusions This phase I/II trial of SBRT provides data to inform patients of the potential toxicities with a 5 fraction SBRT schedule for centrally located NSCLC 12 Gy/5 fr cohort had a 7.2% probability of DLT Although rates of toxicity pre-specified as DLT were low, Determination of the optimal SBRT dose needs to await analysis of efficacy data

31 SUMMARY NRG Oncology Lung Cancer Research Robust Portfolio Recent Major Observations Participatory in Basket and Bucket Trials Portfolio Complementary to Other Groups