New Investigator Experience: RTOG 3515 / PACIFIC-4 Cliff Robinson, MD Washington University in St. Louis “An Introduction to NRG Oncology” 7/18/19

Conflicts of Interest Stock – Radialogica Research Grants – Varian, Elekta, Merck Consulting – Astra Zeneca, EMD Serono Speaking – Varian, ViewRay

Circ 2005 – First RTOG Meeting?

SBRT for Early Stage NSCLC PubMed (courtesy D. Moghanaki)

Copyright 2018 American Medical Association. From: Long-term Results of Stereotactic Body Radiation Therapy in Medically Inoperable Stage I Non–Small Cell Lung Cancer JAMA Oncol. Published online May 31, 2018. doi:10.1001/jamaoncol.2018.1258 At 5 years: 20.0% (7.3% for primary only) 10.9% 23.6% Figure Legend: Patterns of Failure Among 23 Patients Experiencing Progression on NRG Oncology RTOG 0236Distant indicates uninvolved lobes of the lung and extrathoracic sites (15 failures); local, primary tumor and involved lobe (13 failures [4 primary tumor and 9 involved lobe]); and regional, hilar or mediastinal lymph nodes (7 failures). Date of download: 6/11/2018 Copyright 2018 American Medical Association. All Rights Reserved.

Late failure rates – tumor size n=821 Freedom from First Failure (Death Competing Risk) 1y 2y 3y <=2 cm 80.3 69.1 62.8 >2-3 cm 74.1 65.1 60.2 >3-7 cm 67.2 56.9 51.1 Washington University - Unpublished

NCCN Guidelines Feb 2018 IB: Peripheral T2a, N0 I: Central T1-2a, N0 Stage IA (-) mediastinal nodes Operable Surgical Resection Inoperable Definitive RT (SBRT) Stage IB, Stage II (-) mediastinal nodes Operable Surgical Resection Inoperable N0 Definitive RT (SBRT) Consider Adjuvant Chemo (Category 2B) High Risk Ib-IIb N1 Definitive Chemoradiation IB: Peripheral T2a, N0 I: Central T1-2a, N0 II: T1-2ab, N1; T2b, N0 IIB: T3, N0 IA: Peripheral T1abc, N0

Reducing SBRT failures Effective adjuvant therapy needed Cytotoxic chemo NCCN Category 2B recommendation for “high risk” based on surgical data. Challenging in frail SBRT population Immunotherapy well tolerated in Stage III and IV population

PACIFIC – CRT +/- adjuvant durva for stage III 713 pts, 2:1 randomized Durva q2wk 10 mg/kg or placebo up to 12 mo PFS 17.2 mo vs. 5.6 mo OS NR vs. 28.7 mo Well tolerated G3/4 AEs – 30.5% vs. 26.1% Pulmonary – 4.8% vs. 2.6% Antonia et al, NEJM 2018

Scientific Rationale Durva effective after chemoradiation in PACIFIC Increasing evidence of synergy between IO + radiation Radiation therapy  Immunogenic cell death Higher fraction doses  increased antigen release and uptake by APCs Increased T cell infiltration into TME Upregulation of PD-L1 expression

Scientific Rationale Clinical data w SBRT and IO (Pembro) 72 advanced NSCLC patients: pembro alone vs pembro + SBRT ORR 41% vs 19% favoring pembro + SBRT Median PFS was 6.4 vs 1.8 mos (favor combined therapy); HR 0.55 (CI 0.31 – 0.98, p = 0.04) No increase in treatment-related toxicity (G3+ 17% vs. 22%) PEMBRO-RT study – ASCO 2018 abstr 9023

Networking, in person meetings, phone calls 2/17-7/17 Networking, in person meetings, phone calls 1/17

NCI protocol template

Networking, in person meetings, phone calls NCI .CTEP ..CIB …NCTN …CCCT ….TMSC 8/17 2/17-7/17 11/17-12/17! SWOG NRG CTEP: Cancer therapy evaluation program. CIB: Clinical investigations branch. NCTN: National Clinical Trials Network. CCCT: Coordinating Center for Clinical Trials. TMSC: Thoracic Malignancy Steering Committee. Networking, in person meetings, phone calls 1/17 2/18 Work together! 2-6/18 Re-write concept..

Alternate route! SWOG / NRG S1914 RTOG 3515 / AZ PACIFIC-4 No case credits / AZ $$$ SWOG / NRG S1914 Case credits / NRG $

Key Secondary Endpoint: PACIFIC 4 / RTOG 3515 Schema Up to 28 Days N=630 1:1 Durva 1500mg q 4 wks x 24 mos Primary Endpoint: PFS Key Secondary Endpoint: OS Lung Cancer Mortality Patient Screening Baseline Scan Submit Tumor samples Inclusion Criteria Clinical Stage I/II node negative (T1 – T3 N0) Medically inoperable or refuse surgery ECOG PS 0-2 All comers SOC definitive SBRT R Placebo q 4 wks x 24 mos Stratifications: By size Central vs. peripheral Additional Key points NSCLC proven by histology / cytology Tissue submission mandated – core preferred but will accept FNA samples for translational analysis SOC SBRT taking place during screening. SBRT planning can occur before study enrollment Randomization within 7 days of completion of SOC SBRT

PACIFIC-4 / RTOG 3515 An International Trial! USA Canada UK, Belgium, France, Germany, Israel, Italy, Spain, Netherlands, Poland South Korea, Japan, NEW = China

Rationale for 24 months treatment duration Recurrence risk highest in first 24 months after SBRT Recurrences predominantly outside of radiation field Checkmate 153 (metastatic setting) suggestion of longer treatment benefit (> 1 yr) Senthi et al. Lancet Oncol. 2012 Aug;13(8):802-9.

My view of being a RadOnc PI of a Pharma Trial Design Involved in discussions of overall trial design, though final decisions made by AZ leadership Provide clinical data for stats Develop radiotherapy section Protocol editing Execution Address almost daily concerns from sites and countries about protocol vs. their own processes Site liaisons => country leads => AZ protocol leads => me, then in reverse. . . Coordinate w/RTOG on credentialing/QA Case reviews (share the wealth – Percy Lee, Shankar Siva) TBD!

SBRT Credentialing “Dear Lindsey,   Washington University School of Medicine (RTF# 1075 NCI# MO011) has completed the following credentialing requirements for RTOG 3515. -Facility Questionnaire was updated on 2018-12-17 -Lung Phantom was approved with Eclipse - Acuros on 2018-03-09 -IGRT Soft Tissue was completed Your site has passed the RT credentialing requirements for RTOG 3515 utilizing 3D-CRT and IMRT technique for flattening-filter-free (FFF) photon beams. This notification acts as your credentialing letter.”

SBRT Credentialing Fail 

Case Submission TRIAD DICOM submission Timely submission of data key, since no requirement for rapid review

Case QA Pass 

Predictors of failure – ctDNA Chaudhuri et al, Cancer Disc 2017

Thank you! @SBRT_CR