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

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

3. Circ 2005 – First RTOG Meeting?

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

5. 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, doi: /jamaoncol
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.

6. 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Washington University - Unpublished

7. 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

8. 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

9. 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 mo
Well tolerated
G3/4 AEs – 30.5% vs. 26.1%
Pulmonary – 4.8% vs. 2.6%
Antonia et al, NEJM 2018

10. 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

11. 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

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

13. NCI protocol template

14. 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..

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

16. 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

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

18. 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 Aug;13(8):802-9.

19. 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!

20. 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
-Lung Phantom was approved with Eclipse - Acuros on
-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.”

21. SBRT Credentialing
Fail 

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

23. Case QA
Pass 

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

25. Thank you!
@SBRT_CR