ROLE OF RADIATION THERAPY FOR RESECTABLE LUNG CANCER

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1 AFA From Bench to Bedside From KK DT1 10/27/ :04 PM 01 ROLE OF RADIATION THERAPY FOR RESECTABLE LUNG CANCER Hak Choy, MD University of Texas Southwestern Medical Center Dallas, Texas, USA

2 Orchestrating the instruments of lung cancer treatment Early Stage NSCLC: SBRT 02 Sexy and Top Advances with Radiation Therapy for Lung caner LAStage NSCLC: IGRT Advanced Stage NSCLC: SBRT

3 The Second Movement: Role of Radiation Therapy Inoperable early stage NSCLC 2. Operable early stage NSCLC 3. Stage IV NSCLC 4. Potential role of RT in combining with anti-tumour immunotherapeutics

4 The Second Movement: Role of Radiation Therapy Inoperable early stage NSCLC 2. Operable early stage NSCLC 3. Stage IV NSCLC 4. Potential role of RT in combining with anti-tumour immunotherapeutics

5 Stereotactic Body Radiation Therapy Stereotactic Body Radiation Therapy 05 Esophagus Bronchus Pulmonary vein Lung Chest wall Cord Skin RTOG 0236: 2000 cgy X 3

6 Local Control (%) RTOG 0236: Local Control / / / / / / / / / / / / / / / / / / / / / / / month local control = 98% (CI: 84%-100%) PFS in overall population 1 failure within PTV, 0 within 1 cm of PTV 0 Fail: 1 Total: Months After Start of SBRT Patients at Risk Timmerman. ASTRO 2009.

7 Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer 07 RTOG 0236: Primary (In-field + Marginal) Tumour Recurrence 60-month Primary tumour recurrence = 7% PFS in overall population Timmerman R et al. JAMA. 2010;303:

8 08 Cost-Effectiveness of Stereotactic Body Radiation Therapy vs Surgical Resection for Stage I Non-Small Cell Lung Cancer Anand Shah, MD, MPH, et al. J Thorac Cardiovasc Surg. 2012;143:

9 09 Total SBRT $14,821

10 010 Surgeon s fee $1,690-$985 Anaesthesiologist $482

11 011 Surgeon s fee $1,690-$985 Anaesthesiologist $482 + Hospital fee $46,210- $16,206

12 012 Total SBRT $14,821 Surgeon s fee $985-$1,690 Anaesthesiologist $482 Hospital fee: $16,206-$46,210 Total Surgery: $18,378-$47,677

13 Cost-Effectiveness of Stereotactic Radiation, Sublobar Resection, and Lobectomy for Early Non-Small Cell Lung Cancers in Older Adults 013 A. Comparison of sublobar resection to SABR B. Comparison of lobectomy to SABR Lobectomy PFS in overall population PFS in overall population Smith et al. J Geriatr Oncol. 2015;6:

14 The Second Movement: Role of Radiation Therapy Inoperable early stage NSCLC 2. Operable early stage NSCLC 3. Stage IV NSCLC 4. Potential role of RT in combining with anti-tumour immunotherapeutics

15 Stereotactic Ablative Radiotherapy vs Lobectomy for Operable Stage I NSCLC: A Pooled Analysis of Two Randomised Trials 015 Joe Y Chang, et al. Lancet Oncol. 2015;16:

16 ACOSOG Z4099 / RTOG PIs: Hiran C. Fernando, MD (ACOSOG); Robert Timmerman, MD (RTOG) N=420 Traditional phase III randomised trial Patients randomised to either surgery or SABR after consent Primary endpoint = 3-year overall survival

17 Pre-randomisation 017 The NSABP B-06: mastectomy to lumpectomy/xrt had very poor accrual when originally opened for enrollment NSABP re-designed the trial to utilise a randomisation that occurred prior to asking the patient to participate The re-design led to successful accrual that allowed the trial to answer the question

18 STABLEMATES Trial Schema Defined High-Risk Stage I NSCLC Screen Eligible Patients / Pre- Randomise N = 304 Consent to Accept Randomisation Assignment A c c e p t N = 254 R e j e c t N = 50* *Anticipated (actual assignment rate will be monitored) Arm 1: Sublobar Resection N = 127 Arm 2: SAbR N = 127 Consent to Be Observed After Standard of Care Therapy A c c e p t N = 45 R e j e c t N = 5* Follow for Overall Survival, Toxicity, and Patterns of Failure 018 Follow for Overall Survival Failure to Consent (Off Study)

19 The Second Movement: Role of Radiation Therapy Inoperable early stage NSCLC 2. Operable early stage NSCLC 3. Stage IV NSCLC 4. Potential role of RT in combining with anti-tumour immunotherapeutics

20 Is There a Role for Consolidative Stereotactic Body Radiation Therapy Following First-line Systemic Therapy for Metastatic Lung Cancer? A Patterns-of-Failure Analysis 020 Careful assessment of pattern of failure (POF) Local (L, existing sites) or distant (D, new sites) Brain mets scored separately 64 patients with stage IIIB-IV NSCLC Median time to progression = 3.9 months 91% L only failure in 64%, L+D in 27%, D only in 9% 1st-line therapy fails to control gross disease in 91%

21 Treatment in Stage IV NSCLC 021 How do you treat stage IV NSCLC patients after 1st-line systemic therapy? Current paradigm: Maintenance chemotherapy Continue targeted therapy until development of T790M or L1196M Observation with initiation of 2nd-line therapy at time of progression Some 30%-50% of patients who progress thru 1st-line chemo/targeted therapy do not receive further therapy PS being one reason (related to toxicity) Proposed paradigm: Locally ablative treatment with hypofractionated radiotherapy + maintenance chemotherapy after 4-6 cycles/month of chemo/targeted therapy

22 A Phase II Trial of 2 nd -line Erlotinib (Tarceva ) in Combination With Stereotactic Body Radiation Therapy (SBRT) for Patients With Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC) 022 UTSW/U Denver Trial NSCLC 1. Progressed after prior systemic therapy 2. 6 discrete lesions 3. Eligible for erlotinib and SBRT to all lesions 4. unscreened Week 1 Begin erlotinib 150 mg/d Weeks 2-4 Continue erlotinib Begin SBRT to all involved sites of disease* Post-SBRT Erlotinib until disease progression or unacceptable toxicity Systemic SBRT! *VERY CONSERVATIVE SBRT DOSES, eg, 1 19 Gy, 3 11 Gy, 5 8 Gy.

23 023 J Clin Oncol Oct patients with stage IV NSCLC who had progressed through platinum-based chemotherapy Erlotinib and concurrent SBRT to all sites (up to 6) Pattern of Failure Number (%) out of 23 patients Sites of Failure by Patient: Within SBRT treated area 1 (4) Outside SBRT field 6 (26) None 17 (74) Distant Failure Sites Liver 4 (17) Brain 2 (9) Pancreas 1 (4) Lymph node 1 (4)

24 024 J Clin Oncol Oct patients with stage IV NSCLC who had progressed through platinum-based chemotherapy Erlotinib and concurrent SBRT to all sites (up to 6) Dramatically improved median PFS and OS compared to historical controls

25 025 J Clin Oncol Oct 27 JCO. December 1, 2014 vol. 32 no. 34: Best of JCO 2015 Thoracic Oncology Edition is a collection of the most-accessed clinical research articles recently published in the Journal of Clinical Oncology (JCO) focusing on thoracic oncology. Access Best of JCO 2015 Thoracic Oncology Edition August 2015.

26 Randomised Phase II Trial Comparing Maintenance Chemotherapy vs SBRT Followed by Maintenance Chemotherapy for Stage IV NSCLC Patients With Limited Metastatic Disease 026 Stage IV NSCLC Patients Any 1 st Line Chemotherapy CR Progression Partial Response Stable Disease Maintenance Chemotherapy SBRT to all sites of disease determined by CT or PET/CT Chemo 6 Locations of Disease = Randomisation Patient Off Study When progression by imaging cannot be adequately addressed by SBRT (either from too many sites of disease progression or failures within previously treated sites with SBRT) Primary End Point PFS Secondary End Points OS, toxicity, biologic correlates, cost-benefit analysis, QoL Longitudinal Biologic Correlates Could include CTCs, cytokines, growth factors, biopsy of recurrences and evaluation of SNPs, deep sequencing, etc

27 027 Why SBRT worked so well even in metastatic lung cancer patients?

28 The Second Movement: Role of Radiation Therapy Inoperable early stage NSCLC 2. Operable early stage NSCLC 3. Stage IV NSCLC 4. Potential role of RT in combining with anti-tumour immunotherapeutics

29 The Second Movement: Role of Radiation Therapy 029 Detectable/Treatable tumor. RT (or SBRT) Undetectable/Untreatable micro metastasis Abscopal effects

30 RT Can Augment Immune Response 030 Abscopal Effects Shiao and Coussens. J Mammary Gland Biol Neoplasia

31 Abscopal Effects of Radiation Therapy 031 Postow et al. N Engl J Med. 2012;366:

32 Abscopal Effects of Radiotherapy After Immunotherapy 032 A 54-y-old male patient received 4 cycles of ipilimumab 3 mg/kg (June to August 2012) followed by palliative whole-brain radiotherapy (WBRT) Grimaldi et al. Oncoimmunology. 2014;3:e28780.

33 Figure 1. Patient survival according to abscopal responses. Kaplan-Meier curves depicting overall survival (OS) curves among patients who received RT after progression with ipilimumab, according to the presence or absence of an abscopal response (present in 11 patients and absent in 10 patients). Groups were compared using the log-rank test; P=

34 Immune Suppression at Multiple Points in the Cancer-Immunity Cycle 034

35 Reversing Immune Suppression at Multiple Points in the Cancer-Immunity Cycle 035 Anti-CTLA4 RT RT RT Anti-PD-1 Anti-PD-L1

36 SBRT: 20 Gy x

37 SBRT: 20 Gy x

38 RADVAX Trial Schema (Stage IV Melanoma) Hypofractionated RT to single index lesion (over 3-7 days) 038 Enrollment Baseline studies and staging RT #1 RT #2 RT #3 ipilimumab iv q3weeks x 4 1 st ipi 5 days after RT Follow up Restaging Stratum 1: lung or bone DL1 8 Gy x 2; DL2 8 Gy x 3 Stratum 2: liver or s.c. DL1 6Gy x 2; DL2 6 Gy x 3 UPCC RADVAX Clinicaltrials.gov NCT Twyman-Saint et al. Nature. April Biosamples and analysis 22 patients enrolled: Lung (n=10); liver (n=3); subcutaneous (n=9) Enrolling stratum 1 at Dose Level 2

39 Tumour Response to SBRT/Ipilimumab 039 Baseline 4d s/p SBRT 2mo s/p ipi #4 SBRT to index lesion Twyman-Saint et al. Nature. April 2015.

40 Tumour response at unirradiated sites (% change from baseline) Clinical Response to SBRT/Ipilimumab 040 Twyman-Saint et al. Nature. April 2015.

41 What is best RT dose and treatment schedule? 2. Does the target matter tumour, stromal, endothelium 3. Encouraging responses, but why is unresponsiveness still common? 4. What are the biomarkers for response? 5. Can additional immune checkpoint blockade be used or combined to improve outcome? Twyman-Saint et al. Nature. April 2015.

42 Proportion Survival RT + Combined CTLA4 and PD-L1/PD-1 Blockade Improves Survival and Provides Long-Term Immunity 042 Anti CTLA4 PD-1 PDL-1 Days Twyman-Saint et al. Nature. April 2015.

43 Conclusions 1. Sub-optimal, protracted fractionation schedules were appropriate in previous decades due to technology limitations 2. SBRT has already been established as standard care for early stage inoperable NSCLC 3. SBRT will likely become mainstream for eradicating/ debulking gross tumours OF ANY CANCER STAGE 4. RT clearly influences multiple points of the Cancer-Immunity Cycle 5. RT with anti-tumour immunotherapeutics can potentially yield effective and durable suppression of tumours, resulting in improved outcomes for lung cancer patients

44 CONVERSATIONS IN ONCOLOGY ORCHESTRATING THE INSTRUMENTS OF LUNG CANCER TREATMENT