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Role of Radiation Therapy for Lung Cancer


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Role of Radiation Therapy for Lung Cancer- Paradigm Shift. Zhongxing Liao.

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Role of Radiation Therapy for Lung Cancer

  1. 1. Role of Radiation Therapy for Lung Cancer - Paradigm Shift Zhongxing Liao, MD Professor of Radiation Oncology
  2. 2. • Early stage NSCLC (SBRT) • Surgically unresectable/inoperable LA- NSCLC (RTOG 617) • Combined with Immunotherapy Outline
  3. 3. • Used by its cytocidal power, • RT biological effect-double strand break in DNA (the target) (Eric Hall, Radiobiology for the Radiologist, 4th ed., page 8) • RT Improve OS by: – LC when tumor is localized – LC to reduce DM • Kill the immune system in TBI Traditional Perception of Role of Radiation in Cancer Treatment 30%, higher with heavy particles 70%, main mechanism
  4. 4. LC n=674 OS=24% LP n=761 OS = 6% P<0.001 MST: 18.6 mo. vs. 15.5 mo. OverallSurvival(%) Months Machtay, ASTRO 05 Local Control and Survival Radiation dose escalation without increase toxicity
  5. 5. • Treatment of choice for non- surgical candidate (LC >90%), • Excellent alternative for surgical candidate (Lancet 2015) Early Stage NSCLC - SBRT
  6. 6. Trial n Dose FU LC % OS % Kyoto 45 12 Gy x 4 32 mo 94 83/72 (3-yr) Stanford 20 15-30 x 1 18 mo ---- ------- Scandinavian 57 15 Gy x 3 35 mo 92 (3-yr) 60 (3-yr) Indiana 70 20-22 x 3 50 mo 88 (3y) 43 (3-yr) RTOG 0236 55 20 Gy x 3 34 mo 97 56 (3-yr) 42 19-30 x 1 15 mo 68 37 (3-yr) Heidelberg 62 15 Gy x 3 28 mo 88 57 (3-yr) Tohoku 31 15 x 3, 7.5x8 32 mo 78/40 71 (3-yr) VU Univ 206 20 x 3 ,12 x 5 7.5 x 8 12 mo 97 64 (2-yr) Selected SBRT Prospective Reports
  7. 7. BED < 100 Gy BED > 100 Gy P-value Local Tumor 43% 8% <0.01 Regional nodal metastasis 21% 9% <0.05 Distant metastasis 26% 19% 0.3 Locoregional failure depends on BED Onishi et al. 2007 Onishi et al., JTO 2007
  8. 8. Increasing Radiation Therapy Dose Is Associated With Improved Survival in Patients Undergoing SBRT for Stage I NSCLC Koshy et al., Int J Radiation Oncol Biol Phys, Vol. 91, No. 2, pp. 344e350, 2015 Overall survival of T2 tumors treated with SBRT stratified by dose; low-dose cohort BED <150 Gy; high-dose BED >150 Gy
  9. 9. SBRT – Curative Treatment for Early Stage NSCLC – Operable Patients Chang et al., Lancet Oncol. 2015 • BED: 112.5 -151.2Gy – 50Gy/12.5 Gy/fx x 4 – 54Gy/18 Gy/fx x 3 – 60Gy/12Gy/fx x 5 • PTV=GTV+3mm • GTV: 110-140% of prescribe dose • Volumetric IGRT/Motion management
  10. 10. • Surgically unresectable/inoperable NSCLC (RTOG 617) –Dose escalation in conventional fractionation showed no OS benefit –Adding Cetuximab in unselected patient did not show OS benefit • Prolonged OTT and Lymphocytes During the Treatment LA-NSCLC – Non Surgery
  11. 11. Intergroup Participation: RTOG, NCCTG, CALGB RTOG 0617 A Randomized Phase III Comparison of Standard-Dose (60 Gy) Versus High-Dose (74 Gy) Conformal Radiotherapy with Concurrent and Consolidation Carboplatin/Paclitaxel +/- Cetuximab In Patients with Stage IIIA/IIIB Non-Small Cell Lung Cancer
  12. 12. RTOG 0617 – OS Bradley et al., Lancet Oncol 2015; 16: 187–99
  13. 13. RTOG 0617 – OS • Cancer death similar • More treatment related death at 74 Gy • Higher Heart V5 • Non compliance to Chemotherapy • Prolonged overall Treatment Time - OTT Bradley et al., Lancet Oncol 2015; 16: 187–99 Cervical Cancer: TCP as a function of total dose (left) and total treatment time (right). Loss of LC with prolonged OTT due to cancer cell repopulation. Huang et al., Int J Radiation Oncol Biol Phys, Vol. 84, No. 2, pp. 478e484, 2012
  14. 14. BED for Different Regimens BED = nd {1+[d/(α/β)} BED[(α/β) =10]: - Conventional Fractionation  72 Gy: 60 Gy in 30 Fx  84 Gy: 70 Gy in 35 Fx  88.8Gy: 74 Gy in 37Fx - Hypofractionation/SBRT  96 Gy: 60 Gy in 10 Fx  106 Gy: 48 Gy in 4 Fx (Japan Oncology Group)  112.5 Gy: 50 Gy in 4 Fx (MD Anderson, PTV)  119 Gy: 70 Gy in 10 Fx (MD Anderson, GTV)  151.2 Gy: 54 Gy in 3 Fx (RTOG, STAR Trial)  180 Gy: 60 Gy in 3 Fx (RTOG, 80% Isodose) Chang
  15. 15. Lymphopenia During Chemoradiation Tang and Liao et al., IJROBP 2014
  16. 16. Lymphopenia and GTV, Survival Tang and Liao et al., IJROBP 2014 OS: p=0.09 LRF: p=0.02 DMSF: p=0.01 Lymphocyte Minimum Log10 GTV -0.13 p<0.0001 Concurrent Chemotherapy -0.21 p<0.0001 Lung v5 -0.28 p=0.0004
  17. 17. Combining Radiotherapy and Cancer Immunotherapy: A Paradigm Shift • Tumor response to RT need T-Cells • RT induces immunogeneic cell death • Adaptive and innate immune response could convert the irradiated cancer into an in situ vaccine that elicits tumor- specific T cells. • Abscopal effect (ie, a tumor response in a metastasis outside RT field, after treatment of another tumor site) • Preclinical and clinical evidence Formenti et al., J Natl Cancer Inst;2013;105:256–265
  18. 18. Youjin Lee et al. Blood 2009;114:589-595©2009 by American Society of Hematology Therapeutic effects of ablative radiation on local tumor require CD8+ T-cells: changing strategies for cancer treatment Effects of Ablative RT is CD8 mediated
  19. 19. Chemotherapy diminishes the effect of radiation-mediated eradication of metastases and T-cell priming Youjin Lee et al. Blood 2009;114:589-595 ©2009 by American Society of Hematology
  20. 20. PD-L1 in tumor cells induced with IR TUBO tumor cells SQ Deng L et al., JCI 2014
  21. 21. Anti-PD-L1 enhance anti-tumor effect with IR that is CD8+ T cell mediated Tumor rechallenge experiment Abscopal Effect experiment Deng L et al., JCI 2014
  22. 22. Waterfall plot: unirradiated tumor measurements in a phase I trial combining radiation and ipilimumab Recapitulation of experiment in mice: resistance to RT and anti-CTLA4 (C4) therapy due to T-cell exhaustion and PD-L1 increases Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer - Twyman-Saint Victor C et al., Nature. 2015 Apr 16;520(7547):373-7
  23. 23. Conclusions: Radiation, anti- CTLA4, and anti PD-1/PD-L1 therapy play distinct complementary roles – Anti-CTLA4 promotes T cell expansion – Radiation shapes the TCR repertoire of expanded peripheral clones – Anti-PD-1/PD-L1 reverses T- cell exhaustion Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer - Twyman-Saint Victor C et al., Nature. 2015 Apr 16;520(7547):373-7
  24. 24. Original Article: Brief Report Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma Michael A. Postow, M.D., Margaret K. Callahan, M.D., Ph.D., Christopher A. Barker, M.D., Yoshiya Yamada, M.D., Jianda Yuan, M.D., Ph.D., Shigehisa Kitano, M.D., Ph.D., Zhenyu Mu, M.D., Teresa Rasalan, B.S., Matthew Adamow, B.S., Erika Ritter, B.S., Christine Sedrak, B.S., Achim A. Jungbluth, M.D., Ramon Chua, B.S., Arvin S. Yang, M.D., Ph.D., Ruth-Ann Roman, R.N., Samuel Rosner, Brenna Benson, James P. Allison, Ph.D., Alexander M. Lesokhin, M.D., Sacha Gnjatic, Ph.D., and Jedd D. Wolchok, M.D., Ph.D. N Engl J Med Volume 366(10):925-931 March 8, 2012
  25. 25. • A patient with metastatic melanoma with slowly progressive disease while receiving ipilimumab underwent radiotherapy for a pleural-based metastasis. • Tumor lesions in nonirradiated sites began to disappear, and titers of antibody against a tumor-associated antigen increased. Postow MA et al. N Engl J Med 2012;366:925-931 N Engl J Med, Volume 366(10):925-931 March 8, 2012
  26. 26. NY-ESO-1 Expression and Antibody Response to Ipilimumab and Radiotherapy. Postow MA et al. N Engl J Med 2012;366:925-931 Flow Cytometry of Peripheral-Blood Mononuclear Cells N Engl J Med, Volume 366(10):925-931 March 8, 2012
  27. 27. Preclinical data in local RT combined with Immnunotherapy Formenti et al., J Natl Cancer Inst;2013;105:256–265
  28. 28. Path Forward: 3 steps 1) Autologous T cell therapy with XRT for NSCLC – Current trial, safe and easy, POC 2) Generate unique radiation induced antigens - Sequence TCR of novel XRT induced antibodies • These can be expanded out for autologous therapy • Can generate XRT specific CAR T 3) Engineered T cells + anti-PD1 – Currently running these experiments in the lab – Currently running multiple IND trials and of anti PD1/CTLA4 and XRT Welsh, Cortez, Seyedin, Hahn et al CCR 2014
  29. 29. DOD Clinical Exploration Grant – Jim Welsh Phase I study to assess safety of combining autologous T cell transfer plus concurrent chemoradiation therapy for patients with stage 3 non-small cell lung cancer
  30. 30. A Phase III, Randomized, Double-blind, Placebo-controlled, Multicenter, International Study of MEDI4736* as Sequential Therapy in Patients with Locally Advanced, Unresectable NSCLC (Stage III) Who Have Not Progressed Following Definitive, Platinum-based, Concurrent Chemoradiation Therapy (PACIFIC) Primary Study Objective(s): Primary Objective: Efficacy of MEDI4736 vs placebo in terms of OS and PFS Secondary Objectives: OS24, ORR, DoR, APF12, APF18, PFS2 and DSR Safety and tolerability PK Immunogenicity Symptoms/HRQOL – EORTC QLQ-C30 v3 and LC13 *MEDI4736: Fully human monoclonal Ab that inhibits PD-L1 binding to PD1 and CD80
  31. 31. • Phase II Trial, 2 stage design – Primary Objective: Safety of MPDL3280A added to carboplatin-paclitaxel chemoradiation for unresectable non-small cell lung cancer – Secondary Objectives: • 6 month, 1 year and median PFS time (historical benchmark from RTOG 0617: 6 mos 75%, 1 yr 50%) • PD-L1 IHC staining on pretreatment tumor biopsy and correlation to 1-year Progress Free Survival (PFS) • Overall Survival (OS) • Incidence of ≥Grade 3 radiation pneumonitis • Blood based immunologic correlates to PFS • Tissue based immunologic correlates to PFS 2014-0722: DETERRED: PD-L1 BlockadE To ERadicate Lung Cancer using Carboplatin, Paclitaxle, and Radiation combinEd with MPDL3280A
  32. 32. Trials of Abscopal Effect of SBRT on Stage IV patients – Jim Welsh • 2013-0882 Phase I/II ipilimumab + XRT: – Phase I completed, no MTD reached – Phase II accruing • 2014-1020 Phase I/II MK- 3475 + XRT in NSCLC: – Phase I accruing soon
  33. 33. Background-NSCLC treatment with nivolumab • 272 squamous cell NSCLC treated with nivolumab (3mg/kg q2 wks) versus docetaxel • Docetaxel median OS: 6 mo, PFS: 2.8 mo • Nivolumab median OS: 9.2 mo, PFS: 3.5 mo* (FDA approved dose)
  34. 34. Baseline, 1 month, every 3 months -Brain MRI -Neurocognitive testing C1 WBRT/SRS C2 2wk C3 6wk C4 10wk C6 12wk C7 14wk C8 16wk C3 4wk C3 8wkNivolumab 3mg/kg Part A: At starting dose DLT Assessment C1 C1 WBRT/SRS C2 3wk C2 3wk C3 6wk C4 9wk C6 11wk C7 15wk C8 17wk C3 6wk C4 12wk Nivolumab 3mg/kg Ipilimumab 1mg/kg Part B At starting dose DLT Assessment Phase I/II trial of Nivolumab and Ipilimumab with radiation for the treatment of intracranial metastases from non-small cell lung cancer
  35. 35. Role of RT in Lung Cancer Treatment – beyond DNA double strand breaks • Early Stage: SBRT Curative treatment, • Dose escalation with Conventional Fractionation had no OS benefit (RTOG 617) • RT and cancer immunotherapy: – RT induced tumor response mediated by T cells – RT induced Abscopal effect – Radiation, anti-CTLA4, and anti PD-1/PD-L1 therapy play distinct complementary roles • BED >100 Gy needed for eliminating the cancer on site or induce the immune response • RT dose, fractionation, sequence with immunotherapy to be defined
  36. 36. Kob-Koon Ka