Role of Radiation Therapy for Lung Cancer

- Paradigm Shift

Zhongxing Liao, MDProfessor of Radiation Oncology

• Early stage NSCLC (SBRT)• Surgically

unresectable/inoperable LA-NSCLC (RTOG 617)

• Combined with Immunotherapy

Outline

• 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

LC n=674 OS=24%LP n=761 OS = 6%P<0.001

MST:18.6 mo. vs. 15.5 mo.

Ove

rall

Sur

viva

l (%

)

MonthsMachtay, ASTRO 05

Local Control and Survival

Radiation dose escalation without increase toxicity

• Treatment of choice for non-surgical candidate (LC >90%),

• Excellent alternative for surgical candidate (Lancet 2015)

Early Stage NSCLC - SBRT

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 57.5 x 8

12 mo 97 64 (2-yr)

Selected SBRT Prospective Reports

BED < 100 Gy BED > 100 Gy P-valueLocal Tumor 43% 8% <0.01Regional nodal metastasis

21% 9% <0.05

Distant metastasis 26% 19% 0.3

Locoregional failure depends on BEDOnishi et al. 2007

Onishi et al., JTO 2007

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

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

• 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

Intergroup Participation: RTOG, NCCTG, CALGB

RTOG 0617A 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

RTOG 0617 – OS

Bradley et al., Lancet Oncol 2015; 16: 187–99

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

BED for Different Regimens

BED = nd {1+[d/(α/β)} BED[(α/β) =10]:- Conventional Fractionation

72 Gy: 60 Gy in 30 Fx84 Gy: 70 Gy in 35 Fx 88.8Gy: 74 Gy in 37Fx

- Hypofractionation/SBRT96 Gy: 60 Gy in 10 Fx106 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

Lymphopenia During Chemoradiation

Tang and Liao et al., IJROBP 2014

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

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

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

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

PD-L1 in tumor cells induced with IR

TUBO tumor cells SQ

Deng L et al., JCI 2014

Anti-PD-L1 enhance anti-tumor effect with IR that is CD8+ T cell mediated

Tumor rechallenge experiment Abscopal Effect experimentDeng L et al., JCI 2014

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

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

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 MedVolume 366(10):925-931

March 8, 2012

• 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

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

Preclinical data in local RT combined with Immnunotherapy

Formenti et al., J Natl Cancer Inst;2013;105:256–265

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 T3) 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

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

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 PFSSecondary Objectives:OS24, ORR, DoR, APF12, APF18, PFS2 and DSRSafety and tolerabilityPKImmunogenicitySymptoms/HRQOL – EORTC QLQ-C30 v3 and LC13

*MEDI4736: Fully human monoclonal Ab that inhibits PD-L1 binding to PD1 and CD80

• 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

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

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)

Baseline, 1 month, every 3 months-Brain MRI-Neurocognitive testing

C1

WBRT/SRSC2 2wk

C36wk

C4 10wk

C6 12wk

C7 14wk

C8 16wk

C3 4wk

C3 8wkNivolumab 3mg/kg

Part A: At starting dose

DLT Assessment

C1

C1

WBRT/SRSC2 3wk

C2 3wk

C3 6wk C4 9wkC6

11wkC7

15wkC8

17wk

C3 6wk C4 12wk

Nivolumab 3mg/kg

Ipilimumab 1mg/kg

Part BAt 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

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

Kob-Koon Ka