Radiation Therapy and Immunotherapy: New Frontiers

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1 Radiation Therapy and Immunotherapy: New Frontiers Nevada Oncology Society Fall Meeting November 16 th, 2017 Anshu K. Jain, MD Radiation Oncologist, Ashland Bellefonte Cancer Center Assistant Clinical Professor, Yale School of Medicine

2 Disclosures No relevant financial disclosures We will be discussing investigational uses of immunotherapy

3 Objectives Brief overview of radiotherapy immunogenic effects Describe preclinical evidence for combination therapy Review clinical evidence of and challenges for checkpoint blockade combination therapy Brief overview of ongoing and future trials

4 Durvalumab Atezolizumab Avelumab Nivolumab Pembrolizumab Nature Reviews Drug Discovery 12, (2013)

5 NEJM 2012;366:

6 Stereotactic Body Radiation Therapy (SBRT) A paradigm shift in how radiation therapy is delivered over past decade Stereotactically localized, high dose RT Common dose regimens range from Gy in 3-8 fractions (in U.S. defined as 5) Radiosurgery often one fraction, can also be ablative Demands substantial technical considerations Tumor motion, immobilization, image guidance Higher biologically effective dose = effective ablation of tumor

7 Immunogenic Effects of RT ABSCOPAL EFFECT Damage Associated Molecular Patterns (DAMPs) Tumor Associated Antigens (TAAs) Neoantigen presentation of tumor supporting stroma Vascular Normalization (improved lymphocyte extravasation) Nat Rev Clin Oncol Aug;13(8):516-24

8 RT Alone: Preclinical Evidence SBRT elicits CD8+ T-cell immune response resulting in improved response (Lee et al. Blood 2009) Conventional fractionation not able to elicit similar response Other studies have demonstrated similar findings on facilitation of: antigen presentation priming of peripheral T-cells infiltration of tumor antigen specific T-cells.

9 RT Alone: Preclinical Evidence Data suggests a complex fractionation and dose-dependent relationship Threshold dose for immune stimulation Ceiling dose above which immunosuppression may prevail Impact of dose on longevity of immune response

10 Combination Therapy: Preclinical Evidence Immunostimulatory Pathway anti-cd137; anti-cd40 Immunosuppressive Pathway RT and CTLA-4 blockade; RT and PD1 blockade o Mediated by CD8+ T-cell antitumor activity o RT enriched immune effector cells Combination immunotherapy may be superior Various mechanisms (exhaustion, etc.)

11 Combination Therapy: Preclinical Evidence Hypofractionated regimens may be superior to single fx regimen 1 2 Clin Cancer Res 2009;15(17): )

12 Clinical Evidence Mostly Retrospective but some emerging prospective reports Primarily in melanoma patients Primarily ipi Improved survival in patients receiving ipi and SRS for brain metastases vs. WBRT Case reports in NSCLC Mainly ipi Intent of therapy in this case was to generate abscopal effect Limited conclusions to be drawn except proof-ofprinciple Differences in treatment sequencing, RT doses, location of response Golden et al. Cancer Immunol Res 2013

13 Clinical Evidence RADVAX (UPenn) Prospective Phase I/II Trial 22 metastatic melanoma patients Single index lesion treated Adjuvant ipilimumab x 4 Credit: Ramesh Rengan RT completed to 3 of 4 dose levels Unirradiated lesions 18% PR 18% SD 64% PD Nature 520(7547): 373-7, Apr 2015

14 Clinical Evidence Follow-up translation mouse studies reveal important findings PD-L1 expression important determinant of responders vs. non-responders and strongly correlated with worse survival RT+CTLA4 reinvigorates exhausted CD8+ T cell pool, and in part mediated by tumor PD-L1 expression PD-L1 blockade reinvigorates CD8 TILs Radiation diversifies TCR repertoire of TILs from unirradiated tumors Nature 520(7547): 373-7, Apr 2015

15 Ongoing Trials α-pd1 / PD-L1 Most major subsites Newer studies investigating anti-pd1 agents or combination therapy α-pd1 / PD-L1 and α -CTLA4 Shabason and Minn, Semin Radiat Oncol 27:

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17 Future Directions and Challenges Can trials keep pace with drug development? Nature Reviews Drug Discovery 15,

18 Future Directions and Challenges Toxicity? Ablative RT may result in normal tissue antigen presentation and greater IO toxicity, initial reluctance for combined therapy trials Does site of index lesion matter? Possibly. Anecdotal evidence that liver lesions may elicit greater immunogenic effect. Role in Locally Advanced? Numerous questions remain Potential impact on tx of micrometastatic disease in high-risk patients Impact by lymphotoxic therapies (nodal RT; chemo) Current indications include adding immunotherapy as adjuvant tx in locally advanced disease (Adjuvant durvalumab in Stage III NSCLC s/p chemoradiation). Potential Role in Early Stage Lung CA SBRT/SABR already viable alternative to curative surgical resection Not a large impact on nodal (~5%) or distant (~10%) relapse, although SBRT may have slight edge Potential advantage of combined therapy with curative intent SBRT and alternate role as in-situ tumor vaccine with immunotherapy

19 Summary Dose, Fractionation, Sequencing, and Combinations Matter Three fraction regimen popular Optimal sequencing of therapy unknown Numerous combinations being evaluated Resistance to immunoradiotherapy combinations likely through non-redundant immune pathways RT/anti-CTLA4 -> antitumor CD8+ T-cell exhaustion via PD1 pathway Role for combined immune checkpoint blockade

20 Summary Endpoints matter Clinical outcomes: OS and not PFS Biomarkers and -Omics PDL1 expression CD8+ T-cell:T reg; CD8/CD4 Exome and proteosome analysis Role for data science to accelerate hypotheses on optimal sequencing Should all practice decisions come from RCTs?

21 Thank You! Questions?