Radiation Therapy as a Drug and Use in Metastatic Disease

1. Radiation Therapy as a Drug and Use in Metastatic Disease Reframing subatomic particles as medicine Matthew Katz, MD January 2020

2. Conflict of Interest  Partner, Radiation Oncology Associates PA  Stock in Dr. Reddy’s Laboratories, Healthcare Services Group, Mazor Robotics, U.S. Physical Therapy

3.  Overview  Framing Radiation as a drug  Clinical applications  Framework  Patterns of Failure  Possible clinical trials by disease  Strategic Value  Research funding  Influence in cancer care

4. Radiation Therapy  Poorly understood specialty  Used in 50% of cancer patients at some point during cancer experience  Often hard to determine value in treatment efficacy and cost

5. Aim  Reframe radiation therapy as a drug to make easier to compare to other cancer therapies  Efficacy  Design new combination therapies for systemic disease  Consider whether there is a clinically meaningful new role for it in metastatic disease

6. Origins of Radiation Oncology Particle Discovered Nobel X-Ray (photon) 1895 1901 Electron 1897 1906 Proton 1911 Neutron 1932 1935

7. Radiation: The Original Molecular Medicine  Discovery along with x-rays made it seen as mysterious but powerful  Not seen as a medicine but a physical force  Contemporary evaluation of cancer therapies at molecular level makes it reasonable to consider reframing

8. Definition of a Drug “A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.” -- Merriam-Webster Dictionary

9. Mechanism of Action  Radiation damages DNA (or other molecular targets)  Direct action = particles ionize target molecule  Indirect action = H2O+ radical ionizes target molecule

10. Pharmacokinetics of DNA Injury Event Time Comment Atom Ionization 10-12 sec Free radical formation 10-12 – 10-2 sec DNA damage 1 sec to hours Unrepaired DNA or misjoined DNA damage repair Hours to years Tumor  Death, apoptosis Normal tissue  early, late effects

11. Cellular sites of action Tepper & Gunderson, 2015

12. Different from many drugs  No drug receptors for subatomic particles  Cellular sites of action vary given that drug reaches entire cell  Interact with small molecules and ions  May alter biochemistry or function  Is there any receptor antagonist/agonist/inverse agonist activity from radiation, or how it affects response to other drugs

13. Route of Administration  PA (per aeram), by air Tepper & Gunderson, 2015

14. Absorption Photons Electrons Tepper & Gunderson, 2015

15. Comparing Particles

16. Other radiation drugs  PO = I-131 for thyroid cancer  IV = Radium-223  Brachytherapy = topical, interstitial insertion

17. Drug metabolism  Photons = ‘prodrug’  Create orbital electrons, which has biologic effect  Some just pass through patient without interacting  Not clear that there are phase II conjugation reactions  Usually endoplasmic reticulum/cytosol >nucleus  No definite impact of cytochrome P450 on radiation response?

18. Clinical Pharmacokinetics Component Time Comment Route of Administration EBRT: Per aeram Other: PO, IV, topical, interstitial Absorption 3.34 x 10-9 s Bioavailability No tissue binding per se Clearance 3.34 x 10-9 s Excretion No renal/biliary-fecal/skin excretion for external beam but apply with some unsealed sources

19. Volume of Distribution  Controlled by physician, treatment planning and equipment  Not related to plasma proteins or tissue binding  Varies by patient shape, body composition and position  May vary daily and affect dose delivery  Organ motion, varying air/tissue interfaces

20. Radiation reimbursement  Based on manipulating volume of distribution  Not based upon dose but devices/techniques [+/- particles] used for treatment

21. Whole Body vs. Partial Body Syndrome Type 50% Lethal Dose Time to Death Hematopoietic 250-500 cGy 4-8 weeks Gastrointestinal 500-1200 cGy 9-10 days Cerebrovascular 10000 cGy 24-48 hours Disease Dose 5+ year Gr 5 toxicity Breast cancer 4000-6000 cGy 0% Lung cancer* 5000-6000 cGy <1% Prostate cancer 6000-8000 cGy <1% Whole Body Partial Body (conventionally fractionated) *Stereotactic lung RT in 3-5 doses similar to surgery for cT1-2a N0 NSCLC

22. Tepper & Gunderson, 2015 Radiation Manufacturing Plant

23. Value of RT in Metastatic Settin g  Symptom relief/Improving quality of life  Avoidance of systemic therapy toxicity  Lengthening life

24. Risks of RT in Metastatic Setting  Progression free survival isn’t worth much if it’s radiologic and not based upon patient experience  Increases treatment toxicity  Increases financial toxicity

25. Framework  Need to reconceptualize metastatic spectrum better  Define disease states better  Guckenberger et al, Lancet Oncol 2020  Oligometastatis, oligoprogression distinguished  Include molecular biology into solid malignancy staging better, like in hematologic malignancies  Foster et al, JCO 2019  Unique biology may determine whether metastatic growth is focused, slow enough to benefit from RT

26. Patterns of Care  If we’re going to start using radiation in metastatic disease, we need to conduct sophisticated patterns of care studies like we have in curative intent cancers in the 1980s, 1990s  We need anatomical/spatial patterns of failure in treatment naïve and treatment resistant settings

27. Tumor Heterogeneity  Need a better understanding of how to individualize radiation dosing  May require biopsy, molecular data for prognosis, individualization  Scott et al, Lancet Oncol 2017  Better identification of radiation resistance  Kamran et al, Clin Cancer Res 2019

28. Clinical Applications  Reimaging use of radiation therapy beyond its cytotoxicity at higher doses  Priming agent (low vs. high dose)  Antigen presentation  Biologic response modifier for target tissue for drug delivery  Chemosensitizer (low dose)  Reverse of curative intent chemoradiation  Full dose chemotherapy, low dose radiation  Cytotoxic/Ablative agent  Conventional to stereotactic RT doses

29. Example: HER2+ Breast cancer  Increasingly systemic drugs working for non-CNS metastatic disease  Leptomeningeal disease still very challenging for any systemic agents  Higher HER2 expression may improve response to HER2-directed therapy (Scaltriti et al, Nishimura et al, Montemurro et al)  Ionizing radiation can upregulate HER-2 antibody targets in HER2+ and triple-negative breast cancer cell lines and can enhance cell kill effects of trastuzumab (Wattenberg et al)

30. Possible phase I/II clinical trial  Her2+ CNS progression only breast cancer patients  Treat with low dose (20-75 cGy) radiation prior to each intrathecal trastuzumab  MR-targeted to GTV vs. craniospinal CTV  Low-dose hypersensitivity without inducing intrinsic radiation resistance  Permits retreatment of previously irradiated patients

31. Possible uses in systemic disease Disease Stage Role Target Volume Dose/Fx AML CNS2/CN S3 Chemosensitization/syne rgy CTV = craniospinal axis 20-40 cGy w/IT chemotheratpy Breast, Her2+ IV Antigen presentation, synergy MR-targeted GTV vs. craniospinal CTV 25-75 cGy w/ IT trastuzumab DLBCL IVA+B Synergy, increase chemotherapy perfusion GTV = PET+ 25-75 cGy with R-CHOP Melanoma IV Antigen presentation, biologic response modifier GTV = PET+. Treat all vs. one lesion per organ w/metastases 25-150 cGy Myeloma Chemosensitization/syne rgy GTV = MRI+ 25-75 cGy NSCLC IV, PD-L1 >50% Priming immunotherapy +/- consolidative ablation GTV = PET+ 25-100 cGy +/- SBRT NSCLC IV, EGFR+, T790M- Synergy, biologic response modifier GTV = PET+ 25-75 cGy Prostate IV, new dx Consolidation +/- chemosensitization CTV = Prostate + pelvis vs Prostate w/only + LNs Definitive +/- 25-75 cGy

32. Advantages for low dose RT trials  Can start phase I/II trials for combination therapy quickly vs. new drugs with no human data  Low dose RT = 2D, 3D = low cost  Wide availability of linear accelerator makes easier to do trials compared to some targeted drugs

33. Uses in Non-Metastatic Malignancies Malignancy Stage Role Target Volume Bladder cT3 N0-1 or T2, Gr3 Chemosensitization CTV = Whole Pelvis pT4 or N1 Chemosensitization CTV = Whole Pelvis Colon (not rectum) pT3-4, N+ Chemosensitization CTV = Whole Abdomen Gastric cT2-3 or pT3-4, N+ Chemosensitization CTV = Whole Abdomen Glioblastoma Postop, away from chiasm/brainstem Chemosensitization w/full dose temozolomide CTV = GTV+ 3 cm Ovary Bulky Neoadjuvant chemosensitization, biologic response modifier CTV = Whole Abdomen II-III Chemosensitization CTV = Whole Abdomen Pancreas pT3-4 N0, N1 Chemosensitization CTV = Whole Abdomen cT3-4, unresectable Chemosensitization GTV=SBRT, CTV=low dose whole abdomen No established doses, consider 25-50 cGy pre-chemotherapy

34. Assessing Efficacy  Could compare to cancer drugs if agree to use the same endpoints for specific disease states  Cancer control  Toxicity  Cost of treatment  Would opinions about radiation differ if perceived as a drug?

35. Conclusion  Reimagine how we use radiation as something other than purely cytotoxic therapy  Conduct detailed studies to define patterns of failure, test new therapeutic approaches  Patient-centered goals must include treatment toxicity and financial toxicity in the value proposition