ASCO Connection

March 2017

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Does PD-L1 expression matter? Not all patients have the same likelihood of responding to PD-1/PD-L1 pathway inhibition 1,2 PD-L1 expression status may help identify patients most likely to: 1 Respond to PD-1/PD-L1 pathway inhibition alone 2,3 2 Respond to PD-1/PD-L1 pathway inhibition plus inhibition of another immuno-oncology (IO) pathway 3-5 Clinical studies have shown that high PD-L1– expressing patients have demonstrated a higher likelihood of response through blockade of the PD-1/PD-L1 pathwa y 6-8 PD-1/PD-L1 Pathway CTLA-4 Pathway PD-1/PD-L1 Pathway PD-L1 expression is being studied as a way to identify patients who may be eligible for alternate approaches to targeting different pathways 3-9 Clinical studies are being conducted in bladder, SCCHN, and NSCLC to explore the role of PD-L1 expression in identifying patients who might respond to inhibition of the PD-1/PD-L1 pathway and the CTLA-4 pathway 5,10-12 PD-1/PD-L1 Pathway Pathway be eligible for alternate approaches to targeting different pathways 3-9 Clinical studies are being conducted Low PD-L1 Expressers Clinical studies have shown that be eligible for alternate approaches to targeting different pathways High PD-L1 Expressers PD-L1 expression testing may be useful to help identify patients for which IO monotherapy or combination therapies, such as PD-L1 and CTLA-4 pathway inhibitors, may be an option 1,3 • Inhibition of the PD-L1 pathway via monotherapy has demonstrated improvement in multiple tumor types in high PD-L1–expressing patients 6,8,12-16 • Combination therapy targeting nonredundant pathways provides potential for synergistic effects 5,17,18 The immunotherapy landscape is rapidly evolving; and PD-L1 expression status may become an important factor in clinical decisions 1,3 • New therapies, indications, and data expected in the near future may change the treatment paradigm 1,17 • PD-L1 is expressed on a variety of cancer cell types, including bladder, SCCHN, NSCLC, and melanoma 2,19,20 • Knowing a patient's PD-L1 expression status may help determine future IO treatment options 3,5 What science can do: AstraZeneca is leading IO combination research to explore customized treatment for your patients • Numerous clinical trials in multiple tumor types, such as bladder cancer, SCCHN, and NSCLC, are under way evaluating PD-L1 inhibition as monotherapy and in combination with other IO pathways, targeted agents, and chemotherapy 17,21-23 Learn about the IO approaches AstraZeneca is taking at www.azimmuno-oncology.com. Watch mechanism of disease videos on the PD-L1, CTLA-4, and OX40 pathways. View the list of AstraZeneca IO clinical trials. References: 1. Dizon DS, Krilov L, Cohen E, et al. Clinical cancer advances 2016: annual report on progress against cancer from the American Society of Clinical Oncology [published online ahead of print February 4, 2016]. J Clin Oncol. doi:pii:JCO658427. 2. Chen DS, Irving BA, Hodi SF. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587. 3. Mahoney KM, Atkins MB. Prognostic and predictive markers for the new immunotherapies. Oncology. 2014;28:39-48. 4. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med. 2015;372:2006-2017. 5. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumor activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study [published online ahead of print February 5, 2016]. Lancet Oncol. pii:S1470-2045(15)00544-6. doi:10.1016/S1470-2045(15)00544-6. 6. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial [published online ahead of print March 9, 2016]. Lancet. pii:S0140-6736(16)00587-0. doi:10.1016/S0140- 6736(16)00587-0. 7. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small cell lung cancer. N Engl J Med. 2015;372:2108-2028. 8. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-1639. 9. Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369:122-133. 10. Gilbert J, Le Tourneau C, Mehanna H, et al. Phase II, randomized, open-label study of durvalumab (MEDI4736) or tremelimumab monotherapy, or durvalumab + tremelimumab, in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN): CONDOR. J Immunother Cancer. 2015;3 (suppl 2):P152. 11. National Institutes of Health: ClinicalTrials.gov. Study of MEDI 4736 with or without tremelimumab versus standard of care chemotherapy in bladder cancer. https://clinicaltrials.gov/ ct2/show/NCT02516241?term=durvalumab+bladder+tremelimumab&rank=1. Accessed March 23, 2016. 12. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial [published online ahead of print March 4, 2016]. Lancet. pii: S0140-6736(16)00561-4. doi:10.1016/S0140-6736(16)00561-4. 13. McDermott DF, Sosman JA, Sznol M, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a Phase 1a study. J Clin Oncol. 2016;34:833-842. 14. Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med. 2015;373:23-34. 15.Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer. N Engl J Med. 2015;373:123-135. 16. Herbst RS, Baas P, Kim D-W, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non small-cell lung cancer (KEYNOTE-010): a randomised controlled trial [published online ahead of print December 18, 2015]. Lancet. pii:S0140-6736(15)01281-7. doi:10.1016/S0140-6736(15)01281-7. 17. Melero I, Berman DM, Aznar MA, Korman AJ, Perez Garcia JL, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer. 2015;15:457-472. 18. Drake CG. Combination immunotherapy approaches. Ann Oncol. 2012;23(suppl 8):viii41-viii46. 19. Inman B, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata. Cancer. 2007;109:1499-1505. 20. Cedrés S, Ponce-Aix S, Zugazagoitia J, et al. Analysis of expression of programmed cell death 1 ligand (PD-L1) in malignant pleural mesothelioma (MPM). PLoS One. 2015. doi:10.1371/journal. pone.0121071. 21. AstraZeneca. Our pipeline. 2016. https://www.astrazeneca.com/our-science/pipeline.html. Accessed February 1, 2016. 22. National Institutes of Health: ClinicalTrials.gov. Neoadjuvant MEDI4736 concomitant with weekly nab-paclitaxel and dose-dense AC for Stage I-III triple negative breast cancer. https://clinicaltrials.gov/ct2/show/NCT02489448?term=MEDI4736+chemotherapy&rank=8. Accessed April 5, 2016. 23. National Institutes of Health: ClinicalTrials.gov. Durvalumab with or without tremelimumab in advanced incurable solid malignancies receiving standard chemotherapy regimens. https://clinicaltrials.gov/ct2/show/NCT02537418?term=MEDI4736+chemotherapy&rank=3. Accessed April 5, 2016. ©2016 AstraZeneca. All rights reserved. 3243601 4/16

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