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A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma

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A Single Dose of Neoadjuvant PD-1 Blockade Predicts Clinical Outcomes in Resectable Melanoma FOCUS | LETTERS FOCUShttps://doi.org/10.1038/s41591-019-0357-y | LETTERS https://doi.org/10.1038/s41591-019-0357-y A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma Alexander C. Huang 1,2,3,4,16*, Robert J. Orlowski1,11,16, Xiaowei Xu4,5, Rosemarie Mick3,4,6, Sangeeth M. George7,12, Patrick K. Yan 2,7, Sasikanth Manne2,7, Adam A. Kraya1,4, Bradley Wubbenhorst1,4, Liza Dorfman1,4, Kurt D’Andrea1,4, Brandon M. Wenz1,4, Shujing Liu4,5, Lakshmi Chilukuri2,7, Andrew Kozlov4,8, Mary Carberry1,4, Lydia Giles1,4, Melanie W. Kier1, Felix Quagliarello2,13, Suzanne McGettigan1,4, Kristin Kreider1,4, Lakshmanan Annamalai9, Qing Zhao9, Robin Mogg9,14, Wei Xu1,4, Wendy M. Blumenschein9, Jennifer H. Yearley9, Gerald P. Linette1,2,3,4, Ravi K. Amaravadi1,4, Lynn M. Schuchter1,4, Ramin S. Herati1,2, Bertram Bengsch2,15, Katherine L. Nathanson1,3,4, Michael D. Farwell4,8,17, Giorgos C. Karakousis4,10,17, E. John Wherry 2,3,4,7,17* and Tara C. Mitchell 1,4,17* Immunologic responses to anti-PD-1 therapy in mela- Clinical responses to anti-PD-1 therapies can occur rapidly1,2. A noma patients occur rapidly with pharmacodynamic T cell pharmacodynamic response including reinvigoration of exhausted- responses detectable in blood by 3 weeks. It is unclear, how- phenotype CD8 T cells (TEX) can be detected in blood of cancer ever, whether these early blood-based observations trans- patients after a single dose3,4. However, the precise type(s) of T cells late to the tumor microenvironment. We conducted a study in the tumor that respond to anti-PD-1 remains poorly understood. of neoadjuvant/adjuvant anti-PD-1 therapy in stage III/IV Moreover, whereas early immunological responses to checkpoint melanoma. We hypothesized that immune reinvigoration blockade are observed at 3 weeks in blood, the kinetics of immune in the tumor would be detectable at 3 weeks and that this reinvigoration in the tumor and the relationship to pathological response would correlate with disease-free survival. We response and clinical outcomes are unclear. identified a rapid and potent anti-tumor response, with 8 of We conducted a neoadjuvant/adjuvant anti-PD-1 clinical trial 27 patients experiencing a complete or major pathological in stage III/IV resectable melanoma. This approach provided early response after a single dose of anti-PD-1, all of whom remain on-treatment tumor tissue at resection and insights into the mecha- disease free. These rapid pathologic and clinical responses nisms of PD-1 blockade. Our study demonstrated the clinical fea- were associated with accumulation of exhausted CD8 T cells sibility of neoadjuvant/adjuvant anti-PD-1 therapy in melanoma, in the tumor at 3 weeks, with reinvigoration in the blood and identified a rapid pathological and immunologic response observed as early as 1 week. Transcriptional analysis dem- in tumors. Complete pathological responses could be identified onstrated a pretreatment immune signature (neoadjuvant by 3 weeks and correlated with disease-free survival (DFS). Data response signature) that was associated with clinical ben- from early on-treatment resected tumor indicate that TEX, but not efit. In contrast, patients with disease recurrence displayed bystander cells, are a major responding cell type. Studies in an addi- mechanisms of resistance including immune suppression, tional cohort identified reinvigoration of TEX as early as day 7 after mutational escape, and/or tumor evolution. Neoadjuvant the first dose of anti-PD-1. Finally, in patients who developed dis- anti-PD-1 treatment is effective in high-risk resectable stage ease recurrence, potential mechanisms of resistance were identified. III/IV melanoma. Pathological response and immunological analyses after a single neoadjuvant dose can be used to pre- Results dict clinical outcome and to dissect underlying mechanisms A pharmacodynamic immune response can be detected in blood in checkpoint blockade. 3 weeks after initiation of PD-1 blockade3,4. To understand the 1Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 2Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 3Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. 4Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 5Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 6Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 7Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 8Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 9Merck Research Laboratories, Kenilworth, NJ, USA. 10Department of Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. 11Present address: Merck & Co., Inc., Kenilworth, NJ, USA. 12Present address: Bristol-Myers Squibb, Lawrenceville, NJ, USA. 13Present address: Stem Cell Technologies, Vancouver, British Columbia, Canada. 14Present address: Bill & Melinda Gates Medical Research Institute, Cambridge, MA, USA. 15Present address: Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Freiburg, Germany. 16These authors contributed equally: A. C. Huang, R. J. Orlowski. 17These authors jointly supervised this work: M. D. Farwell, G. C. Karakousis, E. J. Wherry, T. C. Mitchell. *e-mail: alexander.huang@uphs.upenn.edu; wherry@pennmedicine.upenn.edu; tara.mitchell@uphs.upenn.edu NatURE MEDICINE | www.nature.com/naturemedicine LETTERS | FOCUS LETTERShttps://doi.org/10.1038/s41591-019-0357-y | FOCUS NATURE MEDICINE a b ViableMixed Necrotic 3 weeks Resectable melanoma α-PD-1 α-PD-1 stage III B/C for 1 dose for 1 year or stage IV Biopsy Resection 1 cm 1 cm 1 cm c d DFS 1.00 30% pCR 0.75 5/27 30 µm 0.50 3/27 Probability 0.25 No. at risk 27 21 15 11 10 31 Pathologic response 0.00 Non-resp 0612 18 24 30 36 42 Complete 30 µm Major Time from surgery (months) e f Pre Week 3 Viable tumor Viable tumor Non-viable tumor P = 0.0002 DFS 1.00 100 Viable tumor ≤ 10%, n = 8 0.75 ) 75 y pCR (Pt 07) 30 µm 30 µm 0.50 50 Viable tumor > 10%, n = 19 Viable tumor Viable tumor Probabilit 0.25 Viable tumor (% 25 Stage-adjusted HR = 0.09, 95% CI 0.0-0.73, P = 0.02 (n = 2) 0.00 (n = 4) 0612 18 24 30 36 42 0 Time from surgery (months) 30 m 30 m Pre Week 3 Recurrence (Pt 20) µ µ Pre Week 3 TIL g h DFS Non-brisk/absent TIL Brisk TIL P = 0.004 1.00 Brisk n = 12 k Bris TIL 0.75 y pCR (Pt 11) 30 µm 30 µm 0.50 Non-brisk/absent n = 15 Non-brisk/absent TIL Non-brisk/absent TIL Probabilit 0.25 Univariate HR = 0.15, 95% CI 0.02-0.66, P = 0.009 0.00 0612 18 24 30 36 42 Non-brisk/absent Time from surgery (months) 30 m 30 m Pre Week 3 Recurrence (Pt 21) µ µ Fig. 1 | Pathologic response and TILs are predictive of clinical outcome after a single dose of anti-PD-1. a, Schema of the neoadjuvant and then adjuvant pembrolizumab clinical trial. b, Representative images of viable, mixed, and necrotic tumors resected at the 3-week post-treatment time point. c, Representative H&E images of pCR and non-response (non-resp) (left) and fraction of patients with complete pathologic response and major pathologic response (right). d, Kaplan–Meier estimate of DFS. e, Representative H&E images (left) and changes in the percentage of viable tumor in pre-treatment and post-treatment tumors (right, n = 20); P value calculated using two-sided Wilcoxon matched-pairs test. f, Kaplan–Maier estimate of DFS stratified according to pathologic response. Cox proportional hazards regression modeling was used to calculate hazard ratio. g, Changes in TIL infiltration in pre- treatment and post-treatment tumors (n = 20); P value calculated using McNemar’s test. h, Kaplan–Maier estimate of DFS stratified according to TIL response. Cox proportional hazards regression modeling was used to calculate hazard ratio. 95% CI, 95% confidence interval; HR, hazard ratio; Pt, patient. early effects of anti-PD-1 in tumors, we conducted an investigator- between surgery and initiation of adjuvant pembrolizumab was initiated clinical trial of neoadjuvant anti-PD-1 (pembrolizumab) 23 days (range 13–39). There were no unexpected adverse events in stage IIIB/C or IV melanoma. All patients underwent baseline (Supplementary Table 2); the rate of grade 3 or higher adverse pretreatment biopsy and received a single dose of pembrolizumab events not attributed to pembrolizumab or to surgery alone was (200 mg), followed by complete resection 3 weeks later and adju- not higher than 30%, the prespecified safety end point (observed vant therapy (Fig. 1a). Twenty-nine patients were enrolled and rate was 0%, P = 0.0002, z test). There were no unexpected delays treated (Supplementary Table 1). Patients proceeded to surgical in surgery or adjuvant pembrolizumab, or unexpected surgical resection at 3 weeks (median 21 days, range 17–42). Median interval complications. NatURE MEDICINE | www.nature.com/naturemedicine FOCUS | LETTERS NATURE MEDICINE https://doi.org/10.1038/s41591-019-0357-yFOCUS | LETTERS We assessed the pathologic response after 1 dose of pembroli- CD8, CD4, and FoxP3+ regulatory T cells (Tregs) was detected in zumab in the resection specimens of 27 patients available at time the blood after anti-PD-1 (Extended Data Fig. 2a), as described3. of data cut-off. Resected tumor had features of completely viable, In the tumor, CD8 T cell proliferation increased (Extended Data mixed viable and necrotic, or completely necrotic tumor on gross Fig.
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