Clinical utility of pembrolizumab in the management of advanced solid tumors: an evidence-based review on the emerging new data

References

• Scapin G, Yang X, Prosise WW, et al. Structure of full-length human anti-PD1 therapeutic IgG4 antibody pembrolizumab. Nat Struct Mol Biol. 2015;22(12):953–958. doi:10.1038/nsmb.312926595420
   PubMed Web of Science ®Google Scholar
• Blank C, Brown I, Peterson AC, et al. PD-L1/B7H-1 inhibits the effector phase of tumor rejection by t cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004;64(3):1140–1145. doi:10.1158/0008-5472.CAN-03-325914871849
   PubMed Web of Science ®Google Scholar
• Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol. 2007;19(7):813–824. doi:10.1093/intimm/dxm05717606980
   PubMed Web of Science ®Google Scholar
• Sharp M, Corp D, Kenilworth NJ: KEYTRUDA® (pembrolizumab) Prescribing Information.pdf. Available from: http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed October 6, 2018.
   Google Scholar
• Ahamadi M, Freshwater T, Prohn M, et al. model-based characterization of the pharmacokinetics of pembrolizumab: a humanized anti-pd-1 monoclonal antibody in advanced solid tumors: pharmacokinetics of pembro in solid tumors. CPT Pharmacometrics Syst Pharmacol. 2017;6(1):49–57. doi:10.1002/psp4.1213927863186
   PubMedGoogle Scholar
• Longoria TC, Tewari KS. Evaluation of the pharmacokinetics and metabolism of pembrolizumab in the treatment of melanoma. Expert Opin Drug Metab Toxicol. 2016;12(10):1247–1253. doi:10.1080/17425255.2016.121697627485741
   PubMed Web of Science ®Google Scholar
• Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non–small-cell lung cancer. N Engl J Med. 2015;372(21):2018–2028. doi:10.1056/NEJMoa150182425891174
   PubMed Web of Science ®Google Scholar
• Zhang T, Xie J, Arai S, et al. The efficacy and safety of anti-PD-1/PD-L1 antibodies for treatment of advanced or refractory cancers: a meta-analysis. Oncotarget. 2016;7:45. doi:10.18632/oncotarget.12230
   Google Scholar
• Wang M, Ma X, Guo L, Xia F. Safety and efficacy profile of pembrolizumab in solid cancer: pooled reanalysis based on randomized controlled trials. Drug Des Devel Ther. 2017;11:2851–2860. doi:10.2147/DDDT.S146286
   PubMed Web of Science ®Google Scholar
• Sznol M, Postow MA, Davies MJ, et al. Endocrine-related adverse events associated with immune checkpoint blockade and expert insights on their management. Cancer Treat Rev. 2017;58:70–76. doi:10.1016/j.ctrv.2017.06.00228689073
   PubMed Web of Science ®Google Scholar
• Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer. 2016;54:139–148. doi:10.1016/j.ejca.2015.11.01626765102
   PubMed Web of Science ®Google Scholar
• Postow MA, Callahan MK, Wolchok JD. Immune checkpoint blockade in cancer therapy. J Clin Oncol. 2015;33(17):1974–1982. doi:10.1200/JCO.2014.59.435825605845
   PubMed Web of Science ®Google Scholar
• Feng S, Coward J, McCaffrey E, Coucher J, Kalokerinos P, O’Byrne K. Pembrolizumab-induced encephalopathy: a review of neurological toxicities with immune checkpoint inhibitors. J Thorac Oncol. 2017;12(11):1626–1635. doi:10.1016/j.jtho.2017.08.00728843363
   PubMed Web of Science ®Google Scholar
• Leroy V, Templier C, Faivre J-B, et al. Pembrolizumab-induced pneumonitis. ERJ Open Res. 2017;3(2):00081–02016. doi:10.1183/23120541.00081-201628480216
   PubMedGoogle Scholar
• Escandon J, Peacock S, Trabolsi A, Thomas DB, Layka A, Lutzky J. Interstitial nephritis in melanoma patients secondary to PD-1 checkpoint inhibitor. J Immunother Cancer. 2017;5:1. doi:10.1186/s40425-016-0205-228105368
   PubMed Web of Science ®Google Scholar
• Wu Z, Lai L, Li M, Zhang L, Zhang W. Acute liver failure caused by pembrolizumab in a patient with pulmonary metastatic liver cancer: A case report. Medicine (Baltimore). 2017;96(51):e9431. doi:10.1097/MD.000000000000943129390572
   PubMed Web of Science ®Google Scholar
• Läubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer. 2015;3:1. doi:10.1186/s40425-015-0057-125648675
   PubMed Web of Science ®Google Scholar
• Geukes Foppen MH, Rozeman EA, van Wilpe S, et al. Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management. ESMO Open. 2018;3(1):e000278. doi:10.1136/esmoopen-2017-00027829387476
   PubMed Web of Science ®Google Scholar
• Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. The Lancet. 2014;384(9948):1109–1117. doi:10.1016/S0140-6736(14)60958-2
   PubMed Web of Science ®Google Scholar
• Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;16(8):908–918. doi:10.1016/S1470-2045(15)00083-226115796
   PubMed Web of Science ®Google Scholar
• Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372(26):2521–2532. doi:10.1056/NEJMoa150309325891173
   PubMed Web of Science ®Google Scholar
• 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. The Lancet. 2016;387(10027):1540–1550. doi:10.1016/S0140-6736(15)01281-7
   PubMed Web of Science ®Google Scholar
• Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1–positive non–small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833. doi:10.1056/NEJMoa160677427718847
   PubMed Web of Science ®Google Scholar
• Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36(18_suppl):LBA4–LBA4. doi:10.1200/JCO.2018.36.18_suppl.LBA4
   Web of Science ®Google Scholar
• Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non–small-cell lung cancer. N Engl J Med. 2018;378(22):2078–2092. doi:10.1056/NEJMoa180100529658856
   PubMed Web of Science ®Google Scholar
• Paz-Ares LG, Luft A, Tafreshi A, et al. Phase 3 study of carboplatin-paclitaxel/nab-paclitaxel (Chemo) with or without pembrolizumab (Pembro) for patients (Pts) with metastatic squamous (Sq) non-small cell lung cancer (NSCLC). J Clin Oncol. 2018;36(15_suppl):105. doi:10.1200/JCO.2018.36.15_suppl.105
   Google Scholar
• Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015–1026. doi:10.1056/NEJMoa161368328212060
   PubMed Web of Science ®Google Scholar
• Balar AV, Castellano D, O’Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483–1492. doi:10.1016/S1470-2045(17)30072-428967485
   PubMed Web of Science ®Google Scholar
• McDermott DF, Lee J-L, Szczylik C, et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): results from cohort A of KEYNOTE-427. J Clin Oncol. 2018;36(15_suppl):4500. doi:10.1200/JCO.2018.36.15_suppl.4500
   Web of Science ®Google Scholar
• Chung HC, Schellens JHM, Delord J-P, et al. Pembrolizumab treatment of advanced cervical cancer: updated results from the phase 2 KEYNOTE-158 study. J Clin Oncol. 2018;36(15_suppl):5522. doi:10.1200/JCO.2018.36.15_suppl.5522
   Google Scholar
• Fuchs CS, Doi T, Jang RW, et al. Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer: phase 2 clinical KEYNOTE-059 trial. JAMA Oncol. 2018;4(5):e180013 10.1001/jamaoncol.2018.0013.29543932
   PubMed Web of Science ®Google Scholar
• Shitara K, Özgüroğlu M, Bang Y-J, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. The Lancet. 2018. doi:10.1016/S0140-6736(18)31257-1
   PubMed Web of Science ®Google Scholar
• Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 2018;19(7):940–952. doi:10.1016/S1470-2045(18)30351-629875066
   PubMed Web of Science ®Google Scholar
• Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956–965. doi:10.1016/S1470-2045(16)30066-327247226
   PubMed Web of Science ®Google Scholar
• Cohen EEW, Soulières D, Le Tourneau C, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. The Lancet. 2018. doi:10.1016/S0140-6736(18)31999-8
   Google Scholar
• Eggermont AMM, Blank CU, Mandala M, et al. Adjuvant Pembrolizumab versus placebo in resected stage III melanoma. N Engl J Med. 2018;378(19):1789–1801. doi:10.1056/NEJMoa180235729658430
   PubMed Web of Science ®Google Scholar
• Mok T, Wu Y-L, Watson PA, Zhang J, Rangwala RA, Lopes G. Phase 3 KEYNOTE-042 trial of pembrolizumab (MK-3475) versus platinum doublet chemotherapy in treatment-naive patients (pts) with PD-L1–positive advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;33(15_suppl):TPS8105–TPS8105. doi:10.1200/jco.2015.33.15_suppl.tps8105
   Google Scholar
• Vuky J, Balar AV, Castellano DE, et al. Updated efficacy and safety of KEYNOTE-052: A single-arm phase 2 study investigating first-line pembrolizumab (pembro) in cisplatin-ineligible advanced urothelial cancer (UC). J Clin Oncol. 2018;36(15_suppl):4524. doi:10.1200/JCO.2018.36.15_suppl.4524
   Web of Science ®Google Scholar
• Frenel J-S, Le Tourneau C, O’Neil B, et al. Safety and Efficacy of pembrolizumab in advanced, programmed death ligand 1–positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. 2017;35(36):4035–4041. doi:10.1200/JCO.2017.74.547129095678
   PubMed Web of Science ®Google Scholar
• Fashoyin‐Aje L, Donoghue M, Chen H, et al. FDA approval summary: pembrolizumab for recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma expressing PD‐L1. Oncologist. 2018 theoncologist.2018-0221. doi:10.1634/theoncologist.2018-0221
   PubMed Web of Science ®Google Scholar
• Tabernero J, Bang Y-J, Fuchs CS, et al. KEYNOTE-062: phase III study of pembrolizumab (MK-3475) alone or in combination with chemotherapy versus chemotherapy alone as first-line therapy for advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma. J Clin Oncol. 2016;34(4_suppl):TPS185–TPS185. doi:10.1200/jco.2016.34.4_suppl.tps185
   Web of Science ®Google Scholar
• Larkins E, Blumenthal GM, Yuan W, et al. FDA approval summary: pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum‐containing chemotherapy. Oncologist. 2017;22(7):873–878. doi:10.1634/theoncologist.2016-049628533473
   PubMed Web of Science ®Google Scholar
• Chow LQM, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34(32):3838–3845. doi:10.1200/JCO.2016.68.147827646946
   PubMed Web of Science ®Google Scholar
• Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: pooled analyses after long-term follow-up in KEYNOTE-012. Br J Cancer. 2018. doi:10.1038/s41416-018-0131-9
   PubMed Web of Science ®Google Scholar
• Burtness B, Harrington KJ, Greil R, et al. KEYNOTE-048: phase III study of first-line pembrolizumab (P) for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Ann Oncol. 2018;29(suppl 8). doi:doi:10.1093/annonc/mdy424
   Google Scholar
• O’Brien MER, Hasan B, Dafni U, et al. EORTC-ETOP randomized, phase 3 trial with anti-PD-1 monoclonal antibody pembrolizumab versus placebo for patients with early stage non-small cell lung cancer (NSCLC) after resection and standard adjuvant chemotherapy: PEARLS (NCT02504372). J Clin Oncol. 2016;34(15_suppl):TPS8571–TPS8571. doi:10.1200/JCO.2016.34.15_suppl.TPS8571
   Web of Science ®Google Scholar
• Ott PA, Elez E, Hiret S, et al. Pembrolizumab in patients with extensive-stage small-cell lung cancer: results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2017;35(34):3823–3829. doi:10.1200/JCO.2017.72.506928813164
   PubMed Web of Science ®Google Scholar
• Ott P, Felip E, Hiret S, et al. OA05.01 pembrolizumab in patients with extensive-stage small cell lung cancer: updated survival results from KEYNOTE-028. J Thorac Oncol. 2017;12(1):S259. doi:10.1016/j.jtho.2016.11.250
   Google Scholar
• Chung HC, Lopez-Martin JA, Kao SC-H, et al. Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158. J Clin Oncol. 2018;36(15_suppl):8506. doi:10.1200/JCO.2018.36.15_suppl.8506
   Google Scholar
• Rudin C, Shen L, Pietanza MC. P2.04-007 KEYNOTE-604: phase 3 randomized, double-blind trial of pembrolizumab/placebo plus etoposide/platinum for extensive stage-SCLC. J Thorac Oncol. 2017;12(11):S2400. doi:10.1016/j.jtho.2017.11.020
   Web of Science ®Google Scholar
• Gadgeel SM, Ventimiglia J, Kalemkerian GP, et al. Phase II study of maintenance pembrolizumab (pembro) in extensive stage small cell lung cancer (ES-SCLC) patients (pts). J Clin Oncol. 2017;35(15_suppl):8504. doi:10.1200/JCO.2017.35.15_suppl.8504
   Google Scholar
• Cedrés S, Ponce-Aix S, Zugazagoitia J, et al. Analysis of expression of programmed cell death 1 ligand 1 (PD-L1) in Malignant Pleural Mesothelioma (MPM). Gangopadhyay N, ed. PLoS One. 2015;10(3):e0121071. doi:10.1371/journal.pone.012107125774992
   PubMed Web of Science ®Google Scholar
• Mansfield AS, Roden AC, Peikert T, et al. B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis. J Thorac Oncol. 2014;9(7):1036–1040. doi:10.1097/JTO.000000000000017724926549
   PubMed Web of Science ®Google Scholar
• Alley EW, Lopez J, Santoro A, et al. Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial. Lancet Oncol. 2017;18(5):623–630. doi:10.1016/S1470-2045(17)30169-928291584
   PubMed Web of Science ®Google Scholar
• Kindler H, Karrison T, Y-H CT, et al. OA13.02 phase II trial of pembrolizumab in patients with Malignant Mesothelioma (MM): interim analysis. J Thorac Oncol. 2017;12(1):S293–S294. doi:10.1016/j.jtho.2016.11.301
   PubMedGoogle Scholar
• Cho J, Ahn M-J, Yoo KH, et al. A phase II study of pembrolizumab for patients with previously treated advanced thymic epithelial tumor. J Clin Oncol. 2017;35(15_suppl):8521. doi:10.1200/JCO.2017.35.15_suppl.8521
   Google Scholar
• Giaccone G, Kim C, Thompson J, et al. Pembrolizumab in patients with thymic carcinoma: a single-arm, single-centre, phase 2 study. Lancet Oncol. 2018;19(3):347–355. doi:10.1016/S1470-2045(18)30062-729395863
   PubMed Web of Science ®Google Scholar
• Necchi A, Briganti A, Raggi D, et al. Interim results from PURE-01: A phase 2, open-label study of neoadjuvant pembrolizumab (pembro) before radical cystectomy for muscle-invasive urothelial bladder carcinoma (MIUC). J Clin Oncol. 2018;36(6_suppl):TPS533–TPS533. doi:10.1200/JCO.2018.36.6_suppl.TPS533
   Web of Science ®Google Scholar
• Rini BI, Powles T, Chen M, Puhlmann M, Atkins MB. Phase 3 KEYNOTE-426 trial: pembrolizumab (pembro) plus axitinib versus sunitinib alone in treatment-naive advanced/metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2017;35(15_suppl):TPS4597–TPS4597. doi:10.1200/JCO.2017.35.15_suppl.TPS4597
   Google Scholar
• De Bono JS, Goh JC, Ojamaa K, et al. KEYNOTE-199: pembrolizumab (pembro) for docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2018;36(15_suppl):5007. doi:10.1200/JCO.2018.36.15_suppl.5007
   Google Scholar
• Schmid P, Park YH, Muñoz-Couselo E, et al. Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): preliminary results from KEYNOTE-173. J Clin Oncol. 2017;35(15_suppl):556. doi:10.1200/JCO.2017.35.15_suppl.556
   Google Scholar
• Nanda R, Liu MC, Yau C, et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): results from I-SPY 2. J Clin Oncol. 2017;35(15_suppl):506. doi:10.1200/JCO.2017.35.15_suppl.50628029304
   PubMed Web of Science ®Google Scholar
• Schmid P, Cortes J, Bergh JCS, et al. KEYNOTE-522: phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo + chemo as neoadjuvant therapy followed by pembro vs placebo as adjuvant therapy for triple-negative breast cancer (TNBC). J Clin Oncol. 2018;36(15_suppl):TPS602–TPS602. doi:10.1200/JCO.2018.36.15_suppl.TPS602
   Google Scholar
• Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379(22):2108–2121. doi:10.1056/NEJMoa180961530345906
   PubMed Web of Science ®Google Scholar
• Cortés J, Guo Z, Karantza V, Aktan G. KEYNOTE-355: randomized, double-blind, phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (PBO) + chemo for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 2018;36(5_suppl):TPS18–TPS18. doi:10.1200/JCO.2018.36.5_suppl.TPS18
   Web of Science ®Google Scholar
• Loi S, Giobbe-Hurder A, Gombos A, et al. Abstract GS2-06: phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic breast cancer: results from the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) study. Cancer Res. 2018;78(4Supplement):GS2–06. doi:10.1158/1538-7445.SABCS17-GS2-06
   Google Scholar
• Eng C. POLE mutations in colorectal cancer: a new biomarker? Lancet Gastroenterol Hepatol. 2016;1(3):176–177. doi:10.1016/S2468-1253(16)30030-928404085
   PubMed Web of Science ®Google Scholar
• McConechy MK, Talhouk A, Leung S, et al. Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis. Clin Cancer Res. 2016;22(12):2865–2873. doi:10.1158/1078-0432.CCR-15-223326763250
   PubMed Web of Science ®Google Scholar
• Fader AN, Diaz LA, Armstrong DK, et al. Preliminary results of a phase II study: PD-1 blockade in mismatch repair–deficient, recurrent or persistent endometrial cancer. Gynecol Oncol. 2016;141:206–207. doi:10.1016/j.ygyno.2016.04.53226905211
   PubMedGoogle Scholar
• Matulonis UA, Shapira-Frommer R, Santin A, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: interim results from the phase 2 KEYNOTE-100 study. J Clin Oncol. 2018;36(15_suppl):5511. doi:10.1200/JCO.2018.36.15_suppl.5511
   Web of Science ®Google Scholar
• Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—results from ROC cohort. J Clin Oncol. 2018;36(15_suppl):106. doi:10.1200/JCO.2018.36.15_suppl.106
   Web of Science ®Google Scholar
• Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520. doi:10.1056/NEJMoa150059626028255
   PubMed Web of Science ®Google Scholar
• Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413. doi:10.1126/science.aan673328596308
   PubMed Web of Science ®Google Scholar
• Le DT, Yoshino T, Jäger D, et al. KEYNOTE-164: phase II study of pembrolizumab (MK-3475) for patients with previously treated, microsatellite instability-high advanced colorectal carcinoma. J Clin Oncol. 2016;34(4_suppl):TPS787–TPS787. doi:10.1200/jco.2016.34.4_suppl.tps787
   Web of Science ®Google Scholar
• Diaz LA, Le DT, Yoshino T, et al. KEYNOTE-177: phase 3, open-label, randomized study of first-line pembrolizumab (Pembro) versus investigator-choice chemotherapy for mismatch repair-deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal carcinoma (mCRC). J Clin Oncol. 2018;36(4_suppl):TPS877–TPS877. doi:10.1200/JCO.2018.36.4_suppl.TPS877
   Web of Science ®Google Scholar
• Shah MA, Bennouna J, Shen L, et al. Pembrolizumab for previously treated metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: phase 2 KEYNOTE-180 study. J Clin Oncol. 2016;34(15_suppl):TPS4139–TPS4139. doi:10.1200/JCO.2016.34.15_suppl.TPS4139
   Web of Science ®Google Scholar
• Doi T, Bennouna J, Shen L, et al. KEYNOTE-181: phase 3, open-label study of second-line pembrolizumab vs single-agent chemotherapy in patients with advanced/metastatic esophageal adenocarcinoma. J Clin Oncol. 2016;34(15_suppl):TPS4140–TPS4140. doi:10.1200/JCO.2016.34.15_suppl.TPS4140
   Google Scholar
• Ott PA, Piha-Paul SA, Munster P, et al. Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal. Ann Oncol. 2017;28(5):1036–1041. doi:10.1093/annonc/mdx02928453692
   PubMed Web of Science ®Google Scholar
• Fontugne J, Augustin J, Pujals A, et al. PD-L1 expression in perihilar and intrahepatic cholangiocarcinoma. Oncotarget. 2017;8:15. doi:10.18632/oncotarget.1560227965467
   PubMedGoogle Scholar
• Bang YJ, Doi T, Braud FD, et al. 525 Safety and efficacy of pembrolizumab (MK-3475) in patients (pts) with advanced biliary tract cancer: interim results of KEYNOTE-028. Eur J Cancer. 2015;51:S112 10.1016/S0959-8049(16)30326-4.
   PubMed Web of Science ®Google Scholar
• Bauml J, Seiwert TY, Pfister DG, et al. Pembrolizumab for platinum- and cetuximab-refractory head and neck cancer: results from a single-arm, phase II study. J Clin Oncol. 2017;35(14):1542–1549. doi:10.1200/JCO.2016.70.152428328302
   PubMed Web of Science ®Google Scholar
• Uppaluri R, Zolkind P, Lin T, et al. Neoadjuvant pembrolizumab in surgically resectable, locally advanced HPV negative head and neck squamous cell carcinoma (HNSCC). J Clin Oncol. 2017;35(15_suppl):6012. doi:10.1200/JCO.2017.35.15_suppl.6012
   Google Scholar
• Machiels J-PH, Licitra L, Rischin D, et al. KEYNOTE-412: pembrolizumab (pembro) in combination with chemoradiation versus chemoradiation alone in locally advanced head and neck squamous cell carcinoma (LA-HNSCC). J Clin Oncol. 2017;35(15_suppl):TPS6090–TPS6090. doi:10.1200/JCO.2017.35.15_suppl.TPS6090
   Google Scholar
• Ghatalia P, Zibelman M, Geynisman DM, Plimack E. Approved checkpoint inhibitors in bladder cancer: which drug should be used when? Ther Adv Med Oncol. 2018. doi:10.1177/1758835918788310
   PubMed Web of Science ®Google Scholar
• Kim S, Koh J, Kwon D, et al. Comparative analysis of PD-L1 expression between primary and metastatic pulmonary adenocarcinomas. Eur J Cancer. 2017;75:141–149. doi:10.1016/j.ejca.2017.01.00428222308
   PubMed Web of Science ®Google Scholar
• Tretiakova M, Fulton R, Kocherginsky M, et al. Concordance study of PD-L1 expression in primary and metastatic bladder carcinomas: comparison of four commonly used antibodies and RNA expression. Mod Pathol. 2017;31:623. doi:10.1038/modpathol.2017.18829271413
   PubMed Web of Science ®Google Scholar
• Robert C, Ribas A, Hamid O, et al. Durable complete response after discontinuation of pembrolizumab in patients with metastatic melanoma. J Clin Oncol. 2018;36(17):1668–1674. doi:10.1200/JCO.2017.75.627029283791
   PubMed Web of Science ®Google Scholar
• Australian Pancreatic Cancer Genome Initiative, ICGC Breast Cancer Consortium, ICGC MMML-Seq Consortium, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421. doi:10.1038/nature1247723945592
   PubMed Web of Science ®Google Scholar
• Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–128. doi:10.1126/science.aaa134825765070
   PubMed Web of Science ®Google Scholar
• Cristescu R, Mogg R, Ayers M, et al. Mutational load (ML) and T-cell-inflamed microenvironment as predictors of response to pembrolizumab. J Clin Oncol. 2017;35(7_suppl):1. doi:10.1200/JCO.2017.35.7_suppl.128034063
   PubMed Web of Science ®Google Scholar
• Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598–2608. doi:10.1158/1535-7163.MCT-17-038628835386
   PubMed Web of Science ®Google Scholar
• Chalmers ZR, Connelly CF, Fabrizio D, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:1. doi:10.1186/s13073-017-0424-228081715
   PubMed Web of Science ®Google Scholar
• Lau E. Mismatch repair deficiency predicts benefit of anti-PD-1 therapy. Lancet Oncol. 2015;16(7):e319. doi:10.1016/S1470-2045(15)00031-5
   PubMed Web of Science ®Google Scholar
• Tazdait M, Mezquita L, Lahmar J, et al. Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: comparison of RECIST 1.1, irRECIST and iRECIST criteria. Eur J Cancer. 2018;88:38–47. doi:10.1016/j.ejca.2017.10.01729182990
   PubMed Web of Science ®Google Scholar
• Sachpekidis C, Hassel JC, Dimitrakopoulou-Strauss A. 18F-FDG PET/CT reveals disease remission in a patient with ipilimumab-refractory advanced melanoma treated with pembrolizumab. Clin Nucl Med. 2016;41(2):156–158. doi:10.1097/RLU.000000000000103926545022
   PubMed Web of Science ®Google Scholar
• Dercle L, Seban R-D, Lazarovici J, et al. 18F-FDG PET and CT scans detect new imaging patterns of response and progression in patients with hodgkin lymphoma treated by anti–programmed death 1 immune checkpoint inhibitor. J Nucl Med. 2018;59(1):15–24. doi:10.2967/jnumed.117.19301128596157
   PubMed Web of Science ®Google Scholar
• Dimitrakopoulou-Strauss A. Monitoring of patients with metastatic melanoma treated with immune checkpoint inhibitors using PET–CT. Cancer Immunol Immunother. 2018. doi:10.1007/s00262-018-2229-6
   Web of Science ®Google Scholar
• Muro K, Chung HC, Shankaran V, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717–726. doi:10.1016/S1470-2045(16)00175-327157491
   PubMed Web of Science ®Google Scholar
• Ayers M, Lunceford J, Nebozhyn M, et al. IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest. 2017;127(8):2930–2940. doi:10.1172/JCI9119028650338
   PubMed Web of Science ®Google Scholar
• Herbst RS, Soria J-C, Kowanetz M, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–567. doi:10.1038/nature1401125428504
   PubMed Web of Science ®Google Scholar
• Ribas A, Dummer R, Puzanov I, et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109–1119.e10. doi:10.1016/j.cell.2017.08.02728886381
   PubMed Web of Science ®Google Scholar
• Conry RM, Westbrook B, McKee S, Norwood TG. Talimogene laherparepvec: first in class oncolytic virotherapy. Hum Vaccines Immunother. 2018;14(4):839–846. doi:10.1080/21645515.2017.1412896
   PubMed Web of Science ®Google Scholar
• Milhem M, Gonzales R, Medina T, et al. Abstract CT144: intratumoral toll-like receptor 9 (TLR9) agonist, CMP-001, in combination with pembrolizumab can reverse resistance to PD-1 inhibition in a phase Ib trial in subjects with advanced melanoma. Cancer Res. 2018;78(13Supplement):CT144. doi:10.1158/1538-7445.AM2018-CT144
   Google Scholar
• Brochez L, Chevolet I, Kruse V. The rationale of indoleamine 2,3-dioxygenase inhibition for cancer therapy. Eur J Cancer. 2017;76:167–182. doi:10.1016/j.ejca.2017.01.01128324751
   PubMed Web of Science ®Google Scholar
• Powles T, Bellmunt J, Petrylak DP, et al. Pembrolizumab (pembro) plus epacadostat or placebo for locally advanced or metastatic urothelial carcinoma (UC) after failure of first-line platinum-containing chemotherapy: KEYNOTE-698/ECHO-303. J Clin Oncol. 2018;36(15_suppl):TPS4586–TPS4586. doi:10.1200/JCO.2018.36.15_suppl.TPS4586
   Web of Science ®Google Scholar
• Balar AV, Plimack ER, Grivas P, et al. Phase 3, randomized, double-blind trial of pembrolizumab plus epacadostat or placebo for cisplatin-ineligible urothelial carcinoma (UC): KEYNOTE-672/ECHO-307. J Clin Oncol. 2018;36(15_suppl):TPS4587–TPS4587. doi:10.1200/JCO.2018.36.15_suppl.TPS4587
   Web of Science ®Google Scholar
• Hamid O, Bauer TM, Spira AI, et al. Epacadostat plus pembrolizumab in patients with SCCHN: preliminary phase I/II results from ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35(15_suppl):6010. doi:10.1200/JCO.2017.35.15_suppl.6010
   Google Scholar
• Cohen EEW, Rischin D, Pfister DG, et al. A phase 3, randomized, open-label study of epacadostat plus pembrolizumab, pembrolizumab monotherapy, and the EXTREME regimen as first-line treatment for recurrent/metastatic head and neck squamous cell carcinoma (R/M SCCHN): ECHO-304/KEYNOTE-669. J Clin Oncol. 2018;36(15_suppl):TPS6090–TPS6090. doi:10.1200/JCO.2018.36.15_suppl.TPS6090
   Web of Science ®Google Scholar
• Long GV, Dummer R, Hamid O, et al. Epacadostat (E) plus pembrolizumab (P) versus pembrolizumab alone in patients (pts) with unresectable or metastatic melanoma: results of the phase 3 ECHO-301/KEYNOTE-252 study. J Clin Oncol. 2018;36(15_suppl):108. doi:10.1200/JCO.2018.36.15_suppl.108
   Web of Science ®Google Scholar
• Long GV, Atkinson V, Cebon JS, et al. Standard-dose pembrolizumab in combination with reduced-dose ipilimumab for patients with advanced melanoma (KEYNOTE-029): an open-label, phase 1b trial. Lancet Oncol. 2017;18(9):1202–1210. doi:10.1016/S1470-2045(17)30428-X28729151
   PubMed Web of Science ®Google Scholar
• Ikeda M, Sung MW, Kudo M, et al. A phase 1b trial of lenvatinib (LEN) plus pembrolizumab (PEM) in patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol. 2018;36(15_suppl):4076. doi:10.1200/JCO.2018.36.15_suppl.4076
   Web of Science ®Google Scholar
• Taylor MH, Rasco DW, Brose MS, et al. A phase 1b/2 trial of lenvatinib plus pembrolizumab in patients with squamous cell carcinoma of the head and neck. J Clin Oncol. 2018;36(15_suppl):6016. doi:10.1200/JCO.2018.36.15_suppl.6016
   Google Scholar
• Rodriguez CP, Wu V, Voutsinas JM, et al. Phase I/II trial of pembrolizumab(P) and vorinostat(V) in recurrent metastatic head and neck squamous cell carcinomas (HN) and salivary gland cancer (SGC). J Clin Oncol. 2018;36(15_suppl):6025. doi:10.1200/JCO.2018.36.15_suppl.6025
   Web of Science ®Google Scholar