Abstract
Nivolumab is a fully human monoclonal antibody blocking PD-1 with demonstrated effectiveness against metastatic urothelial carcinoma. In this review, we describe the pharmacological properties of nivolumab and the treatment of metastatic urothelial carcinoma with this checkpoint inhibitor after the failure of first-line platinum-based chemotherapy. Cancer immunotherapy by checkpoint inhibition offers potential to prolong patient survival with well manageable toxicity although serious immune-related adverse events may occur. The overall response rate to nivolumab after first-line chemotherapy is about 20%. Patients unfit for cisplatin may benefit from first-line cancer immunotherapy. It remains unclear which patient will respond and PD-1/PD-L1 expression alone is not a sufficiently reliable predictive biomarker.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer. Eur. Urol. 71(3), 462–475 (2017).
- 2 A systematic review of neoadjuvant and adjuvant chemotherapy for muscle-invasive bladder cancer. Eur. Urol. 62(3), 523–533 (2012).
- 3 . Cancer statistics, 2017. CA Cancer J. Clin. 67(1), 7–30 (2017).
- 4 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Bladder Cancer v5 (2017).
- 5 Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J. Clin. Oncol. 18(9), 1921–1927 (2000).
- 6 Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, Phase III study. J. Clin. Oncol. 18(17), 3068–3077 (2000).
- 7 ICUD-EAU international consultation on bladder cancer 2012: screening, diagnosis, and molecular markers. Eur. Urol. 63(1), 4–15 (2013).
- 8 Randomized Phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC intergroup study 30987. J. Clin. Oncol. 30(10), 1107–1113 (2012).
- 9 A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J. Clin. Oncol. 10(7), 1066–1073 (1992).
- 10 . First- and second-line therapy for metastatic urothelial carcinoma of the bladder. Curr. Oncol. 18(1), e25–e34 (2011).
- 11 Comparative effectiveness of gemcitabine plus cisplatin versus methotrexate, vinblastine, doxorubicin, plus cisplatin as neoadjuvant therapy for muscle-invasive bladder cancer. Cancer 121(15), 2586–2593 (2015).
- 12 Second-line single-agent versus doublet chemotherapy as salvage therapy for metastatic urothelial cancer: a systematic review and meta-analysis. Ann. Oncol. 27(1), 49–61 (2016).
- 13 . Breakthrough of the year 2013. Cancer immunotherapy. Science 342(6165), 1432–1433 (2013).
- 14 . Gene therapy in urological oncology: principles, strategies and potential. Eur. Urol. 25, 177–181 (1994).
- 15 Long-term survival results of a randomized Phase III trial of vinflunine plus best supportive care versus best supportive care alone in advanced urothelial carcinoma patients after failure of platinum-based chemotherapy. Ann. Oncol. 24(6), 1466–1472 (2013).
- 16 . A randomized Phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN). Ann. Oncol. 28(7), 1517–1522 (2017).
- 17 Avelumab in metastatic urothelial carcinoma after platinum failure (JAVELIN solid tumor): pooled results from two expansion cohort of an open-label, Phase I trial. Lancet Oncol. 19(1), 51–64 (2018).
- 18 Ramucirumab plus docetaxel versus placebo in patients with locally advanced or metastic urothelial carcinoma after platinum-based therapy (RANGE): a randomised, double-blind, Phase III study. Lancet 390(10109), 2266–2277 (2017).
- 19 Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, Phase II trial. Lancet 387(10031), 1909–1920 (2016). •• Atezolizumab, an anti-PD-L1 antibody, was the first immune-checkpoint inhibitor to be approved by the US FDA in May 2016.
- 20 Nanoparticle albumin-bound paclitaxel for second-line treatment of metastatic urothelial carcinoma: a single group, multicentre, Phase II study. Lancet Oncol. 14(8), 769–776 (2013).
- 21 Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: updated results from a Phase I/II open-label study. JAMA Oncol. 3(9), e172411 (2017).
- 22 The development of immunomodulatory monoclonal antibodies as a new therapeutic modality for cancer: the Bristol-Myers Squibb experience. Pharmacol. Ther. 148, 132–153 (2015).
- 23 Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 therapy. Clin. Cancer Res. 20(19), 5064–5074 (2014). • Definition of the predictive role of PD-1 expression.
- 24 Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
- 25 . Clinical significance of programmed death-1 ligand-1 expression in patients with non-small-cell lung cancer: a 5-year follow-up study. Tumori 98(6), 751–755 (2012).
- 26 In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol. Res. 2(9), 846–856 (2014).
- 27 . Current challenges in cancer treatment. Clin. Ther. 38(7), 1551–1566 (2016).
- 28 . Comprehensive molecular characterization of muscle-invasive bladder cancer. Cell 171(3), 540–556 (2017).
- 29 Model-based analysis of nivolumab to support clinical pharmacology profiling in subjects with solid tumors [abstract]. Clin. Pharmacol. Ther. 97(Suppl. 1), S41–S42 (2015).
- 30 Bristol-Myers Squibb Company. Opdivo (nivolumab) injection, for intravenous use: US prescribing information (2015). www.fda.gov/.
- 31 European Medicines Agency. Opdivo 10 mg/ml concentrate for infusion: summary of product characteristics (2015). www.ema.europa.eu/.
- 32 Assessment of drug interaction potential by nivolumab using cytokine modulation data [abstract no. 118]. Presented at: American Society for Clinical Pharmacology and Therapeutics Annual Meeting. New Orleans, LA, USA, March 2015.
- 33 . Clinical impact of checkpoint inhibitors as novel cancer therapies. Drugs 74(17), 1993–2013 (2014).
- 34 Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, Phase II trial. Lancet Oncol. 18(3), 312–322 (2017). •• This is the first published study with nivolumab in metastatic refractory urothelial carcinoma.
- 35 . Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug Discov. 14(8), 561–584 (2015).
- 36 A Phase I study of cabozantinib plus nivolumab (CaboNivo) and ipilimumab (CaboNivoIpi) in patients (pts) with refractory metastatic urothelial carcinoma (mUC) and other genitourinary (GU) tumors. J. Clin. Oncol. 35(Suppl. 6), 293 (2017). • Innovative combination Phase I study with cabozantinib and nivolumab +/- ipilimumab with promising data of overall response rate and survival.
- 37 Association of response to programmed death receptor 1 (PD-1) blockade with pembrolizumab (MK-3475) with an interferon-inflammatory immune gene signature. J. Clin. Oncol. 33(Suppl. 15), 3001 (2015).
- 38 Comprehensive molecular characterization of urothelial bladder carcinoma. Nature 507(7492), 315–322 (2014). • This is the first molecular characterization of bladder carcinoma from the The Cancer Genome Atlas.
- 39 Safety, activity and immune correlates of anti-PD-1 antibody in cancer. N. Engl. J. Med. 366(26), 2443–2454 (2012). •• Statement of immunotherapy regarding safety profile and efficacy.
- 40 Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, Phase I/II trial. Lancet Oncol. 17(11), 1590–1598 (2016).
- 41 Molecular drivers of the non-T-cell-inflamed tumor microenvironment in urothelial bladder cancer. Cancer Immunol. Res. 4(7), 563–568 (2016).
- 42 Impact of tumor mutation burden on nivolumab efficacy in second-line urothelial carcinoma patients: exploratory analysis of the Phase II Checkmate 275 study. Ann. Oncol. 28(Suppl. 5), 1 (2017).
- 43 Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359(6371), 91–97 (2018).
- 44 Economic sustainability of anti-PD-1 agents nivolumab and pembolizumab in cancer patients: recent insights and future challenges. Cancer Treat. 48, 20–40 (2016).