With an estimated 549,000 new diagnoses and 200,000 deaths worldwide in 2018, bladder cancer is the tenth most common type of cancer in men and women.1 The most common type of bladder cancer in the Western world is uroepithelial carcinoma, which accounts for 90% of all cases, and is classified into two subtypes. Non-muscle-invasive urothelial carcinomas (NMIBC) are associated with activation of the receptor tyrosine kinase-Ras pathway, activating mutations in the HRAS or fibroblast growth factor receptor 3 (FGFR3) genes. Muscle-invasive urothelial carcinomas (MIBC) are characterised by alterations in the p53 and retinoblastoma (RB1) pathways. Most patients present with the non-muscle-invasive form of the disease, while up to one-third have the invasive form.2
Patients with high-risk MIBC have a poor prognosis. Radical cystectomy with or without neoadjuvant chemotherapy or concurrent chemoradiation as a bladder-sparing option is the standard treatment for these patients.3 However, even though the surgical technique has improved over the years, around 50% of patients with MIBC will develop metastatic disease after undergoing radical cystectomy, and only 25–35% with high grade (pT3–pT4) tumours are still alive 5 years after surgery.4 For patients with metastatic disease, systemic cisplatin-based chemotherapy is the standard of care, but the median survival is less than 1 year.5 Furthermore, almost half of patients with MIBC are not eligible for cisplatin-based chemotherapy.6 There is, therefore, an urgent unmet need for effective treatment options.
For patients with NMIBC, transurethral resection of bladder with adjuvant intravesical Bacillus Calmette-Guérin (BCG), a live attenuated strain of Mycobacterium bovis, has replaced cystectomy as the standard treatment option.7 However, this treatment is associated with a high rate of resistance and progression: recurrence rate at 5 years is 66% and about 25% of patients will have disease progression.8,9 BCG refractory disease is defined as stage progression at 3 months after adequate BCG induction or persistent high-risk disease at 6 months despite adequate BCG. Finally, BCG relapsing disease is defined as recurrence of high-risk NMIBC after the patient achieves a disease-free state within 12 months after adequate BCG therapy. Radical cystectomy is the standard option for patients with BCG-unresponsive NMIBC.7,8
Bladder cancers have a high rate of somatic mutations,10 which is associated with high response rates to immune checkpoint inhibitors.11 In addition, activation of the programmed cell death -1 (PD-1) pathway has been implicated in resistance to BCG therapy.12 Therefore immune checkpoint inhibitors, particularly those targeting PD-1 and its ligand, programmed death ligand 1 (PD-L1), have emerged as potential treatment options for bladder cancer. Pembrolizumab has received approval from the US Food and Drug Administration (FDA) for the treatment of patients with metastatic or locally advanced uroepithelial carcinoma who are not eligible for cisplatin-containing chemotherapy and those who have disease progression during or following platinum-containing chemotherapy. Approval was based on a number of key clinical trials.12
A number of studies are currently investigating the efficacy and safety of pembrolizumab in less advanced disease states. Data from these studies were presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), which was held on 14–16 February 2019 in San Francisco, California, US.
KEYNOTE-057 is an ongoing single-arm, open-label, phase II trial involving patients with NMIBC who are unresponsive to BCG and are ineligible for cystectomy. The study has two cohorts: cohort A comprises patients with carcinoma in situ (CIS) with or without papillary disease; while cohort B consists of patients with papillary disease without CIS. Patients received pembrolizumab 200 mg every 3 weeks, then underwent with cystoscopy, cytology and a biopsy every 12 weeks for 2 years, followed by every 24 weeks for 2 years and once yearly after that. Patients also had a computed tomography urogram every 24 weeks for 2 years. The primary endpoints were complete response (CR) rates in cohort A and disease-free survival in cohort B.13
At the time of reporting (median follow up: 15.8 months), cohort A comprised 102 patients, of which 1 patient had completed therapy, 78 (76.4%) had discontinued therapy and 23 (22.5%) were undergoing ongoing treatment. The 3-month rate of CR was 40.2%. (95% confidence interval [CI]: 30.6–50.4%) by central assessment. Among the 41 patients who achieved CR at 3 months, 58.5% maintained CR at their last follow up (median: 16.7 month; range: 4.0–26.3) and the duration of response was 12.7 months (range 0+ to 20+ months). The majority (75.0%) of patients had a CR duration exceeding 6 months. Of the patients that experienced recurrance, 15 patients experienced recurrent NMIBC after CR. Subgroup analysis showed that non-white patients, non-US patients, CIS only patients, and PD–L1–negative patients were more likely to achieve a CR. Importantly, at the time of analysis, none of the patients had progressed to muscle-invasive or metastatic disease. Of the patients who did not achieve CR, 40.2% had persistent disease.13
In terms of safety, treatment-related adverse events (AEs) occurred in 64.7% patients; the most common were pruritus (10.8%), fatigue (9.8%), diarrhoea (10.8%), hypothyroidism (6.9%) and maculopapular rash (5.9%). Grade 3/4 treatment-related AEs occurred in 12.6% of patients. One was considered to be treatment-related (colitis in a patient inadequately treated with steroids). Immune-mediated AEs occurred in 18.6% of patients.13
The response rates in KEYNOTE-057 are the highest seen to date and are particularly striking given that 30.0% of these patients had more aggressive disease than CIS alone. However, before this treatment becomes the standard of care, data from phase III studies with longer follow–up periods are needed. There is also a need for more biomarkers to identify patients who are most likely to benefit from a salvage systemic therapy such as pembrolizumab as opposed to those who should undergo a radical cystectomy.
The ongoing AMBASSADOR study (ClinicalTrials.gov identifier: NCT03244384)14 is comparing pembrolizumab with observation alone in patients with locally advanced MIBC. Eligibility criteria include high-risk MIBC or upper tract urothelial carcinoma. Participants must have undergone a cystectomy or nephrectomy within 16 weeks, and must have pT2-4aNx or pTxN+ disease after having undergone neoadjuvant chemotherapy. Alternatively, patients can have pT3–4Nx or pN+ disease post surgery with no chemotherapy. Patients will be stratified by PD-L1 positivity, receipt of prior neoadjuvant chemotherapy and pathologic stage pT2/3/4aN0 versus pT4bNx or N1-3 disease. They will then be randomly assigned to receive 200 mg of pembrolizumab every 3 weeks for 12 months or to observation alone. The primary objectives are disease-free survival and overall survival. Secondary endpoints include safety and tolerability of pembrolizumab in this patient cohort.15
The next step in the clinical development of pembrolizumab in bladder cancer will be in combination with BCG (ClinicalTrials.gov identifier: NCT03711032).16 Other immune checkpoint inhibitors are also being investigated including studies of avelumab, atezolizumab, nivolumab and durvalumab.12 As more treatments become available, it will become increasingly important to optimise patient selection to avoid costly and toxic treatment for those unlikely to respond. After many years of little progress, the treatment paradigm for bladder cancer is being transformed by immune checkpoint inhibitors, offering hope to patients worldwide.
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9. Expert Point of View: Shahrokh Shariat, MD. 2018. Available at:www.ascopost.com/issues/november-10-2018/epov-shahrokh-shariat/(accessed 25 March 2019).
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12. Stenehjem DD, Tran D, Nkrumah MA, et al. PD1/PDL1 inhibitors for the treatment of advanced urothelial bladder cancer.Onco Targets Ther.2018;11:5973–89.
13. UroToday®.ASCO GU 2019: Updated Results of Keynote 057: Pembrolizumab for Patients with High-risk Nonmuscle Invasive Bladder Cancer Unresponsive to BCG. 2019. Available at: www.urotoday.com/conference-highlights/asco-gu-2019/asco-gu-2019-bladder-cancer/110284-asco-gu-2019-keynote-057-phase-ii-trial-of-pembrolizumab-for-patients-with-high-risk-nonmuscle-invasive-bladder-cancer-unresponsive-to-bacillus-calmette-guerin.html (accessed 25 March 2019).
14. ClinicalTrials.gov.Pembrolizumab in Treating Patients With Locally Advanced Bladder Cancer (AMBASSADOR).ClinicalTrials.gov Identifier: NCT03244384. Available at: https://clinicaltrials.gov/ct2/show/NCT03244384 (accessed 27 March 2019).
15. UroToday®.ASCO GU 2019: Pembrolizumab in Muscle-Invasive and Locally Advanced Urothelial Carcinoma – AMBASSADOR versus Observation. 2019. Available at: urotoday.com/conference-highlights/asco-gu-2019/asco-gu-2019-bladder-cancer/110409-asco-gu-2019-alliance-a031501-phase-iii-randomized-adjuvant-study-of-pembrolizumab-in-muscle-invasive-and-locally-advanced-urothelial-carcinoma-ambassador-versus-observation.html (accessed 25 March 2019).
16. ClinicalTrials.gov.Efficacy and Safety of Pembrolizumab (MK-3475) in Combination With Bacillus Calmette-Guerin (BCG) in High-Risk Non-Muscle Invasive Bladder Cancer (HR NMIBC) (MK-3475-676/KEYNOTE-676). ClinicalTrials.gov Identifier: NCT03711032. Available at:https://clinicaltrials.gov/ct2/show/NCT03711032 (accessed 27 March 2019).
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