In the United States, an estimated 81 190 (62 380 men and 18 810 women) new cases of bladder cancer and 17 240 (12 520 men and 4720 women) related deaths occured in 2018. . Although the great majority of patients present with non-muscle-invasive bladder cancer (NMIBC), approximately 20–40% will require treatment for more advanced disease at some point in their disease course. Major advances have occurred in the management of patients with metastatic bladder cancer with the advent of immunotherapy; however, cure remains elusive in almost all patients with metastatic disease. The success of immunotherapy in metastatic disease has led to exciting trials employing immunotherapy in earlier disease states including muscle-invasive disease with the potential to avert progression to metastatic disease, a paradigm that may have the greatest chance for cure.
Before the mid-2000s in both the United States and Europe, most patients who presented with muscle-invasive bladder cancer (MIBC) underwent upfront cystectomy without perioperative chemotherapy [2,3]. Despite randomized clinical trials demonstrating the superiority of cisplatin-based neoadjuvant chemotherapy compared with locoregional treatment alone, neoadjuvant chemotherapy has been underutilized. Between 2006 and 2010, only 16.9% of patients in the National Cancer Database with organ-confined MIBC received neoadjuvant chemotherapy . In 2003, the results of Southwest Oncology Group (SWOG) trial 8710 was published demonstrating a 33% reduction in the risk of death in patients receiving neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) combined with cystectomy as compared with cystectomy alone . The larger BA06 30894 trial with 976 patients demonstrated a 16% reduction in the risk of death and 6% increase in 10-year survival with neoadjuvant cisplatin, methotrexate, and vinblastine (CMV) followed by cystectomy compared with locoregional treatment alone . A meta-analysis including 3005 patients treated on 11 randomized trials of platinum-based combination chemotherapy revealed a significant survival benefit with chemotherapy (hazard ratio 0.86, 95% CI 0.77–0.95, P = 0.003) translating to a 5% absolute improvement in overall survival (OS) at 5 years . A more recent meta-analysis including 3285 patients treated on 15 randomized trials revealed an OS benefit for cisplatin-based neoadjuvant chemotherapy compared with local treatment alone (hazard ratio 0.87, 95% CI 0.79–0.96) . Thus, neoadjuvant cisplatin-based combination chemotherapy is supported by level 1 evidence and represents a standard of care for patients with MIBC . In spite of limited data specific to muscle-invasive disease, the combination of gemcitabine and cisplatin is the most commonly used neoadjuvant regimen based on a randomized phase III study comparing MVAC to gemcitabine and cisplatin in patients with metastatic urothelial carcinoma demonstrating similar survival outcomes with improved tolerability with gemcitabine and cisplatin . A more recent meta-analysis comparing neoadjuvant gemcitabine and cisplatin and MVAC revealed no difference in pathologic complete response (pCR) but a reduced OS with gemcitabine and cisplatin (hazard ratio 1.26, 95% CI 1.01–1.57) . Two phase II trials published concurrently explored the use of accelerated or dose-dense MVAC (ddMVAC) administered every 2 weeks with growth factor support and found the regimen to be well tolerated with promising pCR rates [11,12]. One cross-sectional analysis of 1113 patients who underwent cystectomy found that those who received ddMVAC rather than gemcitabine and cisplatin had a higher pCR rate (OR 2.67, 95% CI 1.50–4.77), and likelihood of downstaging (OR 1.84, 95% CI 1.10–3.09) . Unfortunately, there is no prospective randomized data to inform the optimal neoadjuvant chemotherapy regimen for patients with MIBC.
There is no role for non-cisplatin-based chemotherapy in the neoadjuvant setting . Gemcitabine and carboplatin has demonstrated inferior survival outcomes as compared with studies using cisplatin-based chemotherapy in patients with advanced/metastatic disease. One phase II trial randomized patients with advanced urothelial carcinoma to gemcitabine with cisplatin or carboplatin and demonstrated a lower overall response rate (40.0% versus 49.1%), time to progression (7.7 months versus 8.3 months), and median overall survival (mOS) (9.8 months versus 12.8 months) with gemcitabine and carboplatin . These findings are consistent with the EORTC 30986 study demonstrating inferior outcomes with two different carboplatin-based regimens as compared with studies with cisplatin-based chemotherapy in patients with metastatic disease .
The paradigm for perioperative and specifically neoadjuvant chemotherapy is well established across solid tumor malignancies including breast, colorectal, and lung cancer as well as others [16–18]. Administering neoadjuvant chemotherapy provides for the possibility of tumor downstaging at the time of surgery, which has been associated with improved OS and relapse-free survival (RFS) in breast cancer, rectal cancer, and lung cancer [19–21]. SWOG 8710 demonstrated an improvement in the pCR rate in those receiving neoadjuvant chemotherapy versus cystectomy alone (38 versus 15%, P < 0.001) and a meta-analysis has shown pCR following neoadjuvant chemotherapy to translate to improved OS and RFS [5,22].
Although cisplatin-based neoadjuvant chemotherapy is associated with pathologic downstaging and an OS benefit, over 40% of patients diagnosed with urothelial carcinoma remain ineligible for cisplatin-based chemotherapy [23,24]. Ineligibility is most often secondary to impaired renal function but poor performance status, hearing loss, peripheral neuropathy, and heart failure are also criteria used to exclude cisplatin therapy . Even in those patients eligible to receive cisplatin, a meta-analysis of 13 trials including 886 patients found that the pCR rate for those receiving neoadjuvant cisplatin-based chemotherapy was only 28.6% .
Despite level 1 evidence supporting neoadjuvant chemotherapy, adjuvant chemotherapy is often used. A recent observational study of 5653 patients with pT3–4 and/or pathologic node-positive bladder cancer revealed that OS was greater with adjuvant chemotherapy compared with observation post-cystectomy (hazard ratio 0.70, 95% CI 0.64–0.76), suggesting that patients with locally advanced bladder cancer that did not receive neoadjuvant chemotherapy may be considered for adjuvant chemotherapy . Similarly, a meta-analysis including 945 patients across nine trials evaluating the use of adjuvant cisplatin-based combination chemotherapy as compared with surgery alone, demonstrated an OS [hazard ratio 0.77 (95% CI 0.59–0.99)], and disease-free survival [hazard ratio 0.66 (95% CI 0.45–0.91, P = 0.014)] benefit for adjuvant therapy . The largest phase III adjuvant chemotherapy study published to date, EORTC 30994, randomized 284 of a planned 660 patients to immediate versus deferred chemotherapy at relapse with OS as the primary endpoint. There was a statistically significant benefit in PFS (0.54, 95% CI 0.40–0.73, P < 0.0001) and a trend toward OS benefit (hazard ratio 0.78, 95% CI 0.56–1.08) with immediate chemotherapy .
DEVELOPMENTS IN PREDICTIVE BIOMARKERS
Recent exploration of biomarkers in urothelial carcinoma has led to the discovery of predictive mutations that may help select those patients most likely to benefit from neoadjuvant therapy. In a study of 50 patients who received neoadjuvant cisplatin-based chemotherapy and underwent whole-exome sequencing, a single gene mutation in the nucleotide excision repair gene ERCC2 was enriched in cisplatin responders compared with nonresponders (q < 0.01). These findings were validated in vitro using an ERCC2-deficienct cell line, suggesting that patients harboring a somatic ERCC2 mutation may respond exceptionally well to cisplatin-based chemotherapy . A second biomarker study identified that alteration in one or more of three DNA repair-associated genes (ATM, RB1, and FANCC) predicted response to cisplatin-based chemotherapy (P < 0.001; 87% sensitivity, 100% specificity) and clinical benefit with improved OS (P = 0.033) . Whole-genome mRNA expression profiling of 73 samples of MIBC allowed for the identification of three molecular subtypes, including basal, luminal, and p53-like, the latter subtype associated with resistance to neoadjuvant chemotherapy (P = 0.018) . The presence of a presumed deleterious DNA damage response gene alteration in a phase II study of dose-dense gemcitabine and cisplatin was associated with chemosensitivity (PPV for <pT2N0 of 89%) without recurrence at a mean follow-up of 2 years [31▪]. To harness the predictive power of molecular subtyping, a genomic subtyping classifier was recently developed to determine the population that would benefit most from neoadjuvant chemotherapy. Of four distinct subtypes (claudin-low, basal, luminal-infiltrated, and luminal), basal tumors demonstrated the most improvement in OS with neoadjuvant chemotherapy compared with surgery alone [32▪]. There are several ongoing and planned clinical trials building upon these findings to determine those patients that will benefit most from neoadjuvant chemotherapy.
DEVELOPMENTS IN IMMUNOTHERAPY
The landscape for the treatment of patients with advanced urothelial carcinoma has been transformed with the Food and Drug Administration (FDA) approval of five immune checkpoint inhibitors. Atezolizumab, a programmed death ligand-1 inhibitor (PD-L1) received accelerated approval in May 2016 based on the favorable response rates, PFS, mOS, and tolerability seen in the phase II open-label IMvigor210 trial that enrolled 310 patients with locally advanced or metastatic bladder cancer with progression after platinum-based chemotherapy . The first randomized phase III trial to demonstrate the superiority of immunotherapy as compared with chemotherapy in the second-line setting was KEYNOTE-045 in which 542 patients with locally advanced urothelial cancer with progression following cisplatin-based chemotherapy were randomized to receive pembrolizumab or investigator's choice of chemotherapy [34▪▪]. A significant improvement in mOS (10.3 versus 7.4 months, hazard ratio 0.73, 95% CI 0.59–0.91) with a favorable safety profile was seen with pembrolizumab, leading to its approval in May 2017. The indications for the use of pembrolizumab and atezolizumab were more recently amended to limit use in the first-line setting in cisplatin-ineligible patients to those with demonstrated PD-L1 expression [35▪].
Neoadjuvant immune checkpoint inhibitor monotherapy
On the basis of the success of immune checkpoint inhibitors in the treatment of patients with advanced urothelial cancer, several trials are evaluating the use of immunotherapy in the earlier clinical disease states of NMIBC and MIBC (Table 1). Two recently reported studies have explored the use of immune checkpoint inhibitors in the neoadjuvant setting. Preliminary data from the ABACUS trial, an open-label, single-arm phase II study of neoadjuvant atezolizumab was presented by Powles and colleagues at the 2018 American Society of Clinical Oncology (ASCO) annual meeting. Seventy-four patients with MIBC with residual disease post-transurethral resection of bladder tumor (TURBT) who were candidates for cystectomy but considered cisplatin-ineligible received two cycles of neoadjuvant atezolizumab. The co-primary endpoints of this study were pCR rates and increased CD8 count. Of the 68 patients considered assessable for primary efficacy endpoints, 29% (95% CI 19–42%) achieved a pCR and 40% (95% CI 21–61%) of patients who were PD-L1 positive using the Ventana PD-L1 SP142 assay achieved a pCR. The second primary endpoint sought to determine the increase in CD8 count following neoadjuvant atezolizumab. In all patients with sufficient sample at baseline and cystectomy there was a marked increase in PD-L1 expression (35–73%) and a statistically significant increase in CD8+ cells (P < 0.05), suggesting the ability of atezolizumab to prime the host immune response to attack cancerous tissue [36▪▪].
The second study of immunotherapy use in the neoadjuvant setting explored the use of pembrolizumab in patients regardless of cisplatin eligibility. PURE-01 was an open-label, single-arm phase II study designed to administer three cycles of pembrolizumab prior to radical cystectomy with the primary endpoint of pCR. This trial enrolled 50 patients with MIBC and unlike ABACUS, enrolled 46 patients (92%) who were cisplatin-eligible. There were 21 patients who achieved a pCR (42%, 95% CI 28–57%) and pathologic downstaging to < pT2 was achieved in 27 patients (54%, 95% CI 39–68%). When stratified according to PD-L1 expression, using the Dako 22C3 assay combined positive score, 54.3% of patients with high PD-L1 expression achieved pCR whereas only 13.3% of patients with low PD-L1 expression achieved pCR [37▪▪].
Neoadjuvant immune checkpoint inhibitor with chemotherapy
On the basis of the synergy seen when combining traditional chemotherapy with immunotherapy in other diseases, most notably non-small cell lung cancer , several trials are exploring the use of immunotherapy with concurrent chemotherapy in the neoadjuvant setting. The first reported neoadjuvant study of immune checkpoint inhibitor in combination with chemotherapy was presented by Hoimes et al. at the 2018 European Society of Medical Oncology (ESMO) annual meeting [39▪▪]. In this trial, a cisplatin-eligible cohort of 40 patients with MIBC without metastases received pembrolizumab every 3 weeks for five doses along with four cycles of gemcitabine and cisplatin. Thirty-six patients proceeded to cystectomy [one patient developed thrombotic thrombocytopenic purpura (TTP) and three patients declined cystectomy] of which 40% of patients achieved a pCR and 61% had ypT1N0 or less. There were five grade-4 treatment-related adverse events (three cytopenia, one TTP, one hyponatremia). At 18 months, OS was 81% and disease-specific survival was 90%. These studies offer opportunities for critically important correlative analyses, including the ability to assess for changes in the tumor immune microenvironment following immunotherapy in combination with chemotherapy or other novel agents. A window-of-opportunity trial exploring changes in immune gene signature expression in both blood and tumor samples following neoadjuvant pembrolizumab versus pembrolizumab in combination with a histone deacetylase inhibitor entinostat is planned.
Several trials are currently investigating the use of immune checkpoint inhibitors in the adjuvant setting. In general, the eligibility criteria for these studies include: patients who received neoadjuvant chemotherapy with at least pT2 or node-positive disease at cystectomy; cisplatin-ineligible patients with at least pT3 or node-positive disease at cystectomy; and patients who decline adjuvant cisplatin-based chemotherapy with at least pT3 or node-positive disease at cystectomy. Three adjuvant immune checkpoint inhibitor clinical trials are currently underway: AMBASSADOR (A031501) – a randomized phase III trial of pembrolizumab versus observation in patients with locally advanced bladder cancer postcystectomy (NCT03244384); 2) IMvigor010 – a randomized phase III study of adjuvant atezolizumab versus observation in patients with MIBC following cystectomy (NCT02450331); and CheckMate 274 – a randomized phase III study exploring adjuvant nivolumab versus placebo in patients with locally advanced bladder cancer postcystectomy (NCT02632409). The results of these studies will help to inform whether there is a role for adjuvant immunotherapy in patients at highest risk for recurrent disease.
The landscape for treating bladder cancer has evolved rapidly with the introduction of immune checkpoint inhibitors in patients with advanced disease and clinical trials are underway evaluating a potential role for immune checkpoint inhibitors in earlier disease states including NMIBC and MIBC. Promising preliminary data for immune checkpoint inhibition in the neoadjuvant setting will hopefully lead to the expansion of perioperative chemotherapy to include those patients ineligible for cisplatin-based therapy as well as lead to better pathologic responses with associated improvements in survival outcomes. Enrollment of patients in perioperative clinical trials (Table 1) with embedded correlative studies will advance our understanding of tumor immunology in bladder cancer to better predict those patients who will benefit most from immunotherapy as part of a multidisciplinary treatment regimen.
Financial support and sponsorship
Conflicts of interest
M.M. currently receives contracted institutional research support from Acerta Pharma, Astellas, Bristol-Myers Squibb, Incyte, Merck, Pfizer, Roche/Genetech, Seattle Genetics, Clovis Oncology, Inc., Inovio Pharmaceuticals, AstraZeneca, and X4 Pharmaceuticals. He receives consulting support from BioClin Therapeutics. M.B. is a paid speaker for United Medical Systems and Blue Early Diagnostics, Inc. He receives consulting support from Tolmar Pharmaceuticals. P.E. has no conflicts of interest to disclose.
REFERENCES AND RECOMMENDED READING
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This is the first clinical trial reporting on neoadjuvant chemotherapy (gemcitabine and cisplatin) along with immunotherapy (pembrolizumab) and demonstrated a pathological downstaging (≤pT1) in 61% of patients.