The Current Landscape of Neoadjuvant Chemotherapy/Immunotherapy Combinations in Patients with Clinically Localized, Muscle Invasive Bladder Cancer

Introduction

Bladder cancer is currently the 10^th most commonly diagnosed malignancy worldwide. It is estimated that approximately 110,500 men and 70,000 women are annually diagnosed with bladder cancer worldwide.¹ While the majority of patients are initially diagnosed with non-muscle invasive disease (i.e. carcinoma in situ, Ta, and T1), approximately 25 to 33% of patients are diagnosed with muscle invasive bladder cancer and a meaningful proportion of patients initially diagnosed with non-muscle invasive disease will subsequently progress to MIBC.¹

Radical cystectomy and trimodal therapy (i.e. maximal TURBT, chemotherapy, and radiotherapy) remain standard of care options for treatment of patients with clinically localized, muscle invasive disease.^2,3 However, survival outcomes in this cohort of patients remain limited with five-year survival rates of 70% in patients with bladder-confined disease and 38% in those with extravesical extension and/or lymph node involvement.⁴

Neoadjuvant cisplatin-based chemotherapy combinations have demonstrated five-year overall survival benefits of around 5%⁵ and pathologic complete responses rates of 36 to 42% with contemporary chemotherapy regimens.⁶ Novel immunotherapeutic agents have demonstrated efficacy in patients with metastatic bladder cancer and are increasingly being evaluated in the neoadjuvant setting.⁷ Given their different mechanisms of action, it is hypothesized that combining chemotherapy and immunotherapeutic agents may overcome potential clonal resistance and improve both pathologic responses and survival outcomes. In this Center of Excellence article, we review the latest evidence for chemotherapy and immunotherapy agent combinations in the neoadjuvant setting prior to radical cystectomy in patients with clinically localized, muscle invasive bladder cancer.

Gemcitabine/Cisplatin-based Combinations LCCC1520: Pembrolizumab + Gemcitabine/Cisplatin

LCCC1520 (NCT02690558) was a multicenter, open label, single arm phase II trial of neoadjuvant pembrolizumab + gemcitabine/cisplatin in patients with clinical T2-4aN0/XM0 bladder cancer eligible for radical cystectomy. The first six patients received lead-in pembrolizumab 200 mg once two weeks prior to pembrolizumab 200 mg once on day 1, cisplatin 70 mg/m² once on day 1, and gemcitabine 1,000 mg/m2 once on days 1 and 8 every 21 days for four cycles. Due to poor tolerability, this schedule was subsequently altered with lead-in pembrolizumab removed and cisplatin dose reduced to 35 mg/m². Between June 2016 and March 2020, 39 patients were enrolled and received a median of four cycles of therapy, with 38 of the 39 patients undergoing radical cystectomy. The median time to cystectomy was 46 days after completion of protocol therapy (range, 13-154 days) and was completed within twelve weeks in all but two patients. The proportion of patients achieving ypT0N0 disease was 14/39 (36%), with <ypT2N0 observed in 22/39 patients (56%):

Of the 27 patients who received all four cycles of treatment, pathologic downstaging was observed in 19 (70%). The rate of pathologic downstaging was not significantly different between PD-L1 positive and negative patients (67% v 47%, p=0.25). After a median follow-up of 15.7 months, one-year event-free, recurrence-free, and overall survivals were 89%, 75%, and 91%, respectively. Patients with pathologic downstaging had significantly longer recurrence-free survivals compared to those without pathologic downstaging (median not reached versus 10.9 months, hazard ratio 0.126 [95% CI: 0.027 to 0.593], log-rank p=0.009).

Grade 3 or worse adverse events occurred in 74% of patients, with all patients experiencing at least one grade 1 adverse event. The most common adverse events of any grade were hematologic, including thrombocytopenia (74%), anemia (69%), and neutropenia (67%).⁸

GU14-188: Pembrolizumab + Gemcitabine/Cisplatin

GU14-188 is a phase 1b/2 trial that evaluated the combination of pembrolizumab + gemcitabine/cisplatin in cisplatin eligible patients (cohort 1) and pembrolizumab + gemcitabine in cisplatin ineligible patients (cohort 2). All patients had cT2-4aN0M0 bladder urothelial carcinoma. The dosing schedule in cohort 1 was as follows: pembrolizumab 200 mg every 3 weeks on day 8 for 5 doses, with cisplatin (70 mg/m²) on day 1, and gemcitabine (1000 mg/m²) days 1 and 8 of a 21-day cycle for four cycles, followed by radical cystectomy. In cohort 2, patients received pembrolizumab 200 mg every 3 weeks on day 8 for 5 doses with gemcitabine (1000 mg/m²) on days 1, 8, and 15 of a 28-day cycle for three cycles, followed by radical cystectomy. The trial design and schema are as follows:

Forty-three patients were enrolled in cohort 1. The median time from the last dose to radical cystectomy was 5.3 weeks. Complete pathologic responses were observed in 44.4% of patients and did not correlate with baseline PD-L1 score. <ypT2 pathologic responses were observed in 61.1% of patients (53% of those with cT2 and 74% of those with cT3/4). At a median follow-up of 34.2 months, the estimated three-year recurrence-free, disease-specific, and overall survivals were 63%, 87%, and 82%, respectively. Grade 3-4 cytopenia occurred in 57% of patients. One grade 4 hyponatremia and ten grade 3 events did not preclude patients undergoing radical cystectomy (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection).

In cohort 2 of pembrolizumab + gemcitabine, patients with cT2-4aN0M0 urothelial carcinoma, with or without mixed histology, who were cisplatin-ineligible were enrolled. Five doses of neoadjuvant pembrolizumab were given starting on cycle 1, day 8 of gemcitabine, which was given on days one, eight, and 15 of a 28-day cycle (for three cycles). The primary endpoint of the study was pathologic muscle-invasive response rate defined as ≤pT1N0. Pathologic complete response was observed in 45.2% of patients with <ypT2N0 achieved in 52% of patients. The 12-month relapse-free, disease-specific, and overall survivals were 67%, 94%, and 88.4%, respectively. Grade 3-4 hematologic and non-hematologic adverse events occurred in 44% and 36% of patients, respectively.

BLASST-1: Nivolumab + Gemcitabine/Cisplatin

Presented at ASCO GU 2020, BLASST-1 is a multicenter, phase II trial that evaluated the combination of nivolumab + gemcitabine/cisplatin in patients with muscle invasive bladder cancer (cT2-4aN0-1M0) who were candidates for a radical cystectomy. Patients received cisplatin on day 1; gemcitabine on days 1 and 8; and nivolumab on day 8 every 21 days for 4 cycles followed by radical cystectomy within eight weeks. The primary objective was assessment of pathologic response (≤pT1N0) and the secondary objective was assessment of safety. The trial schema for BLASST-1 is as follows:

Of 41 patients (cT2N0 90%, cT3N0 7%, and cT4N1 3%), pathologic response occurred in 27/41 (66%) patients. Pathologic complete response (pT0, pTis) occurred in 20/41 (49%). With regards to safety, the rate of grade 3-4 adverse events was 10/41 (24%) with the majority of them attributed to gemcitabine and cisplatin (neutropenia, thrombocytopenia, and renal insufficiency). There were 5/41 (12%) patients with any grade adverse events attributed to immunotherapy (rash, hypothyroidism, inflamed lymph nodes, Guillain-Barre syndrome). None of the patients undergoing nivolumab in addition to standard neoadjuvant chemotherapy experienced a delay in time to radical cystectomy and there were no unexpected surgical complications attributable to this neoadjuvant treatment regimen. Currently, a randomized phase III trial, ENERGIZE (NCT03661320), is underway to confirm the results of this study.

NCT02989584-1: Atezolizumab + Gemcitabine/Cisplatin

Originally presented at ASCO 2021 and since published in The Journal of Clinical Oncology in 2022,⁹ this is a multicenter, single arm, phase II trial that evaluated the combination of atezolizumab and gemcitabine/cisplatin in patients with muscle invasive bladder cancer (cT2-T4aN0M0). Patients received a dose of atezolizumab, followed two weeks later by gemcitabine/cisplatin plus atezolizumab every 21 days for four cycles, followed three weeks later by a dose of atezolizumab before radical cystectomy.

Between February 2018 and May 2020, 44 patients were enrolled from five institutions. Among the 39/44 evaluable patients (cT2N0 79%, cT3N0 18%, cT4N0 3%), one patient refused surgery and was considered a non-responder. The primary endpoint was met, with 27 of 39 patients (69%) having non-muscle invasive disease (< pT2N0) at radical cystectomy, including 17 (44%) patients with pathological complete responses (pT0N0). No patient with < pT2N0 relapsed and four (11%) with ≥ pT2N0 relapsed with a median follow-up of 16.5 months (range: 7.0-33.7 months). The most common grade 3-4 treatment-related adverse events were due to chemotherapy and were neutropenia (36%), lymphopenia (16%), and anemia (11%). Grade 3 immune-related adverse events occurred in five (11%) patients with two (5%) requiring systemic steroids. The median time from last dose of chemotherapy to surgery was 7.8 weeks (range: 5.1-17 weeks), and no patient failed to undergo radical cystectomy because of adverse events. Only 4 of 39 (10%) patients had PD-L1 positive tumors, all of whom achieved a <pyT2N0 disease state. The Kaplan-Meier survival curves for recurrence free survival and overall survival are as follows:

SAKK 06/17: Durvalumab + Gemcitabine/Cisplatin

SAKK 06/17 is an open-label, single arm, phase II trial for patients with operable muscle-invasive urothelial carcinoma cT2-T4aN0-1 of the bladder and upper tracts. Treatment consisted of four cycles of neoadjuvant cisplatin/gemcitabine every three weeks in combination with four cycles of durvalumab 1500 mg every 3 weeks followed by resection. Notably, durvalumab was continued after surgery every four weeks for 10 cycles in an adjuvant fashion. The trial schema for SAKK 06/17 is as follows:

There were 61 patients included between July 2018 and September 2019 at 12 sites (11 in Switzerland and one in Germany). The analysis cohort consisted of 58 patients with a median age of 67.5 years. Of note, 5% of patients had upper tract urothelial carcinoma with the remaining patients having MIBC. There were 69% of patients that were cT2, 21% were cT3, and 10% were cT4 stage at diagnosis; 17% were cN1. 95% of patients received all four doses of neoadjuvant durvalumab, 81% received all four cycles of cisplatin/gemcitabine, and 17% switched to carboplatin. Resection was performed in 53 patients (91%; 51 radical cystectomy, two nephroureterectomy), four patients refused surgery, and one patient was deemed unresectable. A negative margin (R0 resection) was achieved in 52 patients (98%). Postoperative complications included Clavien-Dindo III in 13 patients (24%) and IV in 5 patients (9%).

A pathologic complete response was achieved in 34% of patients and <ypT2 disease in a further 26% (total <ypT2=60%). Over a median follow up of 28.1 months (95% CI: 27.8 to 28.4), two-year event-free survival was 76.1% (95% CI: 62.3% to 85.3%):

Among those with <ypT2 disease, two-year event free survival was 92.9% and for those with a complete pathological response (ypT0), two-year event free survival was 100%. In total, grade 3 and 4 adverse events during neoadjuvant treatment occurred in 48% and 27%, respectively. Grade 1, 2, 3, 4 adverse events attributed to durvalumab during overall treatment were identified in 14%, 35%, 19%, and 7% of patients, respectively.

ChiCTR2000037670: Tislelizumab + Gemcitabine/Cisplatin

ChiCTR2000037670 is a multicenter, open-label, single arm phase II study which enrolled patients with cisplatin eligible cT2-4aN0M0 urothelial carcinoma of the bladder planned for radical cystectomy. Eligible patients received tislelizumab (an anti-PD-1 antibody) 200 mg on day 1, cisplatin 70 mg/m2 on day 2, and gemcitabine 1000 mg/m2 on days 1 and 8 of every 21 days cycle for four cycles, following which patients underwent radical cystectomy within six weeks of the last dose. The trial schema is as follows:

At the time of presentation at ASCO 2022, the authors reported the results of the first stage of the trial with 23 eligible patients enrolled as of October 2021. Among these 23 patients, 18 had completed neoadjuvant therapy. The median age was 62 (48-72) years and 8 (44.4%) patients had PD-L1 positive tumors. Among the 18 who had completed neoadjuvant therapy, 17 patients underwent radical cystectomy and one declined cystectomy. In this subset of patients, pre-operative staging was cT2 in 12 patients, cT3 in 3 patients, and cT4a in 2 patients. At the data cut off, among the 22 evaluable patients who had undergone radical cystectomy, 12 (54.5% [90% CI, 35.3-72.9]) patients achieved pathologic complete responses and 17 (77.3% [95% CI 54.6-92.2]) pathologic downstaging. There were no significant differences seen in terms of pathologic complete response (63.6% vs. 45.5%) or downstaging (72.7% vs. 81.8%) rates between patients with PD-L1 positive versus PD-L1 negative tumors.

Grade ≥3 neoadjuvant therapy related adverse events included neutropenia (n = 6), thrombocytopenia (n = 4), anemia (n = 2) and decreased lymphocyte count (n = 1). Eight patients experienced grade 1-2 immune related events, most common of which were pruritus (n = 4) and AST/ALT elevations (n=4). There were no high-grade immune-related adverse events.

AURA Trial: Avelumab + Gemcitabine/Cisplatin versus Avelumab + MVAC

The AURA trial is a prospective, multicenter, randomized, phase II trial for patients with cT2-4aN0-2M0 bladder carcinoma. Cisplatin-eligible patients received cisplatin-gemcitabine plus avelumab or dose-dense MVAC plus avelumab (1:1). The study schema for AURA is as follows:

At the interim analysis data cut-off, 56 cisplatin-eligible patients were evaluable (28 in each arm). The median time from randomization to radical cystectomy was 13 weeks (range: 6.1 to 20.6). The median number of avelumab cycles administered was 4.4 (range: 1 to 7). In the gemcitabine/cisplatin + avelumab arm, ypT0 was achieved in 32% of patients, with <ypT2 in 57% total. Conversely, in the dd-MVAC + avelumab arm, 43% of patients achieved a ypT0 disease state, with a total of 64% achieving a <ypT2 disease state.

The most common grade 3/4 adverse events were thrombocytopenia (29%), acute kidney injury (18%), neutropenia (14%), and anemia (13%). No patients required steroids for immune-related adverse events, and no treatment-related deaths were reported. 

As follows is a tabular summary of pathologic outcomes for neoadjuvant gemcitabine/cisplatin + immunotherapy among the current eight presented/published studies:

*pT0 or pTis

**Given adjuvantly as well for 10 cycles

***Bladder and upper tract urothelial carcinoma

Conclusions

Early phase II trials have demonstrated that the addition of immunotherapeutic agents to the combination of gemcitabine and cisplatin in the neoadjuvant setting for patients with muscle invasive bladder cancer may improve pathologic response rates, with notable ypT0 rates of 55% and 49% with the addition of tislelizumab (ChiCTR2000037670) and nivolumab (BLASST-1). Potentially improved pathologic response rates with these combinations must be balanced against a worsened toxicity profile, and such combinations will likely need to demonstrate a survival benefit in prospective trials before being adopted in clinical practice.


Published: March, 2023