Neoadjuvant Therapies for Bladder Cancer in Cisplatin-ineligible Patients: What Options Do We Have?

EUF-830; No. of Pages 4 E U RO P E A N U R O L O GY F O C U S X X X ( 2 019 ) X X X– X X X

available at www.sciencedirect.com journal homepage: www.europeanurology.com/eufocus

Clinical Consultation Guide – Bladder Cancer

Neoadjuvant Therapies for Bladder Cancer in Cisplatin-ineligible Patients: What Options Do We Have? Arnab Basu a,*, Sarmad Sadeghi b a

Department of Hematology & Medical Oncology, University of Alabama at Birmingham O’Neal Comprehensive Cancer Center, Birmingham, AL, USA;

b

Department of Hematology & Medical Oncology, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA

1.

Introduction

Muscle invasive bladder cancer (MIBC) is a challenging disease. Despite radical cystectomy and pelvic node dissection, up to 50% of patients will experience progression [1]. Neoadjuvant chemotherapy (NAC) with cisplatin-based combination regimens mitigates this risk and is supported by level 1 evidence. The seminal trial of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) demonstrated a 6% survival benefit at 5 yr (57% vs 43%) and an associated median overall survival of 77 versus 46 mo (p = 0.06) [2]. In addition, updated meta-analyses continue to confirm the benefit of cisplatin-based therapy [3]. Despite evidence, it remains underutilized, with approximately 20% of patients in the USA and a mere 2% of patients in low- to middle-income countries availing of NAC [4,5]. 2.

Defining cisplatin ineligibility

While cisplatin is the backbone of NAC, many patients have difficulty in tolerating it. Cisplatin ineligibility has been defined as having Eastern Cooperative Oncology Group (ECOG) performance status 2, creatinine clearance (CrCl) <60 ml/min, grade 2 hearing loss, peripheral neuropathy, or heart failure. These guidelines were initially based on a European Organisation for Research and Treatment of Cancer survey of expert genitourinary oncologists involved in bladder cancer clinical trials. Strict adherence to these guidelines leads to the exclusion of approximately 50% patients from receiving cisplatin [6]. Carboplatin is

occasionally substituted in the community, but given the small benefit seen with cisplatin, it is hypothesized that carboplatin may or may not provide any benefit [7,8]. The substitution of carboplatin for cisplatin is hence not recommended by any consensus guidelines. We opine that in patients with borderline CrCl (60–40 ml/min), full-dose and split-schedule cisplatin (50% dose on day 1, day 2 or day 1, day 8) may be safely administered under careful monitoring [9]. As a caveat, lower-intensity regimens probably have significantly lower efficacy and retrospective data indicate that split-schedule cisplatin has a lower pathologic complete response (pCR) rate compared to regular dosing (32.5% vs 17.5%) [10]. Our institutional approaches are to offer full-dose or split-dose cisplatin-based neoadjuvant therapy to select patients with borderline glomerular filtration rate with close monitoring for toxicities. Single-agent immunotherapy in cisplatin-ineligible patients Immune checkpoint inhibitors (ICIs) are well tolerated in renal insufficiency and are a huge boon for cisplatin-ineligible patients. Since 2016, five ICIs have been approved for use in metastatic bladder cancer. Of these, pembrolizumab and atezolizumab have shown encouraging activity in the neoadjuvant setting in the PURE-01 and ABACUS trials, respectively. PURE-01 used an all-comers design whereby all patients with MIBC were eligible to receive three cycles of pembrolizumab; patients who progressed on immunotherapy alone were then given the opportunity for traditional therapy with dose-dense MVAC before cystectomy.

* Corresponding author. Department of Medical Oncology, University of Alabama at Birmingham O’Neal Comprehensive Cancer Center, Birmingham, AL, USA E-mail address: [email protected] (A. Basu). https://doi.org/10.1016/j.euf.2019.10.017 2405-4569/© 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Please cite this article in press as: Basu A, Sadeghi S, Neoadjuvant Therapies for Bladder Cancer in Cisplatin-ineligible Patients: What Options Do We Have?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.017

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Table 1 – Comparison of trial populations and outcomes for the ABACUS and PURE01.

Sample size (n) Agent Frequency T2 disease (%) T3+ disease (%) Cisplatin-eligible (%) Primary endpoint pCR: unselected (%) pCR :PD-L1+ pCR: PD-L1

ABACUS

PURE-01

68 Atezolizumab 1200 mg every 3 wk  2 77 23 – pCR (T0) rate 29 40 16

50 Pembrolizumab 200 mg every 3 wk  3 37 63 92 pCR (T0) rate 42 53 (CPS > 10%) 13 (CPS < 10%)

pCR = pathologic complete response; CPS = combined positive score.

The primary clinical endpoint was the rate of pathologic complete response (pCR). The trial was a success, with a pCR rate of 40% and pathologic downstaging to less than pT2 in 54% of cases. These responses appeared to be related to PDL1 positivity scores (54% for combined positive scores >10 vs 13% for scores <10) [11]. In this novel trial design, 92% patients were cisplatin-eligible according to the consensus criteria. By contrast, the ABACUS trial of neoadjuvant atezolizumab recruited patients with PT2–4a disease who were ineligible for or refused cisplatin. Atezolizumab was administered in two cycles before radical cystectomy. This trial also met its primary endpoint (pCR >20%) with 29% of total and 40% of PD-L1–positive patients achieving pCR at the interim analysis [12]. Differences in these trials are

Table 2 – Selected ongoing neoadjuvant trials in bladder cancer open for cisplatin-ineligible patients. NCT number (name)

Drugs

Title

Phase

NCT02717156

NCT03518320

Nivolumab

NCT03529890 (RACE IT)

Nivolumab

NCT02812420

Durvalumab Tremelimumab

NCT03674424 (AURA) NCT02845323

Avelumab

A phase II trial of sEphB4-HSA in combination with anti-PD1 antibody pembrolizumab (MK-3475) for solid tumors Window of opportunity study of pembrolizumab alone and in combinations in bladder cancer Nab-paclitaxel plus gemcitabine as first-line therapy for cisplatin-ineligible or cisplatin-incurable advanced urothelial carcinoma sEphB4-HSA before surgery in treating patients with bladder cancer, prostate cancer, or kidney cancer Safety and tolerability of TAR-200 and nivolumab in subjects with muscleinvasive bladder cancer Radio-immunotherapy before cystectomy in locally advanced urothelial carcinoma of the bladder Durvalumab and tremelimumab in treating patients with muscle-invasive, high-risk urothelial cancer that cannot be treated with cisplatin-based therapy before surgery Avelumab as neoadjuvant therapy in subjects with urothelial muscle invasive bladder cancers Neoadjuvant nivolumab with and without urelumab in patients with cisplatinineligible muscle-invasive urothelial carcinoma of the bladder Neoadjuvant pembrolizumab in combination with gemcitabine therapy in Ciseligible/ineligible UC subjects Neoadjuvant atezolizumab in localized bladder cancer A phase Ib study of durvalumab (MEDI 4736) plus tremelimumab followed by concurrent durvalumab plus bladder radiation, based on molecular subtypes in muscle-invasive bladder cancer Neo-adjuvant bladder urothelial carcinoma combination-immunotherapy

2

NCT02767921

Pembrolizumab sEphB4-HSA Pembrolizumab Entinostat Nab-paclitaxel Gemcitabine sEphB4-HSA

NCT03978624 NCT02887248

NCT02365766 NCT02451423 NCT04073160 (TRIO)

Nivolumab Urelumab Pembrolizumab Gemcitabine Atezolizumab Durvalumab Tremelimumab

NCT03387761 (NABUCCO) NCT03520491

Nivolumab Ipilimumab Nivolumab Ipilimumab

NCT03832673 (PECULIAR) NCT03534492 (NEODURVARIB) NCT02365766 (HCRN-GU-188) NCT03773666 (BLASST-2) NCT03747419

NCT03472274 (DUTRENO) NCT03844256 (CRIMI)

Pembrolizumab Epacadostat Durvalumab Olaparib Pembrolizumab Gemcitabine Durvalumab Oleclumab Avelumab Radiation Durvalumab Tremelimumab Radiation Durvalumab Tremelimumab Mitomycin C Capecitabine

NCT04046094

Vitamin C

NCT03702179 (IMMUNOPRESERVE)

A study to test the safety of immunotherapy with nivolumab alone or with ipilimumab before surgery for bladder cancer patients who are not suitable for chemotherapy Pembrolizumab-epacadostat combination to treat muscle-invasive bladder urothelial cancer Durvalumab plus olaparib administered prior to surgery of resectable urothelial bladder cancer Neoadjuvant pembrolizumab in combination with gemcitabine therapy in Ciseligible/ineligible UC subjects A feasibility study of durvalumab  oleclumab as neoadjuvant therapy for muscle-invasive bladder cancer Avelumab and radiation in muscle-invasive bladder cancer Durvalumab plus tremelimumab with concurrent radiotherapy for localized muscle invasive bladder cancer treated with a selective bladder preservation approach Durvalumab (MEDI4736) and tremelimumab in neoadjuvant bladder cancer patients A study of mitomycin C/capecitabine chemoradiotherapy combined with nivolumab monotherapy or ipilumimab and nivolumab, as bladder sparing curative treatment for muscle invasive bladder cancer Intravenous (IV) vitamin C with chemotherapy for cisplatin ineligible bladder cancer patients

2 2 2 2 2 2

2 2 2 2 1b

1b 2

2 2 1b/2 1 2 2

2 1

1

Please cite this article in press as: Basu A, Sadeghi S, Neoadjuvant Therapies for Bladder Cancer in Cisplatin-ineligible Patients: What Options Do We Have?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.017

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summarized in Table 1. These two trials provide the only published evidence for the use of single-agent ICI in the neoadjuvant setting. Combination immunotherapy in cisplatin-ineligible patients Strategies apart from single-agent immunotherapy include the combination of ICIs with chemotherapy. The phase 2 HCRN GU-188 trial is investigating this approach using a combination of gemcitabine and pembrolizumab with (cohort 1) or without (cohort 2) cisplatin in patients with T2–4aN0M0 disease. The primary endpoint is pathologic downgrading to noninvasive disease. At first analysis, 61% of the cohort 1 patients met this endpoint. Interestingly, this outcome did not correlate with PD-L1 tumor status [13]. The results were potentially informative for patients with low PD-L1 expression status for whom neoadjuvant therapy was planned, as low PD-L1 expression predicts poor outcome in the metastatic setting [14]. The AURA trial is a similar neoadjuvant phase 2 trial of the PD-L1 inhibitor avelumab with both cisplatin-eligible and -ineligible arms. Cisplatin-ineligible patients receive avelumab alone or avelumab with gemcitabine and paclitaxel, while cisplatineligible patients receive gemcitabine with cisplatin. The trial will be informative regarding the role of non–cisplatin-based chemoimmunotherapy [15]. Combination ICI with CTLA-4 and PD-1 inhibitors is being investigated in trials of durvalumab and tremelimumab (NCT03234153) and nivolumab in conjunction with ipilimumab (NCT03387761) in the NABUCCO trial. The NABUCCO trial has reported on 22 patients: the pCR rate was 46%, with a further 12% were downstaged to non– muscle-invasive disease. This resulted in a  ypT1N0 rate of 58% (13/22). PD-L1–positive patients had a pCR rate of 60% versus 22% among those who were PD-L1–negative, adding to the data for PD-L1 expression as a biomarker of response. Some 54% of the patients had grade 3 adverse events on trial. The balance between greater toxicity and efficacy for combination immunotherapy will be important to consider in the usually frail cisplatin-ineligible population [16]. Novel agents other than ICIs are also being investigated in the neoadjuvant setting. The BLASST-2 trial will examine durvalumab in combination with the antimetabolite oleclumab in cisplatin-ineligible patients. sEphB4-HSA is a fusion protein that binds to the ephrin-B2 receptor, interacting with angiogenesis and immune infiltration of tumor. A phase 2 trial of pembrolizumab-sEphB4-HSA (NCT02717156) is ongoing and includes a neoadjuvant cohort of cisplatin-eligible and -ineligible patients. Radioimmunotherapy trials include avelumab (NCT03747419) or nivolumab (NCT03529890) in combination with radiation followed by cystectomy. A dual ICI combination of durvalumab and tremelimumab with radiation (NCT03702179) followed by bladder preservation is also being investigated. Several smaller phase 2 trials are ongoing worldwide (Table 2). Randomized phase 3 trials are also evaluating ICIs in the adjuvant setting, including pembrolizumab (AMBASSADOR, NCT03244384), atezolizumab (NCT02451423), and nivolumab (Checkmate 274,

3

NCT02632409). These trials will include cisplatin-ineligible patients. Predictive markers for neoadjuvant therapy Attempts to identify patients who respond to neoadjuvant therapy have had limited success. The recently reported SWOG S1314 trial failed to validate predictive biomarkers for response to neoadjuvant chemotherapy [17]. Tumors with FGFR3 alterations were traditionally considered immunologically cold and possible poor candidates for immunotherapy; however, a recent analysis of the PURE-01 cohort did not find an association with response. The immune190 gene expression assay appeared to predict response to pembrolizumab in the study but has not been prospectively validated [18]. At present, expression of PD-L1 may be the best predictor for response in this setting, despite some ambiguity. 3.

Conclusions

Cisplatin-ineligible patients have a great unmet need in the neoadjuvant setting. ICIs are well tolerated in this population. Atezolizumab and pembrolizumab have shown efficacy and safety in the metastatic and neoadjuvant settings for cisplatin-ineligible patients. New data on ipilimumab and nivolumab are also encouraging. Combination approaches with other ICIs, targeted agents, and radiation therapy are currently under investigation. These therapies, despite early promising signs of efficacy, do not have regulatory approval and should be considered only in the setting of a clinical trial. Conflicts of interest: The authors have nothing to disclose.

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Please cite this article in press as: Basu A, Sadeghi S, Neoadjuvant Therapies for Bladder Cancer in Cisplatin-ineligible Patients: What Options Do We Have?. Eur Urol Focus (2019), https://doi.org/10.1016/j.euf.2019.10.017