For Stage II and IIIA patients with muscle-invasive bladder cancer (MIBC), the mainstay of treatment and current standard of care is neoadjuvant chemotherapy followed by radical cystectomy with lymph node dissection. Definitive chemoradiation is considered in those unfit for surgery or strongly prefer to preserve the bladder. The sentinel study for establishing the role of neoadjuvant chemotherapy was the intergroup study initiated by SWOG-8710, looking at MVAC therapy in Stage II and IIIa MIBC. The study showed an improvement in median overall survival (77 versus 46 months) and an improved pathologic complete response (pCR) rate. While MVAC was the regimen evaluated here, gemcitabine and cisplatin (GC) combinations had proven equivalent in metastatic disease and are routinely used as well. The recently reported SWOG-1314 trial provides insights to support the equivalence of GC for neoadjuvant therapy. However, both these regimens contain cisplatin.
What about the patients who are ineligible for cisplatin? This subgroup consists of a large portion of our muscle-invasive bladder cancer patients (upwards of 50% of patients with MIBC) and thus represents a huge gap in our treatment options given a lack of alternative agents. Cisplatin ineligibility has been defined as having Eastern Cooperative Oncology Group (ECOG) performance status of 2 or greater, creatinine clearance (CrCl) <60ml/min, grade 2 hearing loss, peripheral neuropathy, or heart failure (NYHA Class III). While this is an internationally followed guideline, it is interesting to consider how the criteria for cisplatin-ineligible patients came about. In 2011, there was a survey sent to medical oncologists from five different countries to establish a working diagnosis, and responses from the survey were received from 65 medical oncologists. While there was substantial variability in the definition, a uniform definition was desired and thus the criteria mentioned was proposed and accepted by the NCCN. While it is very reasonable criteria and something we should all consider in our treatment approach, we must all consider the patient first and foremost prior to embarking on a specific treatment course.
As per current consensus guidelines, this group of cisplatin-ineligible patients, if surgically eligible, should proceed directly to cystectomy. There is no defined role for neoadjuvant carboplatin substitution and only a minimal benefit for cisplatin splitting in those with borderline renal function. But given the knowledge that pCR confers significantly better overall survival (OS), what can we do to improve the care of these patients? Are we simply settling for up-front surgery knowing that we can potentially improve the care of these patients? In regard to the potential carboplatin substitution, there have been mixed reports of efficacy in several trials, but to date, there is not enough evidence to support the substitution of carboplatin for cisplatin. As for split-dose cisplatin, 35mg/m2 on Day 1, 2 or Day 1, 8, as opposed to 70mg/m2 on Day 1, the results from studies appear to offer a small increase in pCR, but not to the extent of those receiving standard-dose cisplatin, and thus while not routinely recommended, is worth consideration.
While there are no currently approved neoadjuvant regimens in the cisplatin-ineligible group, there are a lot of trials looking at this population. We know the efficacy of immunotherapy for bladder cancer in the metastatic setting, however, the role in the neoadjuvant period is largely unknown. There have been two recent individual trials that have looked at just that population, PURE-01 and ABACUS. The PURE-01 trial looked at T2 orT3+ N0 urothelial carcinoma, and patients were given three cycles of pembrolizumab prior to radical cystectomy. While this patient population was not specifically designed to assess the cisplatin-ineligible group (92% of the patients were actually cisplatin eligible), the primary outcome of pathologic complete response was 42%, and pathologic downstaging to less than T2 was 54%, which is extremely encouraging. It is worth mentioning that patients with PDL1 > 10%, the pCR was 53%, vs just 13% in the PDL1 <10% cohort, this appears to agree with the findings of poor response to the PD-1 antibody even in the metastatic setting. The caveat to these findings is the relatively low sample size of this trial (n=50).
The other neoadjuvant trial looking at immunotherapy was the ABACUS trial, a single-arm study that looked at 68 cisplatin-ineligible patients, with T2/T3+N0 urothelial carcinoma. These patients were given two cycles of atezolizumab prior to radical cystectomy. This trial, similar to PURE-01, also had a primary endpoint of pCR, and the results are similar to the PURE-01 trial, with a total pCR of 29%, with PDL1 + tumors having a 40% pCR, and the PDL1 – tumors having a 16% pCR. It is worth noting that the PURE-01 trial seemed to assess more Stage III tumors, as opposed to more Stage II tumors in the ABACUS trial, and also had a longer exposure period for immunotherapy prior to cystectomy. CTLA4 combination with PD-1 inhibition has been studied in several cancers including bladder cancer in the metastatic setting. CTLA4 results in wider checkpoint blockade and appears to be of use in cases of low PD-L1 expression in other disease subtypes. Recently at ESMO 2019, the NABUCCO trial, a single-arm trial of 22 patients, appears to show a benefit in pCR with ipilimumab/nivolumab, providing an encouraging signal for further validation. Even though the sample size is low, 40% of patients with lymph node-positive disease achieved complete responses (CR)s. Although the topline pCR rate improved, there was a large difference in PD-L1 CPS >10 vs < 10 (60% vs 22%). However, it appears to have doubled the minimal response rate in the low PD-L1 expression population.
Traditional chemotherapy options continue to be evaluated, gemcitabine with vinflunine in the neoadjuvant setting appears to be equivalent to gemcitabine and carboplatin in the VINGEM trial. A recent California consortium trial showed encouraging activity with an overall response rate (ORR) approximately 50% in a metastatic setting for gemcitabine and eribulin (NCT31390274).
There are several new agents which have been tested in the metastatic setting and have shown remarkable response, which will require further assessment in the neoadjuvant setting. Looking at patients with metastatic muscle-invasive urothelial bladder cancer, upwards of 20% harbor a mutation in the fibroblast growth factor (FGFR)–signaling pathway, specifically the FGFR2 and FGFR3 receptors. Physiologically, FGFR 2/3 receptors play a role in the tyrosine kinase signaling network, which is involved in cell proliferation, differentiation, apoptosis, and migration. This is intriguing because of an FDA approved agent targeting this pathway, erdafitinib, which is approved in the locally advanced patient who progresses beyond cisplatin, as well as in the metastatic setting harboring this mutation. In this setting, a Phase II trial (99 patients) showed an overall response rate of 32.2%. Based on the impressive response in the advanced/metastatic setting, this is a very promising option in the neoadjuvant treatment and will require more data prior to incorporation into practice. However, as an oral targeted therapy, perhaps FGFR blockade is best evaluated in an adjuvant fashion. Indeed, infigratinib, another FGFR inhibitor is being evaluated in the PROOF 302 study for FGFR altered urothelial carcinomas, focusing more on upper tract disease adjuvantly.
Another recent FDA approval in the metastatic setting for MIBC is enfortumab vedotin-ejfv (PADCEV), an antibody-drug conjugate targeting Nectin-4, a protein highly expressed in MIBC was approved in platinum and immunotherapy refractory patients. However, the data in combination with pembrolizumab from the metastatic cisplatin ineligible cohort in the recently reported EV-103 trial at ESMO 2019 showed a response rate approximating 70% and a clinical benefit rate of 90%. This is a major advance in the cisplatin-ineligible population and definitely merits evaluation in the neoadjuvant setting for the future. Sacituzumab govitecan is another ADC with activity in heavily treated metastatic patients that can potentially be evaluated for neoadjuvant therapy in the future.
Finally, immunotherapies and targeted therapies such as infigratinib, nivolumab, pembrolizumab, and atezolizumab among others are being evaluated in large phase III trials in the adjuvant setting, which may be a viable alternative to a neoadjuvant approach after surgery. In conclusion, while there are currently no approved neoadjuvant regimens in those who are ineligible for cisplatin, there are a lot of encouraging approaches, and several agents that warrant further investigation to optimally treat these patients.
Written by: Arnab Basu, MD, MPH, FACP, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama; Charlie Bodine, MD, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama; Sarmad Sadeghi, PhD, MD, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, California
References:
- Grossman, H. Barton, Ronald B. Natale, Catherine M. Tangen, V. O. Speights, Nicholas J. Vogelzang, Donald L. Trump, Ralph W. deVere White et al. "Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer." New England Journal of Medicine 349, no. 9 (2003): 859-866.
- Holmsten, Karin, Niels Viggo Jensen, Lene Sonne Mouritsen, Erika Jonsson, Camilla Mellnert, Mads Agerbæk, Cecilia Nilsson et al. "Vinflunine/gemcitabine versus carboplatin/gemcitabine as first-line treatment in cisplatin-ineligible patients with advanced urothelial carcinoma: A randomised phase II trial (VINGEM)." European Journal of Cancer (2019).
- Necchi, Andrea, Daniele Raggi, Andrea Gallina, Russell Madison, Maurizio Colecchia, Roberta Lucianò, Rodolfo Montironi et al. "Updated Results of PURE-01 with Preliminary Activity of Neoadjuvant Pembrolizumab in Patients with Muscle-invasive Bladder Carcinoma with Variant Histologies." European urology (2019).
- Powles, Thomas, Alejo Rodriguez-Vida, Ignacio Duran, Simon J. Crabb, Michiel Simon Van Der Heijden, Albert Font Pous, Gwenaelle Gravis et al. "A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS)." (2018): 4506-4506. (See also UroToday coverage at ASCO 2018).