New data show that a large subset of patients with muscle-invasive bladder cancer (MIBC) can avoid cystectomy and enjoy long-term, bladder-intact, disease-free survival.
Among 64 study participants who underwent bladder-sparing tumor resection plus systemic chemoimmunotherapy, nearly half had stringently defined clinical complete responses (cCRs) at the 1-year interim analysis.
The new results come from the phase 2 HCRN GU 16-257 trial and were reported by Matt D. Galsky, MD, during an oral abstract session at the American Society of Clinical Oncology (ASCO) 2021 virtual annual meeting.
This treatment approach, which involves transurethral resection of bladder tumor (TURBT) followed by systemic therapy, has long been known to be effective for achieving durable bladder-intact survival in up to 40% of patients with MIBC, commented Galsky, a medical oncologist in the Division of Hematology and Medical Oncology at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City.
Further, these responses are highly correlated with long-term disease-free survival (DFS), he noted.
However, data to advance this treatment paradigm are lacking, he said. He noted three apparent barriers that have prevented the treatment approach from moving forward: (1) a paucity of prospective studies evaluating the approach; (2) inconsistency in defining and measuring cCR across studies; and (3) limited understanding of the role of delayed cystectomy for patients who experience recurrence.
The possibility of recurrence ― which relates to the potential for salvage surgery ― has historically been a critical factor in organ-sparing approaches for most other organ sites, he noted.
“Radical cystectomy is a major operation and requires diversion of the urinary stream, which has life-altering implications,” he continued. “Clearly, if we could identify which patients have their MIBC eradicated with transurethral resection plus systemic therapy alone, a subset of patients can avoid cystectomy and enjoy long-term, bladder-intact, disease-free survival.”
To that end, he and his colleagues designed the HCRN GU 16-257 trial. Armed with emerging data suggesting that mutations in DNA damage response genes (DDR alterations) were sensitive to cisplatin-based chemotherapy and were associated with increased tumor mutational burden (and therefore were potentially sensitive to immune checkpoint blockade), they aimed to test their hypothesis that “a subset of tumors, particularly those harboring DDR alterations, might be exquisitely sensitive to the combination of cisplatin-based chemotherapy plus [programmed cell death 1] blockade.”
For the study, 76 patients were enrolled at seven sites between August 2018 and November 2020. Of those patients, 64 had undergone TURBT and systemic therapy with gemcitabine and cisplatin plus the checkpoint inhibitor nivolumab and had completed post–cycle 4 restaging at the time of data lock. Of those, 31 (48%) achieved a cCR within a median follow-up of 13.7 months.
One patient who achieved a cCR opted for immediate cystectomy; pathology showed that the patient had a low-grade papillary tumor. Six of eight patients who experienced local recurrence also underwent cystectomy.
Study participants were mostly men (79%); the median age was 69 years. They had to be cisplatin-eligible with stage cT2-T4a urothelial bladder cancer to be enrolled; 56% had stage cT2 disease, 32% had cT3 disease, and 12% had cT4 disease.
Treatment included four cycles of gemcitabine, cisplatin, and nivolumab followed by clinical restaging by urine cytology, bladder imaging, cystoscopy, and relevant biopsy.
Patients who achieved a cCR, which the authors stringently defined as having no abnormalities on post–cycle 4 imaging and post–cycle 4 urine cytology and having no evidence of disease greater than low-grade papillary tumors on post–cycle 4 bladder biopsy, were eligible to proceed without cystectomy and receive maintenance nivolumab every week for eight cycles.
Those who didn’t achieve cCR underwent cystectomy.
Treatment was generally safe, and neither of the criteria for stopping the trial early was met. Those criteria included a high rate of immune-mediated adverse events (AEs) of grade 3 or greater and a high rate of muscle-invasive and/or metastatic recurrence among those achieving cCR.
“The AE profile to date has been consistent with other studies, recently reported, combining cisplatin-based chemotherapy with immune checkpoint blockade,” he said.
Genomic testing showed that at 1 year, tumor mutational burden of 10 mut/MB or greater or alterations in ERCC2 were significantly associated with achieving cCR.
These interim findings show that 1-year bladder-intact, recurrence-free survival is possible with TURBT and systemic therapy, Glasky concluded. He noted that additional follow-up is needed to assess the durability of the observed responses and the role of genomic biomarkers in management algorithms ― a key secondary study endpoint.
He and his colleagues will further explore “a suite of genomic and radiomic biomarkers in an effort to refine the ability of cCR to predict long-term, bladder-intact, recurrence-free survival,” he said.
The findings are “very promising,” said invited discussant Andrea Necchi, MD, director of genitourinary medical oncology at IRCCS San Raffaele Hospital and Scientific Institute, Milan, Italy.
The strategy used by Galsky and colleagues appears preferable to other bladder-sparing approaches presented during the session, Necchi said.
Those strategies, which involve combined radiotherapy and immune-checkpoint blockade for MIBC, are also promising, but the “Galsky strategy” provides similar outcomes while circumventing the AEs of local radiotherapy, he explained.
However, longer follow-up and a more in-depth evaluation of the role of biomarkers are needed before the strategy can be used in routine practice, he added.
“My impression is that we should look outside of the tumor – in particular, at circulating tumor DNA,” he said. “The concept of minimal residual disease is quite interesting [in the MIBC setting].”
Incorporation of newer imaging techniques, such as multiparametric MRI, and newer agents, such as FGFR inhibitors and antibody-drug conjugates, into the “rational therapeutic sequence” could lead to “unique strategies to further improve the outcomes in these patients,” he said.
The study was funded by Bristol-Myers Squibb and the V Foundation. Galsky reported financial relationships with multiple companies, including Rappta Therapeutics, Aileron Therapeutics, Astellas Pharma, AstraZeneca, Basilea, BioMotiv, Bristol-Myers Squibb, Dendreon, Dracen, Dragonfly Therapeutics, Janssen, Lilly, Merck, Novartis, NuMab, Pfizer, Seattle Genetics, and Urogen Pharma. Necchi reported relationships with Roche, Merck, AstraZeneca, Janssen, Foundation Medicine, Bayer, Clovis Oncology, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, and Rainier Therapeutics.
American Society of Clinical Oncology (ASCO) 2021: Abstract 4503. Presented June 7, 2021.
Sharon Worcester is an award-winning medical journalist at MDedge News, part of the Medscape Professional Network.
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