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More than 40% of patients with muscle-invasive bladder cancer (MIBC) avoided immediate cystectomy after achieving a clinical complete response (cCR) with a chemoimmunotherapy combination, a prospective study showed.

Overall, 33 of 76 patients with MIBC achieved a cCR by stringently defined criteria following transurethral resection of bladder tumor (TURBT) and treatment with gemcitabine, cisplatin, and nivolumab (Opdivo). All but one of the patients who achieved a cCR opted not to have immediate cystectomy. In the first 24 months after restaging, two patients who achieved cCR had metastatic recurrence versus 11 patients who did not meet criteria for a cCR. One patient in the cCR subgroup died versus eight patients who did not achieve a cCR.

Attaining a cCR had a positive predictive value (PPV) of 0.97 for the composite endpoint of 2-year metastasis-free survival in the cCR subgroup and cCR but opted for immediate cystectomy, reported Matthew Galsky, MD, of the Tisch Cancer Center at Mount Sinai in New York City, and coauthors in .

"Treatment for muscle-invasive bladder cancer is in need of major improvements from both a quality-of-life and an effectiveness standpoint," Galsky said in a statement. "If additional research confirms our findings, this may lead to a new paradigm in the treatment of muscle-invasive bladder cancer."

Bladder cancer specialists have known for some time that a proportion of patients with MIBC obtain long-term disease-free survival after TURBT and chemotherapy when they opt not to have cystectomy, Galsky told MedPage Today. The approach has not become standard of care, in large part because of lack of prospective data to support the strategy and lack of a clear definition for cCR.

Overcoming Barriers

"Our study was really seeking to overcome some of the barriers in a rigorous prospective manner," he said. "Ultimately, what we showed is that there is a subset of patients who are treated with TURBT, followed by chemotherapy plus immunotherapy, that have durable bladder-intact disease-free survival."

"About 40% of patients have a clinical complete response and then about two thirds of those patients have a prolonged bladder-intact disease-free survival. So this applies only to a subset of patients, but it's not an unsubstantial subset of patients," Galsky noted.

Additional prospective studies and phase III studies that confirm the results are still required before the approach can be considered for standard of care, he added.

Currently, the only other bladder-sparing strategy for MIBC involves chemoradiation, which delivers definitive doses of radiation to the bladder, said Daniel Geynisman, MD, of Fox Chase Cancer Center in Philadelphia. The current study showed that it's possible to achieve an excellent response with neoadjuvant chemoimmunotherapy.

"This trial is novel in that it incorporates rigorous clinical staging, immunotherapy both before and after restaging, and allows one to maintain one's bladder with no definitive local therapy such as surgery or radiation," Geynisman told MedPage Today via email. "The authors showed a high rate of a clinical complete response to chemoimmunotherapy and that most of those patients have been able to maintain their bladder with no metastatic disease."

"The great advantage of this approach is that it spares patients the toxicity of a cystectomy and all of its associated complications and quality-of-life limitations," he said.

Single-agent anti-PD-1 immunotherapy followed by cystectomy has led to pathologic (p)CR in 30-40% of patients with MIBC. Because cisplatin may induce favorable immunomodulatory effects, a strong rationale existed for combining the chemotherapeutic agent with immunotherapy, Galsky and coauthors noted. Phase II studies of neoadjuvant gemcitabine, cisplatin, and PD-1/L1 blockade have led to pCR rates of 40-50%, prompting several phase III evaluations.

Integration of biomarkers might further improve selection of patients who could be treated definitively with TURBT and systemic therapy, the authors continued. In particular, alterations in DNA damage repair (DDR) genes have been associated with increased response to anti-PD-1 immunotherapy, leading to the hypothesis that tumors with DDR alterations might be particularly sensitive to chemoimmunotherapy with cisplatin.

Design, Key Results

The accumulation of evidence led to a phase II trial to evaluate TURBT followed by neoadjuvant chemoimmunotherapy as definitive treatment for MIBC. Key features included use of cisplatin-based chemotherapy plus PD-1 blockade, standardized restaging, and translational analyses to explore potential biomarkers. The primary objectives were to estimate the cCR rate and determine the PPV of cCR for a composite outcome measure of 2-year metastasis-free survival in patients choosing not to have immediate cystectomy or eligible patients were cisplatin eligible and had cT2-T4aN0M0 MIBC. Following TURBT, they received four cycles of cisplatin-gemcitabine-nivolumab chemoimmunotherapy followed by restaging, which consisted of MRI of the abdomen and pelvic or chest CT, cystoscopy with template-guided biopsies, and urine cytology. Investigators defined cCR as no evidence of high-grade malignancy on biopsy, no malignant cells by urine cytology, and no definitive evidence of local or metastatic disease on cross-sectional imaging.

The results showed that 43% of patients met criteria for cCR. For the one patient who opted for cystectomy after cCR, pathology revealed low-grade ypTaN0 urothelial cancer. The PPV for achieving the composite endpoint was 97%, exceeding the prespecified threshold of 80%. Median metastasis-free and overall survival (MFS, OS) had yet to be reached for the entire cohort. A post hoc landmark analysis showed that patients who achieved a cCR had significantly longer MFS and OS as compared with patients who did not (P=0.007 and P=0.003, respectively).

Biomarker analyses showed no association between somatic alterations or increased tumor mutational burden and the PPV for cCR. Immunologic analyses showed an association between a higher PD-L1 combined positive rate and cCR but not MFS or OS. Higher levels of pretreatment CD4 T cells and a higher concentration of circulating CD8 T cells during treatment correlated with significantly longer MFS and OS.

The choice of cisplatin as the platinum agent for the study played a major role in the outcome, said Galsky. Previous studies that pooled patients treated with cisplatin or carboplatin showed no significant effect on survival. In contrast, the that evaluated gemcitabine, cisplatin, and nivolumab in the metastatic setting showed an improvement in progression-free and overall survival.

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