A combination of nivolumab (Opdivo), gemcitabine (Gemzar), and cisplatin as neoadjuvant therapy resulted in a pathologic nonmuscle-invasive rate of 66% and a pathologic complete response rate (pCR) of 49% in patients with muscle-invasive bladder cancer (MIBC), according to results from the phase 2 BLASST-1 clinical trial.
“The results are encouraging, and long-term follow-up will further confirm safety,” said Shilpa Gupta, MD, Staff Member, Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, OH, who presented the data at the 2020 Genitourinary Cancers Symposium. “The ongoing phase 3 ENERGIZE trial is being conducted to confirm these results.”
Dr Gupta said that the pCR rate in the trial was higher than rates of approximately 30% that are typically associated with neoadjuvant cisplatin-based chemotherapy regimens, noting that survival is improved in patients who achieve pathologic downstaging of their tumors on neoadjuvant therapy.
“However, a significant number of patients still relapse [which] contributes to early mortality. There is an unmet need to improve pathologic response rates with novel combination therapies and biomarker-driven approaches for better patient selection,” Dr Gupta said.
The BLASST-1 study enrolled patients with nonmetastatic MIBC who received the combination of nivolumab, gemcitabine, and cisplatin. All patients were deemed fit, cisplatin treatment–eligible, and candidates for radical cystectomy. The cutoff for creatinine clearance was ≥50 mL/min.
Patients received treatment with 4 cycles of gemcitabine plus cisplatin; fixed-dose nivolumab was added on day 8 of each cycle. They underwent cystectomy at 6 to 8 weeks after the completion of systemic therapy. In addition, imaging was performed before the study treatment began, and tissue and blood were collected for correlative analyses. Repeat imaging was performed and tissue was collected again at the end of treatment. The primary end point of the trial was pathologic response, which was defined as the pathologic nonmuscle-invasive rate at surgery (<pT2N0).
A total of 41 patients (63% male, 37% female) were enrolled at 3 sites; median age of patients was 66 years (range, 45-82 years). Clinical stage was T2N0 in 90% of patients, T3N0 in 7%, and T2-T4N1 in 3%. Two (4.8%) patients received prior treatment for Bacillus Calmette-Guérin disease.
Evaluable patients included those who completed at least 1 cycle of treatment. A total of 38 patients completed all 4 cycles of treatment, 2 completed 2 cycles, and 1 patient completed only 1 treatment cycle. Overall, 40 patients underwent cystectomy within 8 weeks of completing therapy; 1 patient withdrew consent after 1 cycle and was lost to follow-up but was included in the intent-to-treat analysis.
Of the 27 (66%) patients who met the primary end point and were downstaged to a nonmuscle-invasive status, 14 (51.8%) were downstaged to pT0, 2 (7.4%) were downstaged to pT1, 5 (18.5%) to pTa, and 6 (22.2%) to pTis. The pCR rate, which was defined as downstaged to pT0 or pTis, was 49%.
Of the 39 (39%) tumors assessed for PD-L1 status, 15 (39%) were positive. “There was no correlation between PD-L1–positive status and response,” Dr Gupta noted.
“The majority of adverse events were attributed to chemotherapy. Most of the hematologic toxicities were consistent with what we see with gemcitabine and cisplatin. Most of these were grade 1/2 anemia, neutropenia, and thrombocytopenia,” she said.
Grade 1 or 2 fatigue was reported by 60% of the patients, and grade 1 or 2 nausea was reported by 70% of patients. Increased alanine aminotransferase and aspartate aminotransferase levels were observed in 24% of patients each. A total of 6 (14%) patients had acute kidney injury; all but 1 case was grade 1 or 2 in severity.
Immune-related adverse events included rash (N = 1), hypothyroidism (N = 1), inflamed lymph nodes (N = 2), and Guillain-Barré syndrome (N = 1).
Correlative analyses are continuing. “Ongoing biomarker analyses will help determine predictors of response and resistance to chemoimmunotherapy in muscle-invasive bladder cancer,” Dr Gupta said.
Potential Paradigm Shift
Discussant Andrea Necchi, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, congratulated the investigators for a well-conducted trial.
“Several phase 3 trials are ongoing in this space to evaluate immunotherapy plus chemotherapy before radical cystectomy. I think enfortumab vedotin will also become an important option,” Dr Necchi said.
“The challenge is how to optimally select patients for immunotherapy or immunotherapy combinations. Immune gene signatures should be pursued in the next generation of studies,” he suggested.
“It is good that a phase 3 trial will be conducted for this combination, which has the potential for a paradigm shift,” Dr Necchi stated.