SAN FRANCISCO — Immunotherapy with pembrolizumab (Keytruda) demonstrated promising activity for patients with high-risk, papillary non–muscle invasive bladder cancer (NMIBC) whose condition did not respond to treatment with bacillus Calmette-Guérin (BCG), say researchers reporting new results from the phase 2 KEYNOTE-057 trial.
Used as monotherapy, pembrolizumab conferred a median disease-free survival of 7.7 months after 45 months of follow-up; 43.5% of patients remained disease free at 12 months.
“These results are among the most robust data yet available for any novel systemic therapy in this patient population with papillary high-risk disease,” said lead author Andrea Necchi, MD, of the Vita-Salute San Raffaele University and the IRCCS San Raffaele Hospital and Scientific Institute in Italy.
“This suggests that pembrolizumab monotherapy may be beneficial in this special patient population, in case of BCG-unresponsive disease in patients who decline or elect not to undergo radical cystectomy or who are ineligible for radical cystectomy.”
He added that this population represents “an unmet medical need without or with limited, very limited conventional therapies and with very limited clinical trial opportunities.”
Pembrolizumab is already approved for use in bladder cancer in certain patient populations.
The results (abstract LBA 442) were presented here at the Genitourinary Cancers Symposium (GUCS) 2023.
An expert who was approached for an independent comment noted that cystectomy is major surgery that can have marked impact on quality of life. “Studies such as this are imperative to advance care for patients with BCG-refractory urothelial carcinoma,” said Bradley Alexander McGregor, MD, an expert with the American Society of Clinical Oncology. “This is intriguing data and can be discussed with patients, and with the recent data presented and the current FDA [US Food and Drug Administration] approval, it [pembrolizumab] can be considered.”
However, he pointed out, while quality of life was not markedly lessened, immunotherapy carries a risk of significant toxicities and involves infusions for 2 years. “As such, ongoing studies looking at additional intravesical agents are intriguing,” said McGregor, who is also director of clinical research for the Lank Center of Genitourinary Oncology and serves as a medical oncologist specializing in genitourinary malignancies at the Dana-Farber Cancer Institute, Boston, Massachusetts.
“Most recently, we have seen data on immune cell–activating interleukin-15 superagonist nogapendekin alfa inbakicept, which showed impressive response in just over 80 patients with treatment-refractory NMIBC with CIS [carcinoma in situ].”
These results were published recently in NEJM Evidence, and the manufacturer (ImmunityBio) has said that the product is under review at the FDA for this indication. A decision is expected by May 23, 2023.
Poor Prognosis After Relapse on BCG Therapy
The standard of care for bladder cancer is transurethral resection of bladder tumor followed by intravesical BCG. “The prognosis for patients who do not respond or who relapse after BCG therapy is poor, and the standard-of-care therapy for these patients is still represented by radical cystectomy, according to guidelines,” said Necchi. “The criteria for the definition of adequate BCG and BCG-unresponsive high-risk non–muscle invasive disease are also pretty well established and [are] endorsed by the US FDA for their use in trials investigating any newer therapies in this patient population.”
The KEYNOTE-057 trial explored the safety and efficacy of pembrolizumab monotherapy for patients with BCG-unresponsive high-risk NMIBC who were ineligible for or declined to undergo radical cystectomy. The participants were divided into two cohorts.
Results from cohort A of this study were reported some time ago. This cohort comprised patients with CIS with or without papillary tumors. The clinical complete response rate at 3 months was 40.6%, and the median duration of response was 16 months (Lancet Oncol. 2021;22:919-930). This led to regulatory approval in the United States of pembrolizumab for this population.
“Additional studies are providing compelling data and compelling results with newer therapies or newer combination therapies in this same CIS-based population, but limited data are still available regarding the efficacy of any novel systemic therapy in non-CIS high-grade PT1 or TA disease,” said Necchi.
The latest results come from cohort B, which only included patients (n = 123) with papillary tumors without CIS. Within this cohort, 57 patients (43.2%) had T1 disease. Prior to enrollment, they received a median of 10 BCG installations. Overall, patients received pembrolizumab 200 mg every 3 weeks for a median of 9.5 cycles.
The median follow-up was 45.4 months; 105 patients discontinued treatment. Of those, 71 patients discontinued treatment because of disease recurrence or progression, and 21 did so because of adverse events. Necchi noted that 22 patients completed the 2 years of treatment; at the time of data cutoff, five patients were receiving treatment.
Disease-free survival at 12 months was 43.5% but plateaued after month 24, Necchi explained. Estimated 24- and 36-month disease-free survival was 34.9%.
For the secondary endpoints, estimated 12-month PFS was 88.2%; the median PFS was 44.5 months. The 12-month PFS to invasive or metastatic disease or death was also 88.2%, with a median PFS of 46.2 months. The estimated 12-month overall survival was 96.2%; the median was not reached. A total of 31 patients (23.5%) underwent radical cystectomy after treatment with pembrolizumab was stopped.
Treatment-related adverse events occurred in 97 patients (73.5%). Of these, 19 patients (14.4%) experienced grade 3/4 events (primarily pruritus, thyroid function abnormalities, and fatigue). There were no treatment-related deaths, and immune-related and infusion reactions were uncommon.
Promising Data, Some Concerns
In a discussion of the presentation, Michiel Simon van der Heijden, MD, PhD, of the Netherlands Cancer Institute, Amsterdam, pointed out that for high-risk BCG-refractory papillary disease, it is recommended that freedom from high-risk recurrence at 1 year be considered the most important endpoint and that the target is at least 30%. He noted that this study exceeded that threshold and that other treatments have also met that target.
“But these are retrospective studies and not in the context of a well-controlled clinical trial,” he said. “And I think the pembrolizumab mainly stands out for the robustness of the data with 132 patients, which is the largest prospective clinical trial in this space.”
He added that pembrolizumab probably has clinical activity in this space, though unless there are randomized trials, the magnitude of this activity will be unknown. Although randomized trials are needed, he acknowledged “that it will be quite difficult to find the best comparator arm.”
The KEYNOTE-057 trial was sponsored by Merck Sharp and Dohme, LLC, which markets pembrolizumab. Necchi has relationships with, and/or support from, Bayer, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb (BMS), Foundation Medicine, Janssen, Merck, Roche, Basilea Pharmaceutical, Catalym, Clovis Oncology, GSK, Incyte, Merck Sharp & Dohme, Rainier Therapeutics, Seattle Genetics/Astellas, Gilead Sciences, Ipsen, and Pfizer. Van der Heiden has disclosed relationships with and/or has received support from Gilead Sciences, Astellas Pharma, AstraZeneca/Medimmune, BMS, Janssen, MSD Oncology, Pfizer, Roche/Genentech, Seattle Genetics, 4SC, and Novartis.
Genitourinary Cancers Symposium (GUCS) 2023: Abstract LBA442. Presented February 18, 2023.
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