Pembrolizumab plus trimodality therapy sustains efficacy in muscle-invasive urothelial carcinoma

Adding pembrolizumab (Keytruda) to trimodality therapy (TMT) consisting of chemotherapy, hypofractionated radiotherapy (RT), and transurethral resection of the bladder tumor (TURBT) continued to show promise as a bladder-sparing approach in patients with muscle-invasive urothelial carcinoma (MIUC), according to long-term outcomes from a phase 2 study presented at the 2023 ASCO Annual Meeting.¹

There are ongoing studies aiming to confirm the efficacy of the pembrolizumab regimen in this setting, including the phase 3 KEYNOTE-992 trial (NCT04241185), which is assessing pembrolizumab pluschemoradiotherapy vs chemoradiotherapy alone in patients with muscle-invasive bladder cancer.

An early analysis from this study shared during the 2021 ASCO Annual Meeting showed initial efficacy signals and a tolerable safety profile for the pembrolizumab plus TMT strategy.² The median followed up duration was 23 months (range, 1.6- 62.7) for the outcomes shared at this year’s ASCO Meeting.

Overall, the phase 2 trial (NCT02621151) included 54 patients with cT2 to T4aN0M0 MIBC who declined or who were ineligible for cystectomy. Patients had an ECOG performance status of 0 or 1, estimated glomerular filtration rate of more than 30 cc/min, and no contraindications to pelvic radiotherapy or pembrolizumab. No perioperative chemotherapy was allowed.

Patients received a single dose of pembrolizumab at 200 mg followed in 2 to 3 weeks by maximal TURBT and then whole-bladder RT with twice weekly gemcitabine at 27 mg/m² and pembrolizumab every 3 weeks for 3 doses.

The investigators reported a 2-year bladder-intact disease-free survival (BIDFS) rate of 71%. Metastases-free survival was 78% at 2-years. The median BIDFS and MFS were both 47.4 months. The 2-year overall survival rate was 83%.

When presenting the data, ASCO discussant Maria De Santis, MD, associate clinical professor at the University of Warwick, who was not an investigator on the trial, noted that the 2-year BIDFS rate of 71% did not meet the prespecified study protocol goal, which stipulated that the study was 85% powered to detect a 20% absolute improvement in 2-yr BIDFS rate over 60% historical rate. However, she still sees potential for the addition of pembrolizumab in this setting.

“The added value of pembrolizumab to improve BIDFS remains unclear; however, the addition of an immune checkpoint inhibitor after tri- or tetra-modality therapy might improve long-term outcomes for patients with bladder cancer,” said De Santis.

The median patient age was 74 years, 72% were male, and 83% were Caucasian. Regarding clinical stage, 74% were T2, 22% were T3, and 4% were T4.

Eighty-eight percent of patients (n = 46) completed treatment. Toxicity was the most common reason for treatment discontinuation. Eleven percent of patients (n = 6) received salvage cystectomies.

As of the data cutoff of June 2022, 12 patients (22%) had tumor recurrences, including 3 MIUC, 5 locoregional, and 4 distant. Seven percent of patients (n = 4) had non–muscle invasive only recurrences.

During the study, there were 10 patient deaths. There was 1 death due to treatment toxicity and 3 due to disease progression. The other 6 deaths were due to unrelated/unknown causes.

There were no new safety signals at the long-term follow-up compared with the initial analysis. About one-fourth (24%) of patients had grade ≥3 adverse events (AEs), including cytopenia (n = 7), colitis (n = 5), cystitis (n = 2), polyneuropathy (n = 1), fatigue (n = 1), and hypokalemia (n = 1). Grade ≥3 AEs included colitis in 2 patients, polyneuropathy in 1 patient, and 1 patient who died due to grade 5 colonic perforation.

There are ongoing studies aiming to confirm the efficacy of the pembrolizumab regimen in this setting, including the phase 3 KEYNOTE-992 trial (NCT04241185), which is assessing pembrolizumab pluschemoradiotherapy vs chemoradiotherapy alone in patients with muscle-invasive bladder cancer. The primary end point of this trial is bladder intact event-free survival.

References

1. Economides MP, Milowsky MI, O'Donnell PH, et al. Long-term outcomes of pembrolizumab (pembro) in combination with gemcitabine (gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIUC): A multicenter phase 2 trial. J Clin Oncol 41, 2023 (suppl 16; abstr 4509).doi: 10.1200/JCO.2023.41.16_suppl.4509

2. Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro) in combination with gemcitabine (Gem) and concurrent hypofractionated radiation therapy (RT) as bladder sparing treatment for muscle-invasive urothelial cancer of the bladder (MIBC): A multicenter phase 2 trial. J Clin Oncol 39, 2021 (suppl 15; abstr 4504).