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

Article

"The addition of an immune checkpoint inhibitor after tri- or tetra-modality therapy might improve long-term outcomes for patients with bladder cancer,” said Maria De Santis, MD.

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.

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).

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