GU Cancers 2021 | KEYNOTE-992: pembrolizumab plus chemoRT for MIBC

KEYNOTE-992 study is a Phase III randomized study of pembrolizumab plus chemoradiotherapy compared to placebo plus chemoradiotherapy for patients who have muscle-invasive bladder cancer. So, this study builds on the knowledge that immunotherapy and, in particular, pembrolizumab is active in metastatic bladder cancer and also studies which have demonstrated activity both in patients with muscle-invasive bladder cancer and non-muscle-invasive bladder cancer.

In particular, small studies, such as a study that I’ve led, have shown the safety and encouraging activity signals of combining pembrolizumab with chemoradiotherapy. These studies, which have recruited up to 20 or 30 patients with recently published results, have shown no interaction in terms of a safety signal and encouraging response rates in patients who have undergone chemoradiation and then had pembrolizumab combined with that treatment.

This Phase III study, the KEYNOTE-992 study, will take patients who have muscle-invasive bladder cancer between T2 and T4 invasiveness, with no visible nodal disease on systemic staging who offer bladder preservation. It will randomize those patients to receive pembrolizumab, given every six weeks at a dose of 400 milligrams, commencing at the time of chemoradiation and comparing that to outcomes of men who undergo chemoradiation but are given a placebo every six weeks.

The pembrolizumab or placebo is continued for up to one year. Patients on the study are going to be receiving standard-of-care chemotherapy, which will allow delivery of either cisplatin, or fluorouracil with mitomycin, or biweekly gemcitabine.

The key endpoint for this study is bladder intact event-free survival, which is a meaningful endpoint for patients. That is to measure the proportion of patients who have their bladder intact, so that is avoiding the need for radical cystectomy, or death from any cause, or residual recurrent muscle-invasive bladder cancer, or nodal or distant metastasis.

And the study will enroll patients with the criteria that I’ve mentioned, but it will importantly allow enrolment of patients who are ECOG zero to two. These patients must have histological confirmation of their bladder cancer but, importantly, will exclude patients with diffuse CIS, which is known to be a poor prognostic marker for patients having radiation. It’ll exclude, also, patients with any components with neuroendocrine carcinoma or with poor renal function, such as a creatinine clearance less than 30 or poor bladder function, which is known to correlate with poor quality of life and poor tolerance of radiation.

The study has commanded enrolment across North American sites, European sites, and Australia. It will continue to enroll over the next 12 to 24 months, aiming to enroll over 600 patients and hoping to report outcomes in probably three to five years time.