Early Efficacy Shown With Gemcitabine/Cabazitaxel/Pembrolizumab in NMIUC

Gemcitabine in addition to cabazitaxel (Jevtana) and intravenous (IV) pembrolizumab (Keytruda) has demonstrated promising early efficacy in heavily pretreated patients with high-risk non-muscle invasive urothelial carcinoma (NMIUC), according to a study presented at the 2022 American Urological Association Annual Meeting.

According to Vignesh Packiam, MD, gemcitabine given in addition to docetaxel has become a common sequential intravesical regimen given as treatment for patients with NMIUC. Still, there are still patients who experience disease recurrence after receiving gemcitabine and docetaxel due to developed resistance to docetaxel, Packiam explains.

Because of this, investigators, including Packiam, believe that cabazitaxel may be able to play a role in salvaging responses in this patient population. A retrospective analysis was performed with 13 patients (18 units) who were treated with the combination of gemcitabine, cabazitaxel, and pembrolizumab, with a 3-month or more evaluation.

Those enrolled received 6 weekly endoluminal 50 cc instillations of sequential 1g gemcitabine for 90 minutes and 5mg of cabazitaxel for 90 minutes in addition to concomitant IV pembrolizumab given at a dose of either 200 or 400mg. Further, patients were administered maintenance treatment 2-4 weeks until disease progression or unacceptable toxicities were shown.

The primary end point of the study was complete response (CR) at 3 months, which was defined as no disease on cystoscopy, bladder/upper tract wash cytology or for-cause biopsies. Additionally, tolerability and adverse events were examined.

Of those enrolled in the study, the median age was 77 years with prior treatments of BCG exposure in 93% of patients and gemcitabine/docetaxel exposure in 100% with additional docetaxel-containing regimens in 79% of patients.

Findings showed that at 3 months, the time of the first evaluation, 86% patients and 89% of treated units had CR. At 6 months post-treatment evaluation, 79% of patients and 83% of units had a CR, and at 12 months, the CR rate was 50% and 62%.

Overall, the study showed that in patients with more advanced, treatment-refractory disease, adding pembrolizumab to treatment with cabazitaxel plus gemcitabine could improve responses as well as their duration.

In an interview with Targeted Oncology^TM, Packiam, urologist, assistant professor of Urology, University of Iowa Hospitals and Clinics, discussed the research of gemcitabine plus cabazitaxel and pembrolizumab (Keytruda) in patients with NMIUC who are unresponsive to docetaxel.

Targeted Oncology: What is some background of this study examining gemcitabine, cabazitaxel, and pembrolizumab in NMIUC?

Packiam: This project is looking at outcomes of a novel regimen for patients with treatment refractory, non-muscle invasive bladder cancer. This is looking at 2 different endoluminal agents, which are gemcitabine, and cabazitaxel in conjunction with an intravenous agent, pembrolizumab

How do gemcitabine and cabazitaxel fit into the care of patients with unresponsive non-muscle invasive bladder cancer?

Our institution has had good success utilizing gemcitabine and docetaxel, which are 2 different chemotherapies used sequentially. It was initially explored for patients with BCG unresponsive disease. Although now with the persistent BCG shortage, we've evaluated this more and more for BCG naive bladder cancer as well. We've noticed that even though the response rate to this agent is very promising, there are some patients that have recurrences to this regimen as well.

We were looking for an effective salvage option for patients who recurred despite receiving gemcitabine/docetaxel. We know from prostate cancer that resistance can eventually form from exposure to docetaxel. In those patients, cabazitaxel is an alternative agent, which has shown to have some efficacy. That was the rationale for utilizing gemcitabine and cabazitaxel within the urinary system.

At the same time, there has been a recent FDA approval of pembrolizumab, which is an intravenous checkpoint inhibitor, although there are concerns about suboptimal long term efficacy. The 1-year complete response for pembrolizumab monotherapy is only 19%, so our hope was with combining these agents, we could develop a more effective treatment regimen for these patients.

How was this study conducted?

This regimen was offered to patients who were heavily pretreated. The median number of prior complete intravascular inductions was for in this cohort. It was a heavily pretreated population of patients who either had too many comorbidities considered to be a reasonable surgical candidate for cystectomy or a patient who had been refusing radical cystectomy. We looked back over the past 2 years for patients who have received this regimen and retrospectively identified 13 patients who received this regimen with a total of 18 treated units. Thirteen were bladder, and 15 renal units, which were which had the presence of carcinoma on side 2 or positive cytology.

What were some of the findings of the initial evaluation?

We found that at initial evaluation, which was a restaging procedure performed at 3 months, there was an 86% complete response rate in the overall cohort with 89% complete response when you're considering each unit separately for the upper tracks and the bladder. The 3-month evaluation was fairly thorough with cystoscopy in situ performed for all patients, random bladder biopsies, prostatic urethral biopsies, and upper tract washings. When we continued surveillance at 6 and 12 months, we noticed that the complete response rate was 79% for patients at 6 months, and 50% for patients at 12 months, which is relatively favorable and promising compared to other agents in this type of paper patient population.

What do your findings tell you about optimal dosing?

We noticed that there was significant bladder toxicity that developed in 5 of these patients. Some of this may have been a result of their heavy pre-treatment history, with alternative regimens used prior to them receiving this treatment regimen. A few patients had to have treatment holidays from the gemcitabine side cabazitaxel to allow their bladders to recover. One patient did require a cystectomy due to end stage bladder symptoms. The optimal dosing is definitely something that we're still exploring.

What can you tell me about the prospective study which will further dive into this topic?

This study has transitioned into a prospective protocol through our cancer center where we are going to more rigorously look for the optimal dosing regimen. It is something that's exciting and I think it's going to help us figure out the efficacy of this regimen and additionally evaluate safety and dosing parameters.

Reference:

Packiam V, McElree I, Steinberg RL, et al. Sequential endoluminal cabazitaxel and gemcitabine with pembrolizumab for docetaxel-unresponsive non-muscle invasive urothelial carcinoma of the upper and lower urinary tracts. Presented at: 2022 American Urological Association Annual Meeting; May 13-16. New Orleans, LA. Abstract PD26-07.