Neoadjuvant Radioimmunotherapy Demonstrates Feasibility in Locally Advanced Urothelial Carcinoma

The addition of nivolumab (Opdivo) to radiation therapy prior to radical cystectomy demonstrated feasibility and safety in patients with locally advanced urothelial carcinoma, according to data from the phase 2 RACE IT trial (NCT03529890) presented at the 2022 ESMO Congress.

Data from RACE IT showed that among evaluable patients with locally advanced urothelial bladder cancer (n = 31), 87.1% of patients completed treatment, meeting the primary end point of the study.¹ Additionally, patients experienced a radiological overall response rate of 70.9% and a 12-month disease-free survival rate of 90.6%.

These data warrant further prospective clinical trials to evaluate the viability of neoadjuvant radioimmunotherapy in patients with locally advanced bladder cancer, according to Sebastian C. Schmid, MD.

“Radioimmunotherapy in locally advanced bladder cancer seems to be an interesting option, as it is applicable irrespective of kidney function and other cisplatin-ineligibility criteria,” Schmid said. “In comparison with other new treatment strategies, all of [these approaches] are in phase 2 trials, [including RACE IT], and all of them are exploratory in nature. [Comparing these treatments] can only be answered with further clinical trials.”

In an interview with OncLive^®, Schmid, an oncologist at Rechts der Isar Medical Center, Technical University of Munich, Germany, discussed the results of the RACE IT trial, what the data mean for patients with locally advanced urothelial carcinoma, and the next steps for researching neoadjuvant radioimmunotherapy in this patient population.

OncLive^®: What is the current treatment landscape for patients with locally advanced urothelial carcinoma? What did the RACE IT trial aim to address?

Schmid: This trial investigated patients with locally advanced bladder cancer, and these patients have a poor prognosis. [These are] patients who have stage T3 or T4 cancer. Our trial also included patients with pelvic lymph node metastases.

If these patients are treated with surgery alone, they have a poor prognosis. [The overall survival rate is less than] 50% after 5 years in those with stage T3/T4 disease, and [the 5-year OS rate] is approximately 20% to 30% in patients with pelvic lymph node metastases. This is a group who needs better treatment, and neoadjuvant chemotherapy didn’t add much [benefit]. Recent papers show that complete response [CR] rates are only around 15% to 20% [with neoadjuvant chemotherapy], so there is room for improvement.

With the advent of checkpoint inhibitors, there are interesting combinations to explore. One of these combinations includes the [addition] of checkpoint inhibitors to radiation therapy. Radiation therapy has immune-stimulating effects, which help the checkpoint inhibitors. They also have immune-depressing effects, and these can be counteracted by the immune checkpoint inhibitors. You have the potential for synergistic effects, making this combination very interesting.

What methods were used during the RACE IT trial to evaluate the combination of radiotherapy and immunotherapy?

We decided to use this as a neoadjuvant therapy. Patients got a treatment regimen consisting of checkpoint inhibition with nivolumab at 240 mg intravenously every 2 weeks for 4 cycles, and radiation therapy at 50.4 Gy. This was followed by cystectomy.

What key efficacy data were presented at the 2022 ESMO Congress?

We included 33 patients, and what we found was a pathologic CR rate of [downstaging to] ypT0 of 38.7%. This was a patient population with locally advanced [urothelial carcinoma, potentially with] pelvic lymph node metastases, making it a really advanced patient population. We found that the rate of downstaging to ypT1 or less was 58.1%. These are good results overall.

Additionally, the disease-free survival rate at 12 months was 90.6%. In this population, these are very interesting data.

What excited you about these findings?

There are 2 points that are exciting. One point is that the [efficacy of] radioimmunotherapy is independent of kidney function. A lot of [patients with] bladder cancer have kidney problems, and you can [administer] neoadjuvant [radioimmunotherapy], even if patients are ineligible for cisplatin-based chemotherapy.

The other point [involved future research] to see how [radioimmunotherapy] will do compared with immunotherapy alone and other combination therapies. Comparative phase 3 trials are needed to explore that.

What further research is needed to learn more about this approach with neoadjuvant radioimmunotherapy?

What we can do with the data we have now and what is ongoing is to look at other important factors, such as quality of life for patients during radioimmunotherapy. In a publication that is planned, we will show more detailed data on adverse effects. This is something which we can generate from the data.

There are also translational projects where we will look at possible predictive markers for radioimmunotherapy. Overall, there is a lot of research that can be done with the study.

What unmet needs for patients with bladder cancer do you hope to see addressed in the future?

In trials addressing these groups, an interesting question is: Do we have predictive markers like circulating tumor DNA? That should always be included when planning trials. Moreover, it is always important to include quality of life, because it is not only the amount of life, but also the quality of life, that matters to patients.

Another question that is the focus of research is: When can we stop radioimmunotherapy in good responders and not do surgery? We are looking at these bladder sparing approaches, which are often discussed. However, bladder sparing approaches are not very applicable in the [locally advanced] patient population. In the locally advanced population, you still have a relatively high amount of patients with positive lymph nodes at final pathology, which wouldn’t have been seen with clinical imaging.

This is not the population for bladder sparing strategies. In the past, we have seen that bladder sparing strategies works best if you have a locally confined bladder tumor. This is ideally completely resected. This discussion always pops up, but I’m not sure whether this is the right population for discussing these bladder sparing approaches.

Reference

1. Schmid SC, Schiller K, Lewerich J, et al. RACE IT: A prospective, single arm, multicenter, phase II-trial to assess safety and efficacy of preoperative radiation therapy before radical cystectomy combined with immunotherapy in locally advanced urothelial carcinoma of the bladder. Ann Oncol. 2022;33(suppl 7):S1442. doi:10.1016/j.annonc.2022.08.081