Daniel J. George, MD, discusses the impact that ADCs have had on the evolving treatment landscape of bladder cancer, long-term outcomes with immunotherapy in metastatic renal cell carcinoma, and highlighted current and ongoing research at the Duke Cancer Institute.
Daniel J. George, MD
Progress in the treatment landscape for genitourinary (GU) cancer care has been made with the addition of new therapies, such as antibody drug conjugates (ADCs), specifically in bladder cancer. Patients who are ineligible for platinum-based chemotherapy have experienced significant improvements in their survival rates with the use of ADCs, Daniel J. George, MD, said.
“We’re excited about the development of [ADCs] in the refractory setting and upfront settings. There are ongoing trials looking at these agents in the neoadjuvant setting, comparing with chemotherapy, as well as in the frontline metastatic setting. We hope we're going to see even greater responses and benefits with these agents as we move them up earlier in the disease natural history,” George explained in an interview with OncLive® following a State of the Science Summit™ on GU cancer, which he chaired.
George, a professor of medicine and a professor in surgery at the Duke Cancer Institute in Durham, North Carolina, discussed the impact that ADCs have had on the evolving treatment landscape of bladder cancer, long-term outcomes with immunotherapy in metastatic renal cell carcinoma (RCC), and highlighted current and ongoing research at the Duke Cancer Institute.
George: ADCs have revolutionized cytotoxic therapy for advanced bladder cancer in patients who are refractory to or ineligible for platinum-based chemotherapy. In patients who are refractory to platinum-based chemotherapy and previously treated with immune-oncology [IO] therapy, we’ve seen a dramatic overall response rate [ORR] with sacituzumab govitecan-hziy [Trdelvy] and enfortumab vedotin-ejfv [Padcev], much higher than with historical second-line chemotherapy. Durable responses have been seen as well, and that’s really been an unmet need in the field. Now we have accelerated approval of both drugs.
In addition, enfortumab vedotin has completed a phase 3 study compared with physician’s choice chemotherapy in this refractory setting and demonstrated an overall survival benefit over chemotherapy, and this trial led to the full approval of the agent in this setting. Most recently, it’s been studied in combination with pembrolizumab [Keytruda] in a cisplatin-ineligible patient population and demonstrated a high response rate of almost 70% in this difficult-to-treat patient population, with durable responses and survival.
We have a new expectation for patients with intermediate- or poor-risk metastatic RCC. In years past, in the tyrosine kinase era, the 5-year survival for that population was close to 10% or 20%. Now we’re seeing a 5-year expected survival for that population that’s closer to the 40% to 50% range. It’s remarkable to see how much this immunotherapy has changed the outlook for patients. That’s based on the minimum 5-year follow up from the CheckMate-214 study that was recently published.
This trial also suggests that there’s room for improvement, particularly in the patients who have early progression or the patients that still may die from the disease within the first 2 years. Therefore, there have been some studies that have evaluated triplet combinations. Although we do see improvements in survival with the triplet of ipilimumab, nivolumab, and cabozantinib [Cabometyx], for example, the results are tempered by increased toxicity.
The future will be understanding where there are opportunities to use triplets, either altogether or sequentially, as an adaptive approach, like in the PDIGREE study [NCT03793166], which has a lead in for nivolumab plus ipilimumabfor up to 4 cycles, followed by randomization to nivolumab vs nivolumab pus cabozantinib in patients with less than a complete response, or other novel agents that may be tested in that space.
There’s also room on the back end for patients who progress on frontline immunotherapy, whether it’s with a second IO agent, like ipilimumab, or it’s in combination with a TKI. There’s a lot of research in that space with other novel combinations, with some novel mechanisms of action, and clear benefits to subsequent therapy in these intermediate- and poor-risk patients.
First, we presented a case of a patient with locally advanced prostate cancer and discussed the various treatment options, including novel hormonal agents in combination with radiotherapy, the idea of consolidative radiotherapy for locally advanced disease, and the use of PSMA-PET imaging to determine who has regional or microscopic metastatic spread vs those with localized disease. A lot has changed in how we manage these patients with otherwise difficult to control localized disease.
Another case we discussed was in kidney cancer, with the use of adjuvant immunotherapy and where who may be appropriate. Specifically, in patients who have inflammatory profiles, patients who have sarcomatoid elements, patients who have particularly high-risk features, and patients who have a single metastatic site resected. In our tumor board cases, [we highlighted] patients who are at highest risk for disease recurrence. Although it’s not 100%, these are the patients who might benefit the most from the use of an adjuvant therapy.
The main message is that we need to have more meetings, whether that is in your local community, regional meetings, or national meetings. These are great opportunities to get caught up with the field because it’s changing, not just every year, but almost every meeting. In addition, multidisciplinary interactions are critical, because a lot of what we’re doing now is moving therapies up into the curative setting or into settings where we can get to a minimal disease state in the metastatic setting. We are going to want to use agents more rapidly and not wait for disease progression. Some of those agents aren’t drugs, they’re directed radiotherapy, surgeries, or nuclear medicine radioligand therapies. Having a multidisciplinary team that meets someplace to discuss cases and updates in the field and practice patterns is critical.
We are doing some studies right now in the perioperative surgical setting for prostate cancer where we’re looking at low doses of radiation therapy, as well as novel combinations of PARP inhibitors and hormonal therapy in that setting. We’re going to be looking at some of those strategies with novel hormonal agents and PARP inhibitors with radiation therapy. For patients with more aggressive intermediate- and high-risk localized prostate cancer, we have some novel opportunities to offer patients who might otherwise be difficult to cure.
In RCC, we’re part of the Kidney Cancer Research Consortium and we have several phase 1/2 studies in patients who are refractory to their frontline therapy. We also have some novel frontline combinations for patients who have some intermediate- or poor-risk features who are motivated with good performance status for doublet or triplet clinical trial therapy.
Finally, in bladder cancer, we’re doing several studies in the neoadjuvant setting combining IO therapy, comparing against neoadjuvant chemotherapy. We’d be happy to coordinate care with local services to deal with muscle invasive or locally advanced bladder cancer.