Expansion of Frontline Immunotherapy Regimens Improves Prognosis, Increases Optimism in Urothelial Cancer

Peter H. O'Donnell, MD

The expansion of tools and treatment options for patients with bladder cancer with the addition of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda), as well as nivolumab (Opdivo) plus gemcitabine/cisplatin, to the first-line arsenal has led to a shift in optimism and changing mindsets regarding prognosis for both patients and providers, according to Peter H. O’Donnell, MD, who added that more research is needed to identify which patients are most likely to respond to these regimens.

To continue pushing the needle forward in urothelial cancer, oncologists are now awaiting results from ongoing studies with immunotherapy in the perioperative setting; considering questions around re-treatment with immunotherapy-based regimens in the event of recurrent disease; and exploring combinations of antibody-drug conjugates (ADCs) with or without immunotherapies in later lines, O’Donnell detailed in an interview with OncLive^®.

“My main message to providers is don’t think that it’s still 1995, because the tools have changed dramatically,” said O’Donnell, who is a faculty physician and associate professor of medicine at the University of Chicago in Illinois. “Therefore, the optimism and outlook that we have for patients [with bladder cancer] coming through our door should be completely different.”

In the interview O’Donnell shared his insights on exciting developments in bladder cancer treatment, including the significance of having enfortumab vedotin plus pembrolizumab for patients with locally advanced or metastatic bladder cancer, and ongoing efforts to move these agents into earlier lines; how emerging agents in non–muscle-invasive bladder cancer (NMIBC) could engender earlier intervention and improved survival; and how combination regimens with ADCs and immunotherapy could improve response rates beyond those seen with the current standard of care (SOC).

OncLive: How have data from the the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which supported the FDA approval of enfortumab vedotin plus pembrolizumab,1 shifted the treatment paradigm in urothelial cancer?

O’Donnell: Enfortumab vedotin plus pembrolizumab has revolutionized the way we’re treating [patients with] metastatic urothelial cancer. It has completely changed the paradigm. We used to think that all patients have to get platinum [chemotherapy] as their first treatment. That’s been turned upside down now because survival [outcomes with] enfortumab vedotin plus pembrolizumab [were] nearly double [that of] platinum-based therapy. It’s hard to argue with that, and I find myself hard pressed to justify giving anything but this regimen in the frontline setting.

Nivolumab plus gemcitabine/cisplatin² has also joined the first-line urothelial cancer treatment arsenal alongside enfortumab vedotin plus pembrolizumab. What is the significance of having this additional regimen available for patients?

The urothelial cancer field had [conducted] prior trials looking at the idea of combining immunotherapy with platinum-based chemotherapy, but it had not panned out. The difference [in the phase 3 CheckMate-901 study (NCT03036098)] was that this was a cisplatin-only treated population where the immunotherapy was being combined. Now we see a positive trial. The biggest takeaway from that dataset is that there are patients who can [achieve] a complete response [CR] with cisplatin-based therapy combined with immunotherapy in [the form of] a triplet regimen, and that those CRs [can be] quite durable. That was the most eye-catching part of those data. The other take-home [message] is that there is maintenance therapy built into that triplet. It’s a triplet upfront but [it involves] maintenance nivolumab in that trial. [This] recapitulates the data that we had seen before [indicating] that maintenance immunotherapy makes a difference in this disease.

What factors could help identify patients who may achieve a CR with the nivolumab triplet and help guide treatment decision-making?

Those are probably patients who we knew about before who have lymph node only or lymph node–predominant disease, a lack of liver metastases, and a lack of bone metastases. These patients are much more likely to [achieve] a durable CR. [However], they might be the same patients who also experience durable responses with enfortumab vedotin plus pembrolizumab. [Identifying those factors is] not helping us choose a regimen, it’s probably just identifying patients who are likely to do better overall.

Could enfortumab vedotin with or without pembrolizumab have utility in the perioperative setting prior to the development of metastatic or locally advanced disease?

[This regimen is] being studied right now in the perioperative setting, and we will await those data. There have been some early data already released about enfortumab vedotin as a single agent in the preoperative space, and there’s been data on immunotherapy in the preoperative space. The combination is showing tremendous efficacy in the metastatic setting. We wonder if that will also bear fruit in the perioperative space, but [that remains] to be seen. If we do see positive data there, the question will become, “What are we going to do in the first line [for] metastatic disease if a patient should progress after getting enfortumab vedotin plus pembrolizumab the perioperative setting?” That’s when we will [have to ask,] “How long has it been since they received these agents, and what is the advantage of switching [therapy] if the patient recurs?” Those will be the types of questions [we ask], which are great questions to have, because we now have many active agents.

What ongoing research in early-stage bladder cancer is generating excitement?

We’re seeing an explosion of agents that are being approved or are likely to be approved in the near future in NMIBC. If we start to see more activity there, it’s hopefully going to prevent patients from having MIBC and therefore [developing] metastatic disease. We get this possible survival benefit by capturing patients even before they [develop] metastatic [disease]. There’s a lot of excitement there. There are exciting data coming out for some of these new intravesical therapies showing high response rates and durability. If that [continues to prove] true, then we have a chance to [improve] disease [outcomes], as the chance for cure is before the patient [presents with] metastatic [disease] in most cases.

As the development of ADCs for patients in later lines continues, what questions must be answered to successfully grow this treatment class?

[One of] the questions on the table now is [whether] we are going to be combining ADCs or combining ADCs and then [adding] immunotherapy. The response rate we’re seeing for enfortumab vedotin plus pembrolizumab right now is approximately 70%. Can we think about regimens that push that response rate to [higher] levels that we never thought were possible? That’s on the table as being something to strive for with these combinations. The [issue] will be tolerability. When we start adding more agents, [we must ask whether] these patients are going to be able to tolerate so many agents together. [Additionally,] do we think about selecting patients based on the likelihood of expression of a given marker and what the mechanisms of resistance are? If a patient progresses on 1 ADC, is it because they’re resistant to the target, or is it the payload being resistant? Those questions will determine how we think about future ADCs.

What is your main message for colleagues regarding the impact of these advances and research on the bladder cancer realm?

It’s such an exciting time in bladder cancer treatment. For most providers, this was a disease where we had essentially 1 option for many decades: platinum-based chemotherapy. For many patients, it was carboplatin-based therapy, and we know that that [doesn’t produce very] durable [responses] for most patients. There was a tendency for providers to [have a] real pessimistic view when a patient with bladder cancer would come into their clinic, knowing that the tools we had were not very promising. This has completely changed. There is an opportunity to salvage even patients who are rapidly progressing. If a patient has a performance status that’s rapidly declining, and it’s because of cancer, agents such as enfortumab vedotin can resurrect those patients and it happens over and over again.

References

1. FDA approves enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial cancer. FDA. December 15, 2023. Accessed May 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-enfortumab-vedotin-ejfv-pembrolizumab-locally-advanced-or-metastatic-urothelial-cancer
2. FDA approves nivolumab in combination with cisplatin and gemcitabine for unresectable or metastatic urothelial carcinoma. FDA. March 6, 2024. Accessed May 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-nivolumab-combination-cisplatin-and-gemcitabine-unresectable-or-metastatic-urothelial