Clinical Trials and New Techniques Advance the Bladder Cancer Treatment Landscape

Treatment for patients with bladder cancer has seen significant advancement in the past decade in the form of targeted therapies and minimally invasive surgical techniques, along with new research showing the potential for avoiding surgery altogether with neoadjuvant therapy.

Jahan Aghalar, MD, a medical oncologist with New York Cancer and Blood Specialists and assistant clinical professor at the Mount Sinai Hospital, sat down with Targeted Oncology^TM for an interview on updates to the field of treatment during Bladder Cancer Awareness Month. In the discussion, Aghalar highlights several clinical trials that have shown the use of neoadjuvant chemotherapy but also how immunotherapy has impacted the second line of treatment for these patients.

Jahan Aghalar, MD

Medical Oncologist

New York Cancer and Blood Specialists

Assistant clinical professor

Mount Sinai Hospital

New York, New York

Treatments like avelumab [Bavencio] have shown prolonged survival for patients with advanced or metastatic urothelial carcinoma as a maintenance therapy in the expanded role for checkpoint inhibitors in this space.¹ Moreover, targets like FGFR mutations that are common among patients with bladder cancer have led physicians to pursue this pathway and the success of clinical trials has led them to even better treatments.²

What are some of the biggest changes in the bladder cancer field?

The advent of immunotherapy and the role that it plays within various settings now in bladder cancer is probably the most impactful change. Initially the usage of checkpoint inhibitors had shown progression free survival benefits [PFS], along with overall survival [OS] benefits in the second-line metastatic urothelial carcinoma setting and the locally advanced setting. That's been a sphere, which historically we didn't have many good treatment options to offer these patients. Previously, these patients were offered second-line chemotherapies and single agents that had very low response rates, [and now] with immunotherapy that changed the paradigm of this disease, extending OS and allowing a therapy that's better tolerated with an improvement in the duration of response.

Since the initial FDA approval of checkpoint inhibitors such as pembrolizumab [Keytruda] in the second line setting,³ there's been various other approvals within other settings that have benefited patients with bladder cancer specifically, those patients who were...non-candidates for platinum therapy in the first-line metastatic setting. We now have an indication for the usage of nivolumab [Opdivo] in the adjuvant setting after having a cystectomy with high-risk features.⁴

That has also improved recurrence-free survival for those patients. [For] patients who have non-muscle invasive bladder cancer who are looking to spare their bladder and avoid cystectomy, nivolumab also has a role in that setting, specifically for patients with bacillus Calmette-Guérin–refractory disease. Lastly, in patients who have metastatic bladder cancer and have already undergone 4 to 6 cycles of platinum-based chemotherapy, we now have the option of using avelumab, another checkpoint inhibitor, as a form of switch maintenance therapy, which has demonstrated a PFS and OS for these patients.

Has the standard of care for these patients shifted along with the changes in the field?

For those patients who have muscle invasive bladder cancer, are otherwise fit with a good performance status, and who would be candidates for cisplatin, the standard of care would be to offer these patients neoadjuvant cisplatin-based chemotherapy. It's always been debatable, in terms of which is the optimal neoadjuvant regimen to use [between] cisplatin plus gemcitabine vs using dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin [dd-MVAC]. Recently, there was the VESPER trial [NCT01812369] that suggested perhaps dd-MVAC does have improvements in terms of OS and pathologic complete response rates, compared with cisplatin plus gemcitabine.5 So perhaps the standard of care has changed somewhat with the VESPER trial to consider our patients receive dd-MVAC, if they are fit enough to tolerate such a regimen.

At this juncture, the current standard of care to try to push for these patients to have cisplatin based neoadjuvant chemotherapy, but ongoing trials are still looking at the role of immunotherapy or antibody-drug conjugates for these patients. However, I think it has changed for those patients who have metastatic disease, as the usage of immunotherapy is an option now for those patients who are not chemotherapy candidates in the first-line setting. [Moreover,] the usage of immunotherapy as an option for switch maintenance therapy in those patients who established stable disease after receiving chemotherapy has certainly been practice-changing data, which we learned from the Javelin-100 trial [NCT02603432].

As I alluded to before, about 8 years ago, the only thing that we had to offer patients in the second-line setting with metastatic disease was just single-agent chemotherapies, such as docetaxel or pemetrexed, and that is hardly being used any further now that we have various choices to pick from, with [treatments like] enfortumab vedotin [Padcev], sacituzumab govitecan-hziy [Trodelvy], or erdafitinib [Balversa] for those patients who have activating FGFR point mutations.

What relevant targets are there in this disease for targeted therapies?

The FGFR mutation has, for a long period of time, been recognized as a very common point mutation that patients with urothelial carcinoma harbor, in approximately 25% to 30% of patients. So, with the advent of erdafitinib being an FGFR receptor inhibitor, it's clear that knowing [FGFR has] been a common target in bladder cancer helped lead to the development of this drug.

In terms of immunotherapy, we've known for decades that urothelial carcinoma has immunogenicity to it, with the usage of BCG in those patients who have non-muscle invasive bladder cancer. So, the hope that the usage of systemic checkpoint inhibitors was very high when these drugs came out of the market and I'm sure that was a big driving force in developing the current indications that we have for usage of immunotherapy for [patients with] bladder cancer. NECTIN-4 is a protein predominantly expressed on urothelial carcinoma cells, and that is specifically targeted with enfortumab vedotin…which also played a big role in developing this drug as an antibody-drug conjugate to target NECTIN-4.⁶

What are some of the newer surgery methods for these patients making a difference in their treatment?

I have shared some patients with urologists within my geographic region who have performed the laparoscopic technique, and even the very elderly patients do quite well and have a quick turnaround time in terms of how long they need to remain in the hospital. I think patients who we feared would not be appropriate open radical cystectomy candidates can still potentially be considered for using a minimally invasive technique with using the laparoscopic approach.

Now that we are also understanding there are patients who are responding tremendously well to neoadjuvant chemotherapy, there's now some exciting research looking into seeing whether or not patients who've developed T0 disease after neoadjuvant chemotherapy can be spared from surgery and we just keep a close eye on them with active surveillance. There's some exciting data that's emerging suggesting that there is a subset of patients who can even potentially be treated with chemotherapy alone, and then carefully watched. So, we are waiting to see whether that may be an approach that we can offer to more patients in the future.

What is your advice for community oncologists treating patients with bladder cancer?

As exciting as [recent advancements have been], in terms of the improvements that we've been able to achieve over the last 10 years, is that we could still do better and we hope to push the bar higher by improving OS for these patients. Ultimately, once patients reach the metastatic state this becomes a lethal disease and we hope improve outcomes for the future of patients that reach this point.

I would always encourage community oncologists to keep in mind clinical trial options. I think there's not a 1 size fit all for every single patient approach and we should keep in mind the patients’ priorities in terms of whether bladder-sparing techniques would be a priority for a patient is something that we need to consider and offer it to patients who may be appropriate candidates. For patients who have various comorbidities also, we need to keep that in mind when we are choosing systemic therapy treatment options to ensure those would be the treatment options that would not only be the most effective for them, but the most tolerable.

^References

^{1. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788}

^{2. FDA grants accelerated approval to enfortumab vedotin-ejfv with pembrolizumab for locally advanced or metastatic urothelial carcinoma. FDA. April 3, 2023. Accessed May 24, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/}

^{3. Xiao JF, Caliri AW, Duex JE, Theodorescu D. Targetable pathways in advanced bladder cancer: FGFR Signaling. Cancers (Basel). 2021;13(19):4891. doi:10.3390/cancers13194891}

^{4. Reynolds S. immunotherapy after surgery shows long-term benefits for high-risk bladder cancer. National Cancer Institute. March 21, 2023. Accessed May 24, 2023. https://www.cancer.gov/news-events/cancer-currents-blog/2023/bladder-cancer-nivolumab-adjuvant-therapy}

^{5. Pfister C, Gravis G, Fléchon A, et al; VESPER Trial Investigators. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine and cisplatin as perioperative chemotherapy for patients with nonmetastatic muscle-invasive bladder cancer: results of the GETUG-AFU V05 VESPER trial. J Clin Oncol. 2022;40(18):2013-2022. doi:10.1200/JCO.21.02051}

^{6. Rodler S, Eismann L, Schlenker B, et al. Expression of nectin-4 in variant histologies of bladder cancer and its prognostic value-need for biomarker testing in high-risk patients? Cancers (Basel). 2022;14(18):4411. doi:10.3390/cancers14184411}