Sonpavde Navigates the Evolving Bladder Cancer Landscape

Guru Sonpavde, MD

In the era of immunotherapy, particularly considering its impact on genitourinary malignancies, many experts are looking to PD-1/PD-L1 inhibitors for their patients with urothelial carcinoma. However, chemotherapy is still a big player in the advanced-disease setting, making the treatment landscape quite varied.

Chemotherapy

Guru P. Sonpavde, MD, bladder cancer director, Dana-Farber Cancer Institute, navigated through the treatment landscape of urothelial carcinoma during a presentation at the 2018 OncLive^® State of the Science Summit™ on Genitourinary Cancers.The biggest unmet need in the bladder cancer space is the treatment of cisplatin-ineligible patients, says Sonpavde. Patients with urothelial carcinoma who are ineligible to receive cisplatin have suboptimal survival with chemotherapy. Given that cisplatin plus chemotherapy improves survival in the advanced disease setting, it makes sense to give neoadjuvant chemotherapy before radical cystectomy in high-risk locally advanced or muscle-invasive bladder cancer, Sonpavde explains.

In the phase III SWOG 8710 trial, investigators gave 3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin over 12 weeks to patients with resectable muscleinvasive bladder cancer. Findings showed that the median overall survival (OS) with the combination increased to 77 months versus 46 months in the cystectomy-alone group.

“How good is adjuvant chemotherapy? Unfortunately, we do not have good adjuvant trials for bladder cancer post-radical cystectomy. These patients are frequently not in good condition to receive adjuvant chemotherapy,” said Sonpavde.

Although there are no ongoing adjuvant trials, retrospective studies and meta-analyses are supportive of adjuvant chemotherapy. For example, the POUT trial, a phase III randomized trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer, was stopped prematurely because the disease-free survival endpoint was met at the interim analysis with a hazard ratio of 0.49 (95% CI, 0.31-0.76; P = .001).¹

Some patients are not fit for radical cystectomy or refuse it. Historically, these patients have been offered radiation therapy, Sonpavde explained. Radiation plus cisplatin has been offered to well-selected patients, usually without hydronephrosis. Survival up to 5 years has been observed for those without hydronephrosis.

Current chemoradiation for patients with locally advanced bladder cancer is 5-fluorouracil plus mitomycin-C, but not many data exist on recurrence after chemoradiation, Sonpavde said.

In the post-platinum setting, taxanes have been used to treat patients with urothelial carcinoma in the United States, and vinflunine is often used outside of the United States. The median OS with vinflunine is suboptimal at 6.9 months,² and the median survival of a patient taking a taxane is similar in the range of 7 to 9 months, Sonpavde said.

Some special second-line therapy situations that do not often get discussed include recurrence after 1 year after perioperative platinum therapy. Ordinarily, if patients are more than 1 year out from perioperative neoadjuvant or adjuvant platinum therapy, platinum is repeated.

“Some retrospective data do suggest that if you repeat platinum- based therapy in patients who are more than 1 year out from preoperative cisplatin chemotherapy, you might get similar outcomes compared with patients who got first-line chemotherapy with cisplatin who had not had previous preoperative cisplatin,” said Sonpavde.

Immunotherapy

Patients less than 1 year out of preoperative platinum therapy receive a different second-line therapy.“This is the era of immunotherapy,” said Sonpavde. “There is a lot of ‘push and pull’ in the immune system, and there are pathways that are inhibiting the immune system” from working in patients with bladder cancer.

Urothelial carcinoma has a high somatic mutation burden; it has the fourth highest of all cancers behind melanoma, squamous cell carcinoma of the lung, and lung adenocarcinoma, Sonpavde noted. Therefore, it is rational to expect immunotherapy to work well in this setting. Second-line therapy has been revolutionized by the approvals of 5 PD-1/PD-L1 inhibitors, he added.

In muscle-invasive bladder cancer, an increased infiltration of CD8-positive T cells can signify a good prognosis. In nonmuscle- invasive bladder cancer, PD-L1 expression is associated with poor outcomes when patients receive Bacillus Calmette-Guérin (BCG). PD-L1 also correlated with stage and grade—meaning that the higher the stage, the higher the expression.

Moreover, Sonpavde highlighted data from the phase III KEYNOTE-045 study, updated findings of which were presented at the 2018 Genitourinary Cancers Symposium.³ In the initial publication, there was an improvement in OS from 7.4 months with chemotherapy to 10.3 months with pembrolizumab (Keytruda), while progression-free survival did not improve. The hazard ratio improved from 0.73 to 0.70, which Sonpavde said is “a good sign.” Although PD-L1 is used as a predictor of response to immunotherapy, it is not the only marker for response to pembrolizumab.

“All subgroups seemed to benefit from pembrolizumab, regardless of PD-L1 expression,” said Sonpavde. “There is a dogma out there that immunotherapy yields very delayed responses, but that was not the case. The median time to response was the same with chemotherapy and pembrolizumab, at about 2.1 months.”

The duration of response with pembrolizumab was most impressive, added Sonpavde. While pembrolizumab is not the only approved PD-1 inhibitor in the post-platinum setting, it is the only one that has shown improvement in OS in the phase III setting.

Currently, durvalumab (Imfinzi), nivolumab (Opdivo)—both of which are approved in the second-line setting, in addition to avelumab (Bavencio)—and the combination of nivolumab and ipilimumab (Yervoy) are all being investigated in phase III trials for the first-line setting of advanced urothelial carcinoma.

“Given the availability of first-line pembrolizumab and atezolizumab for cisplatin-ineligible patients, the selection of patients for PD-1/PD-L1 inhibitors versus carboplatin-based combination chemotherapy and optimal sequencing requires investigation,” Sonpavde concluded.

Looking ahead, a plethora of new agents are emerging in the pipeline, such as enfortumab vedotin, FGFR3 inhibitors, neoantigen peptide vaccines, pan-HER inhibitors, and mTOR inhibitors.

References

1. Birtle AJ, Chester JD, Jones RJ, et al. Results of POUT: a phase III randomised trial of perioperative chemotherapy versus surveillance in upper tract urothelial cancer (UTUC). In: Proceedings from the 2018 Genitourinary Cancers Symposium; February 8-10, 2018; San Francisco, California. Abstract 407. meetinglibrary.asco.org/record/157669/abstract.
2. Gerullis H, Wawroschek F, Köhne CH, et al. Vinflunine in the treatment of advanced urothelial cancer: clinical evidence and experience. Ther Adv Urol. 2017;9(1):28-35. doi: doi: 10.1177/1756287216677903.
3. Bellmunt J, De Wit R, Vaughn DJ, et al. Two-year follow-up from the phase 3 KEYNOTE-045 trial of pembrolizumab (pembro) vs investigator’s choice (paclitaxel, docetaxel, or vinflunine) in recurrent, advanced urothelial cancer (UC). J Clin Oncol. 2018;36 (suppl 6S; abstr 410). doi: 10.1200/JCO.2018.36.6_suppl.410.