Pushing Immunotherapies Toward the Frontline in Bladder Cancer

Previous studies have strongly indicated the benefits of using immunotherapies to treat bladder cancer, including a phase I study that demonstrated that patients with PD-L1 expression on their immune cells (ICs) had higher response rates to the PD-L1 inhibitor atezolizumab (Tecentriq).¹Further, the results suggested that due to the lack of renal toxicity with the agent, patients with bladder cancer, who are often older and have a higher incidence of renal impairment, may be better able to tolerate atezolizumab than chemotherapy.

In the phase I KEYNOTE-012 trial that studied pembrolizumab (Keytruda) in patients with advanced urothelial cancer, the overall response rate (ORR) was 25%, with 3 complete responses (CRs; 11%) and 4 partial responses (14%).²The study concluded that the PD-1 inhibitor demonstrated durable antitumor activity, with a higher response rate seen in patients with positive PD-L1 expression.

At the 2016 ASCO Annual Meeting, the safety and efficacy of durvalumab (MEDI4736) in patients with advanced urothelial bladder cancer were presented. The ORR was 31% (95% CI, 17.6-47.1) in the 42 evaluable patients, 46% (95% CI, 28-66) in the PD-L1—positive subgroup (≥25% in the tumor cells [TCs] or ICs) (TABLE), and 0% in the PD-L1–negative subgroup.³It was determined that durvalumab had a manageable safety profile and showed evidence of significant clinical activity in heavily pretreated PD-L1—positive patients.

The phase Ib JAVELIN Bladder 100 trial investigated the safety and efficacy of avelumab as a second-line therapy.⁴Avelumab showed clinical activity, including 1 CR, an ORR of 18.2%, and a disease control rate of 56.8%. The drug was also well tolerated with a low rate of grade 3/4 toxicities, no renal toxicity, and no treatment-related deaths.

These studies laid excellent groundwork for phase II studies, which, according to Bellmunt, lead to more promising information, and potential FDA reviews and approvals, as in the case of the phase II Check- Mate 275 study. The study investigated nivolumab (Opdivo) in previously treated patients with mUC showed that the confirmed ORR was 19.6% (95% CI 15.0—24.9) in all patients, and 16.1% (95% CI, 10.5-23.1) in patients with low to no PD-L1 expression.⁵Patients with positive PD-L1 expression on ≥5% of cells showed an ORR of 28.4% (95% CI, 18.9-39.5). These results led to a recent approval for the agent in metastatic urothelial carcinoma following progres- sion on a platinum-containing regimen (see page 7).

Atezolizumab was approved by the FDA for the treatment of patients with urothelial carcinoma based on results of a phase II trial (see page 7). The study showed durable activity and good tolerability in patients with locally advanced and metastatic urothelial carcinoma (mUC) who have progressed following a platinum-based chemotherapy regimen.⁶

Higher levels of PD-L1 expression (≥5%) on ICs were associated with an increased response, showing a 26% ORR compared with a 15% ORR overall. “In the Nature paper, it was initially a 45% ORR1; nowhere, despite the same PD-L1 staining, the response rates go down to 26%. But there is still quite consistent data in the whole patient population, including 8 months of median survival in the second- and third-line setting,” explained Bellmunt, associate professor of medicine, Harvard Medical School, and director, Bladder Cancer Center, Dana-Farber Cancer Institute/Brigham and Women’s Hospital.

Bellmunt compared treatment with atezolizumab to chemotherapy in cisplatin-ineligible patients. In the chemotherapy trial, the ORR was 36%, with a median OS of 9.3 months for patients receiving gemcitabine and carboplatin.⁷At 1 year, 37% of patients were still alive. Whereas in the IMvigor 210 trial, atezolizumab in the frontline setting demonstrated an ORR of 23% (95% CI, 16-31) and a CR rate of 9%. For the entire study population (n = 119), the median OS was 15.9 months, with 70% of responses ongoing.⁸“This is obviously beyond what we see in chemotherapy in the first-line,” Bellmunt commented, “and more data are needed in this setting.” The durability and favorable toxicity profile make atezolizumab an attractive alternative to chemotherapy.

Pembrolizumab was also assessed in the first-line setting, in the KEYNOTE-052 trial, for cisplatin-ineligible patients with advanced urothelial cancer. The ORR at a median follow-up of 8 months was 24% (95% CI, 16.0-33.6).⁹These strong results led to a priority review for the agent by the FDA in in the first-line; the agent is also being reviewed in the second-line (see page 14). Among PD-L1—positive patients, pembrolizumab showed an ORR of 36.7% (95% CI, 19.9-56.1), defined by a combined positive score of ≥10% on TCs and ICs.

References:

1. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in meta- static bladder cancer. Nature. 2014;515(7528):558-562. doi:10.1038/nature13904.
2. Plimack ER, Bellmunt J, Gupta S, et al. Pembrolizumab (MK-3475) for advanced urothelial cancer: up- dated results and biomarker analysis from KEYNOTE-012. J Clin Oncol. 2015;33(suppl; abstr 4502).
3. Massard C, Gordon MS, Sharma S, et al. Safety and e cacy of durvalumab (MEDI4736), an anti-pro- gramed cell death ligand-1 immune checkpoint inhibitor, in patients with advanced urothelial bladder can- cer. J Clin Oncol. 2016;34(26):3119-3125. doi:10.1200/JCO.2016.67.9761.
4. Apolo AB, Infante JR, Hamid O, et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with metastatic urothelial carcinoma from the JAVELIN solid tumor phase 1b trial: analysis of safety, clinical activity, and PD-L1 expression. J Clin Oncol. 2016;34(suppl; abstr 4514).
5. Galsky MD, Retz M, Siefker-Radtke AO, et al. E cacy and safety of nivolumab monotherapy in patients with metastatic urothelial cancer (mUC) who have received prior treatment: results from the phase II CheckMate 275 study. Abstract presented at: ESMO 2016 Congress; October 8, 2016; Copenhagen, Denmark. Abstract LBA31.
6. Rosenberg JE, Ho man-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicenter, phase 2 trial. Lancet. 2016;387(10031):1909-1920. doi:10.1016/S0140-6736(16)00561-4.
7. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are un t for cisplatin- based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191-199. doi:10.1200/JCO.2011.37.3571.
8. Bellmunt J, Balar A, Galsky MD, et al. IMvigor 210: updated analyses of rst-line (1L) atezolizumab (atezo) in cisplatin (cis)-ineligible locally advanced/metastatic urothelial carcinoma. Presented at: 2016 ESMO Annual Meeting; October 7-11, 2016; Copenhagen, Denmark. Abstract 782PD.
9. Balar A, Bellmunt J, O’Donnell PH, et al. Pembrolizumab (pembro) as rst-line therapy for advanced/ unresectable or metastatic urothelial cancer: Preliminary results from the phase II KEYNOTE-052 study. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA32.