Despite these promising early results, phase III findings were less clear. The phase III IMvigor211 study comparing atezolizumab with chemotherapy failed to show an improvement in OS for those with high PD-L1 expression.4
In this group, the median OS was 11.1 versus 10.6 months for chemotherapy (HR, 0.87; 95% CI, 0.63-1.21).
In the overall study population of the IMvigor211 study there was a small improvement in OS with atezolizumab versus chemotherapy (8.6 vs 8.0 months; HR, 0.85; 95% CI, 0.73-0.99). More strikingly, however, was a significant prolongation in the median duration of response with the PD-L1 inhibitor versus chemotherapy (21.7 vs 7.4 months)
In the phase III KEYNOTE-045,5
there was a clear improvement in OS with pembrolizumab compared with chemotherapy for pretreated patients with urothelial carcinoma. Across all participants in the study, the median OS with pembrolizumab was 10.3 versus 7.4 months for chemotherapy (HR, 0.73; 95% CI, 0.59-0.91; P
= .002). For those with PD-L1–positive disease, the median OS was 8.0 versus 5.2 months, for pembrolizumab and chemotherapy, respectively (HR, 0.57; 95% CI, 0.37-0.88; P
= .005). The median duration of response was not yet reached.
"Pembrolizumab is the only drug that has so far shown level 1 evidence," said Necchi. "We have conflicting results coming from very similar studies, regarding subpopulations of patients based on PD-L1 expression. One takeaway from these results is that the duration of response for the responders are quite similar between the 2 studies."
Given the inconsistent findings with PD-L1, the search for a better biomarker has been under way for immunotherapy since it was initially introduced. The FGFR
alteration has shown promise in studies, Necchi noted, as the mutation is associated with non-T-cell inflamed bladder tumors. If these findings are validated, they could help inform future treatment sequences, Necchi suggested.Novel Agents, Combinations Explored
Several other immunotherapy agents have also gained FDA approval for the second-line treatment of patients with urothelial carcinoma, Necchi noted. These agents include nivolumab, durvalumab, and avelumab, which have all shown similar results to those demonstrated by pembrolizumab and atezolizumab. There are phase III studies currently exploring each of these agents.
Additionally, he noted, there are other combination approaches under exploration, although these results are still very early. In findings presented at the 2017 ESMO Annual Meeting,6
the combination of cabozantinib and nivolumab with or without ipilimumab showed activity across genitourinary tumors, particularly urothelial carcinoma. The ORR across all tumors and treatment combinations was 33%.
"These response rates are quite high, but I say, let's wait for the phase III studies, where the combination of ipilimumab and nivolumab is being looked at in the frontline," said Necchi.
The addition of the IDO inhibitor epacadostat to pembrolizumab represents another promising combination strategy on the horizon for patients with urothelial carcinoma. In a phase I/II study presented at the ASCO Annual Meeting,7
the ORR with the combination was 35%, which consisted of a CR rate of 8%. The disease control rate was 53%.
"Pembrolizumab and epacadostat is also being investigated in the first-line setting," said Necchi. "It is interesting to note that epacadostat has no activity in bladder cancer as a single-agent but the combination with the immune checkpoint inhibitor is quite promising, and is being tested in a phase III."Response Kinetics Need Further Study
Outside of discovering new agents and combinaitons, there is potential to continue treatment with the immunotherapies beyond progression, perhaps due to a high rate of pseudoprogression, wherein the tumor grows before shrinking. Although, this phenomenom is rare, Necchi noted.
In findings from the IMvigor210 study,8
responses were seen in 5 patients who continued treatment with atezolizumab beyond progression (3.6%). The median OS in the post-progression setting was 8.6 months for those continuing immunotherapy versus 6.8 months for those switching to another treatment. In those who received no further treatment, the median OS was 1.2 months.
"These patients had lymphodominant disease and good performance status since the beginning," said Necchi. "The optimal duration of treatment and the optimal interruption of treatment is still far to be understood. This is still a point that needs to be further discussed."
Hyperprogression is another concern that is not yet understood, Necchi noted, while adding that he has very rarely seen this problem. In this scenario, treatment with the immunotherapy causes the tumor to grow rapidly. "There is a need to understand this process and to achieve a selection of the population not to give immune checkpoint inhibitors."
- Balar AV, Castellano D, O'Donnell PH, et al. First-line pembrolizumab in cisplatin-ineligible patients with locally advanced and unresectable or metastatic urothelial cancer (KEYNOTE-052): a multicentre, single-arm, phase 2 study. Lancet Oncol. 2017;18(11):1483-1492.
- Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet. 2017;389(10064):67-76.
- Rosenberg JE, Hoffman-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, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.
- Powles T, Loriot Y, Duran I, et al. IMvigor 211: a phase III randomized study examining atezolizumab vs. chemotherapy for platinum-treated advanced urothelial cancer. Abstract presented at: EACR-AACR-SIC Special Conference 2017; June 24-27, 2017; Florence, Italy. Abstract 606.
- Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;376(11):1015-1026. doi: 10.1056/NEJMoa1613683.
- Nadal R, Mortazavi A, Stein M, et al. Final results of a phase I study of cabozantinib (cabo) plus nivolumab (nivo) and cabonivo plus ipilimumab (Ipi) in patients (pts) with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. Abstract presented at: 2017 ESMO Congress; September 8-12, 2017; Madrid, Spain. Abstract 846O.
- Smith DC, Gajewski T, Hamid O, et al. Epacadostat plus pembrolizumab in patients with advanced urothelial carcinoma: Preliminary phase I/II results of ECHO-202/KEYNOTE-037. J Clin Oncol. 2017;35 (suppl; abstr 4503).
- Necchi A, Joseph RW, Loriot Y, et al. Atezolizumab in platinum-treated locally advanced or metastatic urothelial carcinoma: post-progression outcomes from the phase II IMvigor210 study. Ann Oncol. 2017. doi: 10.1093/annonc/mdx518 [Epub ahead of print].