Pembrolizumab, Atezolizumab New Standards for Bladder Cancer

Andrea Necchi, MD

A wealth of new clinical trial data for immune checkpoint inhibitors has recently been reported for the treatment of patients with metastatic muscle-invasive urothelial carcinoma, with the PD-1 inhibitor pembrolizumab (Keytruda) and the PD-L1 inhibitor atezolizumab (Tecentriq) leading the pack of promising agents.

In May 2016, the immune checkpoint inhibitors gained initial approvals for patients with urothelial carcinoma in the second-line setting following treatment with a platinum-based chemotherapy, setting the stage for a wave of new therapies. For select patients, these agents have now become the standard of care, with ongoing studies exploring combination approaches, and phase III results now available showing improvements in overall survival (OS).

In the first-line setting, the utility of these agents is currently less clear, as phase II findings led to EMA and FDA approvals for both pembrolizumab and atezolizumab for cisplatin-ineligible patients with metastatic urothelial carcinoma. In this setting, in the absence of phase III results, cisplatin-eligible patients should continue to receive chemotherapy and a clinical trial should be considered before administering immunotherapy, said Andrea Necchi, MD, during a presentation at the 2017 European Multidisciplinary Meeting on Urological Cancers (EMUC).

"Atezolizumab and pembrolizumab are well-tolerated with durable responses seen in the urothelial carcinoma patients who are not eligible for chemotherapy," Necchi, a medical oncologist at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, said during his presentation at the EMUC meeting. "The results are supporting the use of immunotherapy, the patients respond very long term, allowing them to avoid chemotherapy for the long-term. This is one of the most important results of the last decade."

Frontline Patient Populations Differ

Frontline approvals for pembrolizumab and atezolizumab were based on findings from the phase II KEYNOTE-052 and IMvigor210 studies. The KEYNOTE-052 study treated 370 patients at a median age of 74 years with pembrolizumab, and in the frontline cohort of the IMvigor210 trial, 119 patients at a median age of 73 years received atezolizumab.

"There were differences between the populations in the studies, which may have impacted the overall results," Necchi said. "These factors included the proportion of patients with upper tract tumors, visceral metastases, and those with an ECOG performance status of 2."

Overall, there were more patients with high-risk characteristics in the pembrolizumab trial. In the KEYNOTE-052 and IMvigor210 trials, respectively, the rates of those with ECOG performance status 2 were 42% versus 20% and 85% compared with 66% had visceral disease. The primary tumor location was in the renal pelvis or upper urinary tract for 19% and 28% of patients, respectively.

In the KEYNOTE-052 trial,¹ the objective response rate (ORR) was 24%, which included a complete response (CR) rate of 5%. When including stable disease, the disease control rate was 47%. The median duration of response was not yet reached and the 6-month OS rate was 67%. Median OS has not yet been reached.

In the IMvigor210 trial,² the ORR was 23%, with a CR rate of 9%. The disease control rate was 47%. The median OS was 15.9 months. "The immunotherapy option can be included in the recommendation for cisplatin ineligible fit patients in the first line, based on the results of these studies," Necchi said.

There are several phase III studies currently exploring immunotherapy in the first-line setting for those with metastatic bladder cancer. The KEYNOTE-361 (NCT02853305) and the IMvigor130 (NCT02807636) studies are exploring pembrolizumab and atezolizumab with or without chemotherapy compared with chemotherapy alone. Additionally, the DANUBE trial is exploring the PD-L1 inhibitor durvalumab (Imfinzi) with the CTLA-4 inhibitor tremelimumab (NCT02516241) and the CheckMate 901 trial is looking at the anti—PD-1 agent nivolumab (Opdivo) with the CLTA-4 inhibitor ipilimumab (Yervoy) (NCT03036098).

Clinical trials are also starting to explore these agents in patients with non-muscle invasive bladder cancers (NMIBC), Necchi noted. The single-arm phase II KEYNOTE-057 study is enrolling participants with high-risk NMIBC who are unresponsive to bacillus Calmette-Guérin (BCG) therapy (NCT02625961). Additionally, studies are ongoing to assess neoadjuvant treatment with pembrolizumab prior to cystectomy for patients with muscle-invasive bladder cancer (NCT02736266).

Second-Line Data Mixed

In the second-line setting, the first agent to gain approval was atezolizumab, based on cohort 2 of the phase II IMvigor210 trial.³ In this study, 310 platinum-pretreated patients received atezolizumab, with an ORR of 15%, which included a CR rate of 5%. The median OS was 7.9 months.

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."

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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).
8. 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].