Plimack Recaps 2017 Immunotherapy Approvals in Bladder Cancer

Angelica Welch
Published: Thursday, Nov 30, 2017

Elizabeth Plimack, MD
Elizabeth Plimack, MD
It has been a landmark year for immunotherapy in bladder cancer with the approval of 5 checkpoint inhibitors across first and second line. These approvals were recapped during a presentation by Elizabeth Plimack, MD, at the 2017 SUO Annual Meeting.1

Nivolumab (Opdivo) was approved in February for the second-line treatment of patients with locally advanced unresectable or metastatic urothelial carcinoma following progression on a platinum-containing therapy. This approval was based on findings from the phase II CheckMate-274 study, which showed on overall response rate (ORR) of 19.6% for nivolumab in patients with platinum-refractory metastatic disease.2 The median progression-free survival (PFS) was 2.0 months, and median overall survival (OS) was 8.74 months.

Following an earlier approval in 2016 for second-line use, atezolizumab (Tecentriq) was approved as a frontline treatment in April 2017 for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma. This approval was based on data from the single-arm phase II IMvigor210 trial, where the ORR with atezolizumab was 23.5% (95% CI, 16.2-32.2), including a complete response (CR) rate of 6.7%.3

“Higher mutation load is associated with improved response and survival in patients with atezolizumab,” said Plimack, noting that this relationship was statistically independent of other predictors of response.

May brought about an explosion of FDA approvals in bladder cancer, beginning with durvalumab (Imfinzi). An accelerated approval was granted to the PD-L1 inhibitor for the treatment of locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This approval was based on the phase I/II Study 1108, which showed an ORR per blinded independent central review of 17.0% (95% CI, 11.9-23.3).

Shortly after durvalumab, came the approval of avelumab (Bavencio) in the same setting. This approval was based on the urothelial carcinoma cohorts in the JAVELIN Solid Tumor trial. The ORR was 13.3% (95% CI, 9.1-18.4) among 226 patients who had been followed for at least 13 weeks, and was 16.1% (95% CI, 10.8-22.8) among 161 patients who had been followed for at least 6 months.

“[Checkpoint inhibitors] are here, and they are here to stay,” said Plimack.

Pembrolizumab (Keytruda) rounded out the May approvals with designation both in the frontline for those who are cisplatin ineligible, and in the second-line setting.

The second-line approval of pembrolizumab was based on KEYNOTE-045, in which single-agent pembrolizumab reduced the risk of death by 27% compared to chemotherapy.4 At the time of approval, median OS for patients receiving pembrolizumab was 10.3 months (95% CI, 8.0-11.8) compared with 7.4 months (95% CI, 6.1-8.3 months) for chemotherapy.

Updated KEYNOTE-045 results from ESMO 2017 were presented by Plimack at SUO. The hazard ratio for OS was 0.70 (95% CI, 0.57-0.86; P = .0003). The median OS was 10.3 months (95% CI; 8.0-12.3) for pembrolizumab and 7.4 months (95% CI; 6.3-8.3) with chemotherapy. The 1-year OS rates were 44.4% versus 30.3%, respectively. Plimack also reported that quality of life was better at all time points with pembrolizumab.

The frontline approval of pembrolizumab was based on the phase II KEYNOTE-052 trial, which enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy.5 At a median follow-up of 7.8 months, the ORR was 28.6% (95% CI, 24-34) and the median response duration was not reached (range, 1.4-17.8 months). The CR rate was 7% and the partial response rate was 22%.

Despite the excitement that these approvals have brought to the field, work still needs to be done to better select patients for treatment. It is still unclear which subset responds best to PD-1/PD-L1 inhibition, said Plimack.

“Even using [the] tested and validated biomarker [PD-L1] doesn’t really help make a decision about who to recommend pembrolizumab to,” said Plimack.

Other remaining questions revolve around duration of response, delayed toxicities to checkpoint blockade, and overcoming resistance.

Plimack also cautions that these data cannot be extrapolated to patients who are eligible for cisplatin, as cisplatin is the best option for that population. “Randomized trials in the cisplatin-eligible population are needed before PD-1 [checkpoint inhibitors] replace cisplatin as first-line standard of care.”


  1. Plimack E. Bladder Cancer: Currently Approved Immunotherapy. Lecture presented at the 18th Annual Meeting of the Society of Urologic Oncology. November 29, 2017.
  2. Galsky MD, Retz M, Siefker-Radtke AO, et al. Efficacy 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. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA31.
  3. 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.
  4. Bellmunt J, de Wit R, Vaughn DJ, et al. Keynote-045: open-label, phase III study of pembrolizumab versus investigator’s choice of paclitaxel, docetaxel, or vinflunine for previously treated advanced urothelial cancer. Presented at: 2016 SITC Annual Meeting; November 9-13, 2016; National Harbor, MD. Abstract 470.
  5. Balar A, Bellmunt J, O’Donnell PH, et al. Pembrolizumab (pembro) as first-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.

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