There were monumental advances in the treatment of bladder cancer during the year 2017, with five approvals for checkpoint inhibitors in both the first and second line setting
There were monumental advances in the treatment of bladder cancer during the year 2017, with five approvals for checkpoint inhibitors in both the first and second line settings.
Elizabeth Plimack, M.D., recapped these advances during the 2017 Society of Urologic Oncology (SUO) Annual meeting.
Opdivo (nivolumab) 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 2 CheckMate-274 study, which showed on overall response rate (ORR) of 19.6 percent for Opdivo in patients with platinum-refractory metastatic disease. 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, Tecentriq (atezolizumab) 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 2 IMvigor210 trial, where the ORR with Tecentriq was 23.5 percent, including a complete response (CR) rate of 6.7 percent.
“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 Imfinzi (durvalumab). 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 1/2 Study 1108, which showed an ORR per blinded independent central review of 17 percent.
Shortly after Imfinzi, came the approval of Bavencio (avelumab) in the same setting. This approval was based on the urothelial carcinoma cohorts in the JAVELIN Solid Tumor trial. The ORR was 13.3 percent among 226 patients who had been followed for at least 13 weeks, and was 16.1 percent among 161 patients who had been followed for at least six months.
“[Checkpoint inhibitors] are here, and they are here to stay,” said Plimack.
Keytruda (pembrolizumab) 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 Keytruda was based on KEYNOTE-045, in which single-agent Keytruda reduced the risk of death by 27 percent compared to chemotherapy.4At the time of approval, median OS for patients receiving Keytruda was 10.3 months compared with 7.4 months for chemotherapy.
Updated KEYNOTE-045 results from ESMO 2017 were presented by Plimack at SUO. The median OS was 10.3 months for Keytruda and 7.4 months with chemotherapy. The one-year OS rates were 44.4 percent versus 30.3 percent, respectively. Plimack also reported that quality of life was better at all time points with Keytruda.
The frontline approval of Keytruda was based on the phase 2 KEYNOTE-052 trial, which enrolled 370 patients with locally advanced or metastatic urothelial carcinoma who were deemed not eligible for cisplatin-containing chemotherapy. At a median follow-up of 7.8 months, the ORR was 28.6 percent and the median response duration was not reached. The CR rate was 7 percent and the partial response rate was 22 percent.
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.”