Positive patient outcomes with immunotherapy in bladder cancer8 Nov 2015
An investigational immunotherapy demonstrated significant activity in two recent trials of metastatic urothelial cancer, suggesting the agent could represent the first major therapeutic advance in the field in 30 years, urologic oncologists reported.
A fourth of patients with high levels of PD-L1 expression achieved objective responses with atezolizumab (formerly MPDL3280A) in a phase 2 trial. The response rate increased with the level of PD-L1 expression, although responses were observed across all levels of expression.
"What came from this study is that PD-L1 expression seems to be a marker of efficacy in bladder cancer, as it is in lung cancer, and as it is in melanoma. PD-L1 expression quite well predicts the objective response rate with this agent in bladder cancer. If you look at overall survival, certainly it seems to be much better with PD-L1 expression in bladder cancer", commented Bernard Escudier, MD, of Gustave Roussy Institute in Villejuif, France.
Clinical details of a phase 2 study
Escudier reviewed data from a presentation at the ECC by Jonathan Rosenberg, MD, of Memorial Sloan Kettering Cancer Center in New York City. The phase 2 IMvigor 210 trial involved 316 patients enrolled by investigators in Europe, the U.S., and Canada. All of the patients had progressive disease during or after first-line cisplatin-based chemotherapy, and 40% of the patients had received two or more prior lines of therapy.
Patients received an intravenous dose of atezolizumab every 21 days, and treatment continued until loss of clinical benefit. The primary endpoint was objective response rate, as assessed by central review and by treating physician. A positive trial result was defined as an overall response rate of at least 10%, the historical response rate in metastatic urothelial cancer with existing therapy
Investigators prospectively evaluated PD-L1 expression in tumor specimens, using an investigational immunohistochemistry (IHC) assay. However, confirmed PD-L1 expression was not a requirement for entry to the trial. The data showed that 208 patients had tumors with detectable PD-L1 expression, (IHC 1/2/3) including 100 patients who had medium- and high-level expression (IHC 2/3).
No new or unexpected adverse events were observed during the study
The primary analysis, including 311 patients, showed:
- An objective response rate of 15% in all patients, irrespective of PD-L1 expression.
- The response rate increased PD-L1 expression by 18% in patients with IHC 1/2/3 tumors and 27% among patients with IHC 2/3 tumors
- Investigator-assessed response rates were 18% (all comers), 21% (IHC 1/2/3), and 26% (IHC 2/3)
- Treatment with atezolizumab led to 12 complete responses and 35 partial responses
- An additional 15 patients had unconfirmed responses
- Median duration of response had yet to be reached, but the lower level of the confidence interval was 6.0 months.
- Median progression-free survival was 2.1 months and did not vary by PD-L1 expression
- Survival data remain immature but a preliminary analysis showed a median overall survival of 7.9 months in the entire study populations, 7.6 months in the IHC 0/1 subgroup, and not yet reached in the IHC 2/3 subgroup.
No new or unexpected adverse events were observed during the study. Overall, 15% of patients had treatment-related grade 3/4 adverse events, the most common being fatigue (2%), decreased appetite, pyrexia, arthralgia, dyspnea, anemia, liver enzyme elevation (ALT), pneumonitis, hypertension, and hypotension (1% each).
A phase 3 study is already active
The IMvigor 210 trial enrolled a second cohort of patients who were ineligible for first-line cisplatin chemotherapy. Results in that cohort will be reported at a later date. A phase 3 randomized trial has already begun, comparing atezolizumab and standard-of-care chemotherapy in relapsed metastatic urothelial cancer.
Pembrolizumab (Keytruda), the only approved PD-L1 inhibitor, also is being evaluated in a phase 3 trial of advanced urothelial cancer. Results from that trial and from the phase 3 atezolizumab trial will determine whether the early enthusiasm for PD-L1 inhibition in urothelial cancer is justified, Escudier and Fay noted: “we look at these trials and see response rates around 30% with longer overall survival. Probably these drugs will be part of our arsenal to treat bladder cancer very soon."Source: MedPage Today