Predictive data from two major financial research and consulting firms, UBS and GlobalData, have supported atezolizumab [MPDL3280A] as a major player in the immunotherapy race for bladder cancer.
Thomas Powles, MD
Predictive data from two major financial research and consulting firms, UBS and GlobalData, have supported atezolizumab [MPDL3280A] as a major player in the immunotherapy race for bladder cancer, following encouraging news from the phase II IMvigor 210 trials.1,2
A July 13, 2015 statement from Roche, the agent’s developer, noted that PD-L1 status coincided with responses to atezolizumab and that adverse events (AEs) were consistent with previous experiences, although data from the open-label phase II study, were not yet made publicly available at the time of the statement.3
The drug received the first Breakthrough Therapy Designation from the US Food and Drug Administration (FDA) for a bladder cancer immunotherapy, based on phase I data4released May 31, 2014 at the ASCO Annual Meeting, which showed the agent reduced tumors in 43% of patients with previously treated metastatic urothelial bladder cancer (UBC) whose tumors were characterized as positive for the programmed death ligand-1 (PD-L1).
“Really there has been no FDA-approved therapy for these patients with relapsed disease after platinum-based therapy, which is extraordinary when we consider the frequency of this group of patients, and their life expectancy is short, at only 7 months,” said presenter Thomas Powles, MD, clinical professor of genitourinary oncology, Barts Cancer Institute at the Queen Mary University of London, at the 2014 Meeting. “It is a challenging population to treat.”
According to findings presented at the 2015 ASCO Annual Meeting,5patients with the highest level of PD-L1 expression (IC2/3) experienced the most positive outcomes for the primary endpoint, with an objective response rate (ORR) of 50%. However, in the IC3 group (n = 12), the ORR was 67% (95% CI, 35-90), with a complete response (CR) rate of 33%. In the IC2 group (n = 34), the ORR was 44% (95% CI, 27-62). The CR rate was 15%. In patients with the lowest levels of PD-L1 expression (IC0/1), the ORR was 17% (95% CI, 7-32).
Median progression-free survival (PFS) in the IC2/3 group (n = 48) was 6 months, with a 1-year rate of 39%. At a 14-month follow-up, the median overall survival (OS) in this group had not been reached, with a 1-year rate of 57%. In the IC0/1 group, the median PFS was 1 month, and the median OS was 7.6 months. The 1-year PFS and OS rates were 10% and 38%, respectively.5
“In this trial, 20% of patients made a full recovery, while 57% with the highest PD-L1 expression levels were still alive 1 year after treatment,” said Cai Xuan, PhD, GlobalData's analyst covering oncology and hematology in a press release from the company.1
Challenges With PD-L1 Companion Diagnostics
According to Xuan, PhD, this observation, along with similar results for other PD-1 inhibitors in development for various cancers, opens up a market for companion biomarker tests that can be used to identify patients who would likely benefit from PD-1/PD-L1-targeted therapies.1
Although some progress has been made using PD-L1 as a predictive biomarker, many key opinion leaders agree that PD-L1 constitutes a very challenging marker for which to develop immunohistochemical (IHC) assays, and PD-L1 may not be the best indicator for patient selection.
“All of the different companies with drugs have various assays that test different things, so it is not as if a patient who is positive [for PD-L1] will be positive using another assay,” said Jason J. Luke, MD, assistant professor of medicine at University of Chicago Medicine in a June 2015 interview withTargeted Oncology. “That is very confusing to patients, and makes it very difficult. It is also confusing as to how we are going to take this forward, because there is no assay that everyone is using,” he said.
“I think that it [PD-L1] will help to identify those patients likely to respond, but it is not an absolute test,” said Daniel P. Petrylak, MD, lead author on the phase Ia study and director of the Signal Transduction Research Program at Yale Cancer Center, during a July 29, 2015 interview withTargeted Oncology. “Since there is a 17% response rate in patients treated with atezolizumab who are PD-L1 negative by IHC, I would not deny the patient the opportunity to receive this drug based on the assay. Clearly, there are other factors involved in resistance/progression.”
Daniel P. Petrylak, MD
Watch and Wait
GlobalData expects atezolizumab to face strong competition in the bladder cancer treatment arena, especially from Bristol-Myers Squibb’s Opdivo (nivolumab) and Merck’s Keytruda (pembrolizumab), which have also been targeted toward patients with locally-advanced and/or metastatic bladder cancer, with the possibility of expanding to multiple indications within the bladder cancer setting in the future.1
“With regards to future indications, Roche currently has a broader development program for atezolizumab in bladder cancer, with the IMvigor 211 phase III trial evaluating the drug in comparison with standard-of-care chemotherapy in patients with relapsed urothelial bladder cancer,” Xuan said. “Additionally, the IMvigor 010 phase III trial will evaluate atezolizumab as an adjuvant therapy in early-stage, PD-L1-positive, muscle-invasive bladder cancer patients, who are at risk of recurrence. The potential to expand into multiple indications will make this drug an important player in a wave of long-awaited bladder cancer treatment innovation.”
Despite ongoing research, Petrylak advised caution regarding the recent research predictions. “This trial [IMvigor 010 phase III trial] will take time to accrue patients and then will need more time for follow-up. So I don’t anticipate that it will mature in the near future. In the near future, “I think that we will have to wait for the results from the IMvigor 210 trial, which has an untreated platinum ineligible arm in the trial,” he said.
The UBS Global Research report predicted the catalyst for the bladder cancer pivotal data to come in September 25 to 29 2015 at the European Cancer Congress(ESMO), and stated that this should allow data submission to US and perhaps ex-US regulatory agencies.2