Daniel P. Petrylak, MD
PD-1/PD-L1 agents have shown significant potential for the treatment of urothelial bladder cancer, Daniel Petrylak, MD, from Yale Cancer Center, noted in a recent interview with OncLive.
“Immunotherapies are showing positive response rates and improving survival compared to the standard of care. PD-1 and PD-L1 agents seem to have the greatest activity [among immunotherapy agents] in bladder cancer,” says Petrylak, who serves as a professor of Medicine and of Urology, co-director, Signal Transduction Research Program at Yale. “Additionally, the toxicities of these agents are not as severe as chemotherapy.”
Both atezolizumab (MPDL3280A) and pembrolizumab (Keytruda) have shown promising results in recent clinical trials, he adds.
Petrylak was an investigator on the phase II IMvigor 210 study, which examined atezolizumab in 311 heavily pretreated metastatic patients with urothelial bladder cancer who have poor prognostic factors. All of the patients had progressed during or following platinum-based chemotherapy.
Median treatment duration was 12 weeks (range, 0-46 weeks). When results were evaluated according to the degree of PD-L1 expression on immune cells in all patients, significant overall response rate (ORR) improvements across all groups were seen that increased with higher PD-L1 expression. ORR by RECIST 1.1 was 15% (P
= .0058) in all patients, 18% (P
= .0004) in patients with any PD-L1 expression, and 27% (P
= .0001) in the subgroup with PD-L1 expression >5%. Progression-free survival (PFS) after a median follow-up of 24 weeks was 2.1 months across all groups.1
Promising results from a phase I trial of atezolizumab led to a breakthrough designation from the FDA in 2014. In this trial, PD-L1 expression in immune cells evaluated by immunohistochemistry (IHC) also correlated with response, PFS, and median survival in patients treated with atezolizumab.
“About one-third of patients express high levels of PD-ligand in their immune cells,” says Petrylak. “Overall, approximately half of those patients responded to these drugs. Survival was at least 14 months in these patients in the phase I trial.”
The anti–PD-1 antibody pembrolizumab is also being investigated in bladder cancer.
In a phase Ib multicohort study of pembrolizumab in patients with PD-L1–positive advanced urothelial bladder cancer, the drug demonstrated a 24.1% ORR, a complete response of 10.3%, and a partial response of 13.8%. Median OS was 9.3 months and 58% of patients were alive after 6 months.2
Despite these successes, many challenges still remain regarding the use of PD-1/PD-L1 agents.
Toxicities with immunotherapies, while less severe than with chemotherapy, still require significant management. This is something oncologists are still learning, says Petrylak.
“Education will be needed for oncologists to understand toxicities that are particular to immunotherapies, including diarrhea, lung-based issues, and skin disorders,” he added.
Toxicity management will become even more of a challenge when combinations incorporating PD-1/PD-L1 agents begin to be utilized, he said. Currently, there are studies investigating combination immunotherapies with chemotherapies, immunotherapies with angiogenic therapies, and other agents within the bladder cancer space.
“The performance status of each patient must be considered before treatment, because sometimes the toxicities with combinations are unpredictable,” said Petrylak.
The PD-L1 test in itself also presents challenges. Because there is no standardization, PD-L1 tests sold by different companies produce different results.
“The PDL1/PD1 diagnositic tests are imperfect, as some patients who are PDL1 negative respond to treatment,” said Petrylak. “That is one of the biggest issues.”
A greater understanding of the relationship between PD-1/PD-L1 and response to PD-1 inhibitors is also needed. Patients who test negative for PD-L1 have, in some cases, responded positively to PD-1/PD-L1 inhibitors, says Petrylak. Potential for response may also expand outside of PD-1/PD-L1 agents to other immunotherapies or targeted therapies.
“We need to understand who responds, who doesn’t respond, and how to design rational trials for the treatment of this disease,” said Petrylak. “There are a lot of different targets being pursued. There are a whole bunch of different studies that are trying to increase the overall survival.”
Rosenberg J, Petrylak D, Abidoye O, et al. Atezolizumab in patients (pts) with locally-advanced or metastatic urothelial carcinoma (mUC): results from a pivotal multicenter phase II study (IMvigor 210). Presented at: 2015 European Cancer Congress; September 25-29; Vienna, Austria. Abstract 21LBA.
Plimack ER, Gupta S, Bellmunt J, et al. A phase Ib study of pembrolizumab in patients with advanced urothelial tract cancer. Presented at: ESMO 2014 Congress; September 26-30, 2014; Madrid, Spain. LBA23A.