Targeted Oncology
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The Rapid Uptake of Immunotherapy in Bladder Cancer

Lisa Miller
Published Online: Jun 16,2017

Immunotherapy agents have been rapidly absorbed into the treatment paradigm for various cancer types. Nowhere is this more obvious than in the treatment for patients with bladder cancer. In May alone, 3 checkpoint inhibitors were approved for use in bladder cancer, bringing the total of checkpoint inhibitors approved in this field to 5 agents.


Following such a surge in such a short time, it can be difficult to keep track of the new drugs, what sets them apart, and where we stand in treating patients with bladder cancer with immunotherapy.

HISTORY OF IMMUNOTHERAPY IN BLADDER CANCER


Prior to 2016, Bacillus Calmette-Guérin (BCG) was the only immunotherapy agent to show activity in patients with urothelial carcinoma, the most common type of bladder cancer. Originally created as a tuberculosis vaccine in the 1920s,1 BCG is a unique strain of mycobacterium bovis that activates the immune system and induces an in ammatory response. The drug was FDA-approved for use in bladder cancer in 1990, and it was the first signal that urothelial carcinoma is an immune-responsive tumor.2 BCG remains a standard of care in patients with high-risk non–muscle invasive bladder cancer.1,3


Following BCG, studies investigated the use of interferons as a potential therapy for patients with bladder cancer, particularly those with non–muscle invasive disease.1 Yet, they were unable to provide a benefit in these patients.


“Bladder cancer has, in fact, been one of the first diseases for which immunotherapy was active, and we need to go back [more than] 15 years ago [to] when BCG was shown to be effective,” Joaquim Bellmunt, MD, PhD, said in a presentation on immunotherapy options in bladder cancer. “Since then, nothing has happened—until quite recently when the checkpoint inhibitors came.”


BEGINNING OF THE CHECKPOINTS IN BLADDER CANCER


Atezolizumab (Tecentriq) was the first checkpoint inhibitor to be approved for use in bladder cancer (F I G U R E ). The PD-L1 inhibitor was approved by the FDA on May 18, 2016, for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) whose disease has progressed during or after platinum-based chemotherapy or within 12 months of having received platinum-containing chemotherapy, either before or after surgery. The accelerated approval was based on data from the phase II IMvigor 210 study, which investigated atezolizumab in patients with locally advanced or mUC. It had previously received a breakthrough therapy designation for patients with PD-L1–positive metastatic bladder cancer in March 2016.

In the IMvigor 210 study, atezolizumab demonstrated an overall response rate (ORR) of 14.8% (95% CI, 11.1%-19.3%) among 310 patients.4 By PD-L1 expression, atezolizumab showed an ORR of 26% (95% CI, 17.7%-35.7%) in patients with expression ≥5% on tumor-in ltrating immune cells and 9.5% (95% CI, 5.9%- 14.3%) in patients with expression below 5% (n = 210). The median duration of response (DOR) was not reached.


Ten patients discontinued treatment due to adverse events (AEs) and 3 patients died due to sepsis, pneumonitis, or intestinal obstruction. Grade 3/4 AEs included urinary tract infection (9%), anemia (8%), fatigue (6%), dyspnea (4%), and hematuria (3%).


Although the drug was approved regardless of PD-L1 expression, the PD-L1 assay Ventana PD-L1 (SP142) was approved at the same time as a complementary diagnostic.


On February 2, 2017, nivolumab (Opdivo) was granted an accelerated approval in the second line as well. The treatment was approved for use in patients with locally advanced unresectable or mUC following progression on a platinum-containing regimen based on ndings from the phase II CheckMate-275 trial; the PD-1 inhibitor had received a breakthrough therapy designation for this indication in June 2016. Nivolumab was also approved for patients who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.5


The ORR in the CheckMate-275 trial was 19.6% of 270 patients with platinum-refractory metastatic urothelial carcinoma with complete responses (CRs) in 3%.6 The median progression-free survival (PFS) was 2.0 months, and the median overall survival (OS) was 8.7 months. The median DOR was not reached in this trial either.


Among patients with PD-L1 expression on ≥1% of cells, the median PFS was 3.55 months and the OS was 11.3 months compared with 1.87 months and 5.95 months in those with no PD-L1 expression, respectively.


The most common AEs during the trial were fatigue (16.7%), pruritus (9.3%), diarrhea (8.9%), decreased appetite (8.1%), hypothyroidism (7.8%), nausea (7.0%), asthenia (5.9%), rash (5.9%), and pyrexia (5.6%). Treatment-related AEs were experienced by 64.4% of patients; 17.8% were grade 3/4. Quality of life was also improved from baseline, according to Global Health Status Scale measurements.


The FDA recommended a at dose of 240-mg nivolumab intra- venously in urothelial carcinoma every 2 weeks.5


Atezolizumab was granted an additional indication by the FDA on April 17, 2017, for the frontline treatment of cisplatin-ineligible patients with locally advanced or mUC based on a cohort of cisplatin-ineligible, treatment-naïve patients from the same IMvigor 210 trial. This was the rst checkpoint inhibitor to be granted an approval in the rst-line setting in bladder cancer.


The ORR was 23.5% (95% CI, 16.2%-32.2%) from the 119 eligible patients in the cohort, with a CR rate of 6.7%.7 The median PFS was 2.7 months (95% CI, 2.1-4.2), and the median OS was 15.9 months (95% CI, 10.4 to not estimable).


Patients with PD-L1 expression ≥5% (n = 32) had an ORR of 28.1% (95% CI, 13.8%-46.8%), with a CR rate of 6.3%. In those with PD-L1 expression below 5%, the ORR was 21.8% (95% CI, 13.7%-32.0%) and the CR rate was 6.9%. Additionally, an association between tumor mutation load and response was noted.


In this cohort, 5 patients discontinued atezolizumab therapy and 5 patients died, due to sepsis, cardiac arrest, myocardial infarction, respiratory failure, and respiratory distress. An additional patient had in ammation of the brain due to the herpes simplex virus and disease progression. Similar common grade 3/4 AEs were experienced in this cohort, including fatigue (8%), urinary tract infection (5%), anemia (7%). Additional grade 3/4 AEs included diarrhea (5%), increase in the level of creatinine in the blood (5%), increase of the liver enzyme alanine transaminase (4%), hyponatre- mia (15%), decreased appetite (3%), and back/neck pain (3%).


Both approvals for atezolizumab were contingent upon results from the phase III con rmatory study, IMvigor 211.






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The Rapid Uptake of Immunotherapy in Bladder Cancer
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