The recent 2016 American Society of Clinical Oncology (ASCO) Conference, held in June, was the scene of tangible excitement after Roche’s approval of its PD-1 immune checkpoint inhibitor Tecentriq (atezolizumab) in advanced bladder cancer. In an area that has been at a standstill for the last 20 years, Tecentriq has garnered a high level of interest within the industry in recent times. For that reason, the approval is significant as experts say the drugcould herald in a new treatment paradigm of metastatic bladder cancer. Additionally, fast on the heels of its approval as a second-line therapy, following failure on platinum-based chemotherapy, there is already excitement of a potential expansion into the first-line setting.
Abstract 4500 presented the eagerly awaited results of Cohort 1 in Tecentriq’s Phase II, single-arm IMvigor 210 trial, consisting of treatment-naïve locally advanced/metastatic bladder cancer patients who were cisplatin-ineligible. In this cohort, 119 patients were treated with Tecentriq once every three weeks until disease progression. The primary endpoint was confirmed overall response rate (ORR), and the secondary endpoints were duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. The ORR reported for this trial was 24% in all patients (28% in patients with high PD-L1 levels on tumor-infiltrating immune cells [ICs]), with 7% being complete responses (CR) at a median follow-up of 14.4 months. 75% of responses were ongoing at the time these data were presented. Median overall survival (mOS) was reported to be 14.8 months.
The durable CRs seen with Tecentriq treatment are extremely significant in advanced stage bladder cancer, as the disease is currently almost uniformly fatal. Durable responses are rarely observed in this setting, even with cisplatin-based chemotherapy. For cisplatin-ineligible patients, carboplatin-gemcitabine (Gem Carbo) is the most commonly used frontline therapy. In a previous study of advanced stage patients given Gem Carbo treatment (EORTC Study 30986), the ORR was 36%, with a mOS of 9.3 months. Though results from different trials should be compared with caution, it appears that despite a slightly lower ORR for Tecentriq in the IMvigor 210 trial, the patients who do respond to the drug are gaining significant overall survival benefit compared to existing treatment options.
Further evidence supporting this observation is in the 1-year OS rate, which was 37% for Gem Carbo in the EORTC study versus 57% for Tecentriq in the IMvigor 210 trial. What remains to be seen is how durable the long-term responses seen with Tecentriq treatment are. In the Gem Carbo study, the 5-year OS rate was effectively 0%. Thus, if the durable CRs seen with Tecentriq so far hold up, label expansion of the drug into the first-line setting is almost certain. In addition, Tecentriq’s superior tolerability profile compared with chemotherapy works heavily in its favor, given the poor performance status of the average metastatic bladder cancer patient. In the treatment-naïve cohort of IMvigor 210, Tecentriq was well-tolerated, with a 6% treatment discontinuation rate and no treatment-related deaths reported. Most treatment-related AEs were grades 1-2, and no decline in renal function was observed in patients who had a pre-existing renal impairment. Importantly, 34% of patients did not report treatment-related AEs. This is in stark contrast to chemotherapy-treated patients, who commonly experience grade 3-4 AEs in this setting.
Given the advanced age of most bladder cancer patients at diagnosis, it is estimated that up to 40% cannot receive cisplatin-based therapy due to renal impairment or other co-morbidities. If Roche can win a label expansion for Tecentriq in the first-line setting, it can further solidify its expected dominance in the bladder cancer market as this would mean a larger target patient pool and potentially longer duration of therapy as compared with its current approval in the second line. This will depend on results from a larger randomized trial with the appropriate carboplatin-based chemotherapy comparator arm, and continued follow-up data from the patients who have confirmed CR in the current IMvigor 210 study.