By: Stephanie Hawthorne, Ph.D., Senior Director, Clinical & Scientific Assessment, Kantar Health and Tari Awipi, Ph.D., Associate Consultant, Clinical & Scientific Assessment, Kantar Health
Approximately 70% to 80% of patients with newly diagnosed bladder cancer will present with superficial or Stage I bladder tumors. Patients with these superficial tumors can often be cured, but those with muscle-invasive or metastatic disease are cured less often and are treated with surgery, irradiation or a combination of modalities that includes systemic therapy. Platinum doublets are widely utilized as first-line treatment in patients with metastatic disease, but minimal options exist for those failing that treatment. No drugs are approved in relapsed/refractory metastatic bladder cancer in the U.S., and the single compound with European approval, Javlor (vinflunine, Pierre Fabre), produced a meager 8.6% response rate and 3.0-month progression-free survival (PFS) in a Phase III trial.1 Thus any serious contender in this setting is a great cause for excitement. With immunotherapy already such a hot topic, atezolizumab (MPDL3280A, Genentech/Roche) is generating considerable enthusiasm.
Atezolizumab is a human monoclonal IgG1 anti-PD-L1 antibody that inhibits the interaction of the PD-1 receptor with the PD-L1 ligand. In June 2011, a “first-in-human” Phase I (NCT01375842, PCD4989g) trial was initiated to assess atezolizumab in patients with locally advanced or metastatic solid or hematologic malignancies. Preliminary results2,3 from this study in the cohort of patients with advanced bladder cancer were so encouraging that it led to the U.S. Food and Drug Administration (FDA) awarding atezolizumab Breakthrough Therapy status as treatment of relapsed/refractory, PD-L1-positive bladder cancer.
In the Sunday Proffered Papers session on genitourinary cancers at the 2015 European Cancer Congress, a packed auditorium eagerly awaited the results of the Phase II IMvigor 210 trial.4 Data was presented from Cohort 2 of the study, which included 311 patients who were previously treated with platinum-based therapy (Cohort 1 includes platinum-ineligible patients). Atezolizumab was administered at 1200 mg IV every three weeks until loss of clinical benefit. The Ventana PD-L1 (SP142) CDx Assay was used to prospectively stratify participants into three PD-L1-based subgroups based on PD-L1 expression levels in immune cells. IC (tumor-infiltrating immune cell) levels were defined as IC0 for patients with PD-L1 expression in less than 1% of cells (33%, n=103), IC1 for patients with PD-L1 expression in more than 1% but less than 5% of cells (35%, n=108), and IC2/3 for patients with PD-L1 expression in 5% or more of cells (32%, n=100).
The overall response rate (ORR) was 9% in patients with IC0 expression level, 10% in IC1, 27% in IC2/3, and 15% across all patients. PFS was 2.1 months in all PD-L1 cohorts, although beyond the median there appeared to be a greater PFS in the IC2/3 cohort (PFS at six months was approximately 35% for IC2/3 and 20% for IC0/1). Median duration of response was not reached in any subgroup (range 0+ to 43 months). Median overall survival was 7.9 months across all patient cohorts; median OS was 6.7 months in IC0/1 patients and was not reached in IC2/3 patients. The safety profile of atezolizumab was similar to what has been observed in other tumor types, with 15% of patients experiencing a Grade 3/4 adverse event; treatment discontinuations were infrequent (3%), but dose modifications due to adverse events were common (27%).
What is most striking about these data is that these are patients who had been heavily treated. Seventy-eight percent had prior systemic regimen treatment for metastatic disease, and 20% had already completed three or more prior lines of therapy. Compared with the 8.6% ORR, 3.0-month PFS, and 6.9-month OS achieved with Javlor in a second-line population, these results are a huge leap.
With such positive Phase II data, Roche intends to seek regulatory approval, with U.S. and European filings expected to occur in early 2016. Guidance from the company is that they will seek approval in the specific subset of patients with PD-L1-positive disease, although the exact definition of “positivity” intended to be sought is unclear. If they follow their lead from non-small cell lung cancer, the regulatory filing may be limited to patients with IC2/3 PD-L1 expression levels. This would be a wise move, considering that the ORR and PFS were strongest in this patient cohort, although arguably the high unmet need in metastatic bladder cancer could justify the use of atezolizumab in a broad patient population.
In the U.S., accelerated approval of atezolizumab in this indication is highly likely given the lack of any approved therapies for relapsed patients and with the drug having already received Breakthrough Therapy designation in this indication. An accelerated approval will give atezolizumab a significant first-to-market advantage over its closest competitor in the immuno-oncology space, Keytruda® (pembrolizumab, Merck & Co.). Keytruda is currently being studied in a Phase III trial for relapsed/refractory metastatic bladder cancer, with a trial design that is nearly identical to that of atezolizumab’s Phase III trial in this setting, although Merck’s trial started a few months ahead of Roche’s, lending importance to an accelerated market launch. For a disease that until recently has had so few treatment options, the results from the 2015 European Cancer Congress are truly “IMvigor-ating”.
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