Adjuvant Atezolizumab Misses DFS Endpoint in Muscle-Invasive Bladder Cancer

Levi Garraway, MD, PhD

Adjuvant treatment with atezolizumab (Tecentriq) did not significantly improve disease-free survival (DFS) compared with observation in patients with muscle-invasive bladder cancer, missing the primary endpoint of the phase III IMvigor010 trial (NCT02450331).¹

The safety profile of the PD-L1 inhibitor was consistent with previously reported studies, and no new safety signals were identified.

“Reducing the risk that muscle-invasive urothelial cancer will recur after surgery is very difficult, and we are disappointed that we were not able to significantly prolong disease-free survival,” Levi Garraway, MD, PhD, chief medical officer, and head of Global Product Development for Genentech (Roche), the developer of atezolizumab, stated in a press release. “We remain committed to exploring the potential benefits of immunotherapy for more people with early cancers.”

Additional treatment options for patients with muscle-invasive bladder cancer following surgery are necessary, as approximately half of patients will develop disease recurrence within 2 years, Genentech stated in the press release.

In the international, open-label, controlled, phase III IMvigor010 trial, investigators evaluated the efficacy and safety of adjuvant treatment with atezolizumab compared with observation in 809 people with muscle-invasive bladder cancer who are at high risk for recurrence following surgical resection. In the atezolizumab arm, the PD-L1 inhibitor was administered at 1200 mg intravenously on day 1 of each 21-day cycle for 16 cycles.

To be eligible for enrollment, patients must have had histologically confirmed muscle-invasive urothelial cancer of the bladder or upper urinary tract, absence of residual disease and absence from metastasis, full recovery from cystectomy or nephroureterectomy within 14 weeks of following surgery, an ECOG performance status ≤2, and adequate hematologic and end-organ function.

Those who were treated with any approved anti-cancer therapy within 3 weeks prior to starting on study, had adjuvant chemotherapy or radiation following surgery, a malignancy other than urothelial cancer within 5 years prior to day 1 of cycle 1, had significant cardiovascular disease, severe infections within 4 weeks prior to day 1 of cycle 1, a history of autoimmune disease, and previously underwent allogeneic stem cell or solid organ transplant were not permitted to enroll.

The primary endpoint was investigator-assessed DFS; secondary endpoints include overall survival (OS), investigator-assessed disease-specific survival, distant metastasis-free survival, non-urinary tract recurrence-free survival, adverse events, patients with anti-therapeutic antibodies to atezolizumab, European Quality of Life Group 5-Dimension 5-Level Self Report Questionnaire Health Utility Score, and pharmacokinetics.

Previously, atezolizumab combined with chemotherapy demonstrated an improvement in progression-free survival (PFS) compared with placebo and chemotherapy in patients with locally advanced or metastatic urothelial carcinoma.² In the international, phase III IMvigor130 trial, investigators randomized 1213 patients 1:1:1 to receive atezolizumab plus platinum-based therapy and gemcitabine, atezolizumab monotherapy, or placebo plus platinum-based therapy and gemcitabine.

At a median follow-up of 11.8 months, the final median PFS was 8.2 months with atezolizumab plus chemotherapy compared with 6.3 months with chemotherapy plus placebo, leading to an 18% reduction in the risk of disease progression or death (HR, 0.82; 95% CI, 0.70-0.96; one-sided P = .007).

However, atezolizumab/chemotherapy did not showcase a statistically significant improvement in OS. At the interim analysis, the median OS was 16.0 months and 13.4 months with atezolizumab/chemotherapy and placebo/chemotherapy, respectively (HR, 0.83; 95% CI, 0.69-1.00; one-sided P = .027), which was clinically meaningful, but did not cross the prespecified interim efficacy boundary for significance.

In the intent-to-treat population, the median OS with atezolizumab monotherapy was 15.7 months and was 13.1 months for chemotherapy/placebo (HR, 1.02; 95% CI, 0.83-1.24).

Atezolizumab is currently approved by the FDA for the frontline treatment of patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and whose tumors express PD-L1, or those who are not eligible for any platinum-based chemotherapy, regardless of PD-L1 status. The PD-L1 inhibitor is also indicated for the treatment of patients with locally advanced or metastatic urothelial cancer whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving a platinum-containing chemotherapy, either before or after surgery.

References

1. Genentech provides an update on phase III study of Tecentriq in people with muscle-invasive urothelial cancer [news release]: San Francisco, CA. Genentech. Published January 23, 2020. https://bit.ly/38yk7x1. Accessed January 23, 2020.
2. Grande E, Galsky MD, Arranz Arija JA, et al. IMvigor130: a phase III study of atezolizumab with or without platinum-based chemotherapy in previously untreated metastatic urothelial carcinoma. Ann Oncol. 2019;30(suppl_5):v851-v934. doi: 10.1093/annonc/mdz394.