No survival boost with add-on bevacizumab in frontline metastatic bladder cancer

Jason M. Broderick

Adding the angiogenesis inhibitor bevacizumab (Avastin) to standard first-line chemotherapy did not improve overall survival (OS) in patients with metastatic urothelial carcinoma, according to findings from the phase 3 CALGB 90601 trial published online in the Journal of Clinical Oncology.1

At a median follow-up of 76.3 months, the median OS was 14.5 months with the addition of bevacizumab (B) to standard frontline gemcitabine and cisplatin (GC), versus 14.3 months with placebo plus GC (GCP; HR, 0.87; P = .14).

“The addition of bevacizumab did not improve OS over GC chemotherapy alone. Although there was a modest improvement in progression-free survival (PFS), these results do not change the standard of care, which remains initiation of first-line therapy with cisplatin-based combination chemotherapy for medically eligible patients,” lead study author Jonathan E. Rosenberg, MD, Memorial Sloan Kettering Cancer Center, New York, NY, and coauthors wrote.

The double-blind phase 3 CALGB 90601 (Alliance) trial enrolled 506 patients with metastatic urothelial carcinoma who had no prior chemotherapy in the metastatic setting and had not received neoadjuvant or adjuvant chemotherapy in ≤12 months. Individuals with a history of brain metastasis, significant bleeding or arterial thrombotic events occurring within the previous 6 months, or congestive heart failure were not eligible for enrollment.

Patients were randomized to GCB (n = 252) or GCP (n = 254) between July 2009 and December 2014. The primary study end point was OS. Secondary end points included PFS, objective response rate (ORR), and safety.

Overall, patient characteristics were well balanced between the 2 arms. Seventy-four percent of patients were aged <70 years, 92% were White, and 78% were male. Across the population, 87% of patients had preoperative chemotherapy, and 69% had visceral metastases. At baseline, 54% of patients had an ECOG performance status of 0, 45% had a status of 1, and that status was not available for just under 1% of patients. The primary tumor site was the bladder for 74% of patients, upper tract for 21%, and “others” for 5%. Ninety-one percent of patients had measurable disease at baseline.

The median PFS was 8 months with GCB versus 6.7 months with GCP (HR, 0.77; P = .016). The ORRs were 40.4% versus 36.4%, respectively (P = .56).

Regarding safety, the overall incidence of grade ≥3 adverse events was comparable between the 2 study arms. As expected, adverse events associated with bevacizumab, such as hypertension and proteinuria, occurred at higher rates in the GCB arm.

“Much work remains to be done to improve outcomes of patients with metastatic urothelial carcinoma. The…US Food and Drug Administration approval of avelumab as maintenance therapy was based on a 7.1-month improvement in OS in patients who have had stable disease or response to platinum-based chemotherapy. The approvals of enfortumab vedotin and erdafitinib provide new options for patients with progressive disease after platinum chemotherapy and/or immunotherapy,” Rosenberg et al wrote in their conclusion.

“In the coming years, improved understanding of the association of molecular biomarkers and response to chemotherapy may allow for optimal patient selection for treatment; these studies are ongoing and use specimens from this and other trials,” the authors added.

Reference

1. Rosenberg JE, Ballman KA, Halabi S, et al. Randomized phase III trial of gemcitabine and cisplatin with bevacizumab or placebo in patients with advanced urothelial carcinoma: Results of CALGB 90601 (Alliance) [published online ahead of print May 14, 2021]. J Clin Oncol. doi: 10.1200/JCO.21.00286