FDA News

FDA approves three drugs for advanced urothelial carcinoma

The FDA granted accelerated approval to atezolizumab, avelumab and durvalumab for the treatment of locally advanced or metastatic urothelial carcinoma.

Atezolizumab

The FDA in April approved atezolizumab (Tecentriq, Genentech) — a monoclonal antibody designed to bind with PD-L1 — for initial treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy.

The FDA based the approval on results from 119 patients in one of two cohorts of the phase 2 IMvigor210 study. Patients received 1,200 mg atezolizumab via IV every 3 weeks until disease progression or unacceptable toxicity.

Researchers reported an objective response rate of 23.5% (95% CI, 16.2-32.3); 6.7% of patients achieved complete response and 16.8% achieved partial response. Median duration of response had not been reached.

The most common grade 3 to grade 4 adverse reactions included hyponatremia (15%), fatigue (8%), anemia (7%), urinary tract infection (5%), diarrhea (5%) and increase in the level of creatinine in the blood (5%).

Five patients (4.2%) discontinued treatment due to adverse reactions. Five patients (4.2%) experienced sepsis, cardiac arrest, myocardial infarction, respiratory failure or respiratory distress, which led to death.

Last year, the FDA granted accelerated approval to atezolizumab for second-line treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy.

In May, however, Genentech announced the phase 3 IMvigor211 trial — designed to serve as the confirmatory study to convert the accelerated approval of second-line use to full approval — failed to meet its primary endpoint. Instead, the trial — which included 931 patients — showed atezolizumab did not significantly extend OS compared with chemotherapy.

Avelumab

The FDA granted accelerated approval to avelumab (Bavencio, EMD Serono) for patients whose disease progressed during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

The agency based the approval in part on results of an open-label, single-arm, multicenter study that included 242 patients. Patients received 10 mg/kg IV avelumab every 2 weeks until radiographic or clinical progression or unacceptable toxicity.

Researchers reported an ORR of 13.3% (95% CI, 9.1-18.4) at 13 weeks of follow-up, and 16.1% (95% CI, 10.8-22.8) at 6 months of follow-up.

Median time to response was 2 months (range, 1.3-11); however, median response duration had not been reached.

The most common adverse reactions included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite and urinary tract infection. Six percent of patients died due to adverse reactions. Forty-one percent of patients experienced serious adverse reactions, including urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction and pyrexia.

Durvalumab

The FDA granted accelerated approval to durvalumab (Imfinzi, AstraZeneca), as well as the VENTANA PD-L1 Assay (SP263, Ventana Medical Systems) as a complementary diagnostic for the assessment of the PD-L1 protein.

The agency based its approval of durvalumab in part on data from a single-arm trial that included 182 patients with locally advanced or metastatic urothelial carcinoma. All patients progressed during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Patients received 10 mg/kg durvalumab via IV every 2 weeks.

Researchers reported a 17% (95% CI, 11.9-23.3) confirmed ORR by blinded independent central review. Median response duration had not been reached (range, 0.9+ months to 19.9+ months).

The VENTANA PD-L1 Assay revealed ORRs of 26.3% (95% CI, 17.8-36.4) among 95 patients with a high PD-L1 score, and 4.1% (95% CI, 0.9-11.5) among 73 patients with low or negative PD-L1 scores.

The most common adverse reactions included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema and urinary tract infection.

Forty-three percent of patients experienced grade 3 to grade 4 events. These events included pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency and diabetes.

The FDA granted accelerated approval to atezolizumab, avelumab and durvalumab for the treatment of locally advanced or metastatic urothelial carcinoma.

Atezolizumab

The FDA in April approved atezolizumab (Tecentriq, Genentech) — a monoclonal antibody designed to bind with PD-L1 — for initial treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy.

The FDA based the approval on results from 119 patients in one of two cohorts of the phase 2 IMvigor210 study. Patients received 1,200 mg atezolizumab via IV every 3 weeks until disease progression or unacceptable toxicity.

Researchers reported an objective response rate of 23.5% (95% CI, 16.2-32.3); 6.7% of patients achieved complete response and 16.8% achieved partial response. Median duration of response had not been reached.

The most common grade 3 to grade 4 adverse reactions included hyponatremia (15%), fatigue (8%), anemia (7%), urinary tract infection (5%), diarrhea (5%) and increase in the level of creatinine in the blood (5%).

Five patients (4.2%) discontinued treatment due to adverse reactions. Five patients (4.2%) experienced sepsis, cardiac arrest, myocardial infarction, respiratory failure or respiratory distress, which led to death.

Last year, the FDA granted accelerated approval to atezolizumab for second-line treatment of patients with locally advanced or metastatic urothelial carcinoma whose disease progressed during or after platinum-based chemotherapy.

In May, however, Genentech announced the phase 3 IMvigor211 trial — designed to serve as the confirmatory study to convert the accelerated approval of second-line use to full approval — failed to meet its primary endpoint. Instead, the trial — which included 931 patients — showed atezolizumab did not significantly extend OS compared with chemotherapy.

Avelumab

The FDA granted accelerated approval to avelumab (Bavencio, EMD Serono) for patients whose disease progressed during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

The agency based the approval in part on results of an open-label, single-arm, multicenter study that included 242 patients. Patients received 10 mg/kg IV avelumab every 2 weeks until radiographic or clinical progression or unacceptable toxicity.

Researchers reported an ORR of 13.3% (95% CI, 9.1-18.4) at 13 weeks of follow-up, and 16.1% (95% CI, 10.8-22.8) at 6 months of follow-up.

Median time to response was 2 months (range, 1.3-11); however, median response duration had not been reached.

The most common adverse reactions included fatigue, infusion-related reaction, musculoskeletal pain, nausea, decreased appetite and urinary tract infection. Six percent of patients died due to adverse reactions. Forty-one percent of patients experienced serious adverse reactions, including urinary tract infection/urosepsis, abdominal pain, musculoskeletal pain, creatinine increased/renal failure, dehydration, hematuria/urinary tract hemorrhage, intestinal obstruction/small intestinal obstruction and pyrexia.

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Durvalumab

The FDA granted accelerated approval to durvalumab (Imfinzi, AstraZeneca), as well as the VENTANA PD-L1 Assay (SP263, Ventana Medical Systems) as a complementary diagnostic for the assessment of the PD-L1 protein.

The agency based its approval of durvalumab in part on data from a single-arm trial that included 182 patients with locally advanced or metastatic urothelial carcinoma. All patients progressed during or after platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

Patients received 10 mg/kg durvalumab via IV every 2 weeks.

Researchers reported a 17% (95% CI, 11.9-23.3) confirmed ORR by blinded independent central review. Median response duration had not been reached (range, 0.9+ months to 19.9+ months).

The VENTANA PD-L1 Assay revealed ORRs of 26.3% (95% CI, 17.8-36.4) among 95 patients with a high PD-L1 score, and 4.1% (95% CI, 0.9-11.5) among 73 patients with low or negative PD-L1 scores.

The most common adverse reactions included fatigue, musculoskeletal pain, constipation, decreased appetite, nausea, peripheral edema and urinary tract infection.

Forty-three percent of patients experienced grade 3 to grade 4 events. These events included pneumonitis, hepatitis, colitis, thyroid disease, adrenal insufficiency and diabetes.