Christophe Massard, MD, PhD, discusses ongoing clinical trials evaluating durvalumab, toxicities to be aware of with the agent, and the impact the approval has had in the field.
Christophe Massard, MD, PhD
Based on data from an ongoing clinical trial of durvalumab (Imfinzi) as a treatment for patients with advanced solid tumors, including locally advanced or metastatic urothelial carcinoma, Christophe Massard, MD, PhD, says the recently FDA-approved agent could be an attractive alternative to chemotherapy in the second-line treatment of these patients.
Durvalumab was approved by the FDA last month based on the single-arm phase I/II Study 1108, which included 182 patients with locally advanced or metastatic urothelial carcinoma who experienced disease progression following platinum-containing chemotherapy. In the study, the objective response rate (ORR) per blinded independent central review was 17.0% (95% CI, 11.9-23.3). At the data cutoff, the median duration of response was not reached (range, 0.9+ to 19.9+ months).
Among 95 patients with high PD-L1 expression, the ORR was 26.3% (95% CI, 17.8-36.4). In a cohort of 73 patients with low or no PD-L1 expression, the ORR was 4.1% (95% CI, 0.9-11.5).
In an interview withTargeted Oncology, Massard, medical oncologist, senior consultant of the Drug Development Department and Department of Medical Oncology, and chairman of the Early Drug Development Multidisciplinary Tumor Board, Gustave Roussy Institute, discussed ongoing clinical trials evaluating durvalumab, toxicities to be aware of with the agent, and the impact the approval has had in the field.
TARGETED ONCOLOGY:What was the design of the trial that led to the approval of durvalumab for urothelial carcinoma?
Durvalumab is a selective, high-affinity, engineered human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80. An ongoing, multicenter, phase I/II open-label study (NCT1693562) is evaluating the safety and antitumor activity of durvalumab monotherapy in patients with advanced solid tumors, including locally advanced/metastatic urothelial carcinoma. An interim analysis of 61 patients with urothelial carcinoma in this study indicated that durvalumab was well tolerated and associated with antitumor activity, particularly in patients with PD-L1high disease (≥25% of tumor cells or tumor-infiltrating immune cells express PD-L1), resulting in its breakthrough therapy designation by the US FDA.
In a phase I/II open label study of locally advanced/metastatic urothelial carcinoma patients (n = 191), durvalumab was administered 10 mg/kg every 2 weeks to patients with advanced bladder cancer. Durvalumab shows favorable efficacy and an excellent safety profile in locally advanced/metastatic urothelial carcinoma patients. The data reported here were recently accepted for assessment by the US FDA for a biologics license application under priority review to establish the clinical benefit of durvalumab as a second-line therapy for locally advanced/metastatic urothelial carcinoma.
TARGETED ONCOLOGY:What adverse events were seen on the trial from treatment with durvalumab?
Grade 3/4 treatment-related adverse events occurred in less than 10% of patients. Grade 3/4 immune-mediated adverse events [AEs] occurred in a minority of patients. Among patients with any-grade treatment-related AEs of special interest, patients received systemic steroids.
TARGETED ONCOLOGY:What do you recommend community oncologists do if they see other serious or immune-related AEs?
Durvalumab, like other immune checkpoint blockers, generates atypical types of tumor responses (pseudo progression but also hyper progression). Moreover, they have a specific toxicity profile that is challenging the historical oncologists’ practices, with the need to learn how to deal with the clinical management of immune-related AEs.
Most immune-related AEs remain mild in intensity but between 5% and 10% of patients treated with antiPD-1 immune checkpoint blockers will develop severe, sometimes life-threatening grade 3/4 dysimmune toxicities. For example, it was decided at Gustave Roussy to set up a network of oncologists and organ specialists to manage patients with immune-related AEs. This program is led by Aurélien Marabelle, MD, PhD, Stéphane Champiat, MD, and Olivier Lambotte, MD, PhD.
Targeted Oncology: What else should community oncologists know about durvalumab in general?
Durvalumab 10 mg/kg every 2 weeks was well tolerated in patients with locally advanced/metastatic urothelial carcinoma (n = 191). Treatment-related AEs were mostly grade 1/2, with cumulative incidences of AEs plateauing after early onset.
TARGETED ONCOLOGY:What is the impact of durvalumab’s approval by the FDA?
Massard: This study supports the manageable safety and tolerability of durvalumab administered 10 mg/kg every 2 weeks as monotherapy in patients with solid tumors and confirms its favorable clinical activity in previously treated patients with locally advanced/metastatic urothelial carcinoma for whom prognosis is poor. Durvalumab is clearly a new option for these patients.
TARGETED ONCOLOGY:In your opinion, is there potential for durvalumab to replace chemotherapy?