Fixed-Dose Durvalumab Approved in Europe for Unresectable NSCLC

Author(s):

January 15, 2021 - Durvalumab has been approved in the European Union and the United Kingdom for a fixed-dose option of 1,500 mg every 4 weeks for use in patients with locally advanced, unresectable non–small cell lung cancer whose tumors have a PD-L1 expression of at least 1% and who have not experienced disease progression after platinum-based chemoradiation treatment.

Luis Paz-Ares, MD, PhD

Durvalumab (Imfinzi) has been approved in the European Union (EU) and the United Kingdom for a fixed-dose option of 1,500 mg every 4 weeks for use in patients with locally advanced, unresectable non–small cell lung cancer (NSCLC) whose tumors have a PD-L1 expression of at least 1% and who have not experienced disease progression after platinum-based chemoradiation treatment.¹

The new dosing option for durvalumab is consistent with the dosing for the agent that has been approved for extensive-stage small cell lung cancer (ES-SCLC); this will serve as an alternative option for patients who weigh more than 30 kg rather than the weight-based dosing of 10 mg/kg that is given every 2 weeks.

The decision was based on findings from many trials, including the pivotal phase 3 PACIFIC trial (NCT02125461) and the phase 3 CASPIAN trial (NCT03043872). Data from the former supported the 2-week, weight-based dosing option for use in patients with unresectable stage III NSCLC, while the latter examined a 4-week, fixed-dose during maintenance treatment in patients with ES-SCLC.

“Less-frequent dosing is important for [patients with] cancer and may be particularly relevant right now for those suffering from lung cancer, who are especially vulnerable to complications from COVID-19,” Luis Paz-Ares, MD, PhD, chair of the Medical Oncology Department of the Hospital Universitario Doce de Octubre. “Patients with cancer should be able to focus on living their lives as much as possible and doctors can now offer them a more convenient dosing option that could reduce medical visits by half and help avoid unnecessary risk of exposure to infection in the healthcare setting.”

In November 2020, the FDA gave the green light to durvalumab for use as a fixed-dose regimen use in the approved indications of unresectable stage III NSCLC following chemoradiation and previously treated advanced bladder cancer.

In September 2020, durvalumab was approved in the European Union for use in combination with either etoposide or carboplatin/cisplatin (EP) in the frontline treatment of patients with ES-SCLC based on CASPIAN. Initial results showed that durvalumab plus chemotherapy led to a 27% reduction in the risk of death compared with chemotherapy alone (hazard ratio [HR], 0.73; 95% CI, 0.59-0.91; P = .0047).² The median overall survival (OS) in the investigative arm was 13.0 months versus 10.3 months in the control arm.

In the trial, investigators examined durvalumab plus chemotherapy compared with chemotherapy alone in a total of 268 participants who were randomized to 1 of the following 3 cohorts: durvalumab/tremelimumab and EP given every 3 weeks for 4 cycles followed by durvalumab every 4 weeks until progressive disease with an additional dose of tremelimumab (D+T+EP; n = 268); durvalumab plus EP given every 3 weeks for 4 cycles, followed by durvalumab given every 4 weeks until disease progression (D+EP; n = 268); and EP given every 3 weeks for up to 6 cycles followed by prophylactic cranial irradiation per investigator discretion (EP; n = 269).

To be eligible for enrollment, patients had to be treatment naïve and have ES-SCLC. Notably, those with brain metastases were permitted, as long as they were asymptomatic or treated and were determined to be stable.

In the trial, patients received durvalumab at a dose of 1500 mg; tremelimumab was given at a dose of 75 mg. In all treatment arms examined, etoposide was administered at 80 mg/m² to 100 mg/m² on days 1 through 3 of each 21-day cycle plus either carboplatin given under the curve of 5 mg/mL to 5 mg/mL per minute or cisplatin delivered at 75 mg/m² to 80 mg/m² given on day 1 of each cycle.^3,4

The primary end point of the research was OS, while key secondary end points comprised progression-free survival (PFS), and objective response rate (ORR), along with safety and tolerability.

Updated CASPIAN findings revealed that the durvalumab regimen continued to showcase OS benefit at a median follow-up of 2 years (OS HR, 0.75; 95% CI, 0.62-0.91; P = .0032). The median OS at this time point was 12.9 months versus 10.5 months in the investigative and control arms, respectively. Notably, the OS favored durvalumab irrespective of the companion chemotherapy used. The HR for carboplatin was 0.79 (95% CI, 0.63-0.98) and it was 0.67 for cisplatin (95% CI, 0.46-0.97).

The safety findings from the trial proved to be consistent with what had previously been reported with all the agents examined in the regimens. Of those who received D+T+EP, 70.3% reported grade 3/4 toxicities and just under half, or 45.5%, reported serious toxicities. In the control arm, these rates were 62.8% and 36.5%, respectively.

Previously, in September 2018, durvalumab was approved in the EU as a monotherapy for use in patients with locally advanced, unresectable NSCLC whose tumors had a PD-L1 expression of 1% or greater and who had not progressed after platinum-based chemoradiation based on findings from PACIFIC. Durvalumab was also approved for this indication by the FDA in February 2018.

References

Imfinzi approved in the EU for less-frequent, fixed-dose use in unresectable non-small cell lung cancer. News release. January 15, 2021. Accessed January 15, 2021. http://bit.ly/38MQw5L.
L. Paz-Ares, Y. Chen, N. Reinmuth, et al. Overall survival with durvalumab plus etoposide-platinum in first-line extensive-stage SCLC: results from the CASPIAN study. Presented at: IASLC 20th World Conference on Lung Cancer; September 7-10, 2019; Barcelona, Spain. Abstract OA02.02.
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15):9002. doi:10.1200/JCO.2020.38.15_suppl.9002
Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6