FDA Approves Durvalumab for Fixed-Dose Use in NSCLC, Bladder Cancer Indications

November 20, 2020 - The FDA has approved durvalumab for an additional dosing option, a fixed dose of 1500 mg every 4 weeks, in the approved indications of unresectable stage III non-small cell lung cancer after chemoradiation and previously treated advanced bladder cancer.

The FDA has approved durvalumab (Imfinzi) for an additional dosing option, a fixed dose of 1500 mg every 4 weeks, in the approved indications of unresectable stage III non-small cell lung cancer after chemoradiation and previously treated advanced bladder cancer.

This new dosing option is consistent with the dosing for the agent that has been approved in 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 administered every 2 weeks.

The regulatory decision was based on data from several clinical trials examining the agent, including the phase 3 PACIFIC trial (NCT02125461), which supported the 2-week, weight-based dosing in patients with unresectable stage III NSCLC, and the phase 3 CASPIAN trial (NCT03043872), which examined a 4-week, fixed-dose during maintenance treatment in patients with ES-SCLC.

“This new 4-week dosing option gives doctors the choice to cut the number of visits for critical cancer treatment in half and offers a regimen that is more convenient for patients," Victoria M. Villaflor, MD, clinical professor in the Department of Medical Oncology and Therapeutics Research at City of Hope Cancer Center, stated in a press release. "Additionally, it limits potential exposure to infection in the healthcare environment for a population that is especially vulnerable to complications from COVID-19.”

In March 2020, the FDA approved durvalumab for use in combination with a standard-of-care chemotherapy regimen comprised of etoposide plus either carboplatin or cisplatin (EP) as a first-line treatment for adult patients with ES-SCLC based on data from CASPIAN.

Results demonstrated that with the addition of durvalumab to chemotherapy, a 27% reduction in the risk of death versus chemotherapy alone was achieved (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).2 Moreover, the durvalumab arm also experienced improved median overall survival (OS) versus the control arm, at 13.0 months (95% CI, 11.5-14.8) versus 10.3 months (95% CI, 9.3-11.2), respectively.

In the CASPIAN trial, investigators evaluated the impact of the addition of immunotherapy to chemotherapy versus chemotherapy alone across 3 treatment arms: durvalumab plus tremelimumab and EP administered every 3 weeks for 4 cycles, followed by durvalumab every 4 weeks until progressive disease with an additional dose of tremelimumab (D+T+EP arm); durvalumab plus EP given every 3 weeks for 4 cycles, followed by durvalumab administered every 4 weeks until disease progression (D+EP arm); and EP given every 3 weeks for up to 6 cycles, followed by prophylactic cranial irradiation per investigator discretion (EP arm).

In the trial, durvalumab was administered at a dose of 1500 mg, while tremelimumab was given at a dose of 75 mg. In all arms, patients received etoposide at 80 mg/m2 to 100 mg/m2 on days 1 to 3 of each 21-day cycle, with investigator’s choice of either carboplatin area under the curve of 5 mg/mL to 6 mg/mL per minute or cisplatin at 75 mg/m2 to 80 mg/m2 administered on day 1 of each cycle.3,4

The primary end point of the trial was OS, and secondary end points comprised progression-free survival (PFS), objective response rate (ORR), safety, and tolerability. To eligible for participation, patients had to have treatment naïve ES-SCLC, which was defined as stage IV and classified as T any, N any, M1a or M1b or T 3 to 4. Notably, patients who had asymptomatic or treated brain metastases that were determined to be stable were allowed to participate.

In the trial, 805 patients were randomized to 1 of the 3 treatment arms: 268 were enrolled to the D+T+EP arm, 268 to the D+EP arm, and 269 to the EP arm. The median age of patients was 63 years in the D+T+EP and EP arms and 63 years in the D+EP arm. Additionally, 14.2% of patients had brain or central nervous system metastases in the D+T+EP arm versus 10.4% in the D+EP, and 10.0% in the EP arm. Patients with liver metastases comprised 43.7%, 40.3%, and 38.7% of patients on the D+T+EP, D+EP, and EP arms, respectively.

Updated results from the trial presented during the 2020 ASCO Virtual Scientific Program showed that at a median follow-up of 25.1 months, the median OS in the D+EP arm was 12.9 months (95% CI, 11.3-14.7) compared with 10.5 months (95% CI, 9.3-11.2) in the EP-alone arm (HR, 0.75; 95% CI, 0.62-0.91; P = .0032). Moreover, the OS favored the durvalumab arm irrespective of whether carboplatin (HR, 0.79; 95% CI, 0.63-0.98) or cisplatin (HR, 0.67; 95% CI, 0.46-0.97) was utilized.

At 18 months, the OS rates were highest in the D+EP arm, at 32.0%; this was followed by 30.7% in the D+T+EP arm and 24.8% in the EP arm. The OS rates at 24 months were 22.2%, 23.4%, and 14.4%, respectively.

Moreover, the D+T+EP regimen was not found to lead to a significant improvement in other investigator-assessed measures per RECIST v1.1 criteria. In the D+T+EP group, the median PFS was 4.9 months (95% CI, 4.7-5.9) compared with 5.4 months (95% CI, 4.8-6.2) in the EP group (HR, 0.84; 95% CI, 0.70-1.01). The confirmed ORR reported in the D+T+EP group was 58.4% compared with 58.0% in the EP group; the median duration of response (DOR) was 5.2 months versus 5.1 months, respectively.

The PFS for the D+EP arm versus the EP arm was not formally examined for statistical significance. However, the median PFS with the D+EP combination was 5.1 months (95% CI, 4.7-6.2) versus 5.4 months (95% CI, 4.8-6.2) with EP alone (HR, 0.80; 95% CI, 0.66-0.96). In the D+EP arm, the ORR were 67.9% versus 58.0% in the EP arm (odds ratio, 1.53; 95% CI, 1.08-2.18). The median DOR was 5.1 months in both treatment arms.

Regarding safety, the data proved to be consistent with what was previously reported with the agents used in all regimens evaluated. The rate of grade 3/4 toxicities in the D+T+EP arm was 70.3%, while the rate of serious toxicities was 45.5%. In the EP arm, these rates were 62.8% versus 36.5%, respectively.

Moreover, 21.4% of those in the D+T+EP arm had adverse effects (AEs) that led to treatment discontinuation versus 10.2% of those in the D+EP arm and 9.4% of those in the EP arm. Twelve deaths linked with treatment-related AEs were reported in the D+T+EP arm, along with 6 in the D+EP arm, and 2 in the EP arm.

Durvalumab is approved for use in the curative-intent setting of unresectable, stage III NSCLC following chemoradiation treatment in the United States, Japan, China, Europe, and other countries based on data from the pivotal phase 3 PACIFIC trial. The PD-L1 inhibitor is also approved for the treatment of previously treated patients with advanced bladder cancer in the United States and other countries.

Additionally, the agent also has a regulatory approval in the United States and is under review in Japan and other countries for use in patients with ES-SCLC. In September 2020, the agent was approved in the European Union (EU) for the first-line treatment of patients with ES-SCLC in combination with etoposide plus either carboplatin or cisplatin.

The 4-week, 1500-mg fixed-dosing option for durvalumab is under regulatory review in many other countries, including in the EU.

“The approval of this new dosing option across indications reflects our ongoing commitment to improve the patient experience and ensure continuity of care - a priority at all times, but especially during the pandemic," Dave Fredrickson, executive vice president of the Oncology Business Unit at AstraZeneca, added in the release. "Cancer won’t wait, and it is our job to provide patients with treatment options that acknowledge the challenges the pandemic poses to cancer care, enabling them to visit their physician when truly needed and avoid preventable exposure to healthcare-associated infections.”


  1. Imfinzi approved in the US for less-frequent, fixed-dose use. News release. AstraZeneca. November 20, 2020. Accessed November 20, 2020. https://bit.ly/2UO8NYw.
  2. 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.
  3. 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
  4. 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