December 15, 2020 - The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for an additional dosing option of durvalumab, a fixed dose of 1500 mg every 4 weeks, in the approved indication of locally advanced, unresectable non–small cell lung cancer in adults whose tumors have a PD-L1 expression of at least 1% and who did not have progressive disease after platinum-based chemoradiation treatment.
The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for an additional dosing option of durvalumab (Imfinzi), a fixed dose of 1500 mg every 4 weeks, in the approved indication of locally advanced, unresectable non–small cell lung cancer (NSCLC) in adults whose tumors have a PD-L1 expression of at least 1% and who did not have progressive disease after platinum-based chemoradiation treatment.1
The new dosing option is consistent with the dosing for the agent that has been approved for extensive-stage small cell lung cancer (ES-SCLC). Once approved, this will serve as an alternative option for those who weigh more than 30 mg vs the weight-based dosing of 10 mg/kg that is given every 2 weeks.
The recommendation is based on findings from several clinical trials examining durvalumab, including the phase 3 PACIFIC trial (NCT02125461), which supported the 2-week, weight-based dosing of the agent in patients with unresectable stage III NSCLC, and the phase 3 CASPIAN trial (NCT03043872), which evaluated a 4-week, fixed-dose of the agent during maintenance treatment for those with ES-SCLC.
“The 4-week dosing regimen will decrease the risk of exposure to infection in the healthcare setting, furthering our efforts to ensure continuity of care for [patients with] cancer at high risk of complications during the pandemic,” José Baselga, executive vice president of Oncology R&D at AstraZeneca, stated in a press release. “We look forward to offering [patients with] NSCLC in Europe an option that would reduce medical visits by extending dosing from 2 to 4 weeks.”
In November 2020, the FDA approved durvalumab for this additional dosing option in the approved indications of unresectable stage III NSCLC following chemoradiation and previously treated advanced bladder cancer.
Previously, in March 2020, the FDA approved durvalumab in combination with a standard chemotherapy regimen composed of either etoposide and either carboplatin or cisplatin (EP) for use as a frontline treatment in adult patients with ES-SCLC. The decision was based on findings from CASPIAN, which showed that durvalumab plus chemotherapy reduced the risk of death by 27% vs chemotherapy alone (HR, 0.73; 95% CI, 0.591-0.909; P = .0047).2 The median overall survival (OS) was 13.0 months in the investigative arm vs 10.3 months in the control arm.
Investigators of the CASPIAN trial examined the impact of durvalumab plus chemotherapy vs chemotherapy alone across 3 cohorts: durvalumab plus tremelimumab and EP given every 3 weeks for 4 cycles followed by durvalumab every 4 weeks until disease progression with an additional dose of tremelimumab (D+T+EP); durvalumab plus EP administered every 3 weeks for 4 cycles, followed by durvalumab given every 4 weeks until progressive disease (D+EP); and EP administered every 3 weeks for up to 6 cycles, followed by prophylactic cranial irradiation per investigator discretion (EP).
Participants received durvalumab at 1500 mg, and tremelimumab was administered at 75 mg. In all arms, etoposide was given at 80 mg/m2 to 100 mg/m2 on days 1 to 3 of each 21-day treatment cycle in combination with either carboplatin area under the curve of 5 mg/mL to 6 mg/mL per minute or cisplatin at a dose of 75 mg/m2 to 80 mg/m2 given on day 1 of each cycle.3,4
The primary objective of the trial was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability. Patients needed to have treatment-naïve ES-SCLC, defined as stage IV and classified as T any, N any, M1a or M1b or T 3 to 4, to participate. Those with asymptomatic or treated stable brain metastases were permitted for inclusion.
A total of 805 participants were randomized to 1 of the 3 cohorts; 268 patients received D+T+EP, 268 were given D+EP, and 269 received EP. Approximately 14% of patients had brain or central nervous system metastases in the D+T+EP cohort compared with 10.4% in the D+EP cohort, and 10.0% in the EP cohort. In the D+T+EP, D+EP, and EP arms, 43.7%, 40.3%, and 38.7%, of patients, respectively, had liver metastases.
Updated data from CASPIAN presented during the 2020 ASCO Virtual Scientific Program indicated that at a median follow-up of 25.1 months, the median OS was 12.9 months in the D+EP cohort vs 10.5 months in the EP-alone cohort (HR, 0.75; 95% CI, 0.62-0.91; P = .0032). The OS favored durvalumab regardless of whether carboplatin (HR, 0.79; 95% CI, 0.63-0.98) or cisplatin (HR, 0.67; 95% CI, 0.46-0.97) were given as the companion.
The OS rates at 18 months proved to be highest in the D+EP cohort, at 32.0%. In the D+T+EP and EP-alone cohorts, the OS rates at this time point were 30.7% and 24.8%, respectively. At 24 months, the highest OS rate was 23.4% in the D+T+EP cohort, followed by 22.2% in the D+EP cohort and 14.4% in the EP-alone cohort.
The D+T+EP did not significantly improve other investigator-assessed measures per RECIST v1.1 criteria. The median PFS in the D+T+EP cohort was 4.9 months vs 5.4 months in the EP cohort (HR, 0.84; 95% CI, 0.70-1.01). Moreover, the confirmed ORRs in the D+T+EP and EP cohorts were 58.4% and 58.0%, respectively. Additionally, the median duration of response (DOR) in the D+T+EP cohort was 5.2 months vs 5.1 months in the EP cohort.
Although the PFS in the D+EP cohort vs the EP cohort was not formally evaluated for statistical significance, the median PFS was 5.1 months vs 5.4 months, respectively (HR, 0.80; 95% CI, 0.66-0.96). The ORR in the D+EP cohort was 67.9% vs 58.0% in the EP-alone arm (odds ratio, 1.53; 95% CI, 1.08-2.18). Moreover, the median DOR in both cohorts was 5.1 months.
The safety findings were consistent with prior reports of all drugs in the regimens examined on the trial. In the D+T+EP cohort, 70.3% of patients experienced grade 3/4 toxicities, while 45.5% experienced serious adverse effects. In the EP-alone cohort, these rates were 62.8% vs 36.5%, respectively.
Based on the CASPIAN findings, in September 2020, the agent received approval in the European Union for the frontline treatment of patients with ES-SCLC in combination with etoposide with either carboplatin or cisplatin.
The PD-L1 inhibitor is also approved for use in the curative-intent setting of unresectable, stage III NSCLC after chemoradiation in the United States, Japan, China, Europe, and other countries based on findings from PACIFIC. Durvalumab also has approval for the treatment of previously treated patients with advanced bladder cancer in the United States and other countries.