The evidence supporting this protocol is provided by a phase 3, multicentre, international, randomised trial (CASPIAN) involving 537 patients. This protocol is specifically based on the first two arms which have been reported, which compared platinum (carboplatin or cisplatin), etoposide and durvalumab, with platinum (carboplatin or cisplatin) and etoposide alone, in the first line treatment of patients with extensive stage small cell lung cancer (SCLC). The third arm investigates carboplatin, etoposide, durvalumab and tremelimumab in combination and has not yet been reported.r
Between March 2017, and May 2018, 537 patients with extensive stage SCLC were randomised 1:1, with 268 receiving durvalumab plus platinum–etoposide and 269 receiving platinum–etoposide alone. Platinum-etoposide consisted of etoposide 80–100 mg/m2 intravenously on days 1 to 3 with investigator's choice of either carboplatin AUC 5–6 or cisplatin 75–80 mg/m2 intravenously on day 1 of each 3-week cycle. Patients received up to four cycles of platinum–etoposide plus durvalumab 1500 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy group or up to six cycles of platinum–etoposide every 3 weeks plus prophylactic cranial irradiation (at investigator discretion) in the platinum–etoposide only group. Maintenance therapy was continued until disease progression or unacceptable toxicity.
The primary endpoint was overall survival (OS) in the intention-to-treat population. Secondary endpoints were progression-free survival (PFS), objective response (OR), OS at 18 months, PFS at 6 and 12 months and safety.
Efficacy
After a median follow up of 14.2 months (interquartile range 11.7–17.0), a significant improvement in OS was demonstrated in the durvalumab plus platinum–etoposide group (HR 0.73 [95% CI 0.59–0.91; p=0.0047]). The median OS was 13.0 months (95% CI 11.5–14.8) in patients receiving durvalumab plus platinum–etoposide, compared with only 10.3 months (95% CI 9.3–11.2) in those who received platinum–etoposide alone. At median follow-up of 18 months, 34% (95% CI 26.9–41.0) of patients in the durvalumab plus platinum–etoposide group were alive, compared with only 25% (95% CI 18.4–31.6) in those who received platinum–etoposide alone.r
Median PFS was not significantly different between the two groups, measuring 5.1 months (95% CI 4.7–6.2) with durvalumab plus platinum–etoposide and 5.4 months (4.8–6.2) with platinum-etoposide alone. However, the 12-month PFS rates were notably higher in the durvalumab plus platinum–etoposide group, at 18% (95% CI 13.1–22.5) compared with 5% (95% CI 2.4–8.0) in the platinum–etoposide group.r
Post hoc analysis demonstrated a confirmed OR in 182 (68%) of the 268 patients who received durvalumab plus platinum–etoposide, compared with 155 (58%) of the 269 patients who received platinum–etoposide alone (OR 1.56 [1.10–2.22]).r
Kaplan-Meier curves for overall survival (A) and progression-free survival (B) in the intention to treat populationr
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Forest plot of subgroup analysis of overall survivalr
© Lancet 2019
Toxicity
Any-cause grade 3 or 4 adverse events occurred in 163 (62%) of the 265 patients treated with durvalumab plus platinum–etoposide and 166 (62%) of the 266 patients treated with platinum–etoposide alone.r
Adverse events leading to death occurred in 13 (5%) patients in the durvalumab plus platinum–etoposide group and 15 (6%) in the platinum–etoposide group. Of note, there was no significant group specific mortality identified.
Immune-related adverse events (irAEs) were reported in 52 (20%) of the 265 patients treated with durvalumab plus platinum–etoposide and seven (3%) of the 266 patients treated with platinum–etoposide alone. Most of these events were grade 1 or 2, and grade 3 or 4 irAEs were only identified in 12 (5%) patients in the durvalumab plus platinum–etoposide group and one patient (<1%) in the platinum–etoposide group. Death due to irAEs were from hepatotoxicity in the durvalumab plus platinum–etoposide group and pneumonitis in the platinum–etoposide group, occurring in only one patient in each group. The most common irAEs were grade 1 or 2 thyroid-related events with hypothyroid events affecting 24 patients (9%) treated with durvalumab plus platinum etoposide and two patients (1%) treated with platinum etoposide and hyperthyroid events affecting 14 patients (5%) and none respectively.
Adverse eventsr
© Lancet 2019