Few grade 3 or higher immune-related adverse events were observed in patients treated with first-line durvalumab plus platinum/etoposide for extensive-stage small cell lung cancer (SCLC), according to findings from the safety analysis of the phase III CASPIAN study presented by Özgüroğlu et al at the European Society for Medical Oncology (ESMO) Immuno-Oncology Congress 2019 (Abstract LBA2).
Mustafa Özgüroğlu, MD
Mustafa Özgüroğlu, MD, Professor of Medical Oncology at Cerrahpaşa School of Medicine, Istanbul University−Cerrahpaşa, Istanbul, Turkey, presented results from analyses of safety, pharmacokinetics, and immunogenecity from the open-label phase III CASPIAN study of first-line durvalumab plus platinum/etoposide compared to platinum/etoposide alone in patients with extensive-stage SCLC.
Findings From CASPIAN
Findings from the preplanned interim analysis showed that durvalumab plus platinum/etoposide significantly improved overall survival (OS) as compared to platinum/etoposide alone in patients with extensive-stage SCLC (hazard ratio [HR] = 0.73, 95% confidence interval [CI] = 0.59–0.91, P = .0047).
The rates of all-cause adverse events, as well as adverse events leading to discontinuation, were similar with both treatments—although serious adverse events were numerically lower at 30.9% vs 36.1%, respectively, and immune-mediated adverse events were higher with the addition of durvalumab to platinum/etoposide. This finding prompted Dr. Özgüroğlu and co-investigators to further evaluate safety, pharmacokinetics, and immunogenicity, the study’s secondary endpoints.
CASPIAN enrolled treatment-naive patients with extensive-stage SCLC and World Health Organization performance status of 0 or 1. Patients were randomly assigned to treatment with platinum/etoposide plus 1,500 mg of durvalumab every 3 weeks; platinum/etoposide plus 1,500 mg of durvalumab plus 75 mg of tremelimumab every 3 weeks; or platinum/etoposide every 3 weeks. Investigator’s choice of carboplatin or cisplatin was allowed. In the immunotherapy arm, patients were treated with four cycles of platinum/etoposide, followed by 1,500 mg of durvalumab every 4 weeks until progression; up to six cycles of platinum/etoposide and optional prophylactic cranial irradiation were permitted in the control platinum/etoposide arm.
Safety, Pharmacokinetics, and Immunogenicity
At the ESMO Immuno-Oncology Congress 2019, results from the 265 patients who were treated with durvalumab plus platinum/etoposide and the 266 control patients receiving platinum/etoposide were presented.
The pharmacokinetic analysis showed that serum concentrations of durvalumab were within the expected range. Pharmacokinetic profiles of platinum/etoposide components were similar across both arms. In the durvalumab plus platinum/etoposide arm, 201 patients were evaluated for antidrug antibodies; of these, 11 (5.5%) were positive for antidrug antibodies to durvalumab at baseline only, and no patients were positive for treatment-emergent antidrug antibodies or neutralizing antibodies.
The most common adverse events, grade 3 or 4 adverse events, and serious adverse events in both arms consisted of hematologic toxicities, which were well-managed using standard therapies per local practice. Fewer (50.4%) patients in the durvalumab plus platinum/etoposide arm received colony-stimulating factor, compared to 56.9% of patients in the platinum/etoposide arm; 12.7% vs 20.8% of patients in the respective arms received blood transfusions. When events that coincided with cycles 5 and 6 of platinum/etoposide in the control arm were removed, the overall serious adverse event rates were 30.9% for durvalumab plus platinum/etoposide vs 30.1% for platinum/etoposide. Most immune-mediated adverse events were low-grade endocrine-related adverse events that were managed with corticosteroid or endocrine therapy. Any immune-mediated adverse events occurred in 52 (20%) patients on durvalumab plus platinum/etoposide vs 7 (3%) of patients on platinum/etoposide; of these, 5% vs 1% were grade ≥ 3, respectively. The most commonly reported any-grade immune-mediated adverse events with durvalumab plus platinum/etoposide were hypothyroidism (9%), hyperthyroidism (5%), pneumonitis (3%), and hepatic events (3%). Two percent of patients each had dermatitis/rash, diarrhea/colitis, thyroiditis, and type 1 diabetes. Grade ≥ 3 immune-mediated adverse events reported with durvalumab plus platinum/etoposide included pneumonitis (1%), hepatic events (2%), diarrhea/colitis (0.4%), and type 1 diabetes (2%). The earliest any-grade immune-mediated adverse event was diarrhea/colitis, which was seen at median 28 days after receiving the first dose.
With platinum/etoposide alone, commonly reported any-grade immune-mediated adverse events included hypothyroidism (1%), pneumonitis (1%), and diarrhea/colitis (0.4%); of these, only grade ≥ 3 pneumonitis (1%) was recorded. The first immune-mediated adverse events of dermatitis/rash occurred at a median of 31 days after first treatment dose.
The authors pointed out that the incidence of antidrug antibodies to durvalumab was low and were seen only at baseline. They further remarked that the safety profile of durvalumab plus platinum/etoposide was consistent with previous reports of both durvalumab and platinum/etoposide.
Disclosure: CASPIAN was funded by AstraZeneca. For full disclosures of the study authors, visit academic.oup.com.