From Targeted Oncology
The FDA has approved durvalumab (Imfinzi) in combination with standard-of-care chemotherapy, etoposide and carboplatin or cisplatin, as a frontline treatment for adult patients with extensive-stage small cell lung cancer (ES-SCLC).
New Treatment Option for SCLC
“Until recently, [patients with] small cell lung cancer had few treatment options beyond decades-old chemotherapy, which provided short-duration benefits. Adding durvalumab to first-line chemotherapy now improves survival and improves quality of life. Patients are living longer and they suffer less cancer symptoms. This appears likely to be better than waiting to give immunotherapy on progression,” Jonathan W. Goldman, MD, told Targeted Oncology about the expected impact of the approval. “The durvalumab regimen allows the physician and patient to decide on carboplatin or cisplatin to be given with etoposide. After 4 cycles of the chemoimmunotherapy combination, patients go on durvalumab monotherapy in maintenance, often with very few treatment [adverse] effects.”
Findings from the randomized, multicenter, open-label phase III CASPIAN trial supported the approval of durvalumab in this setting. The trial explored the safety and efficacy of durvalumab in combination with platinum etoposide and/or tremelimumab.
Patients with treatment-naïve ES-SCLC who had a WHO performance status of 0 or 1, adequate organ and marrow function, and who were eligible for first-line platinum-based chemotherapy were enrolled across 209 sites in 23 countries. A total of 805 patients were randomized 1:1:1 to receive either durvalumab plus chemotherapy (n = 268), durvalumab and tremelimumab plus chemotherapy (n = 268), or chemotherapy alone (n = 269). Chemotherapy consisted of etoposide and investigator’s choice of carboplatin or cisplatin.
In the experimental arms, durvalumab was administered at 1500 mg with or without tremelimumab 75 mg given every 3 weeks and chemotherapy for 4 cycles followed by maintenance durvalumab given every 4 weeks.
The primary end point of the study was overall survival (OS) and secondary measurements included progression-free survival (PFS), objective response rate (ORR), and safety.
Outline of Durvalumab/Chemo Combo
Data were released in The Lancet comparing the durvalumab-and-chemotherapy arm with the chemotherapy-alone group as of a planned interim OS analysis. Later, a press release announced that the durvalumab, tremelimumab, and chemotherapy triplet regimen failed to demonstrate an improvement in OS.
According to findings from the durvalumab arm versus the control arm, after a median follow-up of 14.2 months (range, 11.7-17.0), the median OS with durvalumab plus chemotherapy was 13 months (95% CI, 11.5-14.8) compared with 10.3 months (95% CI, 9.3-11.2) with chemotherapy alone (HR, 0.73; 95% CI, 0.59-0.91; P = .0047). At 12 months, the OS rates were 54% and 40% for the durvalumab and chemotherapy arms, respectively, and at 18 months the OS rates were 34% and 25%.
OS analyses consistently favored the durvalumab arm across patient subgroups.
At the time of data cutoff, 43 patients in the combination group remained on treatment versus none in the control group.
Objective responses were seen in 76% of patients treated with durvalumab and platinum etoposide compared with 70% treated with platinum etoposide alone (odds ratio [OR], 1.64; 95% CI, 1.11-2.44). Confirmed objective responses were reported in 68% and 58% of patients in the durvalumab regimen and chemotherapy arms, respectively (OR, 1.56; 95% CI, 1.10-2.22). The median duration of response was 5.1 months in each arm.
Adverse Events with Durvalumab
Rates of adverse events (AEs) were similar between the 2 arms with 98% of patients in the durvalumab arm experiencing AEs and 97% in the chemotherapy-alone arm; grade 3/4 AEs were observed in 62% of patients in each arm. The most common grade 3/4 AEs reported were neutropenia (24% with durvalumab vs 33% with chemotherapy) and anemia (9% vs 18%, respectively).
AEs led to discontinuation in 9% of patients in each group. Additionally, deaths due to AEs occurred in 5% of patients in the durvalumab group and in 6% in the chemotherapy arm.
Immune-mediated AEs were observed in 20% of patients who were treated with durvalumab and platinum–etoposide compared with 3% in the chemotherapy arm, most commonly including hypothyroid and hyperthyroid events of grade 1 or 2.
In an analysis presented at the 2019 ESMO Congress,4 the association of PD-L1 expression with outcome was tested. Few patients demonstrated positive expression on tumor cells (5.1%) or immune cells (22.4%). However, PD-L1 expression was not found to have a signification association with survival or response rate and was not determined to be a predictive biomarker to select patients who could benefit from the addition of durvalumab.
The investigators also looked at the patterns of progression in the 2 arms. The rate of target lesion progression in the durvalumab arm was 42.9% compared with 39.4% in the control group; nontarget lesion progression rates were 24.6% and 2.7%, respectively. A total of 41.4% of patients in the immunotherapy arm developed new lesions at first progression versus 47.2% in the chemotherapy arm. Fewer new lung, liver, and bone metastases were seen in the durvalumab arm compared with the platinum–etoposide arm. The rate of brain metastases was similar between the 2 arms though (11.6% vs 11.5%).
Quality of Life Benefits from Durvalumab
Patient-reported outcome scores tended to favor the addition of durvalumab. Global health status/quality of life especially benefitted from the use of durvalumab and the time to deterioration of functioning also favored the combination arm. The immunotherapy-based treatment was favored across all symptoms collected on the QLQ-C30 and QLQ-LC13 questionnaires.
“While much work remains, it is very exciting to see improvements in small cell lung cancer treatment. Future studies will focus on treatment for limited-stage disease and novel agents to add to maintenance or to the second line,” added Goldman, associate professor at UCLA Hematology & Oncology, associate director of drug development, and director of clinical trials in Thoracic Oncology.