BARCELONA—The typical first-line therapy for newly diagnosed extensive stage small cell lung cancer (ES-SCLC) is etoposide plus platinum agent carboplatin or cisplatin. This has been the case for more than 3 decades with few alternatives. The initial response rates to these therapies tend to be rather high. However, the initial responses are not durable, with relapse frequently occurring within 6-9 months. For this patient population, the median overall survival (OS) with etoposide plus platinum-based chemotherapy is roughly 10 months.
Positive clinical results have been noted in patients with ES-SCLC when utilizing checkpoint inhibitor-based immunotherapy, particularly in the first-line setting. Consequently, further clinical studies evaluating checkpoint inhibitors in ES-SCLC have been undertaken. One such study is the phase III CASPIAN trial (NCT03043872), which is evaluating the anti-PD-L1 monoclonal antibody durvalumab in various combinations with other therapies. At the 2019 World Conference on Lung Cancer (WCLC), results were presented from two arms of the study, one in which patients were treated with durvalumab in combination with etoposide plus platinum agent, and the other with etoposide plus platinum agent alone.
One of the participating clinicians in this international study is Jonathan Goldman, MD, from the Ronald Reagan UCLA Medical Center. In a recent interview with Oncology Times, Goldman discussed some of the findings from this clinical study.
“The combination of durvalumab with etoposide plus platinum displays increased overall survival relative to the comparator arm, with similar numbers of adverse events (AEs) in the two arms,” he noted.
CASPIAN is a phase III, randomized, open-label multi-center international study evaluating durvalumab in combination with either etoposide plus platinum agent or the anti-CTLA-4 monoclonal antibody tremelimumab with etoposide plus platinum agent. The platinum agents included in this study were cisplatin and carboplatin. Patients were randomized in a 1:1:1 manner to the study's three treatment arms:
- Arm 1 (durvalumab + tremelimumab + EP)—durvalumab with tremelimumab and etoposide plus platinum agent;
- Arm 2 (durvalumab + EP)—durvalumab with etoposide plus platinum agent; and
- Arm 3 (EP)—etoposide plus platinum agent.
“The inclusion of a real-world comparator (the EP arm), with up to 6 treatment cycles and with optional prophylactic cranial irradiation, was crucial for the overall design of this study,” Goldman stated.
This study was limited to treatment-naïve patients with ES-SCLC who had a World Health Organization performance status of 0 or 1. Brain metastases were permitted if they were treated and stable, or asymptomatic. The study's primary endpoint is OS. Secondary outcome measures included progression-free survival (PFS), objective response rate (ORR), safety, and tolerability as assessed by AEs.
Data reported at the 2019 WCLC for this study were from Arm 2 and Arm 3; no data were provided for Arm 1. There were a total of 265 patients in the durvalumab + EP arm and 266 in the EP arm. In the durvalumab + EP arm, 208 patients had exposure to carboplatin and 65 received cisplatin. In the EP arm, 208 and 67 patients, respectively, received those same agents. “At the investigator's discretion, patients could choose between carboplatin and cisplatin,” Goldman explained.
For the study's primary outcome, the median OS for the durvalumab + EP arm was 13.0 months (95% CI: 11.5-14.8 months) and 10.3 months (95% CI: 9.3-11.2 months) for the EP arm, affording a hazard ratio of 0.73 (95% CI: 0.591-0.909, P=0.0047). The 12-month survival rates were 53.7 percent and 39.8 percent for the durvalumab + EP and EP arms, respectively, while the 18-month survival rates were 33.9 percent and 24.7 percent for those same study arms.
The ORR values for the durvalumab + EP and EP arms were 67.9 percent and 57.6 percent, respectively. “Interestingly, the responses for the durvalumab + EP arm tended to be more durable, as 22.7 percent of those patients showed a continued response at 12 months, while that same figure was 6.3 percent for the EP responders,” Goldman noted.
For the durvalumab + EP arm, the median PFS was 5.1 months (95% CI: 4.7-6.2 months) and for the EP arm that figure was 5.4 months (95% CI: 4.8-6.2 months). The 12-month PFS rates were 17.5 percent and 4.7 percent for the durvalumab + EP and EP arms, accordingly.
Safety data, as measured by AEs, were fairly similar between the two arms included in this analysis. In the durvalumab + EP arm, 98.1 percent of the patients displayed an AE of any grade, and 61.5 percent had a grade 3/4 AE. In the EP arm, 97.0 percent had an AE of any grade, while grade 3/4 AEs were noted in 62.4 percent of those participants. Serious AEs were noted in 30.9 percent and 36.1 percent of the durvalumab + EP and EP patients, respectively, while 9.4 percent in both arms had AEs leading to treatment discontinuation. “One area where there was a disparity,” Goldman observed, “was in immune-mediated AEs, where 19.6 percent of the durvalumab + EP patients and 2.6 percent of the EP participants had these issues.”
“The standard chemotherapies for patients with ES-SCLC have not drastically changed in decades,” Goldman stated. “Unfortunately, these patients develop resistance to the standard therapies within a matter of months. We were hoping to see synergy between durvalumab and EP in a first-line setting, and with the data obtained in this first interim analysis, we have taken the first steps towards improved survival in this patient population.”
In discussing the rationale for the durvalumab + tremelimumab +EP arm, Goldman explained, “It was hoped that the combination of a second checkpoint inhibitor, the anti-CTLA-4 antibody tremelimumab, with durvalumab would be of benefit to these patients. The clinical data from this arm will be presented at a later date.”
When asked about the future developments for patients with ES-SCLC, Goldman noted, “One area that I am investigating at UCLA is the addition of different agents to maintenance therapies. For example, one class of agents that is currently being considered is PARP inhibitors, possibly with the addition of low-dose chemotherapy.”
Richard Simoneaux is a contributing writer.