Tremelimumab Added to Durvalumab and SoC Fails to Improve OS in ES-SCLC

Jose Baselga

Jose Baselga

The addition of tremelimumab to durvalumab (Imfinzi) and the standard of care (SOC), platinum-based chemotherapy, did not demonstrate a statistically significant improvement in overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC), missing the co-primary end point of the phase III CASPIAN trial (NCT03043872), according to high-level results from the final analysis announced in a press release from Astra Zeneca.¹

The addition of tremelimumab to frontline durvalumab (Imfinzi) and the standard of care (SOC), platinum-based chemotherapy, did not demonstrate a statistically significant improvement in overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC), missing the co-primary end point of the phase III CASPIAN trial (NCT03043872), according to high-level results from the final analysis of the trial announced in a press release from AstraZeneca.¹

“We are pleased to see the sustained and meaningful survival benefit of Imfinzi for patients with small cell lung cancer after more than 2 years median follow-up. We have already received the first global regulatory approval for Imfinzi with etoposide plus either carboplatin or cisplatin and remain on track for more approvals soon as we provide patients an important new 1st-line treatment option,” said José Baselga, MD, PhD, executive vice president, Oncology Research & Development, AstraZeneca, in a press statement.

In terms of safety, all drugs demonstrated a consistent profile with previous reports. These final data will be presented at an upcoming medical meeting.

The phase III trial enrolled a total of 805 patients who were randomized 1:1:1 to either the control arm of platinum—etoposide alone (n = 269), durvalumab plus chemotherapy (n = 268), or the triplet arm of the PD-L1 inhibitor, CTLA-4 inhibitor, and chemotherapy (n = 268).

Previously,results from an interim analysis of the CASPIAN trialwere published in The Lancetand showed that OS was significantly improved with the first-line combination of durvalumab and platinum—etoposide in patients with ES-SCLC.²

The hazard ratio for improvement in OS in the durvalumab group versus the platinum—etoposide group was 0.73 (95% CI, 0.59-0.91;P= .0047). The median OS was 13.0 months in the durvalumab combination arm (95% CI, 11.5-14.8) and 10.3 months in the platinum—etoposide monotherapy arm (95% CI, 9.3-11.2). At 18 months, 34% of patients who received durvalumab were alive (range, 26.9-41.0), and 25% of patients who received platinum–etoposide only were still alive (range, 18.4-31.6).

Grade 3/4 adverse events (AEs) of any cause occurred in 62% of patients in the durvalumab combination arm (n = 163), as well as 62% of patients in the platinum—etoposide monotherapy arm (n = 166). In 5% of patients who were treated with durvalumab (n = 13), AEs led to death. This was also the case for 6% of the patients in the platinum–etoposide monotherapy arm (n = 15).

Immune-mediated AEs were also observed in 20% (n = 52) of the patients in the durvalumab arm and 3% of those in the platinum—etoposide (n = 7), which were predominantly grades 1 and 2 in severity. Grade 3 or higher immune-mediated AEs did occur in 5% of the patients who were treated with durvalumab plus platinum–etoposide (n = 12), and in 1% of those treated with platinum–etoposide only (n = 1). One percent of patients in each group died as a result of an immune-mediated AE, which was hepatotoxicity in the durvalumab plus platinum–etoposide arm and pneumonitis in the monotherapy arm. The most common grade 1/2 immune-mediated AEs in the durvalumab combination arm and the platinum–etoposide monotherapy arm, respectively, were hypothyroid events (9% vs 1%) and hyperthyroid events (5% vs 0%).

The goal of the phase III randomized, multicenter, open-label, comparative study (CASPIAN), was to determine the efficacy of durvalumab or durvalumab and tremelimumab in combination with platinum-based chemotherapy as a first-line treatment of patients with ES-SCLC. The primary end point of the study was OS, and the secondary end points were progression-free survival; objective response rate; the proportion of patients alive and progression-free at 6, 12, and 18 months from randomization; disease-related symptoms, health-related quality of life; the immunogenicity of durvalumab and tremelimumab; the pharmacokinetics of durvalumab and tremelimumab; and changes in WHO/ECOG performance status among participants.

All drugs in the study were administered intravenously. Patients received durvalumab 1500 mg either with or without tremelimumab 75 mg every 3 weeks plus 4 cycles of etoposide 80-100 mg/m² on days 1 to 3 and the investigator’s choice of carboplatin at area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m², which were given on day 1 of each cycle, followed by maintenance durvalumab 1500 mg every 4 weeks. In the control arm, patients received up to 6 cycles of platinum—etoposide.

The study included patients with a histologically or cytologically documented extensive disease. Patients with brain metastases were required to be asymptomatic or treated and stable without the need for steroids and anticonvulsants for at least 1 month before study treatment. Patients were also required to be suitable for treatment with platinum-based chemotherapy in the first-line setting, have an ECOG performance status of 0 or 1, have a life expectancy of more than 12 weeks on day 1, and have no prior treatment with immune-mediated therapy excluding therapeutic anticancer vaccines.

The study excluded individuals who had a history of radiotherapy to the chest prior to systemic therapy or planned consolidation chest radiation therapy, as well as those with paraneoplastic syndrome of an autoimmune nature requiring systemic treatment, active infection, active or previously documented autoimmune or inflammatory disorders, and uncontrolled concurrent illnesses, like interstitial lung disease.

Based on these earlier results from the CASPIAN study, the combination of durvalumab and platinum—etoposide is currently under review for regulatory action in the United States, Europe, and Japan for the treatment of patients with ES-SCLC.In November 2019, the FDA granted Priority Review to durvalumab in patients with previously untreated ES-SCLC, with a Prescription Drug User Fee Act date set for the first quarter of 2020.

References

1. Imfinzi confirmed a sustained overall survival benefit in final analysis of the Phase III CASPIAN trial in 1st-line extensive-stage small cell lung cancer [news release]. Cambridge, United Kingdom: Astra Zeneca; March 17, 2020. https://bit.ly/33oHdEV. Accessed March 17, 2020.
2. Paz-Ares L, Dvorkin M, Cehn Y, et al. Durvalumab plus platinum—etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.Lancet. 2019; 394: 1929—39. DOI: 10.1016/ S0140-6736(19)32222.