Confirmed: OS Better With Immunotherapy in Small Cell Lung Cancer

Pam Harrison

September 13, 2019

BARCELONA, Spain — A second phase III trial supports an overall survival (OS) benefit from adding a programmed cell death ligand (PD-L1) inhibitor to standard chemotherapy compared with standard chemotherapy alone for patients with extensive stage, small cell lung cancer (ES-SCLC), the CASPIAN study indicates.

Last year, investigators from the IMpower133 trial showed for the first time that atezolizumab (Tecentriq, Genentech), another PD-L1 inhibitor, improved OS in patients with ES-SCLC, prolonging life by 30% compared with standard chemotherapy alone, the first advance in the treatment of this disease in many decades. The presentation took place at the IASLC 2018 World Conference on Lung Cancer.

Now, here at this year’s 2019 meeting, another group of investigators demonstrated that the addition of durvalumab (Imfinzi, AstraZeneca) to either carboplatin (Paraplatin, Bristol-Myers Squibb) or cisplatin (Platinol, Bristol-Myers Squibb) plus etoposide (EP), followed by maintenance durvalumab, prolonged survival by 27% compared to chemotherapy alone, despite the fact that patients in the chemotherapy group could receive an additional two cycles of treatment compared with those in the additional durvalumab group.

"Initial response rates to etoposide plus a platinum are high, but responses are not durable and patients treated with EP typically relapse within 6 months of starting treatment with a median OS of approximately 10 months," said investigator Luis Paz-Ares, MD, professor of medicine at Hospital Universitario 12 de Octubre, Madrid, Spain, during a press briefing here.

"CASPIAN showed that first-line treatment with durvalumab plus EP significantly improved OS compared with a robust control arm that allowed up to six cycles of EP and the use of prophylactic cranial irradiation (PCI), suggesting that this is an important new treatment option for ES-SCLC patients," he concluded.

CASPIAN Study Design

Some 268 patients with ES-SCLC were randomly assigned to durvalumab plus EP followed by maintenance durvalumab, while 269 patients received the same backbone EP regimen alone.

Patients had to have a good performance status for study enrollment, but the trial permitted study enrollment of patients with brain metastases, as Paz-Ares observed.

Durvalumab was given at dose of 1500 mg together with EP every 3 weeks for up to 4 cycles followed by the same dose of durvalumab given as maintenance therapy every 4 weeks until disease progression.

In the chemotherapy alone group, EP was given every 3 weeks for up to 6 cycles, plus investigators could use PCI at their discretion. As Paz-Ares noted, approximately 57% of patients in the chemotherapy alone group received 6 cycles of EP and approximately three quarters of the platinum used in the EP regimen was carboplatin.

The average number of doses of durvalumab given to those in the experimental group was 7.

The main finding was an improvement in OS, where the median OS was 13.0 months in the durvalumab plus EP group compared with 10.3 months in the EP group, Paz-Ares reported.

At 12 months following study enrollment, 53.7% of patients in the additional PD-L1 group were still alive compared with 39.8% of those in the EP alone group; at 18 months, 33.9% of patients in the additional durvalumab group were still alive compared with 24.7% of patients in the EP group, for a hazard ratio (HR) of 0.73, Paz-Ares noted.

Progression-free survival (PFS) rates were also in favor of the durvalumab plus EP group: at 12 months, 17.5% of patients in the experimental group were free of progression compared with 4.7% of those in the EP group.

Rates of grades 3 and 4 adverse events (AEs) were very comparable between the two groups, at 61.5% for the durvalumab plus EP group vs 62.4% for the EP alone group.

Similarly, rates of serious AEs were comparable at 30.9% and 36.1% for the durvalumab plus EP group vs EP alone, respectively; rates of AEs leading to discontinuation were identical in both groups at 9.4%.

Immune-mediated AEs however, were unsurprisingly higher at 19.6% in the additional PD-L1 inhibitor group vs 2.6% in the EP alone group.

Modest Improvement?

Commenting on the study, discussant Myung-Ju Ahn, MD, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, suggested that the addition of the PD-L1 inhibitor to standard etoposide plus platinum chemotherapy led to improvements in OS which in her view were "very modest."

Nevertheless, IMpower133 investigator Stephen Liu, MD, Georgetown University, Washington, DC, last year said that  "a reduction in the risk of death by 30% meets our bar for significant improvement" — especially since many trials in ES-SCLC have failed to move the needle forward in any meaningful way, he noted.

Discussant Ahn appeared to eventually agree with Liu, noting that while IMpower133 was the first to show that the addition of an immune checkpoint inhibitor to standard chemotherapy does have clinical benefit in this disease, "CASPIAN confirmed the role of immune checkpoint inhibitors in ES-SCLC," Ahn said.

"And durvalumab plus etoposide and carboplatin or cisplatin can be considered a new standard in ES-SCLC," she concluded.

Paz-Ares declares he has served on advisory boards for AstraZeneca, Amgen, Blueprint, Bayer, MSD, BMS, IPSEN, Novartis, Lilly, Merck, Roche, Sanofi, and AAA. Ahn has disclosed no relevant financial relationships.

IASLC World Conference on Lung Cancer (WCLC) 2019: Abstract PL02.11. Presented September 9, 2019.

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