Another Win for Immunotherapy in Extensive-Stage SCLC

BARCELONA — Adding the PD-L1 checkpoint inhibitor durvalumab (Imfinzi) to standard chemotherapy improved survival in patients with extensive-stage small cell lung cancer (SCLC), the phase III CASPIAN trial found.

Among more than 500 patients, those randomized to durvalumab plus etoposide and platinum chemotherapy (cisplatin or carboplatin) lived a median 13.0 months compared with 10.3 months for those that received the standard chemotherapy regimen alone (HR 0.73, 95% 0.59-0.91), reported Luis Paz-Ares, MD, PhD, of 12 de Octubre University Hospital in Madrid.

“The CASPIAN trial met the primary endpoint,” Paz-Ares said during a press briefing at the World Conference on Lung Cancer (WCLC), calling the combination an “important” new treatment option for patients with extensive-stage SCLC.

The proportion of patients alive at 12 months improved from 39.8% to 53.7% with the addition of durvalumab. And from 24.7% to 33.9% at 18 months. Importantly, he added, all subgroups benefited from the addition of the anti-PD-L1 immunotherapy.

Secondary endpoints for efficacy all favored the investigational combination, with a 67.9% response rate with durvalumab compared with 57.6% with standard therapy. At 12 months, 22.7% of patients in the investigational arm had maintained their response compared with 6.3% in the control arm. Median duration of response, however, was the same for both arms (5.1 months).

With this data, durvalumab will likely join atezolizumab (Tecentriq) as a first-line checkpoint inhibitor option in extensive-stage SCLC. At the 2018 WCLC, the IMpower133 trial showed that adding atezolizumab to etoposide-carboplatin significantly improved progression-free survival (PFS) and overall survival in extensive-stage SCLC, leading to FDA approval in this setting.

WCLC session discussant Myung-Ju Ahn, MD, PhD, of Sungkyunkwan University in Seoul, South Korea, highlighted the similarities between the two studies, ranging from patients’ baseline characteristics, response rates, and survival outcomes.

She said durvalumab plus etoposide and platinum-based chemotherapy should be considered a new standard of care in extensive-stage SCLC, with CASPIAN confirming the results of IMpower133 and the role of anti-PD-1/PD-L1 immunotherapy in the first-line setting.

But Ahn added that the 3-month survival benefit is still “modest” and suggested the need for biomarkers for patient selection. PD-L1 expression has proved to be no help in SCLC. Retrospectively, tumor mutational burden (TMB) has shown promise for SCLC patients treated with nivolumab (Opdivo) plus ipilimumab (Yervoy), but TMB failed to predict outcomes with atezolizumab in IMpower133, even at the highest cutoffs, Ahn noted. TMB fizzled out at this meeting in the setting of non-SCLC.

In CASPIAN, median PFS was no better in the durvalumab arm (5.1 vs 5.4 months with standard chemotherapy). Paz-Ares speculated that this was because patients in the control arm were allowed to have up to six cycles of chemotherapy (vs four in the durvalumab arm), and pointed to the separation of the Kaplan-Meier curves starting at 6 months.

Across the whole study period, PFS favored durvalumab, however (HR 0.78, 95% CI 0.65-0.94), and the 12-month PFS rate improved from 4.7% to 17.5% with the addition of the PD-L1 inhibitor.

Ahn pointed to a possible “maintenance” or “delayed” effect of the continued immune checkpoint inhibition following the upfront combination of chemotherapy plus immunotherapy.

In both arms, 9.4% of patients discontinued treatment for toxicity and there were no new safety signals seen. Aside from immune-mediated adverse events (AEs), rates of AEs were largely similar between the durvalumab and control arms, respectively:

• Any AE: 98.1% vs 97.0%
• Grade 3/4 AEs: 61.5% vs 62.4%
• Serious AEs: 30.9% vs 36.1%
• Immune-mediated AEs: 19.6% vs 2.6%

CASPIAN randomized patients with extensive-stage SCLC to one of three first-line regimens: chemotherapy alone with optional prophylactic cranial irradiation (PCI); durvalumab plus chemotherapy; or durvalumab plus tremelimumab and chemotherapy. Data from the arm containing tremelimumab, an investigational CTLA-4 checkpoint inhibitor, were not presented at WCLC as the arm did not meet the survival endpoint for this interim analysis.

As such, Paz-Ares presented data on the 268 patients that received 1,500 mg durvalumab plus chemotherapy versus the 269 patients that received chemotherapy plus optional PCI. Most patients (>84%) received at least four cycles of chemotherapy. In the standard treatment arm, 57% received all six planned cycles. In the investigational arm, the median number of durvalumab doses was seven, with 24% receiving at least 12 doses.

Patients were stratified by type of chemotherapy, with roughly three-fourths in each arm receiving carboplatin — the remaining were treated with cisplatin. Patients enrolled in CASPIAN had good performance status, health, and organ function, but were allowed to have symptomatic metastases. In each arm, roughly 90% of patients had stage IV disease and about 10% had brain involvement.