Consolidation durvalumab poised to become ‘new standard’ for limited-stage SCLC

Consolidation treatment with the PD-L1 antibody durvalumab following concurrent chemoradiotherapy significantly prolonged overall (OS) and progression-free survival (PFS) in patients with limited-stage small-cell lung cancer (SCLC), as shown in the interim analysis of the phase III ADRIATIC trial.

“With a little over 3 years of follow-up [median, 37.2 months], the median OS with durvalumab was 55.9 months, compared with 33.4 months with placebo, nearly a 2-year advantage,” reported lead investigator Dr David Spigel from Sarah Cannon Research Institute in Nashville, Tennessee, US.

Durvalumab was associated with a 27 percent reduction in the risk of death (hazard ratio [HR], 0.73; 95 percent confidence interval [CI], 0.57–0.93; p=0.0104), with the survival benefit consistently observed across all subgroups, including those defined by age, gender, race, chemotherapy use, radiation schedule, or the use of prophylactic cranial irradiation, Spigel added. [ASCO 2024, abstract LBA5]

Results for the co-primary endpoint of PFS also favoured durvalumab, with an advantage of about 7.4 months over placebo (median, 16.6 vs 9.2 months) during a median follow-up of 27.6 months, according to Spigel. There was a 24-percent decrease in the risk of progression or death (HR, 0.76; 95 percent CI, 0.61–0.95). This PFS benefit with durvalumab was consistent across all predefined subgroups, similar to the pattern observed for OS.

The 3-year landmark OS rates were 56.5 percent with durvalumab and 47.6 percent with placebo, and the respective 2-year landmark PFS rates were 46.2 and 34.2 percent.

In terms of safety, durvalumab treatment for up to 2 years was well tolerated, Spigel said, adding that the safety findings were in line with the established safety profile of the drug as a monotherapy in the postconcurrent chemoradiotherapy setting.

Both the durvalumab and placebo arms received nine cycles of therapy. The frequency of grade 3/4 adverse events (AEs) was 24 percent in each arm, with AEs leading to treatment discontinuation in 16.4 percent of patients in the durvalumab arm compared with 10.6 percent in the placebo arm. Grade 3/4 immune-mediated AEs were seen in 5.3 and 1.5 percent of patients in the respective arms.

Radiation pneumonitis was the most common AE (22.9 vs 23.4 percent). When pneumonitis, radiation pneumonitis, and other lung toxicities were combined, the rates of all-grade pneumonitis were 38.2 percent with durvalumab and 30.2 percent with placebo. Grade 3/4 pneumonitis occurred in 3.1 percent and 2.6 percent of patients, respectively. One patient in the durvalumab arm had a grade 5 pneumonitis-related event. Pneumonitis led to treatment discontinuation in 8.8 and 3.0 percent of patients, respectively.

Being the first phase III study to establish the role of immunotherapy in limited-stage SCLC, ADRIATIC shows that “consolidation durvalumab will become the new standard of care for patients with limited stage SCLC who have not progressed after concurrent chemoradiotherapy,” said Spigel, whose presentation was met with audience acclaim.

Huge survival advantage

Study discussant Dr Lauren Byers from the University of Texas MD Anderson Cancer Center in Houston, Texas, US, echoed Spigel, saying that the ‘groundbreaking’ ADRIATIC establishes consolidation durvalumab as a new standard of care, ushering in a new era for limited-stage SCLC treatment, which has been largely unchanged since the 1980s.

"What truly stands out in ADRIATIC is the magnitude of survival benefit obtained with the addition of anti–PD-L1 therapy," Byers noted. The increase in OS of almost 2 years in limited-stage disease “looks very different” from what has been seen for extensive-stage disease in two landmark trials CASPIAN and IMpower, which was in the range of approximately 2 months.

This huge difference may be related to distinct therapeutic vulnerabilities across four molecular subtypes of SCLC. Byers cited a study wherein she and her colleagues analyzed data from the CASPIAN and IMpower trials and found that two subgroups, identified as 'inflamed' and POU2F3, had higher levels of inflammation and seemed to experience greater benefit from adding anti–PD-L1 therapy.

“Interestingly, in limited-stage SCLC, the POU2F3 and the inflamed subtypes, are actually more frequent than in extensive-stage SCLC,” she noted.

The next step in the research, according to Byers, is “moving beyond one-size-fits-all and towards personalized biomarker-driven approaches for patients with SCLC.”

As the field enters an exciting era where diverse treatment options are available, “we’ll need to be able to think about how we select the best treatment for each patient. And this will require having biomarkers,” she said.

ADRIATIC

ADRIATIC enrolled 730 patients (median age, 62 years; male, 69 percent) with stage I–III limited-stage SCLC (87 percent had stage III disease), a WHO performance status of 0/1, and who had not progressed after concurrent platinum-based chemoradiotherapy. Some patients underwent prophylactic cranial irradiation before randomization.

The patients were randomly assigned to receive either durvalumab 1,500 mg every 4 weeks (n=264), placebo (n=266), or durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks for four doses followed by durvalumab 1,500 mg monthly (n=200). The chemotherapy regimen consisted of four cycles of platinum and etoposide, while the radiation therapy was delivered either over 3 weeks, with options for either a single daily dose of up to 66 Gy or twice-daily doses of up to 45 Gy.

In the interim analysis, the investigators only looked at the difference between the durvalumab and placebo arms.