Consolidation Durvalumab to Become New SOC for LS-SCLC After Chemoradiation

The administration of durvalumab (Imfinzi) as consolidation treatment after concurrent chemoradiation significantly improved survival vs placebo in patients with limited-stage small cell lung cancer (LS-SCLC)—a population that has not seen major therapeutic advances in several decades, according to data from the first planned interim analysis of the phase 3 ADRIATIC study (NCT03703297).

The findings, which were shared during a press briefing at the 2024 ASCO Annual Meeting, revealed that at a median follow-up of 37.2 months (range, 0.1-60.9) in censored patients, the median overall survival (OS) with durvalumab (n = 264) was 55.9 months (95% CI, 37.3-not evaluable) vs 33.4 months (95% CI, 25.5-39.9) with placebo (n = 266), translating to a 27% reduction in the risk of death (HR, 0.73; 95% CI, 0.57-0.93; P = .0104).

Moreover, at a median follow-up of 27.6 months (range, 0.0-55.8), the median progression-free survival (PFS) was 16.6 months (95% CI, 10.2-28.2) with durvalumab vs 9.2 months (95% CI, 7.4-12.9) with placebo, equating to a 24% reduction in the risk of disease progression or death (HR, 0.76; 95% CI, 0.61-0.95; P = .0161).

“In conclusion, durvalumab as consolidation treatment after concurrent chemoradiotherapy demonstrated statistically significant and clinically meaningful improvement in both OS and PFS compared with placebo in patients with LS-SCLC,” David R. Spigel, MD, medical oncologist and chief scientific officer at Sarah Cannon Research Institute, in Nashville, Tennessee, said in a presentation of the data. “The treatment benefit was generally consistent across predefined subgroups for both OS and PFS, and consolidation treatment up to 2 years was well tolerated…Consolidation durvalumab will become the new standard of care [SOC] for patients with LS-SCLC following chemoradiotherapy.”

The current SOC for patients with LS-SCLC is concurrent chemoradiotherapy; however, most patients will relapse within 2 years of treatment, and the 5-year survival rate only ranges from 29% to 34%. The rationale for the ADRIATIC trial was supported by findings from the pivotal phase 3 PACIFIC (NCT02125461) and CASPIAN (NCT03043872) studies, according to Spigel.

“The PACIFIC study looked at the role of durvalumab after concurrent chemoradiotherapy for stage III non–small cell lung cancer, and that demonstrated an improvement in both OS and PFS,” he reported. “But the CASPIAN study also looked at durvalumab with platinum etoposide chemotherapy, and that showed an improvement in OS when used in newly diagnosed patients with extensive-stage SCLC.”

With ADRIATIC, investigators are examining the role of the PD-L1 antibody, durvalumab, with or without the CTLA-4 antibody, tremelimumab (Imjudo), as consolidation therapy after concurrent chemoradiation in those with LS-SCLC. At the 2024 ASCO Annual Meeting, Spigel shared data focused on comparing durvalumab with placebo in this population. Data regarding the combination will be shared at a later date, he noted.

The double-blind, placebo-controlled, multicenter, international, phase 3 ADRIATIC study enrolled patient with stage I to III LS-SCLC, including those with stage I/II inoperable disease. Patients were required to have a World Health Organization performance status of 0 or 1, and they could not have progressed after concurrent chemoradiation. Prophylactic cranial irradiation (PCI) was permitted prior to randomization.

“The chemotherapy used was platinum etoposide, up to 4 cycles, and the radiation therapy could either be once daily up to 66 Gy, or twice a day up to 45 Gy,” Spigel noted.

Participants (n = 730) were randomized to one of three arms: single-agent durvalumab at 1500 mg every 4 weeks, placebo every 4 weeks, or durvalumab at 1500 mg every 4 weeks plus tremelimumab at 75 mg every 4 weeks for 4 doses, followed by durvalumab monotherapy given at 1500 mg every 4 weeks (n = 200). Treatment continued until investigator-determined disease progression, unacceptable toxicity, or up to 24 months. Stratification factors included disease stage (I/II vs III) and whether patients received PCI (yes vs no).

The dual primary end points were OS and PFS by blinded independent central review (BICR) and RECIST 1.1 criteria with durvalumab alone vs placebo. Key secondary end points are focused on examining the OS and PFS by BICR and RECIST 1.1 criteria with durvalumab plus tremelimumab vs placebo. Safety and quality-of-life analyses were also performed, Spigel said.

Additional efficacy data showed that at the 3-year landmark analysis, the OS rates were 56.5% with durvalumab vs 47.6% with placebo. At the 2-year landmark analysis, the PFS rate with durvalumab was 46.2% vs 34.2% with placebo.

Regarding safety, any-grade, all-cause adverse effects (AEs) occurred in 94.3% of evaluable patients who received durvalumab (n = 262) vs 88.3% of those given placebo (n = 265); these effects were grade 3/4 in severity for 24.4% and 24.2% of patients, respectively. Serious AEs occurred in 29.8% of those given durvalumab vs 24.2% of those given placebo.

AEs led to treatment discontinuation for 16.4% and 10.6% of patients, respectively; they resulted in death for 2.7% and 1.9% of patients, respectively. Specifically, two patients on the durvalumab arm experienced treatment-related AEs that proved fatal; causes of death were encephalopathy and pneumonitis.

Moreover, any-grade immune-mediated AEs were reported in 32.1% of those in the durvalumab arm vs 10.2% of those in the placebo arm; these effects were grade 3 or 4 in severity for 5.3% and 1.5% of patients, respectively. Any-grade pneumonitis or radiation pneumonitis occurred in 38.2% of those who received durvalumab vs 30.2% of those given placebo; these effects were grade 3/4 for 3.1% and 2.6% of patients, respectively.
“This study [showed that durvalumab] had a very good safety profile. Looking at grade 3/4 AEs, these [rates] were nearly identical in each arm, at 24%,” Spigel concluded. “…The safety signals were really consistent with what is already known for monotherapy with durvalumab following concurrent chemoradiation.”

After the presentation, Lauren A. Byers, MD, ASCO expert and professor and thoracic section chief in the Department of Thoracic-Head & Neck Medical Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, commented on the study and its significance: “SCLC is one of the most aggressive types of lung cancer. As you heard from Dr Spigel, the treatment for patients with LS-SCLC who are being treated with the intent of cure has not changed since the 1980s. The ADRIATIC trial is a landmark study and provides a new SOC with the addition of immunotherapy for patients with early-stage SCLC who are being treated with a goal of curing their cancer.”

She added, “It’s also an important study because of the magnitude of benefit that patients received with the addition of durvalumab consolidation, with an average improvement in OS around 2 years. This is in contrast to many clinical trials in SCLC, where often, the benefit may only be measured in months. Similar to other lung cancers, and you’ve heard about many advances related to personalization of lung cancer treatment for patients, we now know that SCLCs are really different types of lung cancers. And so, I think one important next step will be to understand who's benefiting the most with the addition of durvalumab and how can we start thinking about personalizing treatment for the different subtypes of SCLC to further build on this and continue to make progress for these patients.”

Reference

Spigel DR, Cheng Y, Cho BC, et al. ADRIATIC: durvalumab (D) as consolidation treatment (tx) for patients (pts) with limited-stage small-cell lung cancer (LS-SCLC). J Clin Oncol. 2024;42(suppl 17):LBA5. doi:10.1200/JCO.2024.42.17_suppl.LBA5