Consolidation therapy with the PD-1 immune checkpoint inhibitor durvalumab is set to become the new global standard of care for patients with limited-stage small cell lung cancer (SCLC), according to groundbreaking data presented at the European Society for Medical Oncology (ESMO) Congress 2024.¹ These findings from the phase III ADRIATIC trial represent the first major progress in the treatment of limited-stage SCLC in nearly 40 years.

After a first interim analysis showed significant improvements in overall survival and progression-free survival with durvalumab vs placebo consolidation in patients with limited-stage SCLC without disease progression after concurrent chemoradiotherapy,² a new subgroup analysis supports the use of durvalumab, irrespective of prior concurrent chemoradiotherapy regimens and use of prophylactic cranial irradiation.

Stephen Liu, MD

Invited discussant of the ADRIATIC trial, Stephen Liu, MD, Director of Thoracic Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center, in Washington, DC, called the -survival results “astounding” and was encouraged by the updated analysis showing improved overall survival across all relevant subsets. Durvalumab consolidation therapy was associated with nearly 2-year longer median overall survival and more than 7-month-longer median progression-free survival compared with placebo in patients with limited-stage SCLC. 

“Consolidation durvalumab consistently improved overall survival and progression-free survival vs placebo across the presented subgroups, further supporting its use as a new standard of care in limited-stage small cell lung cancer,” stated lead study author Suresh Senan, MRCP, FRCR, PhD, Professor of Clinical Experimental Radiotherapy at the Amsterdam University Medical Center, Cancer Center Amsterdam, in the Netherlands.

Suresh Senan, MRCP, FRCR, PhD

Background and Study Details

As Dr. Senan explained, SCLC accounts for approximately 10% to 15% of all lung cancers and is known for its aggressive nature and poor prognosis. Limited-stage disease, where cancer is confined to one side of the chest, represents about 30% of SCLC cases at diagnosis.

The ADRIATIC trial enrolled 730 patients with limited-stage SCLC (stage I/II inoperable) who had completed concurrent chemoradiotherapy without disease progression. Patients were stratified by disease stage and prophylactic cranial irradiation use. Then they were randomly assigned to receive up to 24 months of treatment with 1,500 mg of durvalumab every 4 weeks, placebo, or a combination of durvalumab and the monoclonal antibody tremelimumab.

The study enrolled patients with a World Health Organization performance score of 0 or 1, allowing up to four cycles of platinum-based chemotherapy (cisplatin or carboplatin) with etoposide. Radiotherapy could be administered once or twice daily, and prophylactic cranial irradiation was permitted but not mandated. The dual primary endpoints were progression-free survival and overall survival.

Survival Benefits Across Patient Subgroups

After a median follow-up of 37.2 months, median overall survival was 55.9 months in the durvalumab group vs 33.4 months in the placebo group (hazard ratio [HR] = 0.73, P = .0104). Median progression-free survival was 16.6 months with durvalumab vs 9.2 months with placebo (HR = 0.76, P = .0161). The current analysis focused on subgroups defined by prophylactic cranial irradiation use, chemotherapy regimen, and radiotherapy schedule. Key findings from the subgroup analyses include the following:

• Subgroups With and Without Prophylactic Cranial Irradiation: Among patients who underwent prophylactic cranial irradiation, the 3-year overall survival rate was 62.1% with durvalumab (median not reached) vs 56.5% for placebo (median 42.5 months). In the non–prophylactic cranial irradiation group, the rate was 50.2% with durvalumab (median 37.3 months) vs 37.3% with placebo (median 24.1 months). The 2-year progression-free survival rates also favored durvalumab: in the prophylactic cranial irradiation group, 54.6% with durvalumab (median 28.2 months) vs 38.5% with placebo (median 13.0 months). In the non–prophylactic cranial irradiation group, the rate was 37.1% with durvalumab (median 9.1 months) vs 29.3% with placebo (median 7.4 months).
• Chemotherapy Regimen: Benefit from durvalumab was seen for patients who received either cisplatin or carboplatin. The 3-year overall survival rate with carboplatin was 65.3% for durvalumab (median not reached) vs 46.7% for placebo (median 33.4 months). For cisplatin, the rate was 52.1% for durvalumab (median 41.9 months) vs 48.1% for placebo (median 34.3 months).
• Radiotherapy Schedule: Benefits of durvalumab were seen with both once-daily and twice-daily radiotherapy schedules. Multivariable hazard ratios for overall survival were 0.71 and 0.73 for twice-daily and once-daily groups, respectively.

The safety profile of durvalumab was also generally consistent across all subgroups, with higher rates of grade 3 or 4 treatment-emergent adverse events observed with prophylactic cranial irradiation and carboplatin, said Dr. Senan. However, rates of treatment discontinuation because of adverse events were similar across treatment arms.

“Of note, multivariable analysis showed no significant interactions between durvalumab treatment effect and prophylactic cranial irradiation or concurrent chemoradiotherapy subgroups,” said Dr. Senan. “Ongoing research is exploring the earlier administration of immunotherapy during delivery of concurrent chemoradiotherapy and that newer agents are being incorporated into the treatment of limited-stage SCLC.”

EXPERT POINT OF VIEW

Invited discussant of the ADRIATIC trial, Stephen Liu, MD, Director of Thoracic Oncology at Georgetown University’s Lombardi Comprehensive Cancer Center, Washington, DC, underscored the significance of the ADRIATIC trial. He called the results “astounding,” with a “near 2-year improvement in median overall survival, establishing a new global standard of care.” Dr. Liu noted that although the trial design reflects current practice variations, the subset analyses raised important questions about how they should influence future clinical decisions.

Regarding prophylactic cranial irradiation, Dr. Liu pointed out that only about half of the patients in ADRIATIC received prophylactic cranial irradiation, reflecting evolving views on its use. Although durvalumab showed consistent benefit regardless of prophylactic cranial irradiation use, Dr. Liu cautioned against drawing conclusions about the efficacy of prophylactic cranial irradiation from this trial. He highlighted ongoing studies like SWOG S1827 and PRIMALung (EORTC-1901), which are specifically designed to address the role of prophylactic cranial irradiation in modern treatment of small cell lung cancer (SCLC).

With respect to radiation schedules, Dr. Liu noted that durvalumab’s benefit was consistent across once-daily and twice-daily regimens. However, he warned against inferring superiority of twice-daily radiation based on better outcomes in that subgroup, citing potential selection bias.

Perhaps most intriguing was Dr. Liu’s discussion of the unexpected findings regarding platinum choice. Contrary to established belief, patients who received carboplatin had better outcomes than those who received cisplatin. Dr. Liu called these results “puzzling” and “inconsistent with everything we’ve learned about these agents.” He speculated whether there might be something unique about SCLC in the context of radiation that makes carboplatin a better partner but emphasized this finding requires further investigation.

Dr. Liu concluded by comparing the ADRIATIC results with those of the CASPIAN trial in extensive-stage SCLC. Although both trials showed similar hazard ratios for durvalumab, the magnitude of survival benefit was dramatically different: 2 months in CASPIAN vs 2 years in ADRIATIC. This stark contrast, Dr. Liu argued, underscores the critical importance of early detection in SCLC.

“To really make a big impact, we need to detect these cancers earlier,” Dr. Liu concluded. “Extensive-stage disease is more challenging to treat.”

DISCLOSURE: The ADRIATIC trial was funded by AstraZeneca. Dr. Senan reported financial relationships with AstraZeneca and Merck Sharp & Dohme. Dr. Liu reported financial relationships with AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Candel Therapeutics, Catalyst, Daiichi Sankyo, Elevation Oncology, Genentech/Roche, Gilead Sciences, Guardant Health, Janssen, Jazz Pharmaceuticals, Merck, Merus, Mirati Therapeutics, Novartis, OSE Immunotherapeutics, Pfizer, RAPT, Regeneron, Revolution Medicines, Sanofi, Takeda, and Yuhan.

REFERENCES

1. Senan S, Spigel DR, Cho BC, et al: Durvalumab as consolidation therapy in limited-stage SCLC. ESMO Congress 2024. Abstract LBA81. Presented September 13, 2024.

2. Spigel DR, Cheng Y, Cho BC, et al: ADRIATIC: Durvalumab as consolidation treatment for patients with limited-stage small-cell lung cancer. 2024 ASCO Annual Meeting. Abstract LBA5. Presented June 2, 2024.