Durvalumab after chemoradiotherapy improves survival in limited-stage SCLC

Dr David Spigel - Sarah Cannon Research Institute, Nashville, USA

This was a study called the ADRIATIC study. This was a phase III trial designed to assess the role of immunotherapy in the treatment of patients with limited-stage small cell lung cancer. Limited stage small cell lung cancer is a disease that we haven’t really made much progress in over the last many decades and the standard of care is chemotherapy with radiation given together. But even when you do that most patients have cancer return within two years and relatively few will live beyond five years.

So ADRIATIC was a study that was designed to assess the role of durvalumab, a PD-L1 antibody, with or without a drug called tremelimumab, a CTLA-4 antibody, when used as consolidation after concurrent chemoradiation in patients with limited-stage small cell lung cancer. It was a global randomised double-blind placebo-controlled phase III trial, all patients had limited-stage small cell lung cancer and good performance status and all patients had to have received chemotherapy and radiation together before they were randomised. Then something called PCI, or prophylactic cranial irradiation, was optional, it was up to the treating investigator. The chemoradiation was platinum etoposide for four cycles and radiation was once daily up to 66Gy or twice daily up to 45Gy. The radiation had to have started before the end of the second cycle of chemotherapy.

All patients were randomised to either durvalumab 1500mg IV monthly plus placebo or a combination with tremelimumab. The study was designed for patients to stay on therapy for up to two years unless they had side effects that were intolerable or they had disease progression. The analysis we presented was the primary analysis of durvalumab versus placebo looking at overall survival and progression free survival by blinded independent central review but there was a secondary analysis looking at durvalumab and the CTLA-4 antibody tremelimumab but that part of the study remains blinded for future analysis.

So the results for that durvalumab led to a statistically significant improvement in survival. The hazard ratio was 0.73, so a 27% reduction in the risk of death if you got durvalumab versus placebo. The median survival for durvalumab was 55.9 months versus 33. 4 months, so a 22.5 month improvement, nearly two year improvement in survival, that was highly statistically significant.

So that was the first major finding. The other major finding in the second primary endpoint of the study is that durvalumab led to an improvement in progression free survival. So the hazard ratio for benefit for that was 0.76, a 24% reduction in the risk of death or progression with durvalumab. The median progression free survival was 16.6 months versus 9.2, or a 7.4 month improvement in progression free survival. So the study hit its two main endpoints.

The regimen of durvalumab was safe, most of the toxicity was related to the chemoradiation. About 23% of patients in each arm had something called radiation pneumonitis. There were some additional side effects with durvalumab that included pneumonitis by itself as well as thyroid and skin disorders but nothing that was out of the ordinary with what we expect with durvalumab monotherapy that’s been known because we use it in other settings.

So, in conclusion, ADRIATIC resulted in durvalumab showing an improvement in both overall survival and progression free survival when used after concurrent chemoradiation in limited-stage small cell lung cancer. A major improvement, 22.5 months improvement, in overall survival and a major improvement in progression free survival of 7.4 months. So this, in my view, based on these results, would be a new standard of care for patients with limited-stage small cell lung cancer.