Dr. Antonia And Colleagues Report On The Combination Of...

In this issue of Lancet Oncology, Dr. Antonia and colleagues report on the combination of durvalumab and tremelimumab in patients with non-small cell lung cancer (NSCLC).1 After the recent approvals of nivolumab and pembrolizumab in NSCLC,2, 3, 4 there is a near frenzy of attempts to combine agents with inhibitors of the PD-1 immune checkpoint. Some efforts are based on only the shakiest of scientific evidence. However, the combination of durvalumab, a PD-L1 inhibitor, and tremelimumab, a CTLA-4 inhibitor, has a sound scientific basis. Dual checkpoint inhibition is now an established treatment option for patients with advanced melanoma.5, 6 Yet, concerns about this combination in NSCLC exist. First, as in melanoma, the toxicities of†¦show more content†¦The immaturity of the data is underscored by the disposition at the time of analysis. Patients were more likely to have discontinued based on adverse events than to have had disease progress or be continuing therapy. Although tolerability looked better when only patients receiving tremelimumab 1 mg were analyzed, even in that group, 30% of patients had a related grade 3 adverse event, with 16% of patients discontinuing due to an adverse event and 4% dying from the study therapy. For comparison, in the studies that led to approval of pembrolizumab and nivolumab, grade 3 related adverse events were seen in 7-10.5%, adverse events led to discontinuation of study therapy in 0.2-3.8% and death was related to study treatment in 0-0.3%.2, 3, 4 So, with this increase in toxicity over single agent inhibition of the PD-1 checkpoint, an increase in efficacy would be required to support development of the combination. At the doses of tremelimumab considered tolerable, among PD-L1 positive patients (based on staining in 25% of the cancer cells), the response rate does not appear superior to single agent PD-1 inhibition.2,4 However, among those without high level PD-L1 expression, 4 of 14 patients responded to the combination, while with approved agents, no more than 2 patients would anticipated to respond.2,4 With this data, we