Durvalumab–Tremelimumab Dosage Identified For NSCLC Trials

Durvalumab plus tremelimumab dose-escalation study indicates dosage for non-small-cell lung cancer patients

medwireNews: Phase Ib trial findings have identified tolerable doses for a combined regimen of the anti-programmed death-ligand 1 (PD-L1) agent durvalumab and the anti-cytotoxic T-lymphocyte associated antigen (CTLA)-4 agent tremelimumab for patients with non-small-cell lung cancer (NSCLC).

The dose-escalation study of 102 patients with locally advanced or metastatic disease supports the use of durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg and has been adopted for phase III studies, say Naiyer Rizvi, Columbia University Medical Center in New York, USA, and co-authors in The Lancet Oncology.

Treatment-associated adverse events were reported by 61% of the 18 patients given the agents at this dosage, with 17% developing a grade 3 or 4 adverse event and 17% discontinuing treatment. The most common events of any grade were pruritus, rash, elevated aspartate aminotransferase, diarrhoea and hypothyroidism.

The researchers report that most events were “manageable and generally reversible with standard treatment guidelines”.

However, three patient deaths were associated with doses of durvalumab 10–20 mg/kg every 4 weeks plus tremelimumab 1–3 mg/kg. This included one death from myasthenia gravis complications, one case of pericardial effusion and one due to neuromuscular disorder.

The team also reports that the drug combination showed “evidence of clinical activity”, with a confirmed objective response in 23% of the 26 patients given durvalumab 10–20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg.

This included 22% of nine patients with at least 25% staining for PD-L1 and 29% of 14 patients with less than 25% staining, and the PD-L1-negative group with an objective response included four of the 10 patients who had zero PD-L1 staining.

“The clinical activity of durvalumab plus tremelimumab noted in patients with PD-L1-negative tumours is an important advance, because this population is less responsive to treatment with single drugs that block the PD-1 checkpoint pathway”, the researchers emphasize.

Edward Garon, from David Geffen School of Medicine at the University of California, Los Angeles in the USA, notes in an accompanying comment that phase III trials are already in progress, even though the drug combination has only short-term findings of 18 weeks for objective response and adverse events and a move to phase III studies would usually require further investigation into efficacy, survival and side effects.

“The reason for this aggressive approach is that researchers developing this particular combination have to contend both with competitors who are proceeding quickly with similar combinations for NSCLC and with those who are working to more fully define subgroups with disproportionate benefit and toxic effects”, he explains.

Edward Garon cautions: “Although this accelerated approach has the potential to validate a novel combination more quickly, the potential for negative consequences is real.

“The combination could be developed broadly when subgroups would benefit similarly from single drug PD-1 checkpoint inhibition without the additional toxic effects. Furthermore, the dosing regimen might not yet have been optimised.”


Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 2016; Advance online publication 5 February. DOI: http://dx.doi.org/10.1016/S1470-2045(15)00544-6

Garon EB. The race for combined checkpoint inhibition in NSCLC. Lancet Oncol 2016; Advance online publication 5 February. DOI: http://dx.doi.org/10.1016/S1470-2045(15)00580-X

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