Early Results Back Further Avelumab Development In Solid Tumours

Phase Ia and Ib findings from the JAVELIN Solid Tumor trial support continuing research into the IgG antibody avelumab

medwireNews: Avelumab – a human IgG1 antibody targeting programmed cell death ligand 1 (PD-L1) – has an acceptable safety profile and antitumour activity, including in patients with non-small-cell lung cancer (NSCLC), suggest two sets of findings published in The Lancet Oncology.

In the phase Ia dose-escalation stage of the JAVELIN Solid Tumour trial, 53 patients with metastatic or locally advanced, previously treated solid tumours and adequate end-organ function were given a 1-hour infusion of avelumab 1 mg/kg, 3 mg/kg, 10 mg/kg or 20 mg/kg every 2 weeks.

Dose-limiting toxicity analysis in 18 patients identified just one incident associated with the 20 mg/kg regimen, “and thus the maximum tolerated dose was not reached”, explain James Gulley, from the National Cancer Institute in Bethesda, Maryland, USA, and co-authors.

Common treatment-related adverse events in the whole study population included fatigue (40%), influenza-like symptoms (21%), fever (15%) and chills (11%), while 17% developed grade 3–4 events including autoimmune disorder in three cases, and two cases each of elevated blood creatine phosphokinase and elevated aspartate aminotransferase. Immune-related adverse events attributable to treatment occurred in 8%, 13% and 10% of patients in the 3, 10 and 20 mg/kg groups, respectively.

The researchers say that 8% of the 53 patients had a partial confirmed or unconfirmed response to avelumab therapy and 57% had stable disease, but note that the absolute lymphocyte count and immune cell subsets, including PD-L1 expressing cells, were not affected by avelumab.

“Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing”, the researchers write.

The phase Ib dose-expansion cohort of the JAVELIN Solid Tumor trial looked at the safety of the avelumab 10 mg/kg dose in 184 patients with platinum-resistant or recurrent stage IIIB or IV NSCLC.

James Gulley, who was again lead author, and team explain that patients were eligible to participate if they had squamous or nonsquamous tumour histology, and were not preselected on the basis of PD-L1 expression, or EGFR, KRAS or ALK status.

Over a median of 8.8 months, treatment-related adverse events of any grade included fatigue (25%), infusion-related reaction (21%) and nausea (13%), with 13% of participants experiencing grade 3 or more severe side effects and 9% serious treatment-related events. Immune-related adverse events occurred in 20%, with treatment-related such events in 12%.

A RECIST objective response to avelumab was confirmed in 12% of the patients, including one patient with a complete response and 21 patients with a partial response. A further 38% had stable disease, giving an overall disease control rate of 50%.

“These results with avelumab have provided the rationale for an ongoing phase 3 trial in the second-line NSCLC population and underscore the potential benefits of immunotherapy for patients with this difficult-to treat disease”, the investigators write.

The authors of an accompanying comment say that avelumab is “unique” because it is the only PD-L1 inhibitor that has been shown in preclinical research to induce natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC). But they note this additional effect was not apparent in the phase Ia study cell analysis or antitumour activity.

Athanasios Kotsakis, from the University of Crete in Greece, and Vassilis Georgoulias, from the Hellenic Oncology Research Group in Athens, Greece, also observe that while the avelumab toxicity profile was generally “similar and consistent” to other agents targeting PD-L1 or programmed cell death protein 1, more than 20% of patients in both phase Ia and Ib patients experienced immune-related reactions.

“Avelumab is the unique drug in this category that shows such a toxicity; this could be attributed to the different (IgG1) nature of this antibody, which merits further investigation”, they caution.

The commentators conclude that ongoing phase III research will shed further light on these issues and “hopefully clarify to some extent the precise role of this antibody in the treatment of patients with cancer.”


Heery CR, O’Sullivan-Coyne G, Madan RA, et al. Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial. Lancet Oncol; Advance online publication 31 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30239-5

Gulley JL, Rajan A, Spigel DR, et al. Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial. Lancet Oncol; Advance online publication 31 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30240-1

Kotsakis A, Georgoulias V. Avelumab, an anti-PD-L1 monoclonal antibody, shows activity in various tumour types. Lancet Oncol; Advance online publication 31 March 2017. DOI: http://dx.doi.org/10.1016/S1470-2045(17)30227-9

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