Nivolumab Monotherapy Tolerability For Advanced Melanoma Confirmed

Analysis of data from four clinical trials shows that the side effects of nivolumab monotherapy are generally low grade and resolvable

medwireNews: Pooled safety data for nivolumab monotherapy in advanced melanoma patients confirm that most treatment-related adverse events (AEs) are low grade and can be treated with immune-modulating agents.

The research published in the Journal of Clinical Oncology included 102 patients enrolled in two phase I trials and 474 patients enrolled in two phase III trials; all patients received at least one dose of nivolumab given at a dose of 3 mg/kg every 2 weeks, over a median duration of 3.7 months.

The majority (71.0%) of patients experienced at least one treatment-related AE apparent in at least 5% of patients, most commonly fatigue (24.8%), pruritus (17.2%), diarrhoea (12.7%), rash (12.7%) and nausea (12.0%). Almost half (49.0%) of the patients had at least one AE with a possible immunological aetiology, most commonly affecting the skin (34.0%) and gastrointestinal tract (GI; 13.4%).

In addition, 9.9% of patients had a grade 3 or 4 treatment-related AE, with diarrhoea, fatigue and rash again the most commonly reported side effects. Possible grade 3 or 4 AEs associated with immunological reactions were reported most commonly in the GI tract (1.2%), liver (1.0%) and skin (0.7%).

However, the authors note that a further five patients experienced grade 3 neurological AEs including dizziness, autoimmune neuropathy, central demyelination, involuntary muscle contractions and Guillain–Barré syndrome, the last of which was unresolved 16 weeks later at time of database lock.

In all, 3.0% of patients discontinued study treatment because of AEs, with most (2.1%) discontinuing because of grade 3 or 4 side effects, the researchers add.

Time to onset of treatment-related AEs with an immunological aetiology varied from a median of 5.0 weeks for skin complaints to 7.3 weeks for GI side effects and 10.4 weeks for endocrine AEs to 15.1 weeks for renal events.

“An awareness of the typical timing of onset of immune-related select AEs may aid in their early recognition and management in clinical practice”, say Jeffrey Weber, from the H Lee Moffitt Cancer Center in Tampa, Florida, USA, and co-workers.

The time to resolution of these immunological-related AEs ranged from 1.2 weeks for GI AEs and 6.0 weeks for pulmonary side effects to 18.0 weeks for skin events and 28.0 weeks for endocrine AEs.

A quarter (24.0%) of patients in the phase III trials were given systemic corticosteroids to manage immunological-related AEs, with topical and inhaled corticosteroids given to 16.0% and 1.0%, respectively. Another 0.6% of patients were treated with secondary immunosuppressive agents.

The researchers note that median progression-free survival was 4.7 months and this did not correlate with the presence or number of treatment-related AEs.

By contrast, the objective response rate (ORR) for nivolumab monotherapy was 31.4% and analysis showed that ORR was significantly higher in patients who reported treatment-related AEs of any grade than those who did not (48.6 vs 17.8 %).

The highest ORRs found in those with three or more events of any grade, or those with one or two events, than those with none (84.6 and 46.7 vs 17.8%), although ORR was independent of the number of grade 3 or 4 events.

Nor did ORR vary between patients who were and were not given systemic immune-modulating therapy.

“Appropriate management of select AEs is essential to reduce the risk for severe toxicity and enable nivolumab therapy to be continued where possible, maximizing its potential benefits”, Jeffrey Weber et al emphasize.

“Using the nivolumab safety management guidelines, involving the use of [immune-modulating agents] (primarily systemic corticosteroids), all but one grade 3 to 4 select AE resolved.”

However, the authors caution that “because these data were from clinical trials excluding patients with autoimmune disease, organ dysfunction, and active brain metastases, safety in these contexts requires further study.”


Weber JS, Hodi FS, Wolchok JD, et al. Safety profile of nivolumab monotherapy: A pooled analysis of patients with advanced melanoma. J Clin Oncol; Advance online publication 14 November 2016. DOI: 10.1200/JCO.2015.66.1389

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