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New Nivolumab Dosing
A New Nivolumab Dosing Option for Our Patients With Advanced NSCLC

Released: April 16, 2018

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The development of PD-1/PD-L1 inhibitors in non-small-cell lung cancer (NSCLC) has been rapid, with data from clinical trials showing good tolerability, efficacy, and safety profiles across a range of agents and doses. For example, a phase I study of the PD-1 inhibitor nivolumab evaluated doses of 1, 3, and 10 mg/kg, each given every 2 weeks, in patients with advanced NSCLC. Although the 1-mg/kg dose was not particularly effective, there was no notable difference in efficacy between the 3-mg/kg vs 10-mg/kg doses. Similarly, 3 dosing schedules of pembrolizumab, 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, and 10 mg/kg every 3 weeks, were shown to have similar efficacy and safety in clinical studies. Thus, the initial approval of nivolumab was for 3 mg/kg every 2 weeks, and the PD-1 inhibitor pembrolizumab was approved for 2 mg/kg every 3 weeks.

In 2016, fixed dosing replaced body weight–based dosing for these agents in progressive metastatic NSCLC as follows: nivolumab at 240 mg every 2 weeks, pembrolizumab (for patients with PD-L1 expression ≥ 1%) at 200 mg every 3 weeks, and the PD-L1 inhibitor atezolizumab at 1200 mg every 3 weeks. Although nivolumab had the most-frequent dosing requirement, a recent FDA approval has changed that.

Nivolumab: New Dosing Option
In March 2018, the FDA approved a new dosing option for nivolumab—480 mg every 4 weeks. This dosing schedule is being evaluated in the ongoing phase IIIb/IV CheckMate 384 study, which randomized patients with NSCLC doing well on the every 2 week nivolumab regimen to 480 mg every 4 weeks vs the standard 240 mg every 2 weeks. To date, this study has not reported data. Less frequent dosing furthers our goal of using PD-1 inhibitors to transform NSCLC in some patients into a manageable chronic disease in which patients are minimally encumbered with ongoing monitoring and treatment.

When we contemplate managing NSCLC as a chronic disease, I find data from the CheckMate 153 study to be particularly important to consider. This large, community-based study randomized patients with advanced NSCLC following 1 year on nivolumab therapy to either continue or discontinue nivolumab treatment. The patients who continued nivolumab had significantly better clinical outcomes compared with those who stopped. If we will be treating people for years—which these data support—then it will be preferable to not require patients to come in every 2 weeks.

Implications for Safety
There are 2 important questions regarding safety for this new nivolumab dosing option. First, what are the potential adverse events at the increased, although less frequent, dosing level? Given that we have no published data from CheckMate 384, we must extrapolate from other sources. As I mentioned, PD-1/PD-L1 inhibitors in general have been shown in clinical trials to have good tolerability and safety profiles across a range of doses.

Second, can we promptly identify adverse events when our patients are only coming in every 4 weeks? Although we can rely on patient reporting for symptomatic toxicities, some toxicities can be identified earlier by laboratory testing. Therefore, if thyroid or liver function testing is done less frequently, then the patient may be at risk of more advanced damage. However, this small potential disadvantage needs to be weighed against significantly increased convenience. Practitioners uncomfortable with this recently approved dose and schedule or with concern for a particular patient can still of course used the approved 240 mg every 2 week dosing.

Your Thoughts
Do you plan on using the newly approved 4-week dosing schedule for nivolumab in your patients with advanced NSCLC? If so, for which patients? Please share your thoughts by joining the conversation in the comments box below and responding to the polling question at the right of your screen.