NCCN Guidelines: Nivolumab in Frontline Setting

Richard S. Finn, MD: With this idea of autoimmune events, that would clearly exclude patients. Autoimmune backgrounds or phenomenon would put someone at risk for toxicity from IO [immune-oncology]. Obviously, it is pan-IO. Interestingly, the NCCN [National Comprehensive Cancer Network] guidelines left it open to use single-agent nivolumab in the frontline setting. I don’t know if you have any thoughts on that, Katie?

Katie Kelley, MD: In the NCCN guidelines, inclusion of the nivolumab is based on a couple of considerations. There are some patients who are not good candidates for any antiangiogenic therapy, whether it’s a TKI [tyrosine kinase inhibitor] or bevacizumab. I’ve had a few patients who have nonhealing wound complications after a big surgery, for example. I have also had patients who have a significant thrombotic predisposition or have had clots that are intractable on antiangiogenic therapy. There are some patients for whom we can’t use antiangiogenic therapies, and there are also some patients with poor-risk Child-Pugh B for whom we may not feel comfortable using some of our other agents.

For nivolumab, not only is there not the risk of antiangiogenic toxicity or comorbidity, but there are also some prospective safety data with respect to the CheckMate 040 Child-Pugh B cohort. That included patients with a score of up to B8. There were also some retrospective case series data suggesting that there is no impact on baseline liver function from nivolumab and that the rate of immune-related hepatotoxicity or hepatitis is similar in patients with Child-Pugh B as it is for patients with Child-Pugh A. The NCCN guideline inclusion reflects the fact that there are safety data for nivolumab in these contexts and that, while the CheckMate 459 first-line trial of sorafenib vs nivolumab did not meet its end points and was a negative study, we also know that there was a trend toward benefit, with the caution of interpreting trends like that. But we have the second-line data from CheckMate 040 that led to FDA approval in the second-line setting.

We have quality of life end points that support the use of nivolumab in this context. Overall, in a patient population for whom there is not an alternative good therapy either because of risk of toxicity or Child-Pugh B status, it’s a reasonable thing to consider in the absence of level 1 evidence favoring any other choice.

Richard S. Finn, MD: We can say that for the CheckMate 459 study, which was nivolumab vs sorafenib, while it was a negative study, the response rate was 20% and survival for that single-arm nivolumab group was 16 months.

Katie Kelley, MD: Exactly. I think we all agree that there is potential for benefit with nivolumab; it just did not meet its first-line outcomes.

Tony Bekaii-Saab, MD: If I may say though, Rich.

Richard S. Finn, MD: Yes, of course.

Tony Bekaii-Saab, MD: It’s a reasonable option; it’s more like rolling the dice though, for 2 reasons. The first is that I’m not sure that 20% of patients actually benefit more. It’s probably closer to 10% or less, which is not insignificant. The other thing is, the patients who are not eligible for atezolizumab/bevacizumab and that those you listed, Katie, are those who will not do well overall anyway. I understand that having this option is good, but the problem is that those patients are those who least benefit from therapy overall. It’s good to have that option.

At the same time, I always get concerned, especially with the NCCN guidelines listing these options, that sometimes the fine print doesn’t get read. You want to find a way to emphasize the fine print that says that this is the exception to the rule across the board. I would still think that lenvatinib or sorafenib would be preferable for patients who are eligible for it over nivolumab. I’m guilty as everyone else is, of having treated patients with nivolumab, single agent who exactly fit the patient profile that Katie described. I get concerned about the guidelines, not about the rationale to include it.

Katie Kelley, MD: I agree. I would definitely emphasize that I would consider it for patients who are not candidates for sorafenib or lenvatinib and don’t have a level 1 option, like the open chest wall wound from a bad surgery outcome. That is 1 example that comes to mind. I totally agree.

Transcript edited for clarity.