Melanoma & NSCLC Patients Experience Various Side Effects With Nivolumab

In December of 2014, nivolumab (Opdivo) was approved to treat patients with unresectable or metastatic melanoma following other immunotherapies, and it has shown some promising results.

As of March 2015, nivolumab was also approved by the US Food and Drug Administration (FDA) to treat patients with previously treated metastatic squamous non-small cell lung cancer (NSCLC). This is important because squamous NSCLC does not have the same molecular mutations as we see in adenocarcinoma NSCLC (i.e., KRAS, EGFR, or BRAF mutations) allowing for various corresponding treatment options.

Nivolumab is the first of its class to show improved overall survival in the squamous NSCLC population. This biologic is a fully humanized monoclonal antibody using anti-PD-1 action against tumor cells. The programmed cell death protein 1 (PD-1) is an immune checkpoint inhibitor that stops the T-cell response and has an important role in T-cell function. A tumor cell may secrete a PD-1 ligand, essentially “turning off” the PD-1 activity from the T-cell and hence important immune surveillance and inhibiting apoptosis of tumor cells. This is considered the only immune-oncology option proven to extend survival up to 9.2 months versus 6 months in a phase III clinical trial with docetaxel as one arm of the study.

Recently, I attended an event sponsored by Bristol-Myers Squibb featuring a medical oncologist who shared his experiences with nivolumab. An interesting observation he shared was that the side effects seem to be slightly different in patients with melanoma compared to those with NSCLC. Here is a recap of some differences he shared:

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What was stressed during his experiences was the need to monitor for immune-mediated adverse reactions:

• Pneumonitis (this seems to occur for a longer duration in NSCLC patients versus melanoma patients).
• Colitis (seen in clinical trial in 1% to 2% of NSCLC patients).
• Hepatitis (increase in liver function levels).
• Nephritis (this immune-mediated adverse reaction is very rare, occurring less than 1%, but unique to nivolumab with a rise in creatinine seen and recommendation to stop therapy if creatinine is greater than 6).
• Thyroid dysfunction (suggested checking a thyroid-stimulating hormone level every other month).  
• Other reactions such as myasthenia gravis, multiple sclerosis, and Guillain-Barre can also occur.

Suspicion of an immune-mediated adverse reaction needs to be treated immediately, which may require hospitalization. Referral to respective specialists and use of prednisone at 1-2mg/kg IV with a taper that spans 1 to 4 weeks based on clinical observation of how the patient is responding may also be necessary. Steroid treatment may last up to 12 weeks. Nivolumab may be restarted while the patient is still on steroids as long as the adverse reaction is improving.

Case studies shared were impressive:

• An elderly female patient with NSCLC had not received nivolumab for over 9 months (due to noncompliance). Follow-up scans showed her tumor had not only decreased in size considerably (as witnessed prior at the end of active therapy via scans), but also was stable in 9 months after therapy discontinuation.
• Another case study highlighted a middle-aged man who had purely wild-type molecular study results from his genomic profile and responded to treatment through a clinical trial. Before treatment with nivolumab, this man was so fatigued and short of breath he could not complete any of his activities of daily living. Almost after 2 years on nivolumab, he was back to playing golf and “felt great.”

Clinical trials are underway for NSCLC maintenance considerations with nivolumab as well as combination treatment with a BRAF-inhibitor for melanoma patients. According to the National Cancer Institute, there are over 50 clinical trials underway that include nivolumab in some form. In addition, there are over 900 oncology clinical trials of immunotherapy in various stages of development.

Have you seen nivolumab used for melanoma or NSCLC patients in your facility? If so, do you have any clinical pearls to add?

References:

• Bristol-Myers Squibb (May 14, 2015). Healthcare provider event featuring new indication for nivolumab. Sponsored event, Louisville, KY.
• National Cancer Institute (2015). Clinical Trials Search Results.