Balancing Safety and Efficacy in Adjuvant Therapy

Evan J. Lipson, MD: When I see a patient who is potentially a candidate for adjuvant therapy, I try to lay out the landscape of what the possible options look like. We talk about the benefits of using adjuvant therapy as a treatment strategy. We talk about the potential benefits of using treatment at an early stage where perhaps we’ll delay the return of disease or prevent the return of disease. We talk about the uncertainty around using therapy in the adjuvant setting vs using therapy if and when the disease comes back because it is still a bit uncertain. 

We talk about what the potential risks are for each of the approaches. We talk about the potential toxicities for immune checkpoint blocking therapy, specifically anti–PD-1 treatment. We talk about some of the short-term issues, and we talk about some of the longer-term issues. We also discuss the potential risks of BRAF/MEK therapy. We talk there about pyrexia, rash, and some of the possible impacts on cardiac function. We also talk about the general reversibility of most of the toxicities that you see with the targeted agents. It’s a pretty wide-ranging discussion that we have with patients who are considering adjuvant treatment for melanoma.

In some patients, the decision is quite clear. For example, the decision is clear in patients who have an immunological comorbidity where you’re concerned about exacerbating some underlying condition like severe rheumatoid arthritis. In patients at risk of exacerbating their arthritis or exacerbating some other autoimmune disorder, if targeted therapy is an option there with BRAF/MEK inhibition, then that often becomes the treatment of choice. With patients with a solid organ transplant, for example, BRAF/MEK therapy is an option that’s absolutely at the top of the list there.

There is also a lot about patient preference that comes into play. Some patients would rather come in on say an every 4-week or 6-week basis to get their therapy and not have to worry about taking a medicine on a daily basis at home. There is a lot that goes into these discussions. At the end of the day, it’s a case-by-case consideration in terms of which therapy we recommend for patients.

There is a particular patient population: patients with resected stage IIIA melanoma, for whom we dig down into the risk-benefit analysis. And the reason there is because, in many of the patients with stage IIIA disease, they will be surgically cured after resection of their disease. For some of them, the risk of a serious toxicity with these therapies often outweighs the risk that the disease will come back. There, we have a careful discussion about not just the adjuvant options, but also about observation alone. Some patients, after hearing what the potential risks and benefits of therapy are, especially the patients with stage IIIA, choose to monitor the disease carefully. They know that they’ve got therapy options at the ready if the disease were to come back.

The management of toxicities of the targeted agents is distinct from the management of the immune-related toxicities. For example, BRAF/MEK inhibitors are associated with pyrexia. Pyrexia can be mild, but pyrexia can also be severe and be associated with hypotension, chills, rigors, dehydration, and sometimes renal failure.

Fortunately, for most of the patients getting targeted therapies, the serious toxicities are quite rare, they are in the single digits. Having said that, it’s important to talk about these potential toxicities with patients and discuss what might be the response if these toxicities were to occur. There are well-established guidelines for when to hold the targeted agents and how to restart them, sometimes at the same dose, sometimes at lower dose. There is also guidance about when to permanently discontinue these agents. For example, this is the case in patients with a severe cutaneous reaction, such as a Stevens-Johnson–type syndrome, which can be life-threatening. In patients who are on targeted agents, we often have to discontinue that therapy permanently. 

We have a frank discussion with the patients about exactly what the toxicities could be, and we ourselves make sure that we are armed with guidance about how to manage toxicities of targeted agents vs immunotherapy appropriately.

An important consideration of immunotherapy vs targeted agents is that, in general, the targeted agent toxicities will reverse once the drug is stopped. That’s not an absolute truth, but for the majority of cases, that is the case. The same cannot be said of the toxicities that sometimes occur with immune checkpoint blocking therapies. For example, in patients who experience hypophysitis, which is an immune attack on the pituitary gland, that is often a lifelong toxicity that needs to be managed with replacement hydrocortisone. That needs to be discussed with a patient: you can sometimes get toxicities that will never go away.

In a young woman who is hoping to have a family at some point, it’s important to understand that the endocrine toxicities of some of the immune agents can be lifelong, and these therapies are worth discussing in detail to make sure that patients understand what the long-term consequences of some of the rarer toxicities might be. 

Transcript edited for clarity.