Claire F. Verschraegen, MD, discusses how nivolumab and ipilimumab fit into the treatment paradigm, poses examples of when treatment-related adverse effects might influence which agents to use, and emphasizes the importance of considering the benefits of immunotherapy.
Claire F. Verschraegen, MD
Successful melanoma treatment decisions and sequencing are increasingly being guided by individual patient needs and comorbidities, although first-line immunotherapy, be it a combination or single agent, presents clear anticancer benefits, according to Claire F. Verschraegen, MD.
“It’s [important to] discuss the adverse effects [AEs] and make sure patients understand what [their lives will look like] if they [develop an AE from immunotherapy] to gauge how comfortable they will be choosing a single or double agent,” Verschraegen said.
In an interview with OncLive®, Verschraegen discussed how nivolumab (Opdivo) and ipilimumab (Yervoy) fit into the treatment paradigm both in combination and as single agents, posed examples of when treatment-related AEs (TRAEs) might influence which agents to use, and emphasized the importance of considering the benefits of immunotherapy, which often outweigh the associated risks.
Verschraegen is the director of the Division of Medical Oncology and a professor of medicine at The Ohio State University College of Medicine, the Diane Nye and Michael Rayden Chair in Innovative Cancer Research at Ohio State University, and associate director of translational research at The Ohio State University Comprehensive Cancer Center–James in Columbus, Ohio.
Verschraegen: Two main studies [investigating immunotherapy for metastatic melanoma] have been performed. The latest one was [the phase 2/3] RELATIVITY-047 trial [NCT03470922], which combined nivolumab and relatlimab-rmbw [Opdualag], a LAG-3 inhibitor, and showed a better progression-free survival [with the combination] than with single-agent nivolumab.
An older study is [the phase 3] CheckMate 067 trial [NCT01844505], which investigated the combination of nivolumab plus ipilimumab controlled by single-agent nivolumab or single-agent ipilimumab and showed a better response rate and survival for the combination of ipilimumab plus nivolumab compared with nivolumab alone. [The doublet was also] better than ipilimumab alone.
The benefits of the combination of ipilimumab and nivolumab came at the expense of more toxicity. Therefore, in some patients, it may be worthwhile to just choose a single agent instead of the combination, depending on [factors such as] their comorbidities and background.
With single-agent nivolumab, about 80% of patients complain of AEs. Sometimes, the AEs are as simple as fatigue for a few days, although some of the AEs can be lifelong, like autoimmune thyroiditis that could cause a lack of thyroxine production. These patients need to go on hormone replacement. The same thing can happen for steroids or for insulin, causing diabetes.
Some lifelong AEs can affect patients who receive immunotherapy. However, because we are now seeing some complete remissions [CRs] and hopefully cures in patients treated with immunotherapy, the risk/benefit ratio of dying of the cancer vs living with a chronic condition is in favor of using the immunotherapy.
When you use the combination, [there is a] 95% chance of AEs. Most importantly, the severe AEs of grades 3 and 4 go from about 16% with the single agents to 55% with the combination. When a patient has a grade 3 or 4 AE, it may mean hospitalization or a trip to the emergency room, a situation where they need quick intervention to try to minimize the AEs affecting their quality of life [QOL].
The panel of AEs is the same [with the combination or the single agents]. However, the risk of a lifelong situation may be increased with the combination. We have not fully investigated that, but it would be nice to see which AEs are lifelong and which can be reverted and how long it takes to revert them, because all of this affects the QOL of the patient.
[In a younger patient who might be cured,] you can expect almost a double CR rate with the combination, so it may be worthwhile to bet that they might not have severe AEs and have an increased CR rate, which could be beneficial for long-term survival. [In a patient] at 85 years of age with a life expectancy of 5 to 10 years if they did not have the cancer, it may be better for their QOL to not have additional comorbidities. Most patients at 85 years of age have many comorbidities and go on a single agent to try to minimize the AEs while still [trying to elicit] a response to their immunotherapy treatment.
The challenges are for the indications. Unfortunately, we don’t know who’s going to respond to immunotherapy; there are no helpful biomarkers. Even though you can look at the tumor mutational burden and the expression of PD-L1 on the tumor cells or the T cells, there is still no good correlation telling us [who may or may not respond]. [Some patients in whom] we don’t find any biomarkers still respond to treatment.
In tumors like melanoma and lung cancer, [immunotherapy is] becoming the [standard] frontline therapy because of the benefit margin that we expect from it. Even if there [is some question about] which agents we should use, that’s a discussion we need to have with the patients, reviewing the AEs [with them] and getting their comfort level of what they want to risk for the potential benefit.
It’s not always an easy answer. If patients start with the combination, they will probably have a better outcome that if they start with a single agent [and switch to the combination] if it doesn’t work, although they could still respond to the combination if they fail a single agent. There’s much to consider.
Immunotherapy for melanoma is [our preferred] frontline therapy these days. Studies are even [showing the potential benefit of starting] immunotherapy before surgery, [although these findings] need to be confirmed with additional research. Immunotherapy is so potent in some patients. I’ve seen just 1 dose of immunotherapy get rid of cancers. We don’t have a choice; we have to offer immunotherapy to our patients.
The devil is in the details regarding the subtlety of the patient situation, the extent of the disease, and how you know which [agents] you’re going to select to give your patients a better chance of cure with a great QOL. These are still areas that need more research [so we can better answer these questions].
Another area where we should do more research is in handling arising TRAEs, because the quicker you can intervene, the quicker you can prevent long-term disability. That has not been studied very well. The next wave of research should focus on the management of AEs.
We just started a clinic to do that here at Ohio State. We have a physician who’s a rheumatologist by training [who is looking at all those] autoimmune AEs. Although the diseases that we’re seeing emerge with immunotherapy [are somewhat related to] the autoimmune diseases that are commonly treated by rheumatologists, they are not identical. We are creating a new field of pathologies that we need to understand better, define better, and treat better.
We have a big portfolio of clinical trials for almost every situation that a patient can be in. We have a few trials for patients who fail everything, and we have neoadjuvant trials for patients before they get to surgery. If any patient is interested in being at the front edge of clinical research and helping participate in improving the current care for melanoma, I would encourage them to check what is available for them. If they’re interested, I would be happy if they volunteered for those studies.
At Ohio State, we see many cancer conditions, such as advanced basal cell carcinoma, difficult-to-treat squamous cell carcinoma, Merkel cell carcinoma, and more rare cancers, such as sebaceous carcinoma, as well as genetic conditions that put people at risk of getting skin cancers. We’re always happy to help the community manage [these diseases] as appropriately as possible. We are available for whoever is interested, and we’ll do the best we can in areas that are not generally well studied.