Douglas B. Johnson, MD, an assistant professor of Medicine and Hematology/Oncology at Vanderbilt University Medical Center, discusses the rationale for examining chronic immune-related adverse effects (irAEs) associated with anti–PD-1 therapy in patients with high-risk resected melanoma. 

While anti–PD-1 therapy is generally well tolerated and has yielded positive outcomes in this patient population, a subset of patients has been found to have chronic irAEs associated with this treatment approach, Johnson says. As such, a 

 examining chronic irAEs following anti–PD-1 in patients with high-risk resected melanoma was conducted to better understand the frequency, spectrum, duration, and resolution rate of these chronic toxicities, Johnson explains. Investigators on the study compiled data from several academic institutions on patients who had at least 6 months of follow-up after receiving anti–PD-1 therapy. 

Results from the study demonstrated that 43.2% of patients reported chronic irAEs, defined as persisting beyond 12 weeks after therapy discontinuation, Johnson notes. These chronic irAEs were not necessarily permanent, but they did linger after completing anti–PD-1 therapy, Johnson concludes. 

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Douglas B. Johnson, MD, discusses the rationale for examining chronic immune-related adverse effects associated with anti–PD-1 therapy in patients with high-risk resected melanoma. 


Dr. Johnson on the Rationale for Examining Chronic irAEs Associated With Anti-PD-1 Therapy in Melanoma

Douglas B. Johnson, MD, an assistant professor of Medicine and Hematology/Oncology at Vanderbilt University Medical Center, discusses the risks and benefits associated with anti–PD-1 therapy in patients with stage III resected melanoma.

In a recent study that was published in 

, investigators found that of 387 patients with stage III to IV melanoma, 43.2% who received an anti–PD-1 therapy developed chronic immune-related adverse effects (AEs), defined as those that persisted beyond 12 weeks of anti–PD-1 discontinuation. Despite this, anti–PD-1 agents have demonstrated improved outcomes in patients with melanoma and should still be used in treatment, Johnson says.

For a subset of patients who have very low-risk stage III melanoma, however, it is important to consider whether these agents are necessary, Johnson adds. Although these agents can potentially be used in this population, a discussion about the risks vs the benefits is necessary because due to the possibility of chronic AEs, Johnson concludes.

Douglas B. Johnson, MD, discusses the risks and benefits associated with anti–PD-1 therapy in patients with stage III resected melanoma.


Dr. Johnson on the Risks and Benefits Associated with Anti–PD-1 Therapy in Melanoma

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Douglas B. Johnson, MD, MSCI, assistant professor of medicine, Vanderbilt University Medical Center, clinical director, Melanoma Research Program, Vanderbilt-Ingram Cancer Center, discusses the need to identify novel biomarkers in melanoma.

 mutations and PD-​1/PD-L1 have assisted in treatment selection in the melanoma space, identifying additional biomarkers has been challenging, says Johnson.

In particular, it has been difficult to develop a biomarker that can inform when to use anti​–PD-1 monotherapy, combination therapy​, BRAF/MEK inhibition, or next-generation therap​ies ​such as intratumoral injections or tumor-infiltrating lymphocyte therapy.

Ultimately, ​the lack of biomarkers represent​s a major unmet need in the melanoma space, Johnson concludes.

Douglas B. Johnson, MD, MSCI, discusses the need to identify novel biomarkers in melanoma.








Dr. Johnson on the Need for Novel Biomarkers in Melanoma 

Douglas B. Johnson, MD, MSCI, assistant professor of medicine, Vanderbilt University Medical Center, clinical director, Melanoma Research Program, Vanderbilt-Ingram Cancer Center, discusses the limitations of biomarkers in melanoma.

Identifying novel biomarkers in melanoma has been a challeng​ing area of research, says Johnson.

Initially, PD-L1 expression was evaluated as a way to determine whether patients should receive single-agent PD-1 ​inhibitors or the combination of ​PD-1 plus ​CTLA-4 inhibitors, Johnson explains. However, longer follow-up data have failed to show PD-L1 as a robust biomarker of response.

In addition, since PD-L1 is now used less in melanoma compared with other cancers, ​tumor mutational burden has become a biomarker of interest. Although it appears to correlate with response, the utility of this potential biomarker remains unclear, Johnson concludes.

Douglas B. Johnson, MD, MSCI, discusses the limitations of biomarkers in melanoma.

Dr. Johnson on the Limitations of Biomarkers in Melanoma 

Douglas B. Johnson, MD, assistant professor of medicine, Vanderbilt University Medical Center, clinical director, Melanoma Research Program, Vanderbilt-Ingram Cancer Center, discusses applications of immunotherapy in melanoma.

Immunotherapy is widely used in the treatment of patients with melanoma, both as a single agent and in combination, Johnson says. This modality is now utilized in the adjuvant setting, specifically anti—PD-1 therapy for patients with high-risk stage III disease. Physicians use single-agent nivolumab (Opdivo) or pembrolizumab (Keytruda) following surgical resection, decreasing the risk of recurrence by about 50%, Johnson notes.

In the metastatic setting, physicians can choose between single agent anti—PD-1 therapy or a combination of nivolumab and ipilimumab (Yervoy). This therapy is yielding long-term survival in approximately 40% to 55% of patients with metastatic disease, says Johnson. Another application of immunotherapy is in patients with brain metastases. A recent phase II study showed promising response rates with combination immunotherapy in patients with asymptomatic brain metastases, Johnson adds.

Dr. Johnson on Applications of Immunotherapy in Melanoma

Douglas B. Johnson, MD, assistant professor of medicine, Vanderbilt University Medical Center, clinical director, Melanoma Research Program, Vanderbilt-Ingram Cancer Center, discusses the promise of combination therapy in patients with melanoma.

This biggest advancement in this treatment paradigm over the last several years has been the advent of combination therapies, Johnson says. This includes ipilimumab (Yervoy) plus nivolumab (Opdivo) in terms of immunotherapy combinations, as well as the various BRAF and MEK inhibitor combinations. The rise of these strategies has increased response rates and the proportion of patients who benefit. For example, the combination of anti—PD-1 and anti–CTLA-4 therapy has demonstrated response rates of about 60% compared with 40% with single-agent ipilimumab. In patients with 

-mutant melanoma, the combination of BRAF and MEK inhibition has resulted in impressive response rates of about 70%.

Moving forward, it is going to be a challenge for researchers to expand this benefit even further. Ongoing studies are looking at combining anti—PD-1 therapy with other novel immune agents, targeted therapies, and oncolytic viral therapies. Researchers are hopeful that these strategies under investigation will translate to clinical benefit, Johnson says.

Douglas B. Johnson, MD

Articles

Dr. Johnson on the Rationale for Examining Chronic irAEs Associated With Anti-PD-1 Therapy in Melanoma

Dr. Johnson on the Risks and Benefits Associated with Anti–PD-1 Therapy in Melanoma

Dr. Johnson on the Need for Novel Biomarkers in Melanoma

Dr. Johnson on the Limitations of Biomarkers in Melanoma

Dr. Johnson on Applications of Immunotherapy in Melanoma

Dr. Johnson on Promise of Combination Therapy in Melanoma