Recurrence & Side Effects in Melanoma Patients Treated With Immunotherapy : Oncology Times

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Recurrence & Side Effects in Melanoma Patients Treated With Immunotherapy

Kumar Das, Dibash PhD

doi: 10.1097/01.COT.0000903756.18919.cb
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Adjuvant immune checkpoint blockade (ICB) immunotherapies are successful against many cancers and are used in patients with surgically removed melanomas. Treatment with immunotherapies produces durable benefit for patients with resected melanoma. However, some patients are likely to see their cancer recur and/or have immune-related adverse events (irAEs). These irAEs can cause a lifelong requirement for medications or, in extraordinary cases, death. Consequently, a methodology to discover biomarkers or immunotherapy response and toxicity is a critical need to optimize patient selection for treatment.

Now, a study led by researchers at the Perlmutter Cancer Center in the NYU Grossman School of Medicine has developed a single experimental assay with the potential to simultaneously predict the occurrence of severe side effects or the recurrence of cancer in melanoma patients who have received ICB immunotherapies (Clin Cancer Res 2022;

The research revolved around the set of immune system signaling proteins known as autoantibodies (autoAB). In contrast to antibodies that recognize foreign microorganisms, such as bacteria, viruses, and fungi, autoABs react to proteins in the body's own cells to cause autoimmune disease.

The authors of the current study theorized that certain patients may have higher levels of autoABs before treatment, but not enough to manifest spontaneously. This hidden subclinical predisposition, they hypothesized, would then be triggered by checkpoint inhibitors to cause greater immune-based side effects. Consequently, the group focused their investigation on whether baseline serum autoAb signatures predicted recurrence and severe toxicity in patients treated with adjuvant nivolumab, ipilimumab, or a combination of the two.

The team analyzed prospectively collected data and serum samples from 950 patients with advanced melanoma who received adjuvant checkpoint inhibitor immunotherapy as part of two Phase III randomized controlled trials: 565 from CheckMate 238 (408 ipilimumab vs. 157 nivolumab) and 385 from CheckMate 915 (190 nivolumab vs. 195 ipilimumab plus nivolumab). All patients included in the study had tumors surgically removed and blood samples collected before they received immunotherapy.

Serum autoAbs were profiled employing the HuProt Human Proteome Microarray v4.0, which contains over 21,000 unique proteins attached in specific spots. When an antibody identifies any of the proteins present in a blood sample, those spots glow with the signal, strengthening as the concentration of antibody increases. There were two primary outcomes of interests: 1) recurrence versus no recurrence, and 2) severe irAEs (Grade 3-5) versus no or mild irAEs (Grade 1-2).

Centered on the newly discovered panel of autoantibodies and using statistical modeling, the researchers established a score-based prediction system for each immunotherapy regimen.

“That we identified 283 autoantibody signals shows that the biological phenomena underlying recurrence and toxicity are complex and cannot be driven one or two biomarkers” noted senior study author Iman Osman, MD, the Rudolf L. Baer Professor of Dermatology in the Ronald O. Perelman Department of Dermatology, and a member of Perlmutter Cancer Center at NYU Langone Health.

The analysis revealed similar observations in the patient test cohorts. Individuals with a higher autoAB score for recurrence showed recurrence of cancer after a shorter interval following immunotherapy compared to those with a lower score. Likewise, patients with higher pre-treatment autoAB toxicity scores were more prone to experience serious adverse effects than those with lower scores. Details include the following:

  • Ipilimumab test cohort: High recurrence score was associated with significantly worse recurrence-free survival (RFS) (aHR, 3.21; 95% CI: 1.38-7.45). Severe toxicity score also significantly predicted severe irAEs (aHR, 11.04; 95% CI: 3.84-37.25).
  • Nivolumab independent validation cohort: High recurrence score predicted significantly worse RFS (aHR, 3.60; 95% CI: 1.98-6.55) and outdid a model composed of clinical variables, including PD-L1 expression (P<0.001). Severe toxicity score was a significant predictor of severe irAEs (aHR, 13.53; 95% CI: 2.59-86.65).
  • Ipilimumab plus nivolumab test cohort: High autoAb recurrence score was associated with significantly worse RFS (aHR, 6.45; 95% CI: 1.48-28.02). High severe toxicity score was significantly associated with severe irAEs (aHR, 23.44; 95% CI: 4.10-212.50).

Limitations of the research include that the patients enrolled in CheckMate 238 and CheckMate 915 were treatment-naïve and the study was retrospective in nature.

The researchers, therefore, identified and validated a composite panel of distinct serum autoABs, if found in patients' blood before immunotherapy, has the potential to predict recurrence and irAEs in patients with melanoma upon immunotherapy with two leading checkpoint inhibitors, nivolumab and ipilimumab, and for the combination of the two agents.

“Our results show that the new research test, by predicting whether a patient will respond to a treatment or experience side effects, has the potential to help physicians make more precise treatment recommendations,” stated Paul Johannet, MD, in the Department of Medicine at the NYU Grossman School of Medicine and the study's first author. “With further validation, this composite panel might help patients to better balance the chances of treatment success against severe side effects.”

The authors concluded that “the composite panel of autoantibody signatures can allow for the simultaneous risk stratification of patients according to their likelihood of recurring and suffering severe toxicity.”

Dibash Kumar Das is a contributing writer.

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