Immune checkpoint inhibitors (ICIs) have revolutionized cancer care over the past decade. These drugs can result in robust and durable remissions in melanoma and other cancer types. Despite continual advancements, including combinatorial ICI regimens designed to improve response rates and survival outcomes in patients with advanced melanoma, these drugs have 2 main problems: A large percentage of patients do not respond to ICI treatment and excessive activation of the immune system can lead to significant complications (termed immune-related adverse effects [irAEs]), which can involve almost any organ in the body.

Many biomarkers cannot predict which patients will respond and/or develop a complication from ICIs, as they often fail to fully capture the complexity of the tumor response during treatment. Tissue biopsy–based biomarkers require invasive procedures, and peripheral blood biomarkers cannot account for spatial information of tumors. Neither can account for immune response in multiple organs simultaneously, which can overlook early signs of tumor progression and severe irAEs.

Noninvasive assessment of ICI response both spatially and temporally makes imaging an ideal tool. However, the optimal timing to evaluate ICI response is unclear. Current standard practice is to repeat imaging approximately 3 months after initial treatment. Earlier response assessment with a standard CT scan is often interpreted with caution, as there is no consensus or analytic framework to differentiate between pseudoprogression—where disease response occurs after an initial increase in tumor burden during treatment with ICI—and true disease progression. Although rates of pseudoprogression are unclear for combinatorial ICI therapy, they have been reported in up to 10% of patients treated with ICI monotherapy.

Progressive disease (PD) during early initial response assessment may still be predictive of survival outcomes in patients with advanced-stage melanoma treated with dual-agent ICI therapy. We previously published a study evaluating patients with advanced melanoma treated with the combination of ipilimumab (Yervoy) plus nivolumab (Opdivo) and evaluated radiographic (CT or MRI) response after 1 and/or 2 doses of therapy. We found that achieving a clinical benefit response vs PD per RECIST 1.1 after 2 doses was predictive of progression-free survival (PFS; HR, 0.09; 95% CI, 0.05-0.16; 

 < .001) and overall survival (OS; HR, 0.07; 95% CI, 0.03-0.14; 

 .001) benefit. Furthermore, in a subset of patients who underwent radiographic response assessment after 1 dose of ipilimumab plus nivolumab, early response was also predictive of PFS (HR, 0.16; 95% CI, 0.08-0.33; 

 < .001) and OS (HR, 0.12; 95% CI, 0.05-0.32; 

As neoadjuvant ICI therapy enters the treatment landscape for resectable melanoma, imaging assessment will be increasingly important in evaluating tumor responses before surgery. Conventional CT and MRI imaging methods may be insufficient to characterize outcomes. Discordance between radiographic and pathologic responses has been observed.

Several studies have investigated the utility of 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging in early detection of response to targeted and chemotherapeutic agents in a variety of tumor types. Functional imaging information from 18F-FDG PET can complement data from anatomic imaging studies from CT and MRI. The role of 18F-FDG PET/CT in the early detection of ICI response continues to be an area of ongoing exploration. In one study, melanoma response by 18F-FDG PET/CT at 3 to 4 weeks after starting ICI monotherapy was shown to be indicative of future best response.

In the phase 3 CheckMate 067 trial (NCT01844505), 59% of patients treated with standard-dose ipilimumab plus nivolumab experienced grade 3 to 4 treatment-related AEs.

The effects of these irAEs can have significant financial burdens and impacts on quality of life. Costs associated with managing grade 3 to 4 irAEs can be up to approximately $47,000 per effect.

To date, there are no validated biomarkers to predict the onset or severity of irAEs.Comprehensive spatiotemporal information from 18F-FDG PET/CT can not only allow for assessment and monitoring of treatment efficacy but may also provide predictive information for ICI-induced toxicities. In one of our studies, we found that organ-specific 18F-FDG uptake cutoff values in the bowel, lung, and thyroid can be predictive of developing irAEs in patients with melanoma treated with ICIs before clinical symptoms appear.

Early assessment of treatment response can lead to actionable changes without compromising long-term clinical outcomes. A response-adapted treatment strategy is adopted in the management of advanced classic Hodgkin lymphoma, where early interval FDG PET/CT is often performed after 2 cycles of chemotherapy to guide the appropriateness of treatment deescalation to help minimize treatment-associated toxicities.

Given the unacceptably high rates of severe irAEs in patients with melanoma treated with combinatorial ICIs, efforts to mitigate these AEs with a risk-adapted treatment strategy warrant similar exploration. In the phase 2 ADAPT-IT study (NCT03122522), adaptive dosing of nivolumab plus ipilimumab based on early radiographic assessment displayed comparable response and toxicity rates compared with historical data for conventional administration of the combination in patients with advanced melanoma. Patients received 2 doses of nivolumab plus ipilimumab followed by repeat imaging at week 6. Patients with early favorable antitumor effect (FATE) were transitioned to nivolumab monotherapy, and those without FATE received the remaining 2 induction doses of nivolumab plus ipilimumab followed by nivolumab monotherapy, per standard of care. Although the results of the study are promising for a novel treatment strategy in melanoma management, a larger validation study is warranted. The study also raises the consideration of exploring response assessment after 1 dose of combination ICI.

We have an ongoing pilot study at the University of Wisconsin evaluating the role of 18F-FDG PET/CT and circulating tumor DNA assessment after 1 cycle of combinatorial ICI (nivolumab/relatlimab [Opdualag] or ipilimumab/nivolumab) in patients with advanced stage melanoma. The goals of the study are to accurately predict clinical efficacy (best response and survival) and identify the subclinical onset of irAEs with an early interval 18F-FDG PET/CT 3 to 4 weeks after starting treatment. We anticipate that the results of our study will one day provide clinicians with actionable, quantitative, and clinically relevant decision-making data to optimally balance ICI benefits and risks, potentially improve clinical outcomes, reduce toxicities, and decrease health care costs for many patients.

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Articles

 Functional imaging information from 18F-FDG PET can complement data from anatomic imaging studies from CT and MRI to predict response to ICI therapy.

Vincent Ma, MD

Articles

18F-FDG PET/CT May Serve as Early Interval Response Assessment Tool in Patients Receiving Combinatorial ICI Therapy