ctDNA reduction after tebentafusp predicts OS in uveal melanoma
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Reduction in circulating tumor DNA appeared correlated with longer OS among patients with previously treated metastatic uveal melanoma who received tebentafusp, according to study results presented at the virtual ESMO Congress.
Researchers observed this correlation independent of patients’ response to treatment per RECIST criteria.
“Patients with metastatic uveal melanoma treated with tebentafusp may have clinical benefit even though they do not get tumor shrinkage — or even see growth — on scans,” Alexander N. Shoushtari, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, told Healio. “In this cohort of nearly 100 patients, the changes in cell-free DNA in the blood correlated with their degree of benefit to the drug. Blood-based assessments of circulating tumor DNA [ctDNA] may be a better way to track who benefits from this drug than traditional RECIST [criteria].
“More immediately and practically, because this custom assay is not commercially available, I would advise physicians treating these patients with tebentafusp to avoid stopping the drug too early if there is growth,” Shoushtari added. “I tell my patients that early changes in tumor, even if new lesions appear in obvious visible areas, do not necessarily mean the drug is not helping them in the longer run. Of course, the total clinical picture needs to be carefully considered when deciding whether someone is benefitting from tebentafusp.”
Uveal melanoma is a rare malignancy characterized by low tumor mutational burden. Patients typically derive limited benefit from checkpoint inhibitors and often develop liver metastases. There is no established standard treatment for metastatic disease, according to study background.
Tebentafusp (Immunocore), a novel bispecific protein composed of a soluble T-cell receptor fused to an anti-CD3 immune-effector function, has demonstrated an OS benefit as first-line treatment for uveal melanoma.
Shoushtari and colleagues assessed tebentafusp monotherapy for 127 patients with HLA-A*02.01-positive metastatic uveal melanoma who received at least one prior therapy in the metastatic setting. All patients had measurable disease.
Patients received 20 mcg in week 1, 30 mcg in week 2, and 68 mcg in weeks 3 and beyond.
Researchers reported a 5% overall response rate, with a median response duration of 8.7 months and median OS of 16.8 months.
“The OS in this trial compared very favorably to the historical second-line survival data, but the objective response rate by RECIST 1.1 was quite modest,” Shoushtari said. “Clinically, we had several patients with upfront growth who were treated successfully past progression. So it was a long-standing goal of the whole study team to investigate [ctDNA] in the blood on this trial to see if it correlated with outcomes.”
The majority (n = 116) of patients had ctDNA at baseline, and 70% of evaluable patients had ctDNA reduction by week 9 of tebentafusp treatment.
Researchers determined ctDNA reduction is a more sensitive measure of tebentafusp effect than tumor size.
They also reported a linear correlation between ctDNA reduction and longer OS (R2 = 0.88; P < .0001).
Reduction in ctDNA identified patients who derived an OS benefit regardless of best response by RECIST criteria. Researchers observed this trend among all evaluable patients (HR = 0.56; 95% CI, 0.32-0.95) and among those with progressive disease as best response (HR = 0.44; 95% CI, 0.2-0.94). Results among patients with stable disease as best response did not reach statistical significance (HR = 0.48; 95% CI, 0.16-1.43).
Fourteen percent of patients cleared ctDNA, including some who achieved progressive disease (n = 4) or stable disease (n = 8) as best response. All patients who cleared ctDNA remained alive for least 1 year (HR for OS = 0.14; 95% CI, 0.03-0.57).
“We felt confident that we could detect [ctDNA] in patients with metastatic uveal melanoma because this is a disease with a well-described set of alterations in just a few genes,” Shoushtari told Healio. “It was perhaps a bit surprising just how well the changes on treatment correlated with survival. The almost linear association between the magnitude of reduction and OS is a bit unexpected because clinical trial correlative data are not often that clear cut.”
Shoushtari said research based on the findings from this study can concentrate on “further prospective validation of cell-free DNA assessments in this disease, particularly for patients receiving tebentafusp, as well as biomarkers of benefit that you can detect at baseline.”
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Shoushtari AN, et al. Abstract 1757O. Presented at: European Society for Medical Oncology Congress (virtual meeting); Sept. 17-21, 2021.
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