Tebentafusp Plus Immune Checkpoint Inhibitors for Skin Cancer

The development of immune checkpoint inhibitors (ICIs) has greatly improved first-line treatment outcomes for patients with cutaneous melanoma; however, researchers, led by Omid Hamid, suggested that patients who progress on checkpoint inhibitors lack effective follow-up treatment options. They evaluated the safety and efficacy of tebentafusp, a bispecific gp100×CD3 ImmTAC (immune mobilizing monoclonal T-cell receptor against cancer), combined with durvalumab, tremelimumab, or both.

The study, published in the Journal for ImmunoTherapy of Cancer, reported that tebentafusp plus durvalumab achieved a response rate comparable with the rate seen with the triplet combination. Researchers also noted the safety profile of tebentafusp combination regimens was comparable with that of each individual inhibitor therapy in this population of heavily pretreated patients with metastatic cutaneous melanoma (mCM), most of whom had progressed on prior ICI therapies.

Immune Inhibitors Plus Tebentafusp, Promising Response

The phase 1b clinical trial enrolled 85 patients with HLA-A*02:01-positive mCM to either tebentafusp and durvalumab (n=43), tebentafusp and tremelimumab (n=13), or tebentafusp, durvalumab, and tremelimumab (n=29). Participants had a median of 3 prior lines of therapy, and 76 (89%) had received an anti-programmed cell death ligand 1 (anti-PD-L1) inhibitor.

Treatment consisted of weekly infusions of intravenous tebentafusp plus increasing monthly doses of either or both durvalumab and tremelimumab. The primary end point was the maximum tolerated dose or a recommended phase 2 dose for each combination, and a sensitivity analysis was performed in patients who had progressed on prior anti-PD-L1 therapy.

The maximum target doses for tebentafusp, durvalumab, and tremelimumab were 68 mcg, 20 mg/kg, and 1 mg/kg, respectively. Authors noted the doses were well tolerated, and no maximum tolerated dose was identified. Additionally, there were no new safety signals or treatment-related deaths with the combination regimens.

In an efficacy analysis of 72 patients, the response rate was 14% and the tumor shrinkage rate was 41%. The 1-year overall survival (OS) rate for patients who received tebentafusp and durvalumab was 74% (95% CI, 67-80), which was similar to the rate in those who received the triplet combination at 79% (95% CI, 72-86).

“Tebentafusp can be safely combined with anti-PD-L1 and anti-CTLA-4 in heavily pretreated patients with mCM,” the authors concluded. “Tebentafusp with anti-PD-L1 demonstrated promising OS compared with other investigational therapies in a similar mCM population.”

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