Incredible development for a small population of patients with uveal melanoma but nonetheless a new standard of care. Initial infusions may be complex in terms of close monitoring, as inpatient, till more experience is acquired in community oncology practices.
Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100–positive cells.
In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01–positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator’s choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival.
A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P=0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100–positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported.
Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392. opens in new tab; EudraCT number, 2015-003153-18. opens in new tab.)
Combination vs. placebo improved PFS, where there was improvement in OS as the risk of death was 20% lower but was not significant, in BRAF V600E, the risk of death was reduced by 25%.
For BRAF V600E, NCCN recommends using this regimen in the adjuvant setting.
This was compared to adjuvant niovolumab for 12 months, patients who did not achieve complete response also received adjuvant nivo. Neoadjuvant therapy was for 2 cycles. 12-month event-free survival was 83.7% in the neoadjuvant group and 57.2% in the adjuvant group. 58% had major pathological response in the neoadjuvant group, less than 5% could not get the surgery. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse.
Interesting study showing a strong difference in EFS with neoadjuvant + adjuvant vs. adjuvant alone for stage III/IV melanoma. All patients had disease that was amenable to surgery; EFS at 24 months was 72% vs. 49% in favor of the neoadjuvant group. The hypothesis is that neoadjuvant therapy functionally inhibits the immune checkpoint before antitumor T-cells are surgically resected. This concept is also developing in other cancers, including NSCLC, breast and bladder cancers. This should affect clinical practice.
More may not always be better. Adjuvant Nivo q2-weeks + Ipi q6-weeks was not better than Nivo q4 weeks in reducing recurrences in fully resected stage III-IV melanoma.
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