ctDNA a Viable Surrogate for OS in Previously Treated Metastatic Uveal Melanoma

Alexander Noor Shoushtari, MD

Circulating tumor DNA (ctDNA) was a better predictor for survival than RECIST 1.1 for patients with previously treated, HLA-A*02:01-positive metastatic uveal melanoma (mUM) assigned to tebentafusp (IMCgp100), according to findings presented at the 2021 ESMO Annual Meeting.¹

Lead author Alexander Noor Shoushtari, MD, a medical oncologist on the melanoma service at Memorial Sloan Kettering Cancer Center, said that ctDNA identified patients most likely to derive an overall survival (OS) benefit, regardless of best RECIST response.

“ctDNA is detectable in the vast majority of patients with mUM treated in the second line or above setting with tebentafusp. Seventy percent experienced some form of ctDNA reduction, which is in stark contrast to the 5% RECIST response rate,” he said. “The magnitude of ctDNA reduction had a linear correlation with survival and this was not strongly related to best RECIST response. When you look at those with [ctDNA] clearance, not all of them had a response. In fact, the majority had stable disease or progressive disease. So, we conclude that for tebentafusp ctDNA reduction may be a better surrogate for survival than RECIST.”

Uveal melanoma is a rare disease with a low mutational burden and a poor prognosis. About 50% of patients will develop liver metastases and only few patients derive benefit from treatment with immunotherapeutics. There are no standard-of-care options are available for those with metastatic disease. Patients are typically assigned to frontline trials, where 1-year OS rate has been approximately 50%.

Tebentafusp is a bispecific protein that is made up of a soluble T-cell receptor that is fused to an anti-CD3 immune-effector domain. The agent is designed to target the melanocytic protein gp100, which is often expressed in patients with uveal melanoma.

In data from a meta-analysis published in 2019, second-line tebentafusp monotherapy induced an overall response rate (ORR) of 5% but induced a median OS benefit of 9.0 months compared with historical controls and had superior OS rates at 1 year (62% vs 37%) and 2 years (37% vs 15%).²

Based on these data, investigators hypothesized that ctDNA was a better way to analyze patients who derive benefit. They selected 99 patients from the meta-analysis who had ctDNA at baseline and after week 8 on study.

Investigators found a shallow correlation with a great deal of variability between ctDNA reduction and ORR, which Shoushtari said suggested that ctDNA may be more sensitive than RECIST.

Seventy percent of patients had any evaluable ctDNA reduction. Fourteen (14%) patients cleared ctDNA, but there were no complete responses and only 1 partial response. Best response for most patients was stable disease (n = 8) or progression (n = 4).

“Among those who cleared the ctDNA, most people actually did not have a response; 12 out of 14 had stable disease or progressive disease,” Shoushtari said. “Despite that, all patients with clearance lived for greater than a year, which is better than you would expect for those in the second line setting, historically.”

During the 2021 Virtual AACR Annual Meeting, investigators presented interim data from the phase 3 IMCgp100-202 trial (NCT03070392) comparing tebentafusp vs investigator’s choice of dacarbazine, ipilimumab (Yervoy), or pembrolizumab (Keytruda).³

The primary end point was overall survival (OS) up to 40 months. Secondary end points included safety as defined by the number of patients with treatment emergent adverse events, duration of response, progression-free survival, disease control rate, quality of life, and pharmacokinetics.

At a median follow-up of 14.1 months, the median OS for tebentafusp was 21.7 months (95% CI, 18.6-23.6) compared with 16 months for investigator’s choice (95% CI, 9.7-19.4). The 1-year OS rate in the experimental arm was 73.2% vs 58.8% in the control arm.

Shoushtari noted that patients assigned to tebentafusp had a significant OS benefit, even though the RECIST response rate was just 9.1%“Even amongst those with progressive diseases, the best response, we saw this OS benefit, suggesting that RECIST just isn’t a fantastic way to predict who will benefit from this drug,” he added.

In August the FDA granted a priority review to the biologics license application (BLA) for tebentafusp for the treatment of adults with HLA-A*02:01-positive mUM.4The FDA is expected to decide on the BLA by February 23, 2022, under the Prescription Drug User Fee Act.

References

1. Shoushtari AN, Collins L, Espinosa E, et al. 1757OEarly reduction in ctDNA, regardless of best RECIST response, is associated with overall survival (OS) ontebentafusp in previously treated metastatic uveal melanoma (mUM) patients. Presented at: 2021 ESMO Annual Congress. September 16-21, 2021; virtual. Abstract 17570.
2. Rantala ES, Hernberg M, Kivelä TT. Overall survival after treatment for metastatic uveal melanoma: a systematic review and meta-analysis. Melanoma Res. 2019;29(6):561-568. doi:10.1097/CMR.0000000000000575
3. Piperno-Neumann S, Hassel JC, Rutkowski P, et al. Phase 3 randomized trial compared tebentafusp with investigator’s choice in first line metastatic uveal melanoma. Cancer Res. 2021;81(13). doi:10.1158/1538-7445.AM2021-CT002
4. Immunocore announces that U.S. Food and Drug Administration and European Medicines Agency accept biologics license application and marketing authorization application for Tebentafusp in metastatic uveal melanoma. News release. August 24, 2021. Accessed September 19, 2021. https://bit.ly/3gzS3Qd