Paul Nathan, MBBS, PhD, MRCP, discusses the differences between cutaneous melanoma and uveal melanoma that have led to unique unmet needs for patients with the latter malignancy; updated findings from the IMCgp100-202 trial; and how these findings may influence future clinical practice.
The TCR-directed bispecific antibody tebentafusp-tebn (Kimmtrak) maintained a 3-year overall survival (OS) benefit vs immunotherapy or chemotherapy in previously untreated patients with advanced, HLA-A*02:01–positive uveal melanoma, according to Paul Nathan, MBBS, PhD, MRCP.1,2
The phase 3 IMCgp100-202 trial (NCT03070392) investigated tebentafusp vs investigator’s choice of pembrolizumab (Keytruda), ipilimumab (Yervoy), or dacarbazine in patients with previously untreated, advanced, HLA-A*02:01–positive uveal melanoma. At 3 years of follow-up, tebentafusp (n = 252) elicited a median OS of 21.6 months (95% CI, 19.0-24.3) vs 16.9 months (95% CI, 12.9-19.5) with the agents in the comparator arm (n = 126; HR, 0.68; 95% CI, 0.54-0.87).
Notably, prior data from IMCgp100-202 supported the FDA approval of tebentafusp for the treatment of adult patients with HLA-A*02:01–positive unresectable or metastatic uveal melanoma in January 2022.3
“There’s more to learn about the durability of this drug with longer follow-up of this study,” Nathan said in an interview with OncLive® during the 2023 ESMO Congress.
In the interview, Nathan, a consultant medical oncologist at Mount Vernon Cancer Centre in Northwood, United Kingdom, discussed the differences between cutaneous melanoma and uveal melanoma that have led to unique unmet needs for patients with the latter malignancy; updated findings from the IMCgp100-202 trial; and how these findings may influence future clinical practice.
Nathan: Uveal melanoma is different from cutaneous melanoma. There have been major advances for metastatic cutaneous melanoma, with long-term outcomes and up to 50% of patients being well at 5 years. Eye melanoma is entirely different. Although it originates from a melanocyte, it’s a biologically and genetically different disease, and it’s refractory to most standard therapies.
Only a small proportion of patients with metastatic eye melanoma have a long-term, durable benefit from the [types] of treatments that are now standard of care [SOC] for [patients with] cutaneous melanoma. There’s great clinical need; [uveal melanoma] is a distinct disease with its own problems. That background meant we were looking for [a drug] that could have an effect and be the first intervention that would improve survival outcomes for [patients with] eye melanoma.
Tebentafusp is an ImmTAC. It has 2 parts: it’s a T-cell receptor at 1 end, and it has anti-CD3 Fe fragments, so it binds to T cells in the tumor microenvironment on the other end. I describe it to my patients as a molecular bridge. The T-cell receptor end sticks to the cancer cell, and the anti-CD3 end activates any T cells in that environment. [Tebentafusp activates] the T cells in a way that’s not dependent on the T-cell receptor specificity. The T cells don’t have to be tumor specific, but they’re turned on and introduced to the tumor by the drug. The T-cell receptor end of tebentafusp binds to a peptide that is presented in the context of HLA on the surface of the tumor cells. That’s how T-cell receptors bind to their peptide antigens. The [binding ability] of the T-cell receptor part of tebentafusp depends upon patients having the right HLA haplotype. [We need to conduct] patient selection to make sure patients have the appropriate HLA haplotype.
It was a randomized phase 3 study. Because of the great clinical need in uveal melanoma, the control arm was an investigator’s choice arm. That represents the fact that there wasn’t an adopted SOC before tebentafusp. In the control arm, patients could be treated with either pembrolizumab, ipilimumab, or dacarbazine chemotherapy. Eighty-two percent of the patients were treated with pembrolizumab in the control arm. The experimental arm [received] tebentafusp, and [patients were randomly assigned] 2:1 [to either tebentafusp or control].
Patients needed to have HLA-A*02:01–positive disease or an HLA-A*02:01 haplotype, because that’s an integral part of how the drug works. It needs [HLA] to bind to the tumor cells. This was a first-line study, and patients had to be of good ECOG performance status. [Patients with] first-line, metastatic uveal melanoma with measurable disease and HLA A*02:01–positive [disease were included].
The patient population was representative of what we see in metastatic uveal melanoma. One of the major differences between uveal melanoma and cutaneous melanoma is the hepatotropism [of uveal melanoma]. Most of the patients we see with metastatic disease have hepatic involvement, either only in the liver, or in the liver plus extrahepatic sites. Importantly, the population in the registrational study represented the types of patients we see [in the clinic], because only a small minority of those patients, 4%, had only extrahepatic disease. Most patients had hepatic disease, and that’s where the clinical need is.
There are 2 key [goals] of any intervention. The first is: Is there a benefit? And the second is: Is there a durable benefit? Regarding the [effect a treatment] can have on patients, patients want an initial benefit, but the question is: How long will they benefit for? Because tebentafusp is a novel type of immunotherapy, there is an important question about how durable the benefit is with this type of drug, because we have no previous experience with it. With immune checkpoint inhibitors, a significant group of patients with cutaneous melanoma has long-term, durable benefits. There was an open question about whether there was a durable benefit seen with this drug. At the 3-year landmark [analysis], % of patients [in the tebentafusp arm] were alive, which is significantly more than the [3-year OS rate in the] investigator’s choice arm [18%], with an updated hazard ratio for OS of 0.68 in favor of tebentafusp, showing that a significant number of patients have durable [OS] benefit out to that 3-year landmark. [These data were] accepted for publication in the New England Journal of Medicine because that was an important observation.
Tebentafusp [delivered] benefit across the whole [uveal melanoma] population. With any preplanned subset analysis, there’s not statistical power in those subsets, so [all data will translate to] trends. There are trends toward benefit with tebentafusp compared with investigator’s choice across all preplanned patient subsets.
The safety profile with tebentafusp is interesting because [patients often] have manageable cytokine release syndrome on the first 3 or 4 infusions, which ameliorates over time. Patients require active monitoring for the first few weeks of their treatment, but beyond that, tebentafusp becomes a benign drug to use. The advantage of the long-term data is that we have longer experience with the safety profile. We’ve shown that there’s no late safety profile coming through with tebentafusp. A small group of patients had late worsening of liver function test [results], and that looks to be because of disease progression at that point, rather than being drug related.
With this study, 3 years is an important time point, but future time points will be important as well. The 5-year time point is important, and perhaps time points before then [will also be important].
The next important [area of investigation] for tebentafusp in uveal melanoma is small-volume disease, or microscopic disease. An academic study is investigating minimal residual disease [MRD] detected by circulating tumor DNA [ctDNA]. We reported a change in ctDNA levels on this study as being a sensitive way of identifying patients who were having OS benefit from the drug. We’re doing more work using ctDNA to detect MRD and see whether tebentafusp could offer a benefit [over other therapies] in that setting. Looking in even earlier disease [settings] will still be of great interest.
Across the field, the important [aspect to remember] is that uveal melanoma has a high clinical need, but it’s a classically immunologically cold tumor. It has a low tumor mutational burden. Immune checkpoint inhibitors tend not to benefit most patients with this disease. The paradigm is that with novel immunotherapies, particularly with a T-cell receptor–based therapy, we can induce clinically meaningful activity in a hard-to-treat tumor. That has implications for other tumor types, as well.