A manageable side-effect profile, signal of efficacy, and 36% increase in the recommended phase 2 dose (RP2D) was seen with a step-up dosing regimen of tebentafusp in patients with metastatic uveal melanoma.
A step-up dosing regimen of tebentafusp (IMCgp100) showed a manageable side-effect profile, a signal of efficacy, and led to a 36% increase in the recommended phase 2 dose (RP2D) compared with weekly fixed dosing in patients with metastatic uveal melanoma (mUM), according to data from the phase 1/2 study (NCT02570308) published in the Journal of Clinical Oncology.1
This open-label, international, phase 1 study examined the RP2D of the first-in-class T-cell receptor/anti-CD3 bispecific protein, tebentafusp, in patients with mUM. Investigators used a 3-week step-up dosing regimen in order to evaluate the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of tebentafusp in this patient population.
Enrollment was open to patients with a histologically or cytologically confirmed diagnosis of mUM. Patients must have been human leukocyte antigen-A*0201 positive with an ECOG performance status of 0 or 1 at the time of screening. Phase 2 of the trial also included patients with previously treated uveal melanoma in the metastatic setting.
Tebentafusp was administered at a dose of 20 μg once during week 1, followed by 30 μg once in week 2 to patients with mUM. At the start of week 3, patients were administered 54 μg of tebentafusp. The dose escalation portion of the trial followed using a standard 3+3 design. In the expansion phase of the study, patients were treated with the RP2D of 20-30-68 μg.
The primary end point of phase 1 of the trial was the number of participants with dose limiting toxicities and the primary end point of phase 2 was overall response rate (ORR). Secondary end points between each phase of the trial included progression-free survival, disease control rate, duration of response, time to response, overall survival, minor response rate, number of participants with treatment dose interruptions or reductions, percentage of participants with anti-tebentafusp antibody formation, and pharmacokinetic parameters of AUC, Cmax, Tmax, and t1/2.
Among those enrolled in the trial, the median age was 55 years (range, 34-73 years) for the dose escalation portion and 61 years (range, 45-79 years) for the expansion section. Similar drug exposure and baseline clinical characteristics, including demographics, prior treatment history, extent of disease, and prognostic factors, were seen between both cohorts. However, patients in the dose escalation portion were characterized by a lower prevalence of largest liver metastasis size > 3 cm (5/19, 25%) vs those in the expansion cohort (14/23, 61%).
Further, patients had blood and tumor samples collected for a pharmacokinetics and pharmacodynamics assessment. Treatment efficacy was also examined for all patients as of December 2017, with baseline efficacy data.
A total of 42 eligible patients were enrolled in the trial, all of whom failed a median of 2 treatments. The dose escalation cohort included 19 individuals whereas the dose expansion cohort enrolled 23. Treatment efficacy was assessed using RECIST v1.1 as well as a Kaplan-Meier survival analysis.
Investigators identified 68 μg as the appropriate RP2D. Five of the 42 patients achieved a confirmed partial response, leading to an ORR of 11.9% (95% CI, 4.0-25.6). With a median follow-up of 32.4 months (range, 18-39), the median number of cycles of tebentafusp started was 7.5 (range, 1-41). Patients completed a median of 6 cycles (range, 0-39). The median overall survival was 25.5 months (range, 0.89-31.1 months) and the 1-year overall survival rate was 67%.
Additionally, treatment was associated with increased tumor T-cell infiltration and transient increases in serum inflammatory mediators.
In regard to safety, all patients had experienced at least 1 treatment-emergent adverse event (TEAE) at the time of the data cutoff. The most common TEAEs regardless of attribution were pyrexia (86%), nausea (74%), chills (69%), pruritus (67%), and fatigue (62%). The grade 3 or higher TEAEs that were most frequently reported included abdominal pain (12%), hypotension (9%), fatigue (9%), and hypophosphatemia (9%), and a total of 16 (38%) patients reported having at least 1 serious adverse event (AE).
A total of 9 patients (21%), including 4 patients who had grade 3 or 4 events, had increases in transaminases from baseline. These events generally occurred early in the treatment course in the setting of cytokine release syndrome (CRS). Additionally, discontinuation due to AEs occurred in 2 (4%) patients who experienced CRS and abdominal pain, and no treatment-related deaths occurred.
Overall, promising preliminary clinical benefit of tebentafusp in a previously treated mUM patient population was demonstrated in this phase 1 portion of the trial, and the RP2D was identified as 68 μg.