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AACR: IMCgp100 activity eyed in ocular melanoma


 

FROM THE AACR ANNUAL MEETING

References

The first-in-class immunotherapy IMCgp100 was active in late-stage melanoma, particularly ocular melanoma, in an ongoing, phase I/IIa trial.

Four of 14 patients treated with a weekly regimen in the phase IIa portion of the trial had a partial or complete response by RECIST 1.1, including two partial responses persisting more than 18 months.

Dr. Mark Middleton © 2015 AACR/Todd Buchanan

Dr. Mark Middleton

Responses were observed across a variety of anatomical sites including liver and lung, and in patients refractory to ipilimumab (Yervoy) and pembrolizumab (Keytruda), “suggesting efficacy beyond the use of emerging and licensed treatments for melanoma,” principal investigator Dr. Mark Middleton said at the annual meeting of the American Association for Cancer Research.

The two shorter-lived responses – a partial response for 5.9 months and a complete response for 4.7 months – were in patients with ocular melanoma. One had been treated with surgery only, but the other had significant prior therapy and progressed through surgery, chemotherapy, radiation, and ipilimumab, he said. A third uveal melanoma patient left the trial after receiving what was later determined to be a nontolerated dose.

Progression-free survival in the two ocular melanoma responders was 9 months and 12 months, which bears up very well, compared with chemotherapy and data reported last year with MEK inhibition (JAMA 2014;311:2397-2405), said Dr. Middleton of the University of Oxford, England.

Invited discussant Dr. Antoni Ribas of the University of California Los Angeles Jonsson Comprehensive Cancer Center, commented that the responses were impressive.

“Anyone who’s treated ocular melanoma knows that if there’s a bad disease out there, this is one,” Dr. Ribas said. “It’s the subtype of melanoma that would not respond to any of the other immunotherapies and now we’re seeing responses here.”

The study enrolled patients with stage IV or unresectable stage III melanoma who were HLA-A2 (human leukocyte antigen-A2) positive and had no standard therapeutic options or had an appropriate window between alternative therapeutic options.

Patients had an ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1, three-fourths had M1c disease, and 16 had prior exposure to immunotherapy.

The phase I portion of the trial was designed to determine the maximum tolerated dose (MTD) of IMCgp100, with results reported at last year’s AACR.

IMCgp100 was dosed using a weekly regimen or a high-intensity regimen consisting of four consecutive daily doses in 3-week cycles. The maximum tolerated dose (MTD) for weekly administration was 600 nanograms/kilogram, which was converted to a flat dose of 50 mcg. Dose escalation of the high-intensity regimen is ongoing.

IMCgp100 contains an enhanced T-cell receptor and an anti-CD3 antibody fragment and is designed to redirect T cells to kill gp100-positive melanoma cells.

There is no clear correlation as yet between gp100 expression as measured by immunohistochemistry in the tumors because one patient who measured negative has a response at one of the lower dose levels, Dr. Middleton said.

“This isn’t a CLIA [Clinical Laboratory Improvement Amendments]-validated test, so the value of this, in particular, when taking relatively small samples is uncertain, and our working hypothesis has to be that gp100 expression is required in order to see an effective therapeutic response, albeit the ability to measure it remains uncertain,” he said.

Four dose-limiting toxicities, predominantly grade 3 or 4 hypotension, have been reported and emerged first at the 405 mg/kg dose. Most events resolved within 1-3 days.

One grade 4 hypotension was associated with associated acute respiratory distress syndrome and severe dyspnea in a patient on the MTD and resolved after intensive supportive care. With additional experience managing the potential for hypotension, however, there has been no significant hypotension at the MTD in the expansion phase, Dr. Middleton observed.

A phase 1b/II trial is being planned to evaluate IMCgp100 in combination with the anti–programmed death ligand-1 antibody MEDI4736 and/or the anti-CTLA-4 antibody tremelimumab in metastatic melanoma, according to a recent joint statement from Immunocore, developer of IMCgp100, and MedImmune.

pwendling@frontlinemedcom.com

On Twitter @pwendl

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