Uveal Melanoma: Sequencing Therapy

Richard D. Carvajal, MD: You presented nice work trying to tease out the potential confounding effects of post-progression therapies.

Marlana M. Orloff, MD: This takes us back to an abstract at ASCO 2019 [American Society of Clinical Oncology meeting] where we had observed, and I guess it was how many patients. It was ultimately about 29 patients from a couple of our institutions. A lot of patients that had immune checkpoint inhibitor first got tebentafusp and then got immune checkpoint inhibition afterwards. It did appear that there may have been this re-sensitization of 2 immune checkpoints after exposure to tebentafusp. Again, this was a small cohort of patients but there were patients who say didn’t respond to new checkpoint inhibition, got tebentafusp, and then did respond to immune checkpoint inhibition. Just thinking to ourselves, again going back to the mechanism of action of tebentafusp, if you’re ultimately allowing the immune system to see the cancer maybe then you would ignite some of those natural defense mechanisms like PD-L1 [programmed death-ligand 1] regulation and then you can come in with immune checkpoint inhibition. Interestingly though, in the abstract that you are talking about, it looked like regardless of post tebentafusp treatment the tebentafusp arm still does better. Patients who got tebentafusp then checkpoint inhibition versus investigator’s choice then checkpoint inhibition, the tebentafusp group still does better. But then there is this fancy statistical maneuver that was done that censored patients who got any post therapy and then OS [overall survival] still exist for the tebentafusp arm. Basically, he was trying to model that if you didn’t get patients anything with the OS still stands up versus the immune checkpoint inhibition is that what’s really carrying the prolonged survival in tebentafusp. We really can’t say that. Yes, we ask ourselves is tebentafusp changing the tumor microenvironment? Is it making it more prime for something like checkpoint inhibition? But it may just be doing something else altogether. We really don’t know yet. It’s exciting. 

Richard D. Carvajal, MD: It’s really interesting. I am struck. I do have anecdotal cases of some patients who were treated with checkpoint blockade, clear progression, then put them on tebentafusp. They may or may not benefit for a period of time and then I have retreated them and gotten significant radiographic responses that were the same checkpoint inhibitors. They are anecdotes but they are interesting ones.

Marlana M. Orloff, MD: We all have those anecdotes, which made me a little bit surprised that there wasn’t potentially more to the post CPI [check point inhibitors] after tebentafusp because I thought maybe that’s what was keeping the curve up for prolonged survival, especially for responsive progressive disease.

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