Disease Progression After 1L Therapy and Selection of 2L Therapy in Metastatic Melanoma


Following his review of first-line treatment options in the setting of metastatic melanoma, Sajeve Thomas, MD, considers how he would manage patients at disease progression.


Sajeve S. Thomas, MD: About half our patients are not going to respond to frontline therapy, so the primary resistant group, whether you give ipilimumab/nivolumab, PD-1 therapies, or PD-1 relatlimab, the failure is going to be at least 50% to 60% of these patients at minimum. I would check a CT scan and a brain scan every 3 months. We’re also checking circulating tumor DNA [ctDNA] every 6 to 8 weeks while they’re on therapy. I think that’s something that’s already FDA approved for folks who are on immune therapy. Assessing patients, you should see how do they look, how do they feel, are they doing well, more if they’ve had a lot of symptoms with pain or tumors and you can see that melting down, that’s already a good clinical sign of response. We love to see that. We like to verify with a radiographic response if tumors are stable or shrinking. It is important to see and correlate that with ctDNA data, which shows that the numbers are actually going down or become ... Then that would be the third category of assessment, molecular response, which I think is really exciting and a new field of development. I prefer that still be done on a prospective trial, which we are doing, but it can be done outside of a study as well. Ultimately, if patients are showing new tumors, new progressive disease, and/or [if] they have symptoms that correlate with that, with rising ctDNA levels, I may have a discussion about switching therapy or escalating therapy to other options. Whether we’re going to add on a CTLA4 [inhibitor] or rela at that time point. There are some small studies to support that, especially if they’ve failed PD-1 monotherapy. Do we go to BRAF MEK inhibitors or do we go to more intratumoral therapies, cellular therapies, or other clinical trial options¼? If there’s any concern for pseudoprogressive changes, then we maybe sit on it for a bit of time and check the scan again in about 4 or 6 weeks and see how they’re behaving, to verify if they’re truly progressing or if they’re truly responding.

I think for second-line therapy, what’s available right now outside of clinical trials are obviously checkpoint inhibitors and BRAF MEK targeted therapy, c-kit and NTRK. We want to make sure to consider those as options. The 2 areas of treatment that I really want to emphasize are intratumoral therapies and psychotherapy, which I think is really exciting. We have multiple intratumoral options that I’m seeing some exciting responses [with] under trial this past year. I think everybody we put on intratumoral therapies seems to be responding well. Maybe I’m just being lucky with that. These are treatments using toll-like receptor-9 agonists or ... We also have a modified poliovirus trial, luminous protocol. Folks who failed prior PD-1 therapy and have something palpable or something that we can inject, especially if they have more predominant skin lymph node-dominant disease, it makes a lot of sense to consider intratumoral therapies. We’re seeing good responses.

For folks where they have more systemic disease than TIL [tumor-infiltrating lymphocyte] therapy, cell therapy ... which is currently available on an expanded access program; we can harvest the tumor, isolate the T cells, expand those T cells to the billions, and then typically a median of 20 billion or 30 billion cells is given back as sort of a blood transfusion. They are put in the hospital for roughly 2 weeks to get lymph depletion and also our old drug, IL-2. But ultimately it’s a one-time approach. We’re seeing responses. These are patients who failed multiple other checkpoint inhibitors. The response rate is 30% to 35%. That’s 1 in 3. I have folks who are nearly 5 years out from that one-time therapy despite failure to prior checkpoint inhibitor and targeted therapy. Again, in the second-line situation, a strong consideration for clinical trials ensures tumor therapy and cell therapy for these kinds of patients are responding to some of the options that are available now.

Transcript edited for clarity.

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