Dr. Omid Hamid:
Welcome to The ASCO Post Roundtable Series on Updates in Melanoma. I'm Dr. Omid Hamid, Chief of Translational Research and Immunooncology at The Angeles Clinic and Research Institute, and Co-Director of Cutaneous Malignancies at Cedar Sinai Medical Center. Joining me today are two of my colleagues, Dr. Sapna Patel, and Dr. Ryan Sullivan.
Dr. Sapna Patel:
Hi, I'm Dr. Sapna Patel. I'm a medical oncologist, and Associate professor and Director of the Uveal Melanoma Program at MD Anderson Cancer Center in Houston, Texas.
Dr. Ryan Sullivan:
And I'm Ryan Sullivan. I'm also a medical oncologist, and the Associate Director of the Melanoma Program at the Mass General Cancer Center, and Associate Professor at Harvard Medical School.
Dr. Hamid:
Our final installment will focus on emerging second-line therapies for unresectable and metastatic melanoma. And our patient, Jermaine, is a 55-year-old man initially diagnosed with metastatic melanoma, BRAF-mutant to the lung and liver who was treated with combination checkpoint inhibitor therapy without benefit and at this time shows up in clinic looking for second-line options. Dr. Patel, how do you think about appropriate second-line therapies for a patient like Jermaine?
Dr. Patel:
Jermaine could go by any number of names. He represents a very common clinical scenario in melanoma. We have outstanding treatment options in melanoma, but we are still not necessarily curing and eradicating patients in the front-line setting. Most data would show you with single agent combination immunotherapy and combination targeted therapy, where our cure rate is really still less than about 20% of patients and most patients will move on and need something in the second line.
In the second line, this remains an area of tremendous research. Do you flip a patient to targeted therapy with a BRAF mutation? Do you try alternate immunotherapies? Do you keep a PD-1 backbone going? And in a table that you're seeing, there's a number of options in the second-line setting, and again, none of these are blockbusters. None of these are necessarily solving our problem of metastatic melanoma, they're just improving and incrementally teaching us how we move forward in small steps.
One of the treatments that is really intriguing in this table is in the far right column, TIL therapy. TIL therapy in a heavily pre-treated population as you see, 89% of these patients in this TIL trial, had received prior immunotherapy of some form. The response rate was quite striking of 49%. Dr. Hamid, I wonder for somebody who may not be familiar with TIL therapy, what should we know about what it means to offer a patient TIL therapy? What does it look like, and what are they in for?
Dr. Hamid:
Sure. I think TIL therapy is a therapy that we've all heard of for many, many years and the issue was that it was not available to most. But at this point, through multiple collaborations, it has become available and will be coming onto the landscape of our options for second-line therapy for melanoma. And what it looks at is procuring tumor infiltrating lymphocytes, those T-cells that have gone in and directly attacked tumor in a patient with metastatic melanoma. And initially what it has done is a surgical removal of the melanoma lesion, about 1.5 cm3 is necessary and then that is shipped off. Usually in the past, it had been to one academic center where they did it in a lab, but through newer innovations, there are multiple companies that are working at bringing forth a centralized tumor digestion and growth with interleukin-2 and a rapid expansion with the addition of nutrients to expand that TIL into billions of cells and that is put into a bag and is ready to give to a patient.
Now, during that TIL growth, the patient can be on some sort of bridging therapy and can be okay at home. Ultimately, they come in and get a non-myeloablative, lymphodepleting chemotherapy prior to the TIL infusion, usually a week prior, and that clears out their marrow of the other T-cells and then it's to preference of the TIL infusion. The patient is hospitalized, receives a single infusion of those tumor infiltrating lymphocytes, and then at the current time, the administration of up to six doses of high-dose IL-2.
What should be pointed out is the major portion here is the infusion of the TIL. The high dose IL-2 is given every 8 to 12 hours for six doses, and it's not important that the patient sees all those doses. And what has been the result? Well, you've seen in the recent New England Journal of Medicine publication by John Haanen and others, a TIL vs ipilimumab in the second line.
In short, it was patients who had progressed on anti–PD-1 therapy or had a first-line therapy, about 89% had seen prior PD-1. They received either TIL that was given in two or three centers in the Netherlands or standard ipilimumab for four doses and it was restricted to patients with LDH less than two times upper limit of normal.
What was most striking here, the results that the progression-free survival according to RECIST favored significantly the TIL therapy. In addition, treatment with TIL vs ipilimumab showed a best overall response rate that was much greater than what we saw with ipilimumab, and we look forward to more mature data.
What buoys and strengthens the role for TIL is C-144-01 study, which has been published and presented multiple times and most recently updated at Melanoma Bridge at SITC. Looking at two cohorts of patients who were treated, these patient population all had seen prior PD-1, the majority had been primary refractory.
Over 81% had seen anti–CTLA-4. These were patients who were treated with cryopreserved TIL that was grown centrally at one of the factories. And the patients then received this drug lifileucel, which is the TIL therapy locally. This was 153 patients in 2 cohorts that accrued rapidly and in succession. As you can see on some of these slides, most of the patients were heavily, heavily pretreated. Only 11% of the patients were in second line. The majority had seen three or more lines of therapies. The majority had seen multiple rounds of single agent immunotherapy. What we saw is a high duration of response. What we also saw here is the 2-month overall survival rate, 54% median overall survival rate, 13.9 months, and the highest response rates in second-line therapy here about 31%. Seven patients initially assessed as PR were later confirmed as a complete response and we saw not only durable with over 80% of patients having their first response at 6 weeks, but response that went from stability to partial response, partial response to complete response.
What we find most intriguing about this therapy is it's a one-time therapy, that is that if you respond to TIL, there is no need for recurrent TIL infusions, recurrent IL-2, or anything else. These patients receive a one-time therapy and the toxicity is more related to the first 2 weeks and related to cytopenias due to the lymphodepletion, or toxicities related to the high dose interleukin-2. And so this is currently at the FDA for evaluation and approval. Multiple clinical trials are accruing and looking to improve on this paradigm, but for me, it's not just TIL, as TIL can help a subset of our patients, but it's also other T-cell therapies and other combinations or other non-immunotherapeutic combinations. And I'll ask Dr. Sullivan to tell us a little bit about how he sees this part of the paradigm expanding for second-line melanoma.
Dr. Sullivan:
Thanks, Dr. Hamid. I think the question you've so rightly asked is, do we need TIL or can we utilize other molecules that sort of look like a T-cell on some level but actually aren't a true cellular therapy? And there's an emerging class of drugs called mTACs. These on one end are a T-cell receptor that looks just like a T-cell receptor that would be on the T-cell specific to a peptide that's on and being expressed on a tumor cell. These tend to be HLA-restricted, so you can't just give it to everybody. You have to do sort of a blood banking or a test ahead of time to check their HLA status. But if they have the correct HLA status, then patients may be a candidate for that. On the other end is a T-cell engager, and so essentially you get this interesting evil matchmaker scenario where the molecule binds to a tumor cell, brings in an immune cell, and then the immune cell kills the tumor cell.
The first of these drugs is called tebentafusp-tebn. It's actually FDA approved for uveal melanoma, and the T-cell receptor goes against a gp100 protein. There's another molecule that's being developed that actually goes against the antigen called PRAME. This is highly expressed in uveal melanoma, highly expressed in melanoma, also highly expressed in other diseases like ovarian cancer. And the early clinical data actually looks pretty encouraging with responses in patients with uveal melanoma, responses in cutaneous melanoma, responses in ovarian cancer. And building on that, there are now a series of cohorts looking to combine that with tebentafusp-tebn in uveal melanoma, but also presumably anti–PD-1 antibody in other chemotherapies to really build off of that data. So that's an example of something that's sort of like a T-cell but not quite, and something that you can give off the shelf and don't have to have all that production.
Shifting a little bit to other types of therapies in the second line, there's, really ever since angiogenesis became a viable target in cancer, anti-angiogenic agents were being looked at in melanoma. These include monoclonal antibodies like bevacizumab, but also small molecule inhibitors that target receptor tyrosine kinases like the VEGF receptor or receptors. A recent trial looking in the post–PD-1 setting was the VEGF, sort of dual VEGF/FGFR receptor targeted therapy called lenvatinib plus pembrolizumab. This is the LEAP-004 study and again, a pre-treated patient population; response rates in the 20 to 25% range. But interestingly, the patients who had been treated with ipilimumab and nivolumab seemed to have an even higher response rate. And so there's a lot of interest in studying this combination further. Importantly, it's also possible that this is just an effective anti-angiogenic therapy and the pembrolizumab doesn't matter at all. And so I think targeting angiogenesis should be renewed in our studies and kind of hearkening back to the early and mid aughts, these drugs potentially work and can help our patients.
We talked a little bit about BRAF in the front-line setting, and it's not a viable option. BRAF/MEK combination therapy in the second or third line for BRAF mutated patient makes a lot of sense. The problem is those drugs don't tend to cure anybody in this setting, and so we're always on the lookout for other therapies for patients who've previously been on BRAF-targeted therapy. Another set of patients that we see commonly, about a quarter, 30% of our patients actually have NRAS mutations that also activates the MAP kinase pathway. And so there's actually emerging data pre-clinically that targeting RAF still matters, but maybe targeting in a way where you're blocking the entire BRAF as opposed to just the mutated BRAF, and maybe giving that in combination with either a MEK inhibitor, which MEK is downstream of RAF or even an ERK inhibitor, which is downstream of both RAF and MEK.
And so there's this data that was presented at ESMO of naporafenib in combination either with a MEK inhibitor, and that MEK inhibitor is trametinib or an ERK inhibitor, or actually even a CDK4/6 inhibitor. The data in previously BRAF-mutated, or sorry, BRAF-mutated tumors that were previously treated with BRAF/MEK suggests that this strategy isn't that effective, unfortunately. There was I think maybe one responder in that group, but most patients didn't respond, and most patients progressed quickly. But in the NRAS-mutated population, response rates ranged between 20 and 30%. And this strategy, not only would this combination or these combinations, but other pan-RAF inhibitors plus MEK inhibitors suggest that that's a viable combination that continues to be studied in clinical trials and should be, because there are response rates even in the 30 to 40% range with some of these combinations. I think with that, Dr. Hamid, I'll turn it back over to you for some closing statements.
Dr. Hamid:
Thank you, Dr. Sullivan and Dr. Patel. I mean, I think what we've seen here is that the race is still ongoing and that in the second-line therapy for our patients, the TIL paradigm is making headway. Also second-line options with T-cell therapies and newer therapies that do not require surgery or other toxic or other harder regimens. I agree with you that the VEGF paradigm has made a return and has shown progress and benefit in melanoma, and clearly the majority of this benefit for our patients has come through clinical trials, so they still present a viable option for our patients with metastatic melanoma failing se-line options. And unfortunately this brings us to the end of this case. Please see the other segments for further discussion about the latest data in melanoma or visit ascopost.com. Thank you.
