Exploring TIL Sequencing in Melanoma Based on European Experience

Tumor-infiltrating lymphocyte (TIL) therapy was first approved in the United States based on a phase 2 trial (NCT02360579) of patients with metastatic melanoma and is indicated for patients who have already received immunotherapy and targeted therapy. While moderating a live Case-Based Roundtable event in Cleveland, Ohio, Daniel Olson, MD, assistant professor of medicine at UChicago Medicine, discussed the supporting US trial and another study of TILs performed in Europe. He examined how the findings from both studies emphasize that TILs achieve better outcomes when given earlier in sequence and what this could mean for oncologists going forward.

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Targeted Oncology: What findings outside the United States showcase the use of TILs in melanoma?

Daniel Olson, MD: [We have] some of the European data on TILs. It gets to the question of where you sequence TIL therapy. In the US, the registrational trial was the one done by Iovance [C-144-01; NCT02360579], which was done mostly in patients who had 3 prior lines of treatment.¹ But TIL therapy is a process, and there’s no one stopping somebody else from making TIL therapy in a different country. In the Netherlands and Denmark, they have an academic center where they made their own TIL product with the same ideas as in the National Cancer Institute, and they ran a randomized study.²

The standard of care in Europe was to do PD-1 therapy frontline and then to give patients ipilimumab [Yervoy] afterwards. They don’t give ipilimumab plus nivolumab [Opdivo] in the second line there; it wasn’t approved. I think they’re more constrained on resources. But in this academic center, they then did a randomized study where they did TILs afterwards, or they did the standard of care, which was ipilimumab. It was a randomized study after first-line treatment.

There were almost 170 patients total, balanced in terms of risk factors and BRAF status.² Notably, these patients had not [received] BRAF therapy, but they’d all [received] prior anti–PD-1 therapy and no CTLA-4. As you might expect, TIL therapy did better than ipilimumab based on progression-free survival [PFS] showing substantial benefit with TIL [median, 7.2 months vs 3.1 months with ipilimumab; HR, 0.5; 95% CI, 0.35-0.72; P < .001].² …Overall survival [OS], as you would expect, is better with the TIL product [HR, 0.83; 95% CI, 0.54-1.27]. The adverse events were relatively similar to the other studies.

What can US oncologists conclude from this study despite the differing standard of care?

The takeaway from the study is that the response rate was 50% in these patients.² This is really intriguing. We think about where to use TILs in terms of sequence, and it looks like the response rate goes much higher the earlier you use it.

I’ve gone to subsequent presentations where they’ve shown what this product looks like after patients are treated with ipilimumab/nivolumab or other therapies, and it mimics what we know from the product we use here in the United States [lifileucel; Amtagvi]. It does suggest that the earlier you use it, the better it works.

One of the questions I have is, if a patient progressed on adjuvant PD-1 and then got targeted therapy, do you use ipilimumab/nivolumab first in the second line, or do you use TIL therapy first? I’ve gone both ways. Most people use ipilimumab/nivolumab because that’s what’s most accessible, but I’ve sometimes used TIL a little bit earlier, if I can, just because I know it’s so easy to give ipilimumab/nivolumab afterwards. If you didn’t benefit from TIL, I can give ipilimumab/nivolumab within a week. Whereas if I do ipilimumab/nivolumab, do 3 months and then try and get to TIL therapy, I have that built-in delay. It’s a little bit harder.

I have the conversation with patients and say, “What do you think? This is going to be an intense treatment. It will leave us with another treatment option in our back pocket. But if you’d like to, we can sequence it this way.” I think that’s one of the challenges when you get into the later lines of therapy, being strategic and knowing that with TIL your response rate is between 30 to 50%. With ipilimumab/nivolumab, it’s [closer to] 30%. You just have to think, how am I going to line these therapies up so I can give people as many shots on goal as possible?

I will sometimes offer TIL early, but that’s not the average patient. Most of the time I’m getting referrals later, and patients have already gotten ipilimumab/nivolumab.

Could the lymphodepletion used in TIL therapy impair subsequent use of ICI?

We don’t know for sure. There is a pilot study [NCT05176470] where they gave TIL plus pembrolizumab [Keytruda], and they compared that with the historical rates with just TIL or pembrolizumab. It does seem to be synergistic; it does work even after the conditioning therapy. In the context of TIL, the idea is that some of the resistance mechanisms that are there for checkpoint inhibitor therapy would also be present on TIL so PD-L1 could be expressed and affect how a TIL product works. Combining those 2 might be synergistic. That’s a little bit of a different question, but at least we know when PD-1 inhibitors have been used after conditioning chemotherapy, they still do seem to work. We don’t know for sure. It’s anecdotal evidence, but it does seem to work.

What led to the differences in melanoma standard of care in Europe?

In Europe, the data about using PD-1/CTLA-4 after PD-1 is still only 3 or 4 years old at this point, and it was done in single-arm phase 2 studies. In Europe, that wasn’t enough to approve it, even though it looks like it definitely works, [and there is] very strong evidence that it works better.³ It’s not approved in Europe, so the standard of care in Europe is to use ipilimumab in the second line. Similarly, they don’t allow patients to receive nivolumab/relatlimab [Opdualag] unless they’re PD-L1 negative.

If you look in the melanoma studies for PD-1/CTLA-4 and PD-1/LAG3, the PFS and OS aren’t that different if patients are PD-L1 positive between PD-1 monotherapy and combinations. It’s all subgroup analyses, and we don’t use that to make decisions here, and that’s why people use a lot of combination therapy. But in Europe, they restrict it. I think the reason ipilimumab was the control arm and in general is just because they they’re very strict about what they’re allowed to use in certain circumstances, and that was the standard of care there.

Was PD-L1 status evaluated in the trials of TILs?

I know they’ve looked at it; it wasn’t reported in this trial. In the other [trial], if you look at the subgroups in the paper, there was not a big difference in PD-L1 positive vs negative in TIL therapy.

Do we have any biomarker predicting response to TILs?

No, we don’t. I think we just have clinical parameters or prognostic parameters, like lower volume of disease and earlier lines of treatment. It tends to work better, but we don’t have a PD-L1 or a tumor biomarker that tells us.

What data would support moving TILs forward in sequencing?

There is a trial of TILs plus pembrolizumab vs pembrolizumab [NCT05727904]. We will have data from that. We want some of those long-term end points. Survival does matter, but one that will be an interesting intermediate end point to look at is that there’s data from TIL [therapy] when it’s used across many different lines that if you get a complete response, you’re unlikely to progress at that point. That will be a compelling reason to look at it in the front line. If the complete response rate is high, that might encourage you to think about it in your young, fit patient who wants to swing for a home run. Outside of that, you do want to get more long-term data.

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DISCLOSURES: Olson previously reported consulting fees from Iovance, Obsidian, Novartis, Aadi.

REFERENCES

1. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755

2. Rohaan MW, Borch TH, van den Berg JH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med. 2022;387(23):2113-2125. doi:10.1056/NEJMoa2210233

3. Olson DJ, Eroglu Z, Brockstein B, et al. Pembrolizumab plus ipilimumab following anti-PD-1/L1 failure in melanoma. J Clin Oncol. 2021;39(24):2647-2655. doi:10.1200/JCO.21.00079