Patient Selection Is Crucial for Treatment Decisions in Metastatic Melanoma After PD-1 Inhibition

Stergios Moschos, MD

Although FDA-approved therapies such as lifileucel (Amtagvi) offer additional treatment options for patients with metastatic melanoma who received prior PD-1 inhibition, clinicians must consider a variety of patient-specific factors when deciding on the appropriate treatment for an individual patient, according to Stergios Moschos, MD.

In February 2024, lifileucel was granted accelerated approval by the FDA for the treatment of adult patients with unresectable or metastatic melanoma previously treated with a PD-1 antibody, and if BRAF V600 positive, a BRAF inhibitor with or without a MEK inhibitor. The regulatory decision was supported by data from the phase 2 C-144-01 trial (NCT02360579), which demonstrated that patients who received the recommended dose of lifileucel (n = 73) achieved an objective response rate (ORR) of 31.5% (95% CI, 21.1%-43.4%); the median duration of response (DOR) was not yet reached (NR; 95% CI, 4.1 months-NR).

“[Oftentimes], patients who receive cellular therapies such as lifileucel are a special kind,” Moschos, an associate professor of medicine in the Department of Medicine of the Division of Oncology at the University of North Carolina School of Medicine in Chapel Hill, said in an interview with OncLive^®. “Patients [with] metastatic melanoma that is not proliferating very fast [are good candidates for lifileucel] because the process of [manufacturing the agent] takes [time].”

In the interview, Moschos discussed his approach to treating patients with metastatic melanoma who experience disease progression following checkpoint inhibitor therapy, the current role of cellular therapies in the space, and notable ongoing clinical trials examining agents in the post–PD-1 inhibitor setting.

OncLive: What are some of the current challenges of treating patients with metastatic melanoma, particularly in those who experience disease progression after a checkpoint inhibitor–containing regimen?

Moschos: It’s important to note that not every patient [with melanoma] is eligible for immunotherapy. Immunotherapy is nice, but it shouldn’t be taken for granted. [In terms of immunotherapy], we specifically talk about a class of agents called immune checkpoint inhibitors, which target [1 of] 3 proteins: PD-1, CTLA-4, and LAG3.

If [a patient] is refractory to [treatment with] a PD-1 inhibitor, they have approximately a 25% to 30% chance of responding to a CTLA-4 inhibitor. Most of the data [are with] ipilimumab [Yervoy], but it has to be given in combination with nivolumab [Opdivo], otherwise the regimen is not effective. [Patients] who are refractory to [treatment with] a PD-1 inhibitor can receive a LAG3 inhibitor; the only FDA-approved [regimen] is relatlimab-rmbw plus nivolumab [Opdualag].

What characteristics are you looking for when considering the use of cellular therapy in patients with melanoma, and how could 5-year follow-up data from the C-144-01 study will be presented at the 2025 ASCO Annual Meeting help further inform patient selection?

[There is] a single FDA-approved cellular therapy, lifileucel, which is an adoptive T-cell therapy. Lifileucel has to pass quality control testing, and it has to have at least 7.5 billion cells. Just because you’re able to grow lymphocytes from the tumor does not necessarily mean that this [manufactured product will be considered] a licensed product.

Patient selection is key, and not every patient can [receive this therapy]; these are the patients from whom you [must] harvest tumor [cells] from subcutaneous lesions and lymph nodes because it has not been well studied whether you can grow immune cells from liver, lung, or brain lesions. [Moreover], just because the first scan at 6 weeks shows [tumor] shrinkage, it does not necessarily mean that it will be an ongoing response, because a proportion of these patients do relapse.

We have found that patient selection is very important. Personally, I have found that the key to bringing patients to receiving cellular therapy lies in the use of effective bridging therapy. Bridging therapy is a means to reduce the tumor burden to a level where the effect of the cellular therapy will be greater. It is an extremely dangerous path for [a patient] with uncontrolled tumor growth or high tumor burden to be brought to lymphodepletion followed by cellular therapy because they can potentially die from the toxicities of the lymphodepleting regimen.

It is essential that the moment you identify a patient for adoptive T-cell therapy to identify a bridging therapy. Following [disease] progression after a MEK or PD-1 inhibitor, adding pembrolizumab [Keytruda] plus lenvatinib [Lenvima] should hopefully decrease the tumor burden. The beautiful thing with lenvatinib plus pembrolizumab is that once a patient responds, the median DOR is approximately 9 months. This is 9 months where you are able to bring your patient to a level of tumor burden ideal for cellular therapy to have an effect. I also [use this approach] to increase the chance of having a successful tumor harvest, because VEGF inhibition is important to increase tumor infiltrating lymphocyte [TIL] density. There have been studies that have shown that tumors with a high gene expression signature are non-inflamed. By suppressing the VEGF pathway, you increase the influx of TILs and [thus] increase the chance that you have a successful harvest.

Depending on the circumstances, once patients recover from cellular therapy, I may elect to put them back on bridging therapy until the first scan 6 weeks after the cellular therapy infusion to help those cells have more of an effect. The use of effective bridging therapy is something that perhaps has not been fully described; the study [which] led to the FDA approval [did not use] any bridging therapy. An effective bridging therapy will both increase the [chance of] a successful harvest and decrease the tumor burden to render those cell therapies more effective.

What are some therapeutic alternatives for patients who are not candidates for cellular therapy?

If a patient cannot go through the complex process of adoptive T-cell therapy with lifileucel [an] effective [option] is treating them with pembrolizumab plus lenvatinib. Patients with PD-1–refractory [disease] can have up to 25% to 30% response rates [with this approach]. This is an overlooked, less-marketed treatment but it’s very effective with the ability to shrink tumors and [display] clinical benefit within 1 to 2 weeks.

Another [approach] that is of growing interest is with cellular therapies where you perform leukapheresis and extract CD8-[expressing] cells from the peripheral blood and genetically engineer them to express a viral vector. This class of therapies [uses] a T-cell receptor that recognizes a particular a particular epitope. This treatment must be restricted to patients who have an HLA haplotype that is specific to recognize this receptor. The treatment [in this category] that is the most advanced in clinical development is IMA203. In a single-arm, phase 1/2 trial [NCT03686124] of patients with HLA-A*02:01–positive disease, it [displayed promising] response rates. Everything else [in this class] remains investigational.

Another trial that has generated a lot of interest is [examining] the second-generation oncolytic viral therapy, RP1. In the single-arm, phase 1/2 IGNYTE study [NCT03767348] of patients with PD-1 inhibitor–refractory disease, the addition of RP1 to [nivolumab] has produced an ORR of [approximately] 30% to 35%. [However], we need to be careful because in the phase 3 IGNYTE-3 study [NCT06264180], the number of prior treatments permitted is 2. There’s a difference between patients who have undergone 4 lines of therapy and those who have gone through 2.

[In fact], things are getting so competitive that the FDA has required trials that test agents in the PD-1–refractory setting to occur in a randomized fashion. The trial of IMA203 is a randomized study, the first of its kind in a solid tumor, where a cellular product is being tested against a menu of options. It is also interesting that when these immunotherapies are being tested in a randomized study, [patients in] the control arm [often] cannot receive targeted therapies. It’s interesting that in the physician’s mind, targeted therapies are used more as bridging therapy because [many patients] will ultimately develop resistance to targeted therapy.

Are there any other ongoing clinical trials evaluating targeted therapies in the melanoma space that you find notable?

In the targeted therapy space, there has been some stagnation with respect to adding a third drug to a BRAF/MEK inhibitor backbone. We have had a lot of failures, either because we were not able to escalate the third drug to a biologically effective dose or because the toxicity was very high.

Right now, the only third drugs that can be added to a BRAF/MEK inhibitor backbone are coming from phase 2 studies, such as adding hydroxychloroquine or a BCL-2 inhibitor to dabrafenib [Tafinlar] and trametinib [Mekinist] or a PD-1/PD-L1 inhibitor to a BRAF/MEK inhibitor backbone. There have [also] been smaller studies where a multi-targeted VEGF inhibitor [such as] regorafenib [Stivarga] has been added to a BRAF/MEK inhibitor [regimen] for patients with refractory melanoma [with] brain metastases. Interestingly, there was a recent phase 2 study [NCT02681549] of VEGF inhibitors with immunotherapy that combined bevacizumab with pembrolizumab in patients with PD-1 inhibitor–naive melanoma [with] brain metastases.

[The treatment of] patients with NRAS mutations, such as those with NRAS Q61K mutations, has been much more challenging because single-agent MEK inhibition has not been effective. Therefore, the development [of treatments] is heavily relying on pan-RAF inhibitors, with a handful of them receiving accelerated approval [from the FDA] in combination with a MEK inhibitor. This is a double blockade of the MEK pathway using a pan-RAF and a MEK inhibitor.

In the PD-1 inhibitor–refractory space for patients with NRAS-mutated disease, there has been much less progress In the field of melanoma [with] brain metastases. Introducing bevacizumab with immunotherapy has proved to be a safe option with respect to intracranial hemorrhoids and as a means to spare patients from receiving corticosteroids, which we know suppress the immune system. The introduction of bevacizumab as—at the very least—a steroid-sparing agent may potentially be safe and effective in certain patient subgroups.

Reference

FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed April 30, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma