Neoadjuvant Therapy NCCN Recommendations Take the Melanoma Field in a New Direction

Douglas B. Johnson, MD, MSCI

Data from multiple practice-changing studies demonstrating the efficacy of neoadjuvant therapy led to several changes to the NCCN Clinical Practice Guidelines in Oncology for melanoma in 2024, and ensuring multidisciplinary communication is strong with these critical changes will be key, according to Douglas B. Johnson, MD, MSCI. Johnson, who is vice chair of the Melanoma NCCN Guidelines, also added that the addition of the first approved tumor-infiltrating lymphocyte (TIL) therapy, lifileucel (Amtagvi), represents a major advancement from 2024 in the refractory setting.¹

“In the neoadjuvant setting, it’s important for community oncologists to work with their surgical oncologists and make sure they’re aware of the new guideline changes. In the past, our surgeons would oftentimes do a fantastic surgery and then refer to us. That was the workflow where we wouldn’t see the patient until after surgery, and that was appropriate at that time, but it’s changed,” Johnson said in an interview with OncLive®. “If a patient has a palpable lymph node, an in-transit lesion, or even isolated stage IV [disease], in most cases they shouldn’t go to surgery first. They should see us for a few doses of neoadjuvant therapy and then undergo surgery.”

The Most Notable 2024 NCCN Guideline Revisions in Cutaneous Melanoma:¹

• For systemic therapy for metastatic or unresectable disease in the second- or subsequent-line settings:
  • TIL therapy with lifileucel was added as a preferred regimen
• For systemic therapy considerations:
  • oNivolumab (Opdivo) plus relatlimab-rmbw (Opdualag) was added as a combination option for those with a BRAF V600 mutation who progressed on systemic therapy
• A new section was added for principles of neoadjuvant therapy
• New listings were added for melanomas in other sites
• For stage IIIB microscopic satellites:
  • Adjuvant treatment was revised for first- and second- pathways:
    • PD-1 immunotherapy changed to systemic therapy
    • Single-agent nivolumab and pembrolizumab (Keytruda) were stratified as preferred regimens
    • Dabrafenib (Tafinlar)/trametinib (Mekinist) for BRAF V600-mutated disease was added as a preferred regimen (category 2A)
• For primary treatment of stage III (clinically positive[s]) disease and for nodal recurrence, treatment of recurrence, and disease limited to nodal recurrence:
  • A neoadjuvant therapy options recommendation was added with the following regimens:
    • Pembrolizumab and nivolumab/ipilimumab (Yervoy) as preferred regimens
    • Nivolumab and nivolumab plus relatlimab as other recommended regimens
    • Dabrafenib/trametinib as useful in certain circumstances for BRAF V600-mutated disease
• For stage III (clinically positive[s]) disease, primary wide excision of primary tumor (category 1) plus therapeutic lymph node dissection was added following neoadjuvant therapy options
• Neoadjuvant systemic therapy was added for stage III (clinical satellite/in-transit), limited resectable disease
• For no evidence of disease after local or regional therapy, adjuvant systemic therapy regimens (category 2B) were clarified:
  • Nivolumab, pembrolizumab, and dabrafenib/trametinib (if BRAF V600 mutation positive) were noted as preferred regimens
  • Ipilimumab was noted as useful in certain circumstances if there was prior exposure to anti-PD-1 therapy

The Most Notable 2024 NCCN Guideline Revisions inBasal Cell Skin Cancer:²

• A new preference stratification table added with information from BCC-3, BCC-3A, BCC-5 and old BCC-E sections:
  • For locally advanced disease, sonidegib (Odomzo) and vismodegib (Erivedge) have been added to other recommend regimens and cemiplimab (Libtayo) has been added to useful in certain circumstances
  • For nodal disease, sonidegib (category 2B) and vismodegib have been added to other recommend regimens and cemiplimab has been added to useful in certain circumstances
  • For metastatic disease, vismodegib has been added to other recommend regimens and cemiplimab has been added to useful in certain circumstances

In the interview, Johnson unpacked the NCCN Guideline updates from 2024 and detailed how neoadjuvant as well as TIL therapies have represented notable advancements in melanoma. Johnson is an assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee.

OncLive: What 2024 NCCN guideline updates have had an immediate influence on how you practice in melanoma?

Johnson: The major NCCN update from the past year, which [will also] continue to next year, has been the recommendation of neoadjuvant therapy as a preferred option. For patients with stage III or IV resectable disease, the previous standard of care [SOC] was surgery followed by adjuvant therapy with anti–PD-1 [agents], but more recently, that’s changed given several practice-changing studies that favor neoadjuvant therapy. 

There are 2 options, really even more than that, but 2 major options, based on randomized [trial] data. There’s ipilimumab and nivolumab which is given at the less conventional dose of ipilimumab 1 mg/kg and nivolumab 3 mg/kg for 2 doses prior to surgery. Following surgery based on patients’ pathologic response, we’ll consider either continuing nivolumab or potentially switching therapy if they haven’t had a good response; or if they had a major pathologic response, we’ll consider stopping all therapy at that point.

That has been a major change based initially on the [data from the] phase 2 PRADO study [NCT02977052] that looked at approximately 100 patients who had a 61% major pathologic response [MPR] rate with nivolumab/ipilimumab. More recently, the phase 3 NADINA study [NCT04949113] that was presented at the 2024 ASCO Annual Meeting looked at a larger sample size and confirmed a 59% MPR rate [with nivolumab/ipilimumab]; importantly, that pathologic response rate strongly correlated with subsequent outcomes for the patients who had excellent responses then did extremely well after. That’s become a SOC.

The other [new] SOC was based on the phase 2 SWOG 1801 study [NCT03698019] which evaluated neoadjuvant pembrolizumab vs adjuvant pembrolizumab. The 3 doses of neoadjuvant therapy were given and [the neoadjuvant] arm experienced better than event-free survival [rates] vs the adjuvant arm. It’s not clear what the pathologic response rates are, it’s still being worked out, but clearly improved outcomes [were observed] giving therapy preoperatively rather than [solely] postoperatively.

Based on a couple of other small studies, nivolumab plus relatlimab for a few doses preoperatively as well as a couple of doses of nivolumab [preoperatively], are also options although we don’t have nearly as robust data. That was a major change and update to the NCCN guidelines in the past year to reflect the generally preferred status of neoadjuvant therapy.

Are there any other notable NCCN guideline updates that are important to highlight?

Another major update is the addition of TIL therapy [with] lifileucel being the specific product. This is an intensive therapy—it requires resection of the tumor, isolation of the white blood cells from the tumor, [and] stimulation and proliferation of those T cell products by the company. The patient receives non-myeloablative lymphodepleting chemotherapy and then the TIL product [is] reinfused into them, along with 6 doses of high-dose IL-2, which is also fairly toxic. It’s a very intensive process that requires multiple steps and administration in a licensed center, but it is associated with an approximate 30% response rate, and most of those responses are quite durable.

[Lifileucel is indicated for] patients who have failed anti–PD-1 therapy and BRAF and MEK inhibitor therapy if that’s applicable. It’s a first-in-class therapy; there are no other TIL products [that are] FDA-approved or available for any other tumor type. The addition of that [agent] is important and hopefully it’s the first of many different types of TIL products. It’s important to note that it’s something that can’t just be given off the shelf—this has to be given in licensed centers that have investigators and staff who are experienced with the product and its adverse effects [AEs].

What is key to note for community oncologists who are adapting to recent NCCN guideline changes?

[In the neoadjuvant setting], community oncologists should continue to communicate with their surgical oncologists and other surgical specialists who see some of the patients who have lymph node involvement with melanoma. It is important to alert the pathologists as well. Pathologists need to be aware if the patient’s going to receive some sort of response-directed treatment. If a patient is going to consider stopping ipilimumab/nivolumab after surgery, for example, the pathologist needs to be aware that the patient has received that and be able to quantify what the percentage of cell death is.

For example, if the patient has greater than 90% cell death on the tissue section that would be considered a MPR. That’s very important. If a patient is receiving pembrolizumab and planning to get it after surgery, that’s a bit less critical. It’s nice to know from a prognostic standpoint, but it doesn’t necessarily immediately change what I would recommend doing for the patient. But if someone’s going to make a treatment decision on that it’s important for the pathologist to know. These are the things to note from a neoadjuvant standpoint.

From the treatment refractory standpoint, when thinking about TIL therapy, it is important for community oncologists to know this therapy is out there and potentially get a sense of who’s giving it. I believe [one] company does have a website on who’s licensed and who’s in process of becoming licensed to give the therapy. This sometimes takes a while as someone who’s going through it at the moment. These lists of centers will no doubt be continually updated as more centers get on board. But it is important to have this option in the back of your mind for a patient who has failed available therapy options, and especially for those who have a good functional status and don’t have compromised organ function.

Have you faced any challenges integrating updates to the NCCN guidelines into your practice?

Getting TILs up and running; this is a first-in-class therapy, so it’s a bit different than prescribing a treatment and giving it in the infusion room. There are logistical challenges there, but that’s more of an issue for large academic centers that are giving these therapies.

Integration with surgical oncology and pathology to do some of the neoadjuvant therapy is something that should be thought about from a logistical standpoint—making sure that everyone’s aware of that [is important]. Whenever there’s multi-disciplinary treatment decision making, there’s potential for miscommunication and a lack of being on the same page. Otherwise, our adjuvant treatment, first-line metastatic treatment, and so forth, have not changed a lot in the past year or 2. A few data updates from more recent meetings have [also not only] reinforced our guidelines, but given a bit of nuance to them.

How do you communicate NCCN guideline changes to your patients who are receiving treatment?

If there’s something that seems to be actively changing the SOC, it’s important to communicate that with patients. Oftentimes, changes may affect a next line of therapy, rather than immediately what the patient’s on. In many cases where the patient’s benefiting from therapy, you probably wouldn’t change their therapy just because the guidelines changed.

Oftentimes, it’s more of a discussion when a therapy is not working or when making an initial treatment decision. I don’t necessarily go through guidelines with patients, even though I’m a big believer in the NCCN guidelines as the vice chair of the melanoma panel, but I’ll go through the data more because I believe that’s what the patients want to know. What are the chances that this is going to work? What are the chances of AEs? What are the chances of cure or long-term survival? Those are the important points to discuss with patients.

Is there anything else you want to highlight in the melanoma space regarding the NCCN guidelines?

One other interesting thing for guideline committees and others to deal with is [considering] tumor agnostic approvals. This is something that affects all tumor types when you’re talking about, for example, the recent pan tumor FDA approval of fam-trastuzumab deruxtecan-nxki [Enhertu] for patients with high levels of HER2 [expression], 3+ as far as immunohistochemistry.

How to recommend these kinds of therapies when it’s a situation where we don’t have much data for that tumor type, but we have an FDA approval that spans across tumor types, is something that we’ll all have to think about. [We will be] using medical judgment, but in some cases, biting the bullet and trying something especially if there’s nothing else to offer a patient. That’s something that we’re trying to figure out how to recommend and [consider] in those types of cases. It’s important for all of us to come together and report the outcomes for these situations so we can try to have more data in the future.

References

1. NCCN. Clinical Practice Guidelines in Oncology. Melanoma: cutaneous, version 3.2024. Accessed November 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/cutaneous_melanoma.pdf
2. NCCN. Clinical Practice Guidelines in Oncology. Basal cell skin cancer, version 3.2024. Accessed November 5, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nmsc.pdf