EFS Benefit of Pembrolizumab Is Shown in Neoadjuvant, Adjuvant Setting

With the advance of neoadjuvant therapy in cutaneous melanoma, shown through various trial data including the randomized phase 2 trial SWOG 1801 trial (NCT03698019), clinicians now wield a vital tool in their treatment armamentarium.

Douglas B. Johnson, MD, MSCI, offers a comprehensive exploration of the nuances for using neoadjuvant therapy, addressing various treatment combinations, along with recommendations for first-line systemic therapy during the National Comprehensive Cancer Network 2024 Annual Conference.¹

“Generally speaking, I think most of us prefer neoadjuvant regimens now that we have randomized data with pembrolizumab where we see that neoadjuvant therapy has better outcomes than adjuvant therapy. This is not written in stone; [however], if a patient has a tumor that may compromise an important anatomical location, then you must perform surgery. Not every patient must have neoadjuvant therapy,” Johnson said.

Johnson is associate professor of medicine in the Department of Medicine, coleader of the Translational Research and Interventional Oncology Research Program, and clinical director of melanoma at Vanderbilt- Ingram Cancer Center in Nashville, Tennessee.

Neoadjuvant Regimens

The phase 2 SWOG 1801 trial, was the first randomized study to compare pembrolizumab (Keytruda) in the neoadjuvant vs adjuvant settings^.1,2 Those receiving both neoadjuvant and adjuvant therapy experienced significantly longer event-free survival (EFS) at the median follow-up of 14.7 months (P = .004).² According to investigators, for patients in the neoadjuvant-adjuvant group.

Patients with measurable stage IIIB to IVC melanoma that was suitable for resection were enrolled in the trial and were randomly assigned to 2 treatment groups.

In the neoadjuvant-adjuvant group, 154 patients received 3 doses of neoadjuvant pembrolizumab prior to surgery, followed by adjuvant pembrolizumab. Conversely, in the adjuvant-only group, 159 patients underwent surgery followed by pembrolizumab administration, until disease recurrence or unacceptable toxicity occurred. In the neoadjuvant-adjuvant group, the percentage of patients experiencing grade 3 treatment related adverse events (AEs) was 12% vs 14% in the adjuvant-only group and, according to study investigators, no new toxic effects were identified.

Johnson noted that about 20% of patients progressed on their first scan in the neoadjuvant pembrolizumab group; however, this percentage was similar in the adjuvant-only group. “These data suggest that the patients who progress on pembrolizumab are the patients who probably would have progressed postoperatively as well, and this potentially decreases the concern of losing the opportunity for surgery in certain patients,” Johnson stated.¹

In the multicenter, open-label, phase 2 OpACIN-neo trial (NCT02977052), which is one of the first neoadjuvant studies for this cancer type, Johnson noted, a different neoadjuvant regimen was explored.^1,3 Investigators evaluated 86 patients in 3 varying dosing combinations of neoadjuvant ipilimumab (Yervoy) and nivolumab (Opdivo).¹ Patients were randomly assigned 1:1:1 to one of 3 neoadjuvant dosing regimens:

• Group A (n = 30) received 2 cycles of ipilimumab at 3 mg/kg along with nivolumab at 1 mg/kg intravenously once every 3 weeks.

• Group B (n = 30) underwent 2 cycles of ipilimumab at 1 mg/kg combined with nivolumab at 3 mg/kg intravenously once every 3 weeks.

• Group C (n = 26) was administered 2 cycles of ipilimumab at 3 mg/kg once every 3 weeks, immediately followed by 2 cycles of nivolumab at 3 mg/kg intravenously once every 2 weeks.³

The pathologic response in group A was 80%, in group B it was 77%, and in group C the pathologic response was 65%; the overall response rate (ORR) was 63%, 57%, and 35%, respectively. The percentage of grade 3 to 4 immune-related AEs experienced within the first 12 weeks was 40% in group A, 20% in group B, and 50% in group C.¹ Investigators determined that the dosing schedule for group B (2 cycles of ipilimumab at 1 mg/ kg combined with nivolumab at 3 mg/kg) was the most well tolerated, resulting in a significant pathological response.^1,3

Patients who met the following criteria were considered for the study: 18 years or older, a WHO performance status of 0 or 1, diagnosed with resectable stage III melanoma limited to lymph nodes, and possessing measurable disease as per RECIST version 1.1. Enrollment took place across 3 medical centers located in Australia, Sweden, and the Netherlands.³

An important aspect that emerged from this trial are the evaluable differences in pathologic response, which establishes response as a potential biomarker to incorporate in treatment decision making, Johnson said.¹

The results from the OpACIN-neo trial led to an extension cohort known as the PRADO trial (n=99), which further evaluated the primary dose found in the OpACIN-neo trial. The main goals of the study were to confirm how well this treatment worked after 6 weeks, to determine if surgery could be avoided for those with a major pathologic response and to see if nonresponders could have better results with extra treatment. Investigators found that 72% of patients experienced a partial pathologic response and 61% achieved a major pathologic response.⁴

Another neoadjuvant regimen Johnson addressed was the nivolumab with relatlimab (Opdualag) regimen. In this trial (NCT02519322), patients with resectable clinical stage III or oligometastatic stage IV melanoma received 2 neoadjuvant doses of the dual treatment. This was followed by surgery and then 10 doses of adjuvant combination therapy.^1,5

The combination led to a 57% complete pathological response rate and a 70% ORR among 30 treated patients. The recurrence- free survival rates at 1 and 2 years were 100% and 92%, respectively, in contrast to 88% and 55% (P = .005). There were no grade 3 or 4 immune-related AEs found in the neoadjuvant setting.⁵

In-Transit Disease

For patients with a subcutaneous or cutaneous metastases between the original node and the nodal basin, the guidelines state that neoadjuvant systemic therapy can be considered for these patients, Johnson explained.^1,6 “However, it’s not unreasonable to have an excision and adjuvant therapy or observation following surgery. We don’t have [specific] data for this [recommendation] but have extrapolated from other data, Johnson said.”

There are other options to consider in this setting, such as various forms of the oncolytic virus administered primarily at centers that specialize in this treatment approach, and other options include systemic therapy.

“The optimal regimen is unclear [for neoadjuvant therapy]. Pembrolizumab has the best randomized data, but ipilimumab/ nivolumab and nivolumab/relatlimab [regimens] are more active in other contexts [as explained], and it may be that these [regimens] become more preferred.”

Neoadjuvant Pros and Cons

Advantages of implementing neoadjuvant therapy include that if a tumor is in situ and immunotherapy is started it can generate a wide range of systemic T-cell responses to the tumor. After the tumor is resected, the immune response is maintained with adjuvant therapy and any residual disease is removed by the T cells that are activated.

Conversely, if the tumor is removed and a small amount of residual disease is left it may be challenging to generate an immune response against the residual disease that remains, resulting in a poorer-quality T-cell response, Johnson explained.

Other benefits to neoadjuvant therapy include avoiding unnecessary surgery, it allows a patient to be started on therapy sooner and can ease the surgical procedure. However, the disadvantages are that neoadjuvant therapy can delay surgery and introduce immune-related toxicity that may complicate surgery or delay it. Adjuvant therapy is still a recommended option for patients with high-risk stage II cutaneous melanoma, those with a positive sentinel lymph node, or patients who were referred to the oncologist post surgery.

First-Line Systemic Therapy

First-line therapy in the metastatic setting has many options now, Johnson explained. Some of the trial data that help to narrow down these choices are from the CheckMate 006 study (NCT01721772), which randomly assigned patients with metastatic melanoma to ipilimumab/nivolumab, ipilimumab alone, or nivolumab alone.^1,7

“Considering the long-term data, the overall survival data are undoubtedly statistically significant in favor of the ipilimumab/nivolumab combination with a P value greater than .05,” Johnson said.

The ipilimumab/nivolumab combination is also strongly recommended for patients with untreated asymptomatic brain metastases based on data from the ABC study (NCT02374242).⁸

These patients were randomly assigned to ipilimumab/nivolumab vs nivolumab alone and reported an ORR of 46% vs 20%, respectively, and 56% in patients who were BRAF and MEK naive.

“Considering our historical survival curves for melanoma, we had a 5% longterm survival rate, if that, and now it’s over 50%. That is a 6.5-year, melanoma-specific survival with the ipilimumab/nivolumab combination, which is remarkable,” Johnson said.

REFERENCES:

1. Johnson D. Updates to the management of cutaneous melanoma. April 7, 2024. Accessed May 15, 2024. https://tinyurl.com/4rp8jzye

2. Patel SP, Othus M, Chen Y, et al. Neoadjuvant–adjuvant or adjuvant-only pembrolizumab in advanced melanoma. N Engl J Med. 2023;388(9):813-823. doi:10.1056/nejmoa2211437 SWOG STUDY

3. Rozeman EA, Menzies AM, van Akkooi ACJ, et al. Identification of the optimal combination dosing schedule of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma (OpACIN-neo): a multicentre, phase 2, randomised, controlled trial. Lancet Oncol. 2019;20(7):948-960. doi:10.1016/S1470-2045(19)30151-2

3. Reijers ILM, Menzies AM, van Akkooi ACJ, et al. Personalized response-directed surgery and adjuvant therapy after neoadjuvant ipilimumab and nivolumab in high-risk stage III melanoma: the PRADO trial. Nat Med. 2022;28(6):1178-1188. doi:10.1038/s41591-022-01851-x

4. Amaria RN, Postow M, Burton EM, et al. Neoadjuvant relatlimab and nivolumab in resectable melanoma. Nature. 2022;611(7934):155-160. doi:10.1038/s41586-022-05368-8

5. National Comprehensive Cancer Network Guidelines. Melanoma: cutaneous. Version 2.2024. April 3, 2024. https://tinyurl.com/7wakv7un

6. Robert C, Long GV, Brady B, et al. Five-year outcomes with nivolumab in patients with wild-type BRAF advanced melanoma. J Clin Oncol. 2020;38(33):3937-3946. doi:10.1200/JCO.20.00995.

7. Long GV, Atkinson V, Lo S, et al. Five-year overall survival from the anti-PD1 brain collaboration (ABC Study): Randomized phase 2 study of nivolumab (nivo) or nivo+ipilimumab (ipi) in patients (pts) with melanoma brain metastases (mets). J Clin Oncol. 2021;39(15_suppl):9508-9508. doi:10.1200/jco.2021.39.15_suppl.9508