CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: December 22, 2023
Expiration: December 21, 2024
RELATIVITY-047 Biomarker Analysis: Nivolumab With or Without Relatlimab in Metastatic Melanoma
Evan J. Lipson, MD:
RELATIVITY-047 is a global phase II/III trial comparing nivolumab plus the anti–LAG-3 antibody relatlimab vs nivolumab alone in patients with previously untreated unresectable or metastatic melanoma. As previously reported, the trial met its primary endpoint, demonstrating a significant improvement in progression-free survival (PFS) with nivolumab plus relatlimab over nivolumab alone (median PFS: 10.1 vs 4.6 months; HR: 0.75; P = .006).[Tawbi 2022]
The molecular mechanisms of nivolumab plus relatlimab have not been elucidated; moreover, biomarkers associated with greater benefit from the combination have not been identified. To explore these issues, a biomarker analysis was undertaken evaluating changes in immune cell subsets and in the tumor microenvironment in patients enrolled on RELATIVITY-047.[Lipson 2023] As a part of the exploratory analyses in this trial, we performed interrogations of circulating immune cells and pretreatment tumor specimens from patients in both treatment arms.
Peripheral blood mononuclear cells from 563 patients were subjected to flow cytometry, assessing for the percent changes of 77 prespecified cell subtypes; these included CD8+ cells, CD4+ cells, natural killer (NK) cells, and regulatory T (Treg) cells.
RELATIVITY-047 Biomarker Analysis: Changes in Peripheral Immune Cell Subsets
Evan J. Lipson, MD:
Among the 77 cell populations analyzed, 25 changed significantly more following treatment with nivolumab plus relatlimab than with nivolumab alone.[Lipson 2023] Changes in surface LAG-3+CD4+, LAG-3+CD8+, LAG-3+Treg (FOXP3+CD25+CD4+), and LAG-3+ NK cells were all significantly greater with nivolumab plus relatlimab vs nivolumab alone (P <.0001 for each). Of importance, most of the 25 affected cell types expressed cytoplasmic or surface LAG-3.
RELATIVITY-047 Biomarker Analysis: Changes in LAG-3+ CD4+ T-Cells Among Treatment Responders
Evan J. Lipson, MD:
Analysis of cell subtype changes according to treatment responses found that on-treatment increases in LAG-3+CD4+ T-cells were significantly greater in patients receiving nivolumab plus relatlimab who had an objective response than in those who had progressive disease.[Lipson 2023]
By contrast, among patients receiving nivolumab, there was no significant increase in LAG-3+CD4+ T-cells in patients with an objective response than in patients with progressive disease.
RELATIVITY-047 Biomarker Analysis: PFS Benefit According to Baseline CD8+ T-Cell Levels
Evan J. Lipson, MD:
To better understand how nivolumab plus relatlimab triggers an antitumor immune response, we interrogated the pretreatment tumor microenvironment, using monoplex immunohistochemistry (IHC) staining for MHC-1, MHC-2, and CD8.[Lipson 2023] Neither MHC-1 nor MHC-2 was differentially associated with PFS benefit, although higher expression levels of both markers enriched for efficacy in patients who received either regimen.
However, a different story emerged for CD8 staining. After separating the 474 samples into low, medium, and high CD8 tertiles, the PFS benefit for nivolumab plus relatlimab vs nivolumab was larger in the CD8-low and CD8-medium tertile subgroups relative to the CD8-high subgroup. It should be noted that a previous subgroup analysis demonstrated benefit with relatlimab plus nivolumab predominantly in PD-L1–negative tumors.[Long 2023] However, in this analysis, a substantial percentage of patients in the CD8-low and CD8-medium tertile subgroups had PD-L1–positive tumors, suggesting that some of these patients may benefit from dual therapy.
RELATIVITY-047 Biomarker Analysis: PFS Benefit According to Baseline LAG-3 Levels in High CD8+ Tumors
Evan J. Lipson, MD:
We further interrogated the tumor microenvironment using multiplex IHC to identify CD8+ cells that also expressed LAG-3.[Lipson 2023] Within the high CD8+ tertile, nivolumab plus relatlimab was associated with a PFS benefit over nivolumab in the subset of patients with LAG-3–positive tumors. These results suggest that LAG-3 expression may be a mechanism of resistance to anti–PD-1 therapy, which can be overcome by blocking LAG-3.
RELATIVITY-047 Biomarker Analysis: Clinical Implications
Evan J. Lipson, MD:
This was one of the first exploratory looks at the mechanisms underpinning how nivolumab plus relatlimab confers a PFS benefit in patients with treatment-naive melanoma. We observed more prominent expansion of certain cell subtypes, most of which expressed LAG-3, after nivolumab plus relatlimab vs nivolumab alone. More of those populations were CD4+ rather than CD8+, suggesting a potentially important contributory mechanism of action of LAG-3 blockade. Typically, we think of CD8+ cells as being the workhorse of an antitumor response. However, it may be here that CD4+ cells are doing more work than we had anticipated.
Second, our search for tumor-based biomarkers associated with increased benefit from nivolumab plus relatlimab over nivolumab alone revealed complexity beyond a single biomarker. Continued investigation of the interplay among multiple biomarkers is ongoing to elucidate the mechanism of action of relatlimab and best predict which patients may benefit from the addition of relatlimab to nivolumab therapy.
Neoadjuvant Cemiplimab in CSCC: Single-Arm Phase II Study
Evan J. Lipson, MD:
Another notable abstract from ESMO 2023 evaluated the use of the anti–PD-1 agent cemiplimab as neoadjuvant therapy in patients with resectable cutaneous squamous cell carcinoma (CSCC).[Gross 2023] This multicenter, phase II study enrolled 79 patients with surgically resectable CSCC. In Part 1 of the study, patients received neoadjuvant cemiplimab during 12 weeks before curative-intent surgery. Part 2 took place after surgery: Patients received—at the investigator's discretion—adjuvant cemiplimab, adjuvant radiation therapy, or observation. The primary endpoint of the study was pathologic complete response (pCR) rate by central review. Key secondary endpoints included major pathologic response (MPR) rate, event-free survival (EFS), and overall survival (OS).
Neoadjuvant Cemiplimab in CSCC: Postsurgical Management by Pathologic Response
Evan J. Lipson, MD:
Approximately 50% of patients (40 of 79) experienced a pCR; accordingly, the other groups were substantially smaller in number.[Gross 2023] Among patients who attained a pCR, 60% received observation only after surgery and 30% received cemiplimab.
Neoadjuvant Cemiplimab in CSCC: EFS by Pathologic Response
Evan J. Lipson, MD:
EFS outcomes were reported after a median follow-up of 18.7 months.[Gross 2023] These were generally better among patients with a pathologic response than in those without a pathologic response. The poorest outcomes were observed in the subset of patients who did not go to surgery or did not have a response.
Neoadjuvant Cemiplimab in CSCC: Efficacy
Evan J. Lipson, MD:
The estimated 12-month EFS rate was 89% overall. For patients with pCR, MPR, and partial pathologic responses, 12-month EFS rates were 94.9%, 88.9%, and 100%, respectively.[Gross 2023] For the 22 patients who did not have a response or did not proceed to surgery, the 12-month EFS rate was 72%. The 12-month OS rate for all patients was 92%.
Neoadjuvant Cemiplimab in CSCC: Safety
Evan J. Lipson, MD:
In general, the safety profile associated with neoadjuvant cemiplimab in this patient population mirrors that seen with anti–PD-1 monotherapies in most studies across tumor types.[Gross 2023] The most frequent treatment-emergent adverse events of any grade were diarrhea, fatigue, and increased blood creatinine. No grade ≥3 treatment-emergent adverse events were observed in more than 1 patient.
Neoadjuvant Cemiplimab in CSCC: Clinical Implications
Evan J. Lipson, MD:
This study of anti–PD-1 administered as neoadjuvant therapy in patients with resectable CSCC revealed several important findings. First, in Part 1 of the study, neoadjuvant cemiplimab was associated with a pCR rate of 51% and an MPR rate of 13%, suggesting that this approach is highly active in patients with resectable CSCC. Second, the 12-month EFS for all-comers was 89%, which is encouraging. Among the 40 patients who experienced a pCR, there have been no disease recurrences. The 12-month OS rate was 92% overall and median OS has not yet been reached.
Taken together, these results are encouraging and support the development of a larger randomized study of neoadjuvant/adjuvant cemiplimab for patients with resectable CSCC.
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