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Neoadjuvant immune checkpoint inhibitors in high-risk stage III melanoma.

ABSTRACT: The success of immunotherapy and targeted therapy for metastatic melanoma has generated considerable interest in the adjuvant setting, even though high-risk stage III melanoma (with or without in-transit metastases) still holds a substantial probability of relapse, despite surgical resection and available adjuvant treatments. Based on preclinical and clinical trials in resectable melanoma, immune checkpoint inhibitors can enhance anti-tumor immunity by activating antigen-specific T cells found in the primary site. These tumor-reactive T cells continue to exert their anti-tumor effects on remaining neoplastic cells after resection of the primary tumor, potentially preventing relapses from reoccurring. Several trials in the neoadjuvant setting have been conducted for melanoma patients using checkpoint inhibitors with promising early data, showing an improvement of operability and clinical outcomes. Hence, in this study, we review and discuss the available published and ongoing clinical trials to explore the scientific background behind immunotherapy in the neoadjuvant context.

SUBMITTER: Ferraresi V

PROVIDER: S-EPMC9122306 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Neoadjuvant immune checkpoint inhibitors in high-risk stage III melanoma.

Ferraresi Virginia V Vari Sabrina S

Human vaccines & immunotherapeutics 20211209 3

The success of immunotherapy and targeted therapy for metastatic melanoma has generated considerable interest in the adjuvant setting, even though high-risk stage III melanoma (with or without in-transit metastases) still holds a substantial probability of relapse, despite surgical resection and available adjuvant treatments. Based on preclinical and clinical trials in resectable melanoma, immune checkpoint inhibitors can enhance anti-tumor immunity by activating antigen-specific T cells found i ...[more]

PMID: 34882516

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Project description:ImportanceDespite the clear potential benefits of neoadjuvant therapy, the optimal neoadjuvant regimen for patients with high-risk resectable melanoma (HRRM) is not known.ObjectiveTo compare the safety and efficacy of dual checkpoint inhibitors with anti-programmed cell death protein-1 (anti-PD1) therapy in a neoadjuvant setting among patients with HRRM.Design, setting, and participantsIn this pooled analysis of clinical trials, studies were selected provided they investigated immune checkpoint inhibitor treatment, were published between January 2018 and March 2023, and were phase 1, 2, or 3 clinical trials. Participant data included in the analysis were derived from trials evaluating the efficacy and safety of anti-PD1 monotherapy and the combination of anti-cytotoxic T lymphocyte-associated protein-4 with anti-PD1 in the neoadjuvant setting, specifically among patients with HRRM.InterventionsPatients were treated with either anti-PD1 monotherapy; dual checkpoint inhibition (DCPI) with a conventional dose of 3-mg/kg ipilimumab and 1-mg/kg nivolumab; or DCPI with an alternative-dose regimen of 1-mg/kg ipilimumab and 3-mg/kg nivolumab.Main outcomes and measuresThe main outcomes were radiologic complete response (rCR), radiologic overall objective response (rOOR), and radiologic progressive disease. Also, pathologic complete response (pCR), the proportion of patients undergoing surgical resection, and occurrence of grade 3 or 4 immune-related adverse events (irAEs) were considered.ResultsAmong 573 patients enrolled in 6 clinical trials, neoadjuvant therapy with DCPI was associated with higher odds of achieving pCR compared with anti-PD1 monotherapy (odds ratio [OR], 3.16; P < .001). DCPI was associated with higher odds of grade 3 or 4 irAEs compared with anti-PD1 monotherapy (OR, 3.75; P < .001). When comparing the alternative-dose ipilimumab and nivolumab (IPI-NIVO) regimen with conventional-dose IPI-NIVO, no statistically significant difference in rCR, rOOR, radiologic progressive disease, or pCR was noted. However, the conventional-dose IPI-NIVO regimen was associated with increased grade 3 or 4 irAEs (OR, 4.76; P < .001). Conventional-dose IPI-NIVO was associated with greater odds of achieving improved rOOR (OR, 1.95; P = .046) and pCR (OR, 2.99; P < .001) compared with anti-PD1 monotherapy. The alternative dose of IPI-NIVO also was associated with higher odds of achieving rCR (OR, 2.55; P = .03) and pCR (OR, 3.87; P < .001) compared with anti-PD1 monotherapy. The risk for grade 3 or 4 irAEs is higher with both the conventional-dose (OR, 9.59; P < .001) and alternative-dose IPI-NIVO regimens (OR, 2.02; P = .02) compared with anti-PD1 monotherapy.Conclusion and relevanceIn this pooled analysis of 6 clinical trials, although DCPI was associated with increased likelihood of achieving pathological and radiologic responses, the associated risk for grade 3 or 4 irAEs was significantly lower with anti-PD1 monotherapy in the neoadjuvant setting for HRRM. Additionally, compared with alternative-dose IPI-NIVO, the conventional dose of IPI-NIVO was associated with increased risk for grade 3 or 4 irAEs, with no significant distinctions in radiologic or pathologic efficacy.

Project description:BackgroundImmune checkpoint inhibitors (ICI) have become first-line treatment for metastatic colorectal cancer (CRC) with deficient mismatch repair (dMMR). Despite the remarkable response reported in preliminary trials, the role of ICI in patients with early-stage, operable CRC remains unclear. The aim of this study was to investigate trials on neoadjuvant ICI in operable CRC.Materials and methodsScoping review of clinical trial registries (Clinicaltrials.gov and EU clinical trial registers) and PubMed/Medline database of trials on neoadjuvant ICI for operable CRC was done up to December 2022.ResultsSome 40 trials investigating neoadjuvant ICI for early-stage, operable CRC were identified, including five published trials and three conference abstracts. Preclinical phase I/II trial predominated with only three clinical phase III trials. Few trials investigated neoadjuvant ICI as the only intervention (monotherapy). Trials in rectal cancer were designed for combined ICI with chemo(radio)therapy, only 8 trials stating an MSI/dMMR status for inclusion, one designed for MSS/pMMR only and, the rest agnostic for MMR status. Thirty-eight (95%) trials investigated programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitors. PD-1/PD-L1 inhibitors were combined with vascular endothelial growth factor (VEGF) inhibitor or with cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) inhibitor, in two trials each, respectively. Pathological complete response as primary outcome after surgery was the most frequently used study endpoint. In rectal cancer, six trials included a "watch and wait" strategy for patients with complete clinical response. No "watch and wait" study design for colon cancer after neoadjuvant ICI were identified.ConclusionHigh response rates from neoadjuvant ICI in early-stage colon and rectal cancer are reported in phase I/II studies. Contemporary trial designs are heterogeneous, with few comparable inclusion criteria, use of several drug combinations and durations and, wide variation of endpoints reported. Harmonizing clinical and translational aspects including survival data is needed for improved future trial designs with clinical impact.

Project description:BackgroundImmune checkpoint inhibitors (ICIs) are the standard of care for metastatic cutaneous melanoma (mCM) patients, but their efficacy in young adults aged less than 40 years remains unclear.Materials and methodsWe retrospectively analyzed 303 stage IV melanoma patients of different ages treated with nivolumab, pembrolizumab, or ipilimumab plus nivolumab combination therapy. Clinical data and blood values such as LDH, CRP, and absolute immune cell counts were retrieved from the medical records. Pre-treatment serum concentrations of soluble immune checkpoint proteins were measured using ELISA. In addition, information on frequencies of various T cell subsets in the peripheral blood was collected from a previously reported study (ELEKTRA). Patient characteristics and clinical information was correlated with PFS and OS using univariate and multivariate cox regression analysis.ResultsOf 303 patients, 33 (11%) were ≤ 40 years old. The older patients had a median age of 64 (95% CI: 61-66). Concerning prognostic parameters, there was no difference between the age groups, e.g., in gender, LDH, or the existence of brain or liver metastases. Patients aged ≤ 40 years [p = 0.014; HR: 1.6 (95% CI: 1.1-2.4)], presence of liver metastases [p = 0.016; HR: 1.4 (95% CI: 1.0-1.9)], line of ICI treatment [p = 0.009; HR: 1.4 (1.0-1.9)], elevated LDH [p = 0.076; HR: 1.3 (95% CI: 0.97-1.8)], and brain metastasis [p = 0.080; HR: 1.3 (95% CI: 0.97-1.7)], were associated with shorter PFS in univariate analysis. Multivariate analysis revealed that the patient's age (≤ 40 years) remains a high-risk factor upon adjusting for all potential confounders [p = 0.067; HR: 1.5 (95% CI: 0.97-2.3)]. Blood parameters revealed that patients ≤ 40 years have relatively higher frequencies of activated CD4 T cells (CD4 + Ki67 + CD4 + ICOS +) in the blood, and significantly lower number of basophils and CD45RA- memory T cells, compared to patients above 40 years (p < 0.05). In addition, patients ≤ 40 years experiencing disease progression within 6 months of ICI treatment had increased concentrations of sPDL1 (p = 0.05) and sTIM3 (p = 0.054) at baseline.ConclusionYoung patients with stage IV melanoma may experience shorter progression-free survival upon ICI treatment compared to patients above 40 years and are characterized by fewer basophils and memory T cells in the blood.

Dataset Information

Neoadjuvant immune checkpoint inhibitors in high-risk stage III melanoma.

Publications

Neoadjuvant immune checkpoint inhibitors in high-risk stage III melanoma.

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