<scp>Real-World</scp>Clinical Outcomes in Patients with Locally Advanced or Metastatic Merkel Cell Carcinoma Treated in U.S. Oncology Clinical Practices: Results from<scp>SPEAR-Merkel</scp>

Bhanegaonkar, Abhijeet; Liu, Frank X.; Boyd, Marley; Fulcher, Nicole; Kim, Ruth; Krulewicz, Stan; Smith, Jodi; Cowey, C. Lance

doi:10.1002/onco.13845

Cited by 4 publications

(5 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, the first-line response rate for MCC (~56–62%) is essentially the highest among solid tumors. 31–35 Across multiple trials, the response rate has been similarly high for both VN-MCC and VP-MCC patients. 3 16 36 …”

Section: Discussionmentioning

confidence: 98%

“…Indeed, the first-line response rate for MCC (~56-62%) is essentially the highest among solid tumors. [31][32][33][34][35] Across multiple trials, the response rate Open access has been similarly high for both VN-MCC and VP-MCC patients. 3 16 36 VP-MCC has frequently been used to understand the immunological correlates of response and tumor antigenspecific T cells, due to the invariant MCPyV oncoprotein antigens expressed by these virally driven tumors.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

Church

Pulliam

Longino

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

BackgroundMerkel cell carcinoma (MCC) often responds to PD-1 pathway blockade, regardless of tumor-viral status (~80% of cases driven by the Merkel cell polyomavirus (MCPyV)). Prior studies have characterized tumor-specific T cell responses to MCPyV, which have typically been CD8, but little is known about the T cell response to UV-induced neoantigens.MethodsA patient in her mid-50s with virus-negative (VN) MCC developed large liver metastases after a brief initial response to chemotherapy. She received anti-PD-L1 (avelumab) and had a partial response within 4 weeks. Whole exome sequencing (WES) was performed to determine potential neoantigen peptides. Characterization of peripheral blood neoantigen T cell responses was evaluated via interferon-gamma (IFNγ) ELISpot, flow cytometry and single-cell RNA sequencing. Tumor-resident T cells were characterized by multiplexed immunohistochemistry.ResultsWES identified 1027 tumor-specific somatic mutations, similar to the published average of 1121 for VN-MCCs. Peptide prediction with a binding cut-off of ≤100 nM resulted in 77 peptides that were synthesized for T cell assays. Although peptides were predicted based on class I HLAs, we identified circulating CD4 T cells targeting 5 of 77 neoantigens. In contrast, no neoantigen-specific CD8 T cell responses were detected. Neoantigen-specific CD4 T cells were undetectable in blood before anti-PD-L1 therapy but became readily detectible shortly after starting therapy. T cells produced robust IFNγ when stimulated by neoantigen (mutant) peptides but not by the normal (wild-type) peptides. Single cell RNAseq showed neoantigen-reactive T cells expressed the Th1-associated transcription factor (T-bet) and associated cytokines. These CD4 T cells did not significantly exhibit cytotoxicity or non-Th1 markers. Within the pretreatment tumor, resident CD4 T cells were also Th1-skewed and expressed T-bet.ConclusionsWe identified and characterized tumor-specific Th1-skewed CD4 T cells targeting multiple neoantigens in a patient who experienced a profound and durable partial response to anti-PD-L1 therapy. To our knowledge, this is the first report of neoantigen-specific T cell responses in MCC. Although CD4 and CD8 T cells recognizing viral tumor antigens are often detectible in virus-positive MCC, only CD4 T cells recognizing neoantigens were detected in this patient. These findings suggest that CD4 T cells can play an important role in the response to anti-PD-(L)1 therapy.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

Church

Pulliam

Longino

et al. 2022

J Immunother Cancer

View full text Add to dashboard Cite

show abstract

“…This approval was based on the results of the international phase 2 JAVELIN Merkel 200 study, which demonstrated the effectiveness of avelumab both in patients with chemotherapy‐refractory metastatic MCC (Study Part A) 12 and as first‐line treatment in patients with metastatic MCC (Study Part B) 13,14 . Since then, several retrospective studies have also published real‐world data on avelumab use in MCC as a first‐ or second‐line treatment, confirming findings from the JAVELIN Merkel 200 study 4,8,15–17 …”

Section: Introductionmentioning

confidence: 73%

“…13,14 Since then, several retrospective studies have also published real-world data on avelumab use in MCC as a firstor second-line treatment, confirming findings from the JAVELIN Merkel 200 study. 4,8,[15][16][17] As only three Japanese patients were enrolled in the pivotal JAVELIN Merkel 200 study, post-marketing surveillance (PMS) was required to confirm the safety and effectiveness of avelumab for its approval in Japan. The current PMS presents the results of first-line treatment of avelumab in patients with MCC from an unbiased, allcase surveillance.…”

Section: It Has Since Been Approved In Numerous Countries Includingmentioning

confidence: 99%

Safety and effectiveness of avelumab in patients with Merkel cell carcinoma in general clinical practice in Japan: Post‐marketing surveillance

Uhara,

Kiyohara,

Isei

et al. 2024

The Journal of Dermatology

View full text Add to dashboard Cite

Avelumab, a programmed cell death ligand 1 blocking antibody, was approved for its first indication in Japan in September 2017 to treat unresectable Merkel cell carcinoma (MCC). Given that the pivotal JAVELIN Merkel 200 study only included a few Japanese patients, this post‐marketing surveillance (PMS) evaluated the safety and effectiveness outcomes of patients with MCC who received avelumab in general clinical practice in Japan. This prospective, non‐comparative, multicenter PMS included data from all patients with unresectable MCC who received avelumab between November 22, 2017 (avelumab launch date) and October 31, 2019. The primary objective was to evaluate avelumab safety (i.e., adverse events [AEs], adverse drug reactions [ADRs], and ADRs of safety specifications). The secondary objective was to evaluate avelumab effectiveness (i.e., objective response rate and overall survival [OS] rate). Seventy‐five evaluable patients were included, of whom 81.3% experienced AEs of any grade (57.3% experienced AEs of grade ≥ 3; 41.3% experienced AEs of grade 5) and 61.3% experienced ADRs (14.7% experienced ADRs of grade ≥ 3; no grade 5 ADRs were observed). The most common ADRs were pyrexia (18.7%), infusion related reaction (10.7%), and chills (6.7%). The most common ADRs of safety specifications were infusion reactions (any grade: n = 21 [28.0%]; grade 3 or 4: n = 3 [4.0%]), thyroid dysfunction (n = 7 [9.3%]), and hepatic function disorders (n = 4 [5.3%]). The median observation period was 51 weeks. An objective response was achieved by 34/75 patients (45.3%; complete response, 24.0%; partial response, 21.3%) and 6‐ and 12‐month OS rates were 77.7% and 59.6%, respectively. This PMS confirmed the clinical tolerability and effectiveness of avelumab in patients with MCC, with no new safety concerns. The risk–benefit profile of avelumab was comparable with that observed in clinical trials and remains favorable for use in general clinical practice in Japan.

show abstract

“…The results from SPEAR-Merkel, the first study to evaluate real-world clinical outcomes in 94 patients with la-MCC and m-MCC receiving first-line avelumab ( n = 28), non-avelumab immunotherapies ( n = 26, 19 pembrolizumab, 7 nivolumab), or chemotherapy ( n = 40), also highlight the therapeutic value of avelumab with an overall response rate of 64.3% and a median PFS of 11.4 months, compared to 61.5% with a median PFS of 8.1 months in the non-avelumab immunotherapy group and 42.5% with a median PFS of 6.1 months in patients undergoing chemotherapy [ 105 ]. In a similar real-world setting study involving a cohort of 20 patients with advanced MCC, comparable results were reported (overall RR: 65%; overall median time to treatment failure: 22 months) [ 106 ].…”

Section: The Role Of Immunotherapy In Non-melanoma Skin Cancermentioning

confidence: 99%

Identifying Candidates for Immunotherapy among Patients with Non-Melanoma Skin Cancer: A Review of the Potential Predictors of Response

Zelin

Maronese

Dri

et al. 2022

JCM

View full text Add to dashboard Cite

Background: Non-melanoma skin cancer (NMSC) stands as an umbrella term for common cutaneous malignancies, including basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cSCC), together with rarer cutaneous cancers, such as Merkel cell carcinoma (MCC) and other forms of adnexal cancers. The majority of NMSCs can be successfully treated with surgery or radiotherapy, but advanced and metastatic stages may require systemic approaches such as immunotherapy with immune checkpoint inhibitors (ICIs). Summary: Since immunotherapy is not effective in all patients and can potentially lead to severe adverse effects, an important clinical question is how to properly identify those who could be suitable candidates for this therapeutic choice. In this paper, we review the potential features and biomarkers used to predict the outcome of ICIs therapy for NMSCs. Moreover, we analyze the role of immunotherapy in special populations, such as the elderly, immunocompromised patients, organ transplant recipients, and subjects suffering from autoimmune conditions. Key messages: Many clinical, serum, histopathological, and genetic features have been investigated as potential predictors of response in NMSCs treated with ICIs. Although this field of research is very promising, definitive, cost-effective, and reproducible biomarkers are still lacking and further efforts are needed to validate the suggested predictors in larger cohorts.

show abstract

Real-WorldClinical Outcomes in Patients with Locally Advanced or Metastatic Merkel Cell Carcinoma Treated in U.S. Oncology Clinical Practices: Results fromSPEAR-Merkel

Cited by 4 publications

References 21 publications

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

Transcriptional and functional analyses of neoantigen-specific CD4 T cells during a profound response to anti-PD-L1 in metastatic Merkel cell carcinoma

Safety and effectiveness of avelumab in patients with Merkel cell carcinoma in general clinical practice in Japan: Post‐marketing surveillance

Identifying Candidates for Immunotherapy among Patients with Non-Melanoma Skin Cancer: A Review of the Potential Predictors of Response

Contact Info

Product

Resources

About