Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial

Kim, Sungjune; Wuthrick, Evan; Blakaj, Dukagjin; Eroglu, Zeynep; Verschraegen, Claire F.; Thapa, Ram; Mills, Matthew; Dibs, Khaled; Liveringhouse, C.; Russell, J S; Caudell, Jimmy J.; Tarhini, Ahmad A.; Markowitz, Joseph; Kendra, Kari; Wu, Richard C.; Chen, Dung-Tsa; Berglund, Anders; Michael, Lauren; Aoki, Mia; Wang, Min-Hsuan; Hamaidi, Imène; Cheng, Pingyan; Iglesia, Janis de la; Slebos, Robbert J; Chung, Christine H.; Knepper, Todd C.; Moran-Segura, Carlos M; Nguyen, Jonathan V.; Perez, Bradford A.; Rose, Trevor; Harrison, Louis B.; Messina, Jane L.; Sondak, Vernon K.; Tsai, Kenneth Y.; Khushalani, Nikhil I.; Brohl, Andrew S.

doi:10.1016/s0140-6736(22)01659-2

Cited by 68 publications

(76 citation statements)

References 34 publications

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“…3 Despite extensive (pre)clinical data that demonstrate the radiosensitizing properties of chemotherapeutic drugs, the intolerable side effects of chemotherapy are clinically limiting its applications. [4][5][6] Nanoparticles containing high-Z elements, such as Au nanoparticles, [7][8][9][10][11] Bi(III) chalcogenides, [12][13][14][15] and metal-organic frameworks (MOFs), [16][17][18][19][20] have recently been used as radiosensitizers. While these inorganic nanomaterials provide large X-ray absorption cross-sections that amplify the radiation energy deposited in tumor tissue and improve radiobiological effects, their biosafety has been questioned.…”

Section: Introductionmentioning

confidence: 99%

An iodide-containing covalent organic framework for enhanced radiotherapy

Dong

Zhou

et al. 2023

Chem. Sci.

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Section: Introductionmentioning

confidence: 99%

An iodide-containing covalent organic framework for enhanced radiotherapy

Dong

Zhou

et al. 2023

Chem. Sci.

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“…A retrospective study conducted in Germany observed responses to IPI/NIVO in three out of five anti‐PD‐L1 treatment refractory patients, without grade II or III IRAEs 37 . In addition, a recently publishedrandomized, open label, phase 2 clinical trial (NCT03071406) enrolled advanced stage MCC patients who were either treatment naïve or had received prior anti‐PD‐1 or anti‐PD‐L1 monotherapy to study the effects of IPI/NIVO with or without stereotactic body radiation therapy (SBRT) 38 . The primary endpoint was the ORR (proportion of patients with a CR or PR) in all randomly assigned patients receiving at least one dose of IPI/NIVO.…”

Section: Resultsmentioning

confidence: 99%

“…While not yet FDA‐approved, Nivolumab, a PD‐1 inhibitor has also shown efficacy in treating advanced MCC. Most recently, combination IPI/NIVO has also demonstrated clinical efficacy as a first line for advanced MCC 38 …”

Section: Discussionmentioning

confidence: 99%

“…Most recently, combination IPI/NIVO has also demonstrated clinical efficacy as a first line for advanced MCC. 38 Although checkpoint inhibitors have advanced treatment of MCC, some patients do not respond to the treatment. Thus, identifying biomarkers of responsiveness to immunotherapy will be important in improving treatment stratification in MCC.…”

Section: Discussionmentioning

confidence: 99%

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Best practices in surgical and nonsurgical management of head and neck Merkel cell carcinoma: An update

Duarte-Bateman

Shen

Bullock

et al. 2022

Molecular Carcinogenesis

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Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous neuroendocrine carcinoma. Controversy exists regarding optimal management of MCC as high-quality randomized studies and clinical trials are limited, and physicians are bound to interpret highly heterogeneous, retrospective literature in their clinical practice. Furthermore, the rising incidence and notably poor prognosis of MCC urges the establishment of best practices for optimal management of the primary tumor and its metastases. Herein, we summarized the relevant evidence and provided an algorithm for decision-making in MCC management based on the latest 2021 National Comprehensive Cancer Network guidelines. Additionally, we report current active MCC clinical trials in the United States. The initial management of MCC is dependent upon the pathology of the primary tumor and presence of metastatic disease. Patients with no clinical evidence of regional lymph node involvement generally require sentinel node biopsy (SLNB) while clinically node-positive patients should undergo fine needle aspiration (FNA) or core biopsy and full imaging workup. If SLNB or FNA/core biopsy are positive, a multidisciplinary team should be assembled to discuss if additional node dissection or adjuvant therapy is necessary. Wide local excision is optimal for primary tumor management and SLNB remains the preferred staging and predictive tool in MCC. The management of MCC has progressively improved in the last decade, particularly due to the establishment of immunotherapy as a new treatment option in advanced MCC. Ongoing trials and prospective studies are needed to further establish the best practices for MCC management.

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“…However, the just published randomized, open-label, phase 2 trial on first-line IPI/NIVO±stereotactic body radiation with an impressive ORR of 100% in ICI-naïve patients now gives justified reason to possibly even prefer IPI/NIVO as first-line therapy over PD-L1 or PD-1 monotherapy. 13 Clinical characteristics and other biomarkers might predict response to immunotherapies. MCC shows a particular biology with MCPyV being integrated into ~70% of the tumor genomes, while the remaining 30% presumably are linked to UV irradiation showing a strikingly high tumor mutational burden (TMB).…”

Section: Discussionmentioning

confidence: 99%

Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG

Glutsch

Schummer

Kneitz

et al. 2022

J Immunother Cancer

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Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9% and 26.8 %, respectively. The OS rate at 36 months was 64.3%. Only 3 (21%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.

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Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial

Cited by 68 publications

References 34 publications

An iodide-containing covalent organic framework for enhanced radiotherapy

An iodide-containing covalent organic framework for enhanced radiotherapy

Best practices in surgical and nonsurgical management of head and neck Merkel cell carcinoma: An update

Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG

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