Peptide Receptor Radionuclide Therapy in Merkel Cell Carcinoma: A Comprehensive Review
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* Emran Askari
* Soroush Zarehparvar Moghadam
* Damian Wild
* Ebrahim Delpassand
* Sergio Baldari
* Bernhard Nilica
* Philipp E. Hartrampf
* Grace Kong
* Chiara Maria Grana
* Martin Alexander Walter
* Francesca Capoccetti
* Pashtoon Murtaza Kasi
* Jonathan Strosberg

## Visual Abstract

![Figure1](http://tech.snmjournals.org/https://tech.snmjournals.org/content/jnmt/51/1/22/F1.medium.gif)

[Figure1](http://tech.snmjournals.org/content/51/1/22/F1)

## Abstract

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. **Methods:** We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients. **Results:** Thirty-seven patients with mMCC received PRRT (1–5 cycles) with 177Lu- or 90Y-labeled somatostatin analogs (cumulative activity, 1.5–30 GBq). Radiographic response was available for 19 of 28 patients who received PRRT alone. Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported. **Conclusion:** Our analysis supports the use of PRRT in mMCC with sufficient somatostatin receptor uptake, although the quality of the available evidence is low. Prospective clinical trials are already in development and have started accruing in some parts of the world.

*   PRRT
*   SSTR
*   Merkel cell carcinoma
*   theranostics
*   Lu-177

Merkel cell carcinoma (MCC) is a rare, aggressive skin malignancy. The known risk factors for MCC are immunosuppression and extensive exposure to ultraviolet light. It usually occurs in elderly patients (median age, 70 y); typically arises in the head, neck, or extremities; and is slightly more common in men. Treatments for MCC vary depending on the stage of the disease, from complete surgical resection with or without radiation therapy for localized disease to systemic therapies (immunotherapy or chemotherapy) for metastatic disease. The 5-y survival rates for patients with metastatic disease have been approximately 18% (1*,*2). Although the introduction of immune checkpoint inhibitors has shown promising results, with an approximately 50% objective response, about half of patients with metastatic MCC (mMCC) experience disease progression or resistance.

At least one third of MCC cases express high levels of somatostatin receptors (SSTRs) (3*,*4). In some studies, SSTR expression has been reported in as many as 80%–100% of MCC cases (5). There have even been reports of using SSAs for the treatment of MCC (4). A recent trial of a novel second-generation SSA (pasireotide) allowed MCC patients to participate given the SSTR expression ([NCT01652547](http://tech.snmjournals.org/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01652547&atom=%2Fjnmt%2F51%2F1%2F22.atom)). All this sets the stage for a new therapeutic option of theranostics/peptide receptor radionuclide therapy (PRRT) in MCC.

## MATERIALS AND METHODS

Data on PRRT in MCC exist only in the form of case reports or series. A search for articles or abstracts pertaining to “PRRT” and “MCC” on PubMed, Scopus, and Google Scholar was systematically performed. Articles or abstracts published up to January 2022 were retrieved. The references of all relevant studies were evaluated as well. We also contacted centers that had previously reported experience with SSTR imaging or therapy in mMCC patients (the search strategy and PRISMA flow diagram can be found in Supplemental Figs. 1 and 2; supplemental materials are available at [http://jnmt.snmjournals.org](http://jnmt.snmjournals.org)) (6–26). Overall, 37 patients with mMCC have received PRRT with 177Lu- or 90Y-labeled somatostatin analogs (DOTATATE/DOTATOC) (Table 1; Supplemental Tables 1 and 2). Fifteen and 18 patients received 177Lu-DOTATATE and 90Y-DOTATOC, respectively. Four patients underwent tandem PRRT with 177Lu and 90Y. The number of PRRT cycles ranged from 1 to 5, with the cumulative activity ranging from 1.5 to 30 GBq. Three patients received PRRT in combination with chemotherapy, and 4 patients received PRRT with immune checkpoint inhibitors.

View this table:
[TABLE 1.](http://tech.snmjournals.org/content/51/1/22/T1)

TABLE 1. 
Review of Studies Evaluating Treatment Response to PRRT Monotherapy in mMCC (*n* = 10)

## RESULTS

Of the 37 patients who received PRRT, 18 were excluded because response data were unavailable (Supplemental Tables 1 and 2) or because PRRT had been used in combination with other active treatments (Supplemental Table 1). Consequently, radiographic response was available for 19 of 28 patients who received PRRT alone (not in combination with immunotherapy or chemotherapy). Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported (Table 1).

The median overall survival from the start of PRRT was 5 and 8 mo in patients receiving PRRT alone and in combination with other active treatments, respectively (Table 1; Supplemental Table 1). Median overall survival from diagnosis was 22 mo (Supplemental Table 3; methods for statistical analyses are described in the supplemental materials). Few studies addressed the Merkel cell polyomavirus status or 18F-FDG PET findings, whereas most reported the Krenning score (Supplemental Table 4). No significant difference was noted between Krenning scores in terms of objective response to PRRT (*P* = 0.86).

## DISCUSSION

Because of the small sample size, retrospective nature of the studies, selection bias, and low quality of the evidence, we cannot recommend PRRT for mMCC patients. However, the promising results from the available data lay the foundation for clinical trials in this space. Despite approval of immune checkpoint inhibitors, treatment resistance can occur and a fair proportion do not respond. Five of 7 patients who received PRRT in combination with immune checkpoint inhibitors or chemotherapy showed partial to complete responses, indicating better objective responses in this category than in the PRRT-alone group. Novel therapies or combinations are needed to further improve patient outcome. The ongoing GoTHAM trial ([NCT04261855](http://tech.snmjournals.org/lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04261855&atom=%2Fjnmt%2F51%2F1%2F22.atom)) is one example of a clinical trial evaluating the immunotherapy avelumab with 177Lu-DOTATATE in patients with mMCC. The results of this and other ongoing trials using theranostics might change the management of mMCC patients soon.

## CONCLUSION

Our analysis supports the use of PRRT in mMCC with sufficient SSTR uptake, although the quality of the available evidence is low. Prospective studies in terms of clinical trials are already in development and have started accruing in some parts of the world.

## DISCLOSURE

Jonathan Strosberg has consulted for Novartis and is on the speakers’ bureau for Ipsen. Damian Wild reports personal fees from Ipsen. Pashtoon Murtaza Kasi reports having a consultancy or advisory board role with Natera, Foundation Medicine, Merck/MSD Oncology, Tempus, Bayer, Lilly, Delcath Systems, QED Therapeutics, Servier, Taiho Oncology, Exact Sciences, and Ipsen and has received grant or research funding from Advanced Accelerator Applications, Boston Scientific, and Tersera. No other potential conflict of interest relevant to this article was reported.

#### KEY POINTS

**QUESTION:** Is radioligand therapy with 177Lu-DOTATATE effective and safe in mMCC patients?

**PERTINENT FINDINGS:** Because of the small sample size and low-quality evidence, we cannot recommend PRRT for mMCC patients; however, the available data show promising results, laying the foundation for clinical trials in this space.

**IMPLICATIONS FOR PATIENT CARE:** 177Lu-DOTATATE may be effective in some mMCC patients with high SSTR expression.

## ACKNOWLEDGMENTS

We thank Soheil Yazdani for the patient data of Hamiditabar et al. (17), Sandip Basu for the patient data of Basu et al. (2), and Riccardo Laudicella and Ludovica Crocè for the patient data of Herberg et al. (15). We also thank Paul Nghiem for useful links for collaboration between centers, Tomoko Akaike for thoughtful comments on the manuscript, Lindsay Gunnell for an MCC skin lesion, and Owen Prall for SSTR-staining slides.

## Footnotes

*   Published online Oct. 4, 2022.

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*   Received for publication September 10, 2022.
*   Revision received September 14, 2022.