Lanreotide, a Somatostatin Analogue, in Advanced Merkel Cell Carcinoma: A Prospective Single‐Arm Phase II Study

ABSTRACT

Background

Merkel Cell Carcinoma (MCC) is a rare, aggressive neuroendocrine and epithelial skin cancer. Somatostatin analogues, such as lanreotide, have shown efficacy in managing other neuroendocrine tumors. Retrospective studies suggest that lanreotide may induce partial response or disease stabilization in patients with advanced MCC. To test this hypothesis, we conducted a Phase II, non‐randomized, open trial investigating lanreotide in MCC patients with advanced disease (ClinicalTrials.gov identifier: NCT02351128).

Methods

Patients with Stage IIIB‐IV MCC received lanreotide monotherapy (120 mg every 28 days) at any line of systemic therapy, until disease progression or unacceptable toxicity. The primary endpoint was disease control rate (DCR) (defined as the proportion of patients with complete response, partial response, and stable disease) at 3 months. Secondary endpoints included progression‐free survival (PFS), overall survival (OS), somatostatin receptor (SSTR) tumor expression, and treatment safety.

Results

Between April, 2015, and November, 2016, 35 patients received lanreotide, with 12 evaluable at 3 months. The DCR at 3 months was 33.3% (4) among evaluable patients (all with stable disease) and 11.4% for the full cohort. Statistical analyses showed no significant difference from the expected 20% response rate (p = 0.205 for intention‐to‐treat; p = 0.939 for per‐protocol). Kaplan–Meier analysis revealed median OS and PFS of 3.1 months (95% CI, 2–5.5) and 3.5 months (95% CI, 2.3–5.5), respectively. SSTR tumor expression did not correlate with treatment response.

Conclusion

Although limited by its implementation before the era of immunotherapy, this non‐randomized study shows the limited effectiveness of lanreotide as monotherapy in treating patients with advanced MCC.

Trial Registration

Identifier: NCT02351128

1. Introduction

Merkel Cell Carcinoma (MCC) is a rare but aggressive epithelial and neuroendocrine skin cancer with rising incidence over the past decades [1]. It predominantly occurs on sun‐exposed skin of elderly and immunocompromised patients and follows an aggressive course, characterized by a high recurrence rate despite surgery and radiation therapy. More than half of MCC patients harbor lymph node or distant metastasis at diagnosis or during follow up [2]. Until recently, platinum‐based chemotherapy regimens constituted the standard of care of inoperable advanced disease stages, achieving objective responses in 30 to 60% of cases after the first line of chemotherapy, with a median overall survival of 9 months, according to the US National Cancer Database [2].

The discovery of the Merkel Cell Polyomavirus (MCPyV) in 2008 as the main causative agent of most MCCs [3] has accelerated research into the biology and treatment approaches of MCC. The crucial role of the immune system in controlling this cancer has supported the assessment of antibodies blocking the PD‐1/PDL‐1 immune checkpoint inhibitors (ICI) in advanced MCC stages. Tumor responses occur in approximately half of patients with advanced MCC when ICI are used in the first‐line setting [2]. Avelumab was the first therapy approved in Europe and the USA for patients with advanced MCC [4], followed by pembrolizumab, which was approved by the FDA in December 2018 [5, 6], and retifanlimab in March 2023 [7, 8]. Although ICIs have not been assessed in randomized studies against conventional chemotherapy, the durability of their responses has positioned them as the standard of care in metastatic MCC [9, 10, 11]. However, despite these advances, only half of responders experience sustained benefits from ICIs, due to primary and secondary resistances of unknown mechanisms [9, 12]. Therefore, alternative and/or synergistic therapies are needed.

Various proportions of MCCs harbor mutated tumor suppressor genes (such as TP53, RB1, CDKN2A/B, PIK3CA, PTEN…) and/or overexpress molecular targets (such as CD56, Bcl‐2 family members, receptor tyrosine kinases…) providing a rationale for numerous molecularly‐targeted therapies [13]. Among these, the neuroendocrine differentiation of MCC has logically led to investigate the somatostatin receptors (SSTR) expression. SSTRs are transmembrane proteins expressed in normal tissues, including the brain, adrenal glands, pancreas, and gastrointestinal tract, as well as in various human cancers, particularly neuroendocrine cancers. They constitute the molecular basis for somatostatin receptor‐based imaging and SSTR‐targeted therapies, including somatostatin analogues (SSAs) and peptide receptor radionuclide therapy (PRRT) [14]. Somatostatin analogues are established treatments for well‐differentiated gastroenteropancreatic neuroendocrine tumors expressing somatostatin receptors, whereas their efficacy in poorly differentiated neuroendocrine carcinomas remains unproven [15]. Consistent with its neuroendocrine phenotype, MCC tumors have been shown to be detected by somatostatin receptor‐based imaging in 46% to 92% of cases [16, 17, 18, 19], and to express SSTRs by immunohistochemistry in 56% to 76% of cases [20, 21]. These observations, together with the established efficacy of SSAs in selected neuroendocrine tumors [22], provided the rationale for evaluating lanreotide in advanced MCC. Although limited to retrospective case series, previous reports described disease control or prolonged disease stabilization with lanreotide in a small number of patients with unresectable or metastatic MCC, including one case reported by Kau et al. [23], one by Fakiha et al. [24], and three out of nineteen cases reported by Akaike et al. [19] Based on these preliminary findings, we conducted an open‐label, non‐randomized Phase II trial to evaluate the efficacy of prolonged‐release lanreotide (Somatuline LP) in patients with inoperable locoregional and/or metastatic MCC by assessing tumor response at 3 months of treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [25].

2. Methods

2.1. Patient Population

Merkel‐PHRC was a French, multicenter, open‐label, single‐arm, Phase II trial (NCT02351128) conducted between April 4, 2015, and November 14, 2016, in 35 centers of the Group of Cutaneous Oncology of the French society of dermatology, in compliance with GCP. All patients provided written informed consent.

Eligible patients were aged ≥ 18 years, with histologically confirmed inoperable locoregional and/or metastatic MCC (Stage IIIB to IV according to AJCC 2010 classification used at this time) [26]. As the trial predated immunotherapy, lanreotide was allowed at any treatment line.

Patients needed ≥ 1 measurable lesion (> 20 mm conventional CT or > 10 mm spiral CT) or evaluable clinical targets, Eastern Cooperative Oncology Group—Performance Status (ECOG‐PS) 0–3, no other malignancy within 5 years (except treated non‐melanoma skin cancer or in situ cervical cancer), no concomitant systemic anticancer therapy, and adequate organ function (neutrophils > 1000/mm³, platelets > 100,000/mm³, hemoglobin > 9 g/dL, bilirubin ≤ 3 × ULN, AST/ALT ≤ 2.5 × ULN, creatinine ≤ 1.5 × ULN). Exclusion criteria included untreated chronic disease, active infection, or recent therapy (< 4 weeks post‐chemotherapy, < 14 days post‐radiotherapy/surgery).

Patients received lanreotide 120 mg SC every 28 days until progression or unacceptable toxicity.

2.2. Data Collection

Tumors were assessed clinically or via CT/MRI at baseline and every 3 months per RECIST v1.1, with central review. Intercurrent clinical events (ICEs) were graded per NCI‐CTCAE v4.03 and monitored until 24 months after first dose. Laboratory tests (CBC, AST, ALT, ALP, creatinine, glucose, LDH) were performed at baseline and before each cycle.

SSTR2A, SSTR2C, and SSTR5 tumor expression was analyzed by immunohistochemistry (BenchMark XT, Roche Diagnostics) on available tumor samples. Two pathologists jointly scored staining intensity (0–3) and percentage positivity; SSTR scores (0–300) were calculated and averaged for a combined index [21].

2.3. Study End Points

The primary endpoint was the 3‐month disease control rate (DCR), defined as the proportion of patients achieving complete response, partial response, or stable disease according to RECIST v1.1 criteria.

Secondary endpoints included overall survival (OS), defined as the time from first administration of lanreotide to the date of death; progression‐free survival (PFS), defined as the time from first administration of lanreotide to the first documented tumor progression (based on the CIOMS SUSAR declaration forms); and assessment of the association between tumor responses, SSTR expression levels (SSTR2A, SSTR2C, and SSTR5), and the impact of key prognostic factors such as tumor stage, ECOG performance status, and lactate dehydrogenase (LDH) levels. Exploratory endpoints focused on safety and tolerability.

2.4. Statistical Analyses

The planned sample size of 35 patients was determined using A'Hern's one‐step method [27], with the null hypothesis (H0) set at a DCR < 20% and the alternative hypothesis (H1) at a DCR ≥ 40%. Using a one‐sided alpha level of 5% and 80% power, the study required at least 12 of 35 patients to achieve disease control at 3 months to reach statistical significance.

All analyses were performed on an intention‐to‐treat basis, with the primary endpoint also analyzed per protocol. Quantitative variables were summarized using means with standard deviations or medians with interquartile ranges, while categorical variables were reported as counts and percentages. The 3‐month DCR was compared to the 40% threshold using an exact binomial test. OS and PFS were estimated using the Kaplan–Meier method, and the association of prognostic factors with clinical outcomes was assessed. Continuous variables were compared using Mann–Whitney U or Wilcoxon tests, and time‐dependent changes were analyzed with linear regression. All statistical analyses were performed with Stata version 14.2, R version 4.1.3, and GraphPad Prism version 5.0.1.

No data transformation or imputation of missing values was performed. Continuous variables were inspected for outliers before analysis. Statistical significance was defined as a two‐sided p value < 0.05 unless otherwise specified. The A'Hern design used a one‐sided α of 0.05.

3. Results

3.1. Patients

Between April 4, 2015, and November 14, 2016, 35 patients, enrolled at 33 sites in France (Figure 1), received lanreotide. There were 23 male (65.7%) and 12 female (34.3%). Among the 35 patients, 4 had an unresectable locally advanced disease with regional lymph node involvement (Stage III per AJCC 2010), while the other 31 had distant metastases. The patients ‘mean age was 77.9 ± 8 years (range from 58 to 92 years).

FIGURE 1.

Flow diagram.

Most patients had previously received surgery and radiotherapy. Twelve patients (35.3%) had an ECOG‐PS of 0, 15 (44.1%) had an ECOG‐PS of 1, 6 (17.7%) had an ECOG‐PS of 2, and 1 (2.9%) had an ECOG‐PS of 3. Additional baseline characteristics of the patient population are shown in Table 1.

TABLE 1.

Patient demographics and baseline characteristics of all treated patients.

Patient characteristic	Population (n = 35)
Age, years, mean ± SD	77.9 ± 8
Sex, No. (%)
Female	12 (34.3)
Male	23 (65.7)
Comorbidities, No (%)
Cardiovascular diseases	15 (44.1)
Extracutaneous cancer	6 (17.7)
Other cutaneous cancer	7 (20.6)
Autoimmune diseases	5 (14.7)
Immunocompromised	2 (5.9)
Primary MCC location, No (%)
Limbs	17 (48.5)
Trunk	8 (22.9)
Head or neck	6 (17.1)
Occult primary	4 (11.4)
2010 AJCC stage at diagnosis No (%)
IIIB	4 (11.4)
IV	31 (88.5)
Previous MCC treatment modalities, No (%) a
Surgery alone	5 (17.2)
Surgery and radiotherapy	12 (41.3)
Surgery, radiotherapy and chemotherapy	9 (31)
Chemotherapy alone	0 (0)
Radiotherapy alone	0 (0)
Immunotherapy	1 (3.4)
No treatment	0 (0)
ECOG‐PS, No. (%)
0	12 (35.3)
1	15 (44.1)
2	6 (17.7)
3	1 (2.9)
SSTR staining score expression, mean (range, min‐max)
SSTR2A	39 (0–200)
SSTR2C	162 (0–300)
SSTR5	167 (0–240)
Sum of diameters of CT target lesions, mm, median [25th; 75th percentiles]	78 [47; 121]
LDH, UI, median[25th; 75th percentiles]	386 [239; 474]

Note: Data presented as mean ± SD, Median [25th, 75th percentiles], or number (n) and percentage (%).

Abbreviations: AJCC, American Joint Committee on Cancer; ECOG‐PS, Eastern Cooperative Oncology Group‐Performance Status; LDH, lactate dehydrogenase; SSTR, somatostatin receptor.

^a Data missing for 6 patients.

Twenty‐three patients discontinued treatment before the scheduled 3‐month assessment, including 17 because of documented disease progression, 5 because of death, and 1 because of clinical deterioration. Consequently, they were not evaluable for the per‐protocol assessment of the primary endpoint. However, they were all included in the intention‐to‐treat analysis, in which they were considered as treatment failures, resulting in an overall disease control rate of 11.4% (see Flow diagram).

3.2. Efficacy

The evaluation of lanreotide's efficacy at 3 months could only be carried out on 12 patients (Table 2). When considering all patients, over one‐third progressed or died before reaching the 3‐month primary end‐point (Figure 2B). Among these evaluable patients, the disease control rate at 3 months was 33.3% (n = 4), with no complete response or partial response, all four patients having stable disease. Among the four patients with stable disease, three presented with distant metastases at inclusion, while one had locoregional disease. One patient experienced disease progression immediately after the primary endpoint assessment, whereas the others progressed later, with a median time to progression (for the four patients) of 12.14 weeks (range: 8–52.4 weeks) (Figure 3B). When considering the intention‐to‐treat analysis, which included all 35 patients, the disease control rate was 11.4% (n = 4). The comparison of this 3‐month efficacy to the commonly accepted response rate of 40%, using the binomial exact hypothesis test, did not reveal a significant difference in either the intention‐to‐treat (p = 0.205) or the per‐protocol analysis (p = 0.939). The objective response rate at 3 months was 0% (0).

TABLE 2.

Efficacy of lanreotide.

Patient characteristic	All patients (n = 35)	Evaluable patients (n = 12)
Positive disease control rate at 3 months, % (95% CI) a	11.4 (3.2 to 26.7)	33.3 (9.9 to 65.1)
CR, No. (%)	0 (0)	0 (0)
PR, No. (%)	0 (0)	0 (0)
SD, No. (%)	4 (11.4)	4 (33.3)
NE, No. (%) b	23 (65.7)	NA
PFS, months, median (95% CI) a	3.5 (2.3 to 5.5)	NA
OS, months, median (95% CI)	3.1 (2 to 5.5)	NA

Abbreviations: CR, complete response; NA, not applicable; NE, not evaluable; OS, overall survival; PD, progressive disease; PFS, progression‐free survival; PR, partial response; SD, stable disease.

^a Positive disease control and PFS were investigator‐assessed.

^b A post‐baseline scan was unavailable for these patients.

FIGURE 2.

Best overall response by RECIST 1.1. With lanreotide treatment. (A) Change from baseline in target lesions in evaluable patients treated with lanreotide (n = 12). The y‐axis represents the maximum percentage change in the sum of target lesion diameters from baseline, in accordance with RECIST version 1.1 criteria. The x‐axis represents individual patients. Horizontal dashed reference lines indicate 30% reduction and 20% increase consistent with a partial response and progressive disease, respectively, per RECIST version 1.1 criteria. Best overall response could not be determined in 13 patients due to missing or unevaluable data. (B) Swimmer plot showing lanreotide treatment duration and patient follow‐up (n = 35). Each horizontal bar represents an individual patient, beginning from the first lanreotide (SSA) administration. The primary endpoint is assessed at 90 days post‐inclusion, corresponding to the period between day 60 (indicated by a dotted black vertical line with spaced dots) and day 90 (marked by a second dotted black vertical line with closely spaced dots) following the initiation of lanreotide treatment. Yellow squares indicate treatment discontinuation, red diamonds indicate disease progression, and black crosses indicate death. Patients with Stage III disease per AJCC 2010 disease at treatment initiation are represented by blue lines, while those with Stage IV are represented by purple lines. Evaluable patients at 3 months are indicated to the left of the patient bar: (A), patients with confirmed stable disease response at 3 months; (B), patients with confirmed progressive disease response at 3 months. Abbreviations: RECIST, Response Evaluation Criteria in Solid Tumors; PR, partial response; SD, stable disease; PD, progressive disease.

FIGURE 3.

Kaplan–Meier curves of Overall and Progression‐Free Survival. (A) Kaplan–Meier estimate of overall survival curve in the modified intention‐to‐treat population (n = 35). (B) Kaplan–Meier estimate of progression‐free survival curve in the modified intention‐to‐treat population (n = 35).

Individual patient responses, corresponding to the change in lesion size at 3 months from baseline, are shown in a waterfall plot in Figure 2A. The last four individual bars correspond to stable disease responses, with respective progressions of 14.1%, 11.7%, 11.3%, and 4.8%. No difference in tumor stage (locoregional or metastatic), ECOG‐PS status, or LDH level at inclusion was observed between patients with progression and those with stable disease at 3 months.

The OS was analyzed by a Kaplan Meier survival curve shown in Figure 3A. Twenty‐two deaths (62.9%) were recorded, including at least 13 secondary to tumor progression. Median OS was 3.7 months (95% CI, [2.3; 5.5]). The OS rates at 3 months and 6 months were 62.5% (95% CI, [43.1%; 77%]) and 31.3% (95% CI, [14.5%; 49.7%]), respectively.

The PFS was analyzed by a Kaplan Meier survival curve shown in Figure 3B. At the time of analysis, 28 patients (80%) had a progression. Median PFS was 3.1 months (95% CI, [2; 5.5]). The PFS rates at 3 months and 6 months were 52.3% (95% CI, [34.2%; 67.6%]) and 29.9% (95% CI, [14.6%; 47%]), respectively (Table 2).

3.3. SSTR Expression on Tumor

Tumor expression of SSTR2A, SSTR2C, and SSTR5, as well as the combined expression of these markers, was analyzed in 26 patients, with 8 of them evaluated for the primary endpoint at 3 months (4 with stable disease and 4 with progressive disease) (Figure S1).

When assessing the relationship between SSTR expression and initial disease stage per AJCC 2010, SSTR2C expression was significantly associated with disease stage, distinguishing between Stage III and Stage IV (Figure S1). In contrast, the expression levels of other SSTRs did not differ significantly between patients with Stage III and those with Stage IV disease (Figure S1).

However, no correlation was found between intra‐tumoral marker expression and tumor progression at 3 months (Figure S1). Furthermore, no statistically significant correlation was observed between SSTR marker expression and either PFS or OS (Figure S2).

3.4. Safety

All 35 patients experienced at least one intercurrent clinical event (ICE) of any grade, with 26 patients (74.3%) experiencing a grade ≥ 3 ICE, as shown in Table 3.

TABLE 3.

Intercurrent clinical events in the population.

ICE	Any Grade, No (%)	Grade 3/4, No (%)
Any ICE	35 (100)	26 (74.3)
Any ICE occurring in ≥ 10% of patients
Diarrhea a	13 (37.1)	1 (2.9)
Fatigue	9 (25.7)	2 (5.7)
Anaemia a	7 (20)	3 (8.6)
Anorexy	7 (20)	3 (8.6)
Abdominal pain	6 (17.1)	1 (2.9)
Nausea	6 (17.1)	1 (2.9)
Vomiting	4 (11.4)	1 (2.9)
ICE with grade ≥ 3
Acute kidney injury	2 (5.7)	2 (5.7)
Urinary retention	2 (5.7)	1 (2.9)
Chest pain	2 (5.7)	1 (2.9)
Lymphopenia	2 (5.7)	1 (2.9)
Pulmonary embolism a	2 (5.7)	1 (2.9)
Atrial tachycardia	1 (2.9)	1 (2.9)
Cardio‐respiratory arrest a	1 (2.9)	1 (2.9)
Gastrointestinal hemorrhage	1 (2.9)	1 (2.9)
Jaundice cholestatic	1 (2.9)	1 (2.9)
Streptococcal sepsis	1 (2.9)	1 (2.9)
Femoral neck fracture	1 (2.9)	1 (2.9)
Tumor hemorrhage	1 (2.9)	1 (2.9)
Tumor pain a	1 (2.9)	1 (2.9)
Basal cell carcinoma a	1 (2.9)	1 (2.9)
Melanoma	1 (2.9)	1 (2.9)
Neuralgia	1 (2.9)	1 (2.9)
Circadian rhythm disorder	1 (2.9)	1 (2.9)
Confusion	1 (2.9)	1 (2.9)
Discontinuation because of study drug toxicity	0 (0)	0 (0)
Study drug‐related deaths	0 (0)	0 (0)

Abbreviation: ICE, Intercurrent clinical events.

^a Data were missing in less than 1% of patients.

In our study, the most common ICE involved gastrointestinal disorder in 20 patients (57.1%), including diarrhea (37.1% of patients), abdominal pain (17.1% of patients), nausea (17.1% of patients), and vomiting (11.4% of patients).

The most common grade ≥ 3 ICE was related to metabolism disorder in 5 patients (14.3%), including hyperglycemia in 3 patients and hyperglycemia in 2, and blood disorders for 4 patients (11.8%), with lymphopenia in 2 patients, febrile bone marrow aplasia in 1, and neutropenia in 1.

Preferred term associated with ICE characteristics are shown in Table S1.

4. Discussion

This study represents the first prospective trial evaluating the efficacy of lanreotide, a SSA targeting SSTR2 and SSTR5, in 35 patients with advanced MCC. Although four patients achieved stable disease, the treatment demonstrated limited efficacy when administered as monotherapy. This trial was conducted prior to the era of immunotherapy, when chemotherapy was the primary therapeutic option. Among the 35 patients included, only 12 patients remained evaluable at three months, and the overall response rate (ORR) was 0%, with a disease control rate of 11.4% (95% CI, [3.2; 26.7]).

These results appear less favorable compared to previously reported outcomes in retrospective studies [2, 24]. The discrepancy in outcomes between our prospective study and retrospective data may be explained by differences in patient selection criteria, including several patients with an ECOG‐PS of 2 or higher [28]. Additionally, no concomitant treatment was authorized—for instance, the study design required a one‐month chemotherapy‐free period and a 15‐day radiotherapy washout before lanreotide initiation, which may have influenced treatment response. By contrast, a retrospective analysis of 19 patients with advanced MCC treated with octreotide long‐acting release (Sandostatin LAR) [19] reported a tumor response in eight patients—five of whom had received concomitant radiation therapy, potentially overestimating the efficacy of SSAs.

Our findings also demonstrated no correlation between SSTR tumor expression and tumor progression or progression‐free survival (PFS), confirming results from Akaike et al. [19], who found no association between SSTR expression (measured by imaging or immunohistochemistry) and clinical response to SSAs. Furthermore, even among patients with high SSTR expression, SSA treatment did not yield improved outcomes.

Interestingly, our study identified a significant association between SSTR2C expression and initial disease Stage (III vs. IV), although this did not translate into a prognostic impact on PFS. Given the limited sample size, these findings should be interpreted cautiously.

Our study has several limitations. First, as this was a non‐randomized study, direct quantitative comparisons between lanreotide and standard of care cannot be made. Second, the sample size was small; however, it was expected given the rarity of MCC. Third, the final small evaluable sample of 12 patients shows the aggressiveness of the disease, as 2 thirds of patients experienced intercurrent clinical events related to disease progression before the possibility of being re‐evaluated.

Based on these results, lanreotide does not appear to be an appropriate first‐line treatment for advanced MCC. However, its potential role as a second‐ or third‐line therapy for selected patients who have exhausted chemotherapy or immunotherapy options cannot be entirely excluded, particularly in those with indolent, low‐volume, SSTR‐positive disease who are not candidates for immune checkpoint inhibitors. Furthermore, alternative SSTR‐targeted strategies, such as PRRT, have demonstrated promising activity in small patient cohorts [29]. Combining SSTR‐targeted therapies with immune‐based approaches has also been proposed as a potential synergistic strategy [30, 31]. Beyond a possible additive antitumor effect, PRRT may enhance tumor antigen release and immune activation, thereby providing a biological rationale for combination approaches. Several ongoing Phase II trials are investigating the combination of ICIs with PRRT [28, 32].

In summary, our study demonstrates that, unlike other neuroendocrine tumors, treatment with lanreotide, a somatostatin analogue, is not effective in MCC. However, recent findings suggest that PRRT may offer a more promising approach. The combination of PRRT with ICIs represents a potential therapeutic avenue for patients who do not respond to chemotherapy or PD‐1/PD‐L1 inhibitors and warrants further investigation.

4.1. Ethical Committee Approval

This study was approved by a French personal protection committee (Comité de Protection des Personnes Sud‐Est V; ID‐RCB: 2014–001273‐13; approval no. 14‐CHUG‐35, December 11, 2014). It followed international good clinical practice (GCP) standards (ClinicalTrials.gov ID: NCT02351128), with written informed consent obtained from all patients.

Author Contributions

Ewa Hainaut‐Wierzbicka: investigation, validation, writing – review and editing. Andreea Stefan: investigation, validation, writing – review and editing. Brigitte Dreno: investigation, validation, writing – review and editing. Aude Belbezier: formal analysis, validation, visualization, writing – original draft. Olivier Dereure: investigation, validation, writing – review and editing. Julie de Quatrebarbes: investigation, validation, writing – review and editing. Julie Charles: conceptualization, methodology, investigation, validation, writing – original draft, writing – review and editing. Ouidad Zehou: investigation, validation, writing – review and editing. Stéphane Dalle: investigation, validation, writing – review and editing. Céleste Lebbe: investigation, validation, writing – review and editing. Caroline Dutriaux: investigation, validation, writing – review and editing. Sandrine Mansard: investigation, validation, writing – review and editing. Alain Dupuy: investigation, validation, writing – review and editing. Caroline Gaudy‐Marqueste: investigation, validation, writing – review and editing. Stéphane Mouret: data curation, writing – original draft, visualization, validation. Jean‐Philippe Arnault: investigation, validation, writing – review and editing. Thibault Kervarrec: validation, visualization, writing – review and editing. Henri Montaudié: investigation, validation, writing – review and editing. Yannick Le Corre: investigation, validation, writing – review and editing. Florent Grange: investigation, validation, writing – review and editing. Mahtab Samimi: conceptualization, investigation, validation, project administration, writing – review and editing. Marie‐Thérèse Leccia: conceptualization, funding acquisition, methodology, project administration, supervision, validation, writing – review and editing. Jean‐Louis Quesada: methodology, validation, formal analysis, visualization, writing – original draft.

Funding

This work was supported by PHRC‐K and IPSEN Pharmaceuticals, Inc.

Conflicts of Interest

IPSEN provided financial support for the study but had no role in study design, data analysis, manuscript preparation or the decision to publish.

Supporting information

Figure S1: STTR tumor expression.

A. Comparison of SSTR expression between patients with progressive disease and stable disease at 3 months. Bar plots show the expression levels of SSTR2A, SSTR2C, SSTR5, and the combined SSTR score (mean of SSTR2A, SSTR2C, and SSTR5 staining scores) in tumor samples from patients with progressive disease (n = 4, red) and those with stable disease (n = 4, yellow) at 3‐month follow‐up. B. Proportion of SSTR2A, SSTR2C, SSTR5 and combined expression in tumors from patients with IIIb (4 patients, purple) and IV (20 patients, blue) ADCC stage.*p < 0.05, Mann–Whitney U test for unpaired data, Wilcoxon paired test for paired data and linear regression for time‐dependent comparisons.

Figure S2: SSTR expression and survival outcomes based on disease progression status (follow‐up ending at 51 weeks). Progression‐free survival (PFS) and overall survival (OS) in relation to somatostatin receptor (SSTR) expression levels in tumor samples (n = 26 patients). Scatterplots depict the correlation between expression levels of SSTR2A (green circles), SSTR2C (red squares), and SSTR5 (blue crosses) and (A) progression‐free survival or (B) overall survival in patients treated with lanreotide. *p < 0.05 considered statistically significant. Abbreviations: OS, overall survival; PFS, progression‐free survival; SSTR, somatostatin receptor.

Figure S3: Immunohistochemical staining intensity in representative examples of SSTR: no staining (A, B, C) and moderate (D, E, F) for SSTR2A (A, D), SSTR2C (B, E) and SSTR5 (C, F) cell membrane staining in MCC. Original magnification ×10.

Table S1: Antibodies and dilutions.

Table S2: Description of intercurrent clinical event by PT.

Data Availability Statement

The anonymized data supporting the findings of this study are available from the corresponding author upon reasonable request, subject to applicable ethical and regulatory requirements.