Abstract
Spartalizumab, a humanized anti-programmed death protein 1 (PD-1) MAB, was evaluated in patients with well-differentiated metastatic grade 1/2 neuroendocrine tumors (NET) and poorly differentiated gastroenteropancreatic neuroendocrine carcinomas (GEP-NEC). In this phase II, multicenter, single-arm study, patients received spartalizumab 400 mg every 4 weeks until confirmed disease progression or unacceptable toxicity. The primary endpoint was confirmed overall response rate (ORR) according to blinded independent review committee using response evaluation criteria in solid tumors 1.1. The study enrolled 95 patients in the NET group (30, 32 and 33 in the thoracic, gastrointestinal, and pancreatic cohorts, respectively), and 21 patients in the GEP-NEC group. The ORR was 7.4% (95% CI: 3.0, 14.6) in the NET group (thoracic, 16.7%; gastrointestinal, 3.1%; pancreatic, 3.0%), which was below the predefined success criterion of ≥10%, and 4.8% (95% CI: 0.1, 23.8) in the GEP-NEC group. In the NET and GEP-NEC groups, the 12-month progression-free survival was 19.5 and 0%, respectively, and the 12-month overall survival was 73.5 and 19.1%, respectively. The ORR was higher in patients with ≥1% PD-L1 expression in immune/tumor cells or ≥1% CD8+ cells at baseline. The most common adverse events considered as spartalizumab-related included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased aspartate and alanine aminotransferases (each 14.3%) in the GEP-NEC group. The efficacy of spartalizumab was limited in this heterogeneous and heavily pre-treated population; however, the results in the thoracic cohort are encouraging and warrants further investigation. Adverse events were manageable and consistent with previous experience.
Introduction
Neuroendocrine tumors (NETs) are heterogeneous entities with a pathological interrelation originating from the diffuse neuroendocrine cell system. While NETs are not frequent, their prevalence has been increasing over the last 20 years (Yao et al. 2008).
Neuroendocrine neoplasms (NENs) are comprised of well-differentiated NETs and poorly differentiated neuroendocrine carcinomas (NECs). The World Health Organization classification reported four categories, based on tumor morphology and proliferation index: NET grade 1, NET grade 2, NET grade 3 and NEC. Lung/Thymus NENs are subdivided into four categories according to the WHO 2015 classification: typical carcinoid, atypical carcinoid, large cell NEC and small cell NEC. Typical and atypical carcinoids represent the low/intermediate grade neoplasms and are usually called NETs (Rindi et al. 2018, NCCN 2020).
Optimal therapy for well-differentiated NETs has not been established. Curative surgery is often not possible because the majority of patients present with metastatic disease during diagnosis, with regional or distant tumor spread seen in 50% of patients (Yao et al. 2008). Poorly differentiated NECs are characterized by a high proclivity to metastatic dissemination even in patients with localized tumors along with a poor overall survival (OS) (Strosberg et al. 2010). Standard treatment options for well-differentiated NETs include somatostatin analogs, peptide receptor radiotherapy (PRRT), systemic chemotherapy and targeted drugs (everolimus, sunitinib). Platinum-based chemotherapy is the established first-line therapy in NEC; however, responses are usually short lived (NCCN 2020, McGarrah et al. 2020). Novel treatment options are needed particularly after progression on these standard therapies (Singh et al. 2017).
During tumorigenesis, cancer cells from a wide range of tumor types exploit immune checkpoint pathways, such as programmed death-1 (PD-1), to avoid detection by the adaptive immune system (Darvin et al. 2018, Toor & Elkord 2018). MAB inhibitors of immunological checkpoints, including PD-1 and programmed death-ligand (PD-L) 1, have demonstrated significant antitumor activity in patients with various solid tumors. Although many advances with checkpoint inhibitors were made in other tumor types, the data generated in NETs is limited and it is unknown whether patients with NET may benefit from the advances in immune checkpoint inhibitors as in other solid cell cancers. Immunotherapy has been studied to a limited extend in NENs, demonstrating low objective response rates (Mehnert et al. 2020).
Spartalizumab (PDR001) is a high-affinity, ligand-blocking, humanized IgG4 antibody directed against PD-1 receptor, that blocks the interaction of PD-1 with PD-L1 and PD-L2 (Freeman 2008). Engagement of PD-1 by its ligands, PD-L1 and PD-L2, transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function (Riley 2009). Multiple clinical studies involving spartalizumab have demonstrated antitumor activity in patients with various solid tumors, with a manageable toxicity profile (Calvo et al. 2018, Hong et al. 2018, Lin et al. 2018, Wirth et al. 2018, Sun et al. 2019). In a phase I study of spartalizumab in advanced solid tumors, one patient with histologically confirmed metastatic atypical pulmonary carcinoid achieved a sustained partial response on spartalizumab treatment (Naing et al. 2016).
Here, we present results of a phase II study (NCT02955069) that explored the antitumor activity of spartalizumab in well-differentiated NET (of gastrointestinal, pancreas, and thoracic origin) and poorly differentiated GEP-NEC which have progressed on or after available treatments.
Methods
Patients
This study included adult patients with pathologically confirmed (based on local pathology report) advanced or metastatic, well-differentiated grade 1 or 2 non-functional NET of gastrointestinal, pancreatic or thoracic origin, or metastatic poorly differentiated gastroenteropancreatic NEC (GEP-NEC). Patients were required to have received prior treatment for advanced disease, have radiological documentation of disease progression (NET: based on scans performed ≤12 months apart, with progression documented on scan within 6 months of study entry; GEP-NEC: progression during or after prior treatment), and no active symptoms related to carcinoid syndrome during the last 3 months before the study treatment start. Additional inclusion criteria included an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, presence of ≥1 measurable lesion according to response evaluation criteria in solid tumors (RECIST) 1.1 per Investigator’s assessment, and normal body systems functions.
In the thoracic cohort, prior treatment with everolimus (if lung origin) or any prior systemic therapy (if thymus origin) was required. In the gastrointestinal cohort, treatment with ≥2 prior systemic regimens, including everolimus, was required; whereas, patients in the pancreatic cohort required ≥2 prior systemic regimens including everolimus and/or sunitinib. Prior systemic therapies in both gastrointestinal and pancreatic cohorts could include somatostatin analogs, PRRT, interferon and/or chemotherapy. In the poorly differentiated GEP-NEC group, patients were required to have received ≥1 prior platinum-based chemotherapy regimen.
Major exclusion criteria were well-differentiated grade 3 NET, poorly differentiated NEC of any origin other than GEP, adenocarcinoid, and goblet cell carcinoids (all determined locally); PRRT within 6 months of the prior PD-1 or PD-L1-directed therapy; cryoablation, radiofrequency ablation, or trans-arterial embolization of hepatic metastases within 2 months before the first dose of spartalizumab. Patients with impaired cardiac function or clinically significant cardiac disease, autoimmune disease or active infection requiring systemic treatment, or with a known history of HIV infection, active hepatitis B and hepatitis C virus infections were excluded. Somatostatin analogs were permitted during the study if patients developed functional disease during the course of the trial.
Study design and treatment
In this phase II, single-arm, open-label, multicenter study, patients received spartalizumab 400 mg (30-min infusion) once every 4 weeks (28 days). No dose adjustments were permitted. Treatment continued until confirmed disease progression as per blinded independent review committee (BIRC) or unacceptable toxicity.
The primary endpoint was the confirmed overall response rate (ORR) according to BIRC radiological assessment using RECIST 1.1 (Eisenhauer et al. 2009). The secondary endpoints included the duration of response (DoR), disease control rate (DCR), time-to-response (TTR), progression-free survival (PFS) by RECIST 1.1 and immune-related (ir) RECIST (Nishino et al. 2013), OS, safety, and quality of life (QoL). The cut-off date for the primary analysis was 1 year after the last patient enrolled in the NET group received first dose of spartalizumab.
Assessments and definitions
The ORR was defined as the proportion of patients with confirmed complete response (CR) or partial response (PR) by RECIST 1.1. DCR was defined as the proportion of patients who achieve CR, PR, or stable disease. Tumor response was assessed locally and centrally based on RECIST 1.1 and irRECIST. Imaging assessments for response evaluation were performed every 8 weeks until Cycle 13, and then every 12 weeks until disease progression per RECIST 1.1 or irRECIST per BIRC, death, lost to follow-up or withdrawal of consent.
PFS was defined as the time from the date of first dose to the date of the first documented radiological progression or death due to any cause, as per central review according to RECIST 1.1.
Adverse events (AEs) were assessed and graded according to the Common Terminology Criteria for Adverse Events version 4.03. Patients were followed-up for safety every 30 days up to 150 days following the last dose, or until the start of subsequent antineoplastic medication between 30 and 150 days after the last dose.
The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and EQ-5D-5L questionnaires were used to collect patient-reported outcome (PRO) data to characterize patient’s health-related QoL. PRO data were collected during the screening period (day −28 to day −1), then every 8 weeks from cycle 3 day 1 for the first 13 cycles, followed by every 12 weeks from cycle 13 day 1 during the treatment period, and at the end of treatment visit.
Immunohistochemical staining and assessment for biomarkers were provided by HistogeneX (HistoGeneX Laboratories, Antwerpen, Belgium). PD-L1 staining was performed on a DAKO Autostainer utilizing the rabbit monoclonal anti-human PD-L1 antibody (28-8 clone). Percentages of PD-L1-positive tumor cells and that of PD-L1-positive immune cells were calculated separately for each specimen. CD8 staining was performed on a Ventana Benchmark XT utilizing the mouse monoclonal anti-human CD8 antibody (C8/144b clone). CD8-positive cells were calculated for both tumor area and tumor periphery for each specimen. Staining was performed on either freshly obtained tumor biopsy or archived tumor samples (within 6 months but not >24 months).
Statistical analysis
ORR was summarized using descriptive statistics along with two-sided exact 95% CI separately for well-differentiated NET and poorly differentiated GEP-NEC groups.
In the absence of an established control treatment, ORR reported in the placebo arms of pivotal studies in NET (Kulke et al. 2008, Rinke et al. 2009, Raymond et al. 2011, Yao et al. 2011, Caplin et al. 2014, Strosberg et al. 2016, Yao et al. 2016, Amoroso et al. 2017) served as a reference in the NET group. Based on these studies, the results in the NET group were considered a success if a clinically relevant response rate of ≥10% was observed and the two-sided exact 95% CI excluded the value 3%. In the poorly differentiated GEP-NEC only descriptive analysis was performed due to small sample size in this group.
The DOR was estimated using the Kaplan–Meier method and summarized for all subjects with confirmed best overall response of CR or PR.
Ethics
This study was designed and conducted in accordance with the ethical principles of the Declaration of Helsinki and the ICH Harmonized Tripartite Guidelines for Good Clinical Practice. An independent ethics committee or institutional review board for each study center reviewed the study protocol and its amendments (Supplementary Table 1, see section on supplementary materials given at the end of this article). Patients provided written informed consent before any study procedures and in accordance with local laws and regulations.
Results
Patient disposition and baseline characteristics
Between March 2017 and September 2017, 95 patients were enrolled in the NET group (30, 32, and 33 patients in the thoracic, gastrointestinal, and pancreatic cohorts, respectively) and 21 patients were enrolled in the GEP-NEC group. At the time of study entry, all patients had metastatic, stage IV disease. As of the primary analysis data cut-off date (Aug 10, 2018), the majority of the patients have discontinued treatment (87.1%), primarily due to disease progression (58.6%); 11 patients (9.5%) discontinued due to AEs (Supplementary Table 2).
The majority of patients had ECOG performance status of 0 or 1 in both groups. The PD-L1 expression in tumor cells was ≥ 1% in 13 patients (13.7%) in the NET group and in 2 patients (9.5%) in the GEP-NEC group. The PD-L1 expression in the immune cells was >1% in 15 patients (15.7%) and 8 patients (38.1%) in the NET and GEP-NEC groups, respectively (Table 1).
Demographics and baseline characteristics of patients in the study.
| Well-differentiated NET (n = 95) | Poorly differentiated GEP NEC (n = 21) | |||
|---|---|---|---|---|
| Thoracic cohorta (n = 30) | Gastrointestinal cohorta (n = 32) | Pancreatic cohort (n = 33) | ||
| Age in years, median (range) | 63 (29–78) | 63 (33–85) | 54 (37–79) | 59 (44–74) |
| Female, n (%) | 12 (40) | 14 (44) | 17 (52) | 4 (19) |
| ECOG performance status, n (%) | ||||
| 0 | 12 (40) | 15 (47) | 19 (58) | 13 (62) |
| 1 | 16 (53) | 15 (47) | 10 (30) | 6 (29) |
| 2 | 2 (7) | 2 (6) | 4 (12) | 2 (10) |
| Primary site of cancer, n (%) | ||||
| Ampullary | 0 | 1 (3) | 0 | 0 |
| Appendix | 0 | 0 | 0 | 1 (5) |
| Colon | 0 | 2 (6.3) | 0 | 2 (10) |
| Gall bladder | 0 | 0 | 0 | 1 (5) |
| Thymus gland | 2 (7) | 0 | 0 | 0 |
| Lung | 28 (93) | 0 | 0 | 0 |
| Pancreas | 0 | 0 | 33 (100) | 12 (57) |
| Rectum | 0 | 10 (31) | 0 | 4 (19) |
| Small intestine | 0 | 10 (31) | 0 | 0 |
| Stomach | 0 | 3 (9) | 0 | 0 |
| Duodenum | 0 | 1 (3) | 0 | 1 (5) |
| Ileum | 0 | 2 (6) | 0 | 0 |
| Jejunum | 0 | 1 (3) | 0 | 0 |
| Unknown | 0 | 2 (6) | 0 | 0 |
| Histologic tumor grade,b n (%) | ||||
| 1 | 6 (20) | 4 (13) | 9 (27) | 0 |
| 2 | 24 (80) | 28 (88) | 24 (73) | 0 |
| 3 | 0 | 0 | 0 | 21 (100) |
| Ki-67,c n (%) | ||||
| < 3 | 4 (13) | 4 (13) | 6 (18) | 0 |
| 3–20 | 21 (70) | 25 (78) | 27 (82) | 1 (5)d |
| >20–40 | 3 (10)e | 1 (3)e | 0 | 5 (24) |
| >40 | 0 | 0 | 0 | 14 (67) |
| Number of prior antineoplastic regimens, n (%) | ||||
| 1 | 5 (17) | 0 | 0 | 10 (48) |
| 2 | 12 (40) | 16 ( 50) | 9 (27) | 3 (14) |
| 3 | 7 (23) | 6 ( 19) | 11 (33) | 3 (14) |
| 4 | 5 (17) | 4 (13) | 6 (18) | 3 (14) |
| ≥5 | 1 (3) | 6 (19) | 7 (21) | 2 (10) |
| PD-L1 expression in tumor cells/immune cells of the tumor,f n (%) | ||||
| <1% | 23 (77)/22 (73) | 28 (88)/28 (88) | 23 (70)/22 (67) | 16 (76)/10 (48) |
| 1–10% | 2 (7)/5 (17) | 2 (6)/3 (9) | 5 (15)/7 (21) | 2 (10)/8 (38) |
| > 10% | 2 (7)/0 | 1 (3)/0 | 1 (3)/0 | 0/0 |
| CD8 positive lymphocytes in tumor,f n (%) | ||||
| <1% | 23 (77) | 27 (88) | 24 (73) | 14 (67) |
| 1–10% | 2 (7) | 4 (13) | 3 (9) | 3 (14) |
aThoracic cohort included 6 patients with typical carcinoids and 24 patients with atypical carcinoids; gastrointestinal cohort included 1 patient with typical and 2 patients with atypical carcinoids. bTesting for tumor grade was done locally and not confirmed by central laboratory. cTesting for Ki-67 was not mandatory and done locally, some patients may have missing data. dPatient had Ki-67 20% but grade 3 poorly differentiated GEP-NEC by local pathology report. eAlthough the patients had tumors with Ki-67 > 20% in well-differentiated NET group, they had low mitotic index or well-differentiated NET as per the local pathology report and were not deemed as grade 3. fAnalyses were performed on evaluable tissue samples.
ECOG, Eastern Cooperative Oncology Group; GEP NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumor.
All patients in the study received prior antineoplastic therapies, with 55.8% and 38.1% receiving ≥ 3 regimens in the NET and GEP-NEC groups, respectively (Table 1). The most common last treatment type was targeted therapies (67.4%) in the NET group, and chemotherapy (81.0%) in the GEP-NEC group (Supplementary Table 3).
Efficacy
As of the data cutoff date for the primary analysis, the median duration of follow-up in the study population was 13.4 months (range 11–17 months). In the well-differentiated NET group, the ORR per central radiology review was 7.4% (n = 5; 95% CI: 3.0, 14.6). Therefore, the study did not meet the pre-defined success criteria of ≥10% ORR and the two-sided 95% CI excluding 3% in the well-differentiated NET group. Of note, higher ORR was observed in patients in the thoracic cohort (16.7% (5 patients); 95% CI: 5.6, 34.7), when compared with gastrointestinal cohort (3.1% (1 patient); 95% CI: 0.1, 16.2) and pancreatic cohort (3.0% (1 patient); 95% CI: 0.1, 15.8). All 5 responders in the thoracic cohort had atypical carcinoids. As per the central radiology review, the DCR was 64.2% (95% CI: 53.7, 73.8) in the NET group (Table 2). In the GEP-NEC group, the ORR per central radiology review was 4.8% ((1 patient); 95% CI: 0.1, 23.8) and the DCR was 19.0% (95% CI: 5.4, 41.9) (Table 2). The ORR results were consistent between the central and local radiology in both the groups (Supplementary Table 4). Results based on irRECIST were comparable to that of RECIST (Supplementary Table 5).
Best overall response per RECIST 1.1 by central radiology review.
| Best overall response, n (%) | Spartalizumab 400 mg q4w well-differentiated NET | Spartalizumab 400 mg q4w poorly differentiated GEP-NEC (n = 21) | |||
|---|---|---|---|---|---|
| All (n = 95) | Thoracic cohort (n = 30) | Gastrointestinal cohort (n = 32) | Pancreatic cohort (n = 33) | ||
| Partial response (PR) | 7 (7.4) | 5 (16.7) | 1 (3.1) | 1 (3.0) | 1 (4.8) |
| Stable disease (SD) | 53 (55.8) | 17 (56.7) | 19 (59.4) | 17 (51.5) | 3 (14.3) |
| Confirmed overall response rate (CR + PR) | 7 (7.4); 95% CI: 3.0, 14.6 | 5 (16.7); 95% CI: 5.6, 34.7 | 1 (3.1); 95% CI: 0.1, 16.2 | 1 (3.0); 95% CI: 0.1, 15.8 | 1 (4.8); 95% CI: 0.1, 23.8 |
| Non-PR/non-progressive disease (PD) | 1 (1.1) | 0 | 0 | 1 (3.0) | 0 |
| Disease control rate (CR + PR + SD + non-PR/non-PD) | 61 (64.2); 95% CI: 53.7, 73.8 | 22 (73.3); 95% CI: 54.1, 87.7 | 20 (62.5); 95% CI: 43.7, 78.9 | 19 (57.6); 95% CI: 39.2, 74.5 | 4 (19.0); 95% CI: 5.4, 41.9 |
| Progressive disease (PD) | 29 (30.5) | 5 (16.7) | 11 (34.4) | 13 (39.4) | 14 (66.7) |
| Unknowna | 5 (5.3) | 3 (10.0) | 1 (3.1) | 1 (3.0) | 3 (14.3) |
N, the total number of subjects in the treatment group. It is the denominator for percentage (%) calculation. n, number of subjects who are at the corresponding category. The 95% CI for the frequency distribution were calculated using Clopper–Pearson method.
aIncluded patients with no valid post-baseline assessment, or attained stable disease too early or progressive disease too late.
GEP NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumor; q4w, once every 4 week.
In the NET group, 35 patients (39.3%) experienced any degree of shrinkage of the target lesions, whereas, only 1 patient (6.3%) in the GEP-NEC group showed tumor shrinkage (Fig. 1 and Supplementary Fig. 1).
Best percentage change in size of targeted lesions from baseline (based on central radiology review). In the well-differentiated NET group (n = 89), 35 patients (39.3%) had any degree of tumor shrinkage from baseline and 54 patients (60.7%) had no change or increase in tumor size. Additionally, one patient did not have measurable disease, and five patients had best overall response unknown mainly due to discontinuation prior to the first assessment for various reasons including death (A); whereas, in the poorly differentiated GEP-NEC group (n = 16), 1 patient showed tumor shrinkage (B). The graph in the well-differentiated group does not include tumor lesions in one patient that did not have measurable disease at baseline and five patients that had best overall response unknown. In the GEP-NEC group, five patients without post-baseline tumor assessments were not included (4 patients who died and one patient withdrew consent). GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumors. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
Best percentage change in size of targeted lesions from baseline (based on central radiology review). In the well-differentiated NET group (n = 89), 35 patients (39.3%) had any degree of tumor shrinkage from baseline and 54 patients (60.7%) had no change or increase in tumor size. Additionally, one patient did not have measurable disease, and five patients had best overall response unknown mainly due to discontinuation prior to the first assessment for various reasons including death (A); whereas, in the poorly differentiated GEP-NEC group (n = 16), 1 patient showed tumor shrinkage (B). The graph in the well-differentiated group does not include tumor lesions in one patient that did not have measurable disease at baseline and five patients that had best overall response unknown. In the GEP-NEC group, five patients without post-baseline tumor assessments were not included (4 patients who died and one patient withdrew consent). GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumors. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
Best percentage change in size of targeted lesions from baseline (based on central radiology review). In the well-differentiated NET group (n = 89), 35 patients (39.3%) had any degree of tumor shrinkage from baseline and 54 patients (60.7%) had no change or increase in tumor size. Additionally, one patient did not have measurable disease, and five patients had best overall response unknown mainly due to discontinuation prior to the first assessment for various reasons including death (A); whereas, in the poorly differentiated GEP-NEC group (n = 16), 1 patient showed tumor shrinkage (B). The graph in the well-differentiated group does not include tumor lesions in one patient that did not have measurable disease at baseline and five patients that had best overall response unknown. In the GEP-NEC group, five patients without post-baseline tumor assessments were not included (4 patients who died and one patient withdrew consent). GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumors. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
In the NET group, the DoR for the seven responders was in the range of 49 days to 288 days, and the TTR was in the range of 52 days to218 days. In the thoracic cohort, two responders died after confirmation of tumor response thus limiting evaluation of DoR. One patient died due to respiratory failure (treatment-unrelated fatal respiratory acidosis that occurred following the surgery for intestinal obstruction approximately 4 months after the last dose of spartalizumab). The other patient had myasthenia gravis (considered as treatment-related) approximately 2 months after treatment start, leading to the treatment discontinuation; this patient finally had respiratory failure and died due to worsening myasthenia gravis approximately 4 months later (Fig. 2). In the GEP-NEC group, the DOR in one responder was 270 days, and the TTR was 53 days. This patient had poorly differentiated, grade 3 NEC of pancreatic origin previously treated with two lines of chemotherapy.
Time to onset and duration of response per RECIST 1.1 by central radiology review in the well-differentiated NET group (in the well-differentiated NET group, the duration of response (DOR) in seven patients who achieved PR was in the range of 49 days to 288 days. In the poorly differentiated GEP-NEC group, the DOR (not shown) in one patient who achieved partial response was 270 days). GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumors; RECIST, response evaluation criteria in solid tumors. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
Time to onset and duration of response per RECIST 1.1 by central radiology review in the well-differentiated NET group (in the well-differentiated NET group, the duration of response (DOR) in seven patients who achieved PR was in the range of 49 days to 288 days. In the poorly differentiated GEP-NEC group, the DOR (not shown) in one patient who achieved partial response was 270 days). GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumors; RECIST, response evaluation criteria in solid tumors. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
Time to onset and duration of response per RECIST 1.1 by central radiology review in the well-differentiated NET group (in the well-differentiated NET group, the duration of response (DOR) in seven patients who achieved PR was in the range of 49 days to 288 days. In the poorly differentiated GEP-NEC group, the DOR (not shown) in one patient who achieved partial response was 270 days). GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; NET, neuroendocrine tumors; RECIST, response evaluation criteria in solid tumors. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
In the NET cohorts, the ORR based on central review was 6.8% (5 patients) and 15.4% (2 patients) in patients with baseline PD-L1 expression < 1% and ≥1% in tumor cells, respectively; and was 6.9% (5 patients) and 13.3% (2 patients) in patients with baseline PD-L1 expression < 1% and ≥1% in immune cells, respectively. In patients with <1% and ≥1% CD8+ cells at baseline in the NET cohorts, the ORR was 5.4% (4 patients) and 22.2% (2 patients), respectively. In the GEP-NEC cohort, the 1 patient who showed response had baseline PD-L1 expression of <1% in tumor cells and ≥1% in immune cells, and ≥1% CD8+ cells at baseline (Supplementary Table 6).
The median PFS was 3.8 months in the NET group and 1.8 months in the GEP-NEC group. At month 12, the Kaplan–Meier estimated PFS rate was 19.5% (95% CI: 11.6, 28.9) in the NET group (Fig. 3).
Kaplan–Meier plots of progression-free survival (PFS) and overall survival (OS) based on central radiology review. GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; GI, gastrointestinal; OS, overall survival; PFS, progression-free survival. PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
Kaplan–Meier plots of progression-free survival (PFS) and overall survival (OS) based on central radiology review. GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; GI, gastrointestinal; OS, overall survival; PFS, progression-free survival. PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
Kaplan–Meier plots of progression-free survival (PFS) and overall survival (OS) based on central radiology review. GEP-NEC, gastroenteropancreatic neuroendocrine carcinoma; GI, gastrointestinal; OS, overall survival; PFS, progression-free survival. PD, progressive disease; PR, partial response; SD, stable disease; UNK, unknown. A full color version of this figure is available at https://doi.org/10.1530/ERC-20-0382.
Citation: Endocrine-Related Cancer 28, 3; 10.1530/ERC-20-0382
As of the data cutoff date, 66 patients (69.5%) in the NET group and 3 patients (14.3%) in the GEP-NEC group were alive. The median OS was not estimable for the NET group and was 6.8 months (95% CI: 4.0, 8.6) in the GEP-NEC group. At month 12, the estimated probability of OS was 73.5% (95% CI: 63.0, 81.4) in the NET group and 19.1% (95% CI: 4.8, 40.6) in the GEP-NEC group (Fig. 3).
Safety
The median duration of exposure to spartalizumab was 20.3 weeks in the NET group and 8.9 weeks in the GEP-NEC group. The study drug administration was interrupted in 40 patients (42.1%) in the NET group and in 6 patients (28.6%) in the GEP-NEC group, primarily due to AEs in both groups. The most frequently reported AEs (occurring in ≥ 20.0% of patients), regardless of relationship to spartalizumab, included fatigue (37.9%), pyrexia (27.4%), diarrhea (24.2%), abdominal pain (22.1%) and nausea (21.1%) in the NET group, and dyspnea (28.6%) and nausea (23.8%) in the GEP-NEC group. Grade ≥ 3 AEs, regardless of relationship to spartalizumab, were reported in 48.4% and 57.1% of the patients in the NET and GEP-NEC groups, respectively. The most commonly reported (in ≥ 5% patients) grade ≥ 3 AEs included abdominal pain (6.3%) and anemia (5.3%) in the NET group, and increased gamma-glutamyltransferase (GGT; 14.3%), increased AST (14.3%), increased alanine aminotransferase (ALT; 9.5%), abdominal pain (9.5%), back pain (9.5%), and dyspnea (9.5%) in the GEP-NEC group (Table 3).
Adverse events (AEs).
| Number of patients by preferred term, n (%)a,b | Spartalizumab 400 mg q4w well-differentiated NET (n = 95) | Spartalizumab 400 mg q4w poorly differentiated GEP-NEC (n = 21) | ||
|---|---|---|---|---|
| All grades | Grade ≥ 3 | All grades | Grade ≥ 3 | |
| AEs regardless of relationship to spartalizumab occurring in ≥ 10% of patients in either treatment group | 91 (95.8) | 46 (48.4) | 19 (90.5) | 12 (57.1) |
| Fatigue | 36 (37.9) | 3 (3.2) | 3 (14.3) | 0 |
| Pyrexia | 26 (27.4) | 0 | 2 (9.5) | 0 |
| Diarrhea | 23 (24.2) | 1 (1.1) | 3 (14.3) | 0 |
| Nausea | 20 (21.1) | 0 | 5 (23.8) | 0 |
| Abdominal pain | 21 (22.1) | 6 (6.3) | 2 (9.5) | 2 (9.5) |
| Anemia | 18 (18.9) | 5 (5.3) | 3 (14.3) | 0 |
| Constipation | 18 (18.9) | 1 (1.1) | 3 (14.3) | 0 |
| Decreased appetite | 14 (14.7) | 1 (1.1) | 3 (14.3) | 1 (4.8) |
| Edema peripheral | 14 (14.7) | 0 | 3 (14.3) | 0 |
| Back pain | 13 (13.7) | 2 (2.1) | 2 (9.5) | 2 (9.5) |
| Cough | 13 (13.7) | 0 | 2 (9.5) | 0 |
| Asthenia | 12 (12.6) | 3 (3.2) | 2 (9.5) | 1 (4.8) |
| Hypertension | 12 (12.6) | 3 (3.2) | 0 | 0 |
| Vomiting | 10 (10.5) | 1 (1.1) | 4 (19.0) | 1 (4.8) |
| Dyspnea | 8 (8.4) | 2 (2.1) | 6 (28.6) | 2 (9.5) |
| GGT increased | 6 (6.3) | 3 (3.2) | 3 (14.3) | 3 (14.3) |
| ALT increased | 3 (3.2) | 1 (1.1) | 3 (14.3) | 2 (9.5) |
| AST increased | 1 (1.1) | 0 | 4 (19.0) | 3 (14.3) |
| Spartalizumab-related AEs occurring in ≥ 2 patients in either treatment group | 68 (71.6) | 20 (21.1) | 9 (42.9) | 4 (19.0) |
| Fatigue | 28 (29.5) | 1 (1.1) | 2 (9.5) | 0 |
| Nausea | 10 (10.5) | 0 | 0 | 0 |
| Diarrhea | 9 (9.5) | 0 | 2 (9.5) | 0 |
| Asthenia | 9 (9.5) | 3 (3.2) | 1 (4.8) | 0 |
| Pyrexia | 9 (9.5) | 0 | 1 (4.8) | 0 |
| Decreased appetite | 8 (8.4) | 1 (1.1) | 0 | 0 |
| Rash | 7 (7.4) | 0 | 1 (4.8) | 0 |
| Anemia | 7 (7.4) | 1 (1.1) | 0 | 0 |
| Arthralgia | 6 (6.3) | 2 (2.1) | 0 | 0 |
| Hypothyroidism | 6 (6.3) | 0 | 0 | 0 |
| Constipation | 4 (4.2) | 0 | 0 | 0 |
| Dry mouth | 4 (4.2) | 0 | 0 | 0 |
| Cough | 3 (3.2) | 0 | 1 (4.8) | 0 |
| Proteinuria | 4 (4.2) | 0 | 1 (4.8) | 1 (4.8) |
| GGT increased | 2 (2.1) | 1 (1.1) | 2 (9.5) | 2 (9.5) |
| ALT increased | 2 (2.1) | 1 (1.1) | 3 (14.3) | 2 (9.5) |
| AST increased | 1 (1.1) | 0 | 3 (14.3) | 2 (9.5) |
aAEs by preferred term (common terminology criteria for adverse events version 4.03) are presented in descending frequency of all grades AEs in well-differentiated NET group. bA subject with multiple severity grades for an AE is only counted under the maximum grade.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma-glutamyltransferase increased; Qw4, once every 4 weeks.
A total of 68 patients (71.6%) in the NET group and 9 patients (42.9%) in the GEP-NEC group experienced AEs that were thought to be spartalizumab-related. The most frequent (≥10%) of these included fatigue (29.5%) and nausea (10.5%) in the NET group, and increased AST (14.3%), increased ALT (14.3%) in the GEP-NEC group. Spartalizumab-related grade ≥ 3 AEs were reported in 20 patients (21.1%) in the NET group, including asthenia (3.2%) and arthralgia (2.1%), and in 4 patients (19.0%) in the GEP-NEC group including increased ALT, AST, and GGT (all 9.5%) (Table 3).
Serious AEs (SAE) were reported in 28 patients (29.5%) in the NET group and 6 patients (28.6%) in the GEP-NEC group. The most commonly reported SAEs in the NET group were abdominal pain (6.3%) and pyrexia (3.2%). In the GEP-NEC group, all SAEs were observed in single patients.
During the study treatment period, two deaths have occurred, with both considered as unrelated to spartalizumab treatment. One death in the NET group was reported due to study indication and the other death was due to aspiration pneumonia in the GEP-NEC group.
Patient reported outcomes/QOL
A total of 92 patients (97%) in the NET group and 19 patients (90%) in the GEP-NEC group answered the EORTC QLQ-C30 and EQ-5D questionnaires at baseline. Spartalizumab treatment demonstrated no meaningful change (≥10-point changes) in Global Health Status/QoL scale and functional scales including physical functioning, emotional functioning, social functioning. Spartalizumab treatment had no impact on the health utility and overall health status as indicated by the EQ-5D-5L health index and visual analog scale, respectively. The results were consistent in all NET cohorts. In GEP-NEC, an insufficient number of post-baseline answered questionnaires (n < 10 for all follow-up assessments) were available.
Discussion
This study examined the efficacy and safety of spartalizumab in patients with metastatic well-differentiated NET and GEP-NEC. Relatively low response rates were observed with spartalizumab monotherapy, both in the NET (ORR: 7.4%; 95% CI: 3.0, 14.6) and GEP-NEC (ORR: 4.8%; 95% CI: 0.1, 23.8) groups. Comparable low response rates were observed in the previous non-NET-specific trials as well as NET-specific trials of anti-PD-1 therapies (e.g. pembrolizumab) in a similar patient population (Mehnert et al. 2020, Patel et al. 2020, Strosberg et al. 2020, Vijayvergia et al. 2020).
Within the NET group, spartalizumab treatment was associated with a higher ORR in the thoracic cohort (16.7%; 95% CI: 5.6, 34.7), compared with the gastrointestinal cohort (3.1% 95% CI: 0.1, 16.2) and pancreatic cohort (3.0% 95% CI: 0.1, 15.8); however, a formal statistical comparisons between the cohorts were not performed. All 5 responders in the thoracic cohort had atypical carcinoids. Response to spartalizumab treatment was previously reported in a patient with histologically confirmed metastatic atypical pulmonary carcinoid, who achieved a sustained PR (RECIST 1.1 criteria) following treatment with spartalizumab in a phase I trial in advanced solid tumors (Naing et al. 2016). Results for the irRECIST efficacy endpoints were similar to that of the corresponding RECIST 1.1 results in this study.
In this study, PD-L1 expression was determined separately in tumor cells and in the tumor infiltrating immune cells. Better responses were observed in patients with PD-L1 ≥1% tumor cells or immune cells in the NET group; however, not all tumor samples were evaluable for analyses and the number of responders was too small to conduct statistical analyses (Strosberg et al. 2020).
Efficacy of checkpoint inhibitors correlates positively with the presence of anti-tumor CD8+ T-cells (Hegde et al. 2016). Therefore, a modest response seen in this study could possibly be explained by the overall low baseline CD8+ lymphocyte presence in the tumor (Hegde et al. 2016). The ORR was greater in patients with baseline CD8+ ≥1% in the NET group, and the only responder in the GEP-NEC group had CD8+ ≥1%; however, the majority of patients with elevated intratumoral CD8+ did not respond to spartalizumab and some patients with low intratumoral CD8+ at baseline did show tumor shrinkage. This highlights the fact that intratumoral infiltration by CD8+ is important but not the single factor predicting the efficacy of immune checkpoint inhibitors (Hegde et al. 2016, Dong et al. 2019).
Overall, the safety profile of spartalizumab has been well characterized in the intended target patient population and is consistent with results from previous studies in other solid tumors (Naing et al. 2016, Ando et al. 2018, Calvo et al. 2018, Hong et al. 2018, Lin et al. 2018, Wirth et al. 2018, Yao et al. 2018, Sun et al. 2019, Mehnert et al. 2020, Patel et al. 2020, Strosberg et al. 2020). Safety results indicate that the majority of the AEs can be successfully managed with the existing AE management guidelines used in this setting (Brahmer et al. 2018).
Our study had the advantage of stratifying patients into robustly powered groups, including lung, gastrointestinal and pancreatic NETs. Although the study did not meet the primary objective for the entire cohort of NETs, we did observe a signal of increased response in lung NETs. This should be further explored in future immunotherapy trials, given the limited systemic options available for this population of NETs. The limitations of this study include that the patients were heavily pretreated which could explain the low response rates, similar to previous experience with other anti-PD-1 therapies (Mehnert et al. 2020, Patel et al. 2020, Strosberg et al. 2020). Furthermore, analysis by PD-L1 levels at baseline was limited to the overall NET population. Tumor microenvironment and response to immunotherapies needs further investigation and further work on predictive biomarker is needed. Baseline histologic assessments that included tumor type and grade assessments were performed locally at the study sites, and not centrally. Analyses of microsatellite instability status and tumor mutation burden, the other two potential determinants of tumor response to immune checkpoint inhibitors (Rizvi et al. 2015), were not performed in this study. Ki-67 testing was not mandatory and done locally, and some patients may have missing data.
In conclusion, the safety profile of spartalizumab in both NET and GEP-NEC groups was similar to prior experience with spartalizumab (Naing et al. 2016, Vansteenkiste et al. 2017, Brahmer et al. 2018, Lin et al. 2018, Wirth et al. 2018, Yao et al. 2018), and the efficacy observed in the overall study population was limited, in line with other checkpoint inhibitors in this indication (Mehnert et al. 2020, Patel et al. 2020, Strosberg et al. 2020). Single agent PD-1/PD-L1 inhibitors have not demonstrated clinical utility in an unselected NET population and should not be used outside of clinical trials. The potential for PD-L1 inhibition in the thoracic cohort warrants further investigation.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ERC-20-0382.
Declaration of interest
J C Yao: Consultant or Advisor of Ipsen, Chiasma, Hutchinson Medi Pharma, Advanced Accelerator Applications International, Novartis, Crinetics Pharmaceuticals, Andtarveda; J R Strosberg: Honoraria from Novartis. Consultant or Advisor of Novartis, Lexicon, and Ipsen; Speakers’ Bureau of Ipsen and Lexicon; N Fazio: Honoraria from Novartis, Ipsen, Merck, Sanofi-Aventis, and Advanced Accelerator Applications. Consultant or Advisor of Novartis/Ipsen, Advanced Accelerator Applications, Pfizer, Ipsen, Merck Serono, MSD Oncology, and Wren Laboratories Europe. Research Funding from Novartis, Merck Serono, Ipsen, MSD; M Pavel: Honoraria from Novartis, IPSEN, Pfizer, Lexicon, Advanced Accelerator Applications, and Prime Oncology; Consultant or Advisor of Novartis, IPSEN, Pfizer, Lexicon, and Advanced Accelerator Applications; E Bergsland: Research funding from Merck and Novartis; Li Daneng: Consultant/Advisor of Lexicon, Ipsen, Exelixis, Bayer, and Eisai. Speakers’ Bureau of Lexicon, Ipsen, Advanced Accelerator Applications, Exelixis, and Eisai. Research Funding from Brooklyn ImmunoTherapeutics; S Tafuto: Honoraria from Novartis, Ipsen and Advanced Accelerator Applications; N Raj: Research funding from Novartis and Xencor, Inc; R Guimbaud: Honoraria from Roche, BMS, Amgen, Servier, Novartis, and Ipsen. Consultant or Advisor of Pierre Fabre and AstraZeneca. P Gajate: Consultant or Advisor of Ipsen. Speakers’ Bureau of IPSEN, Pfizer, and Novartis. Received Travel, Accommodations, Expenses from Ipsen, and Pfizer; S Pusceddu: Honoraria from Novartis, Ipsen, Italfarmaco, and Pfizer. Consultant or Advisor of Novartis and Ipsen. Research funding from Ipsen and Pfizer. Travel, Accommodations, Expenses from Ipsen; A Reising, E Degtyarev, M Shilkrut, and S Eddy are employees of Novartis; S Singh: Honoraria from Novartis and Ipsen. Consultant or Advisor of ITM. Research funding from Novartis and EMD Serono. Immediate family members are employees of Sanofi Canada and AstraZeneca; P Ruszniewski, D Halperin, D Campana, S Hijioka, and M Raderer have nothing to disclose.
Funding
This study was sponsored and funded by Novartis Pharmaceuticals Corporation.
Data sharing
Novartis is committed to sharing with qualified external researchers, access to patient-level data, and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.
Acknowledgements
The authors thank the patients and their families, the study investigators, and the study site personnel for their participations and contributions to this study. The authors would like to thank Paola Aimone, MD, Helen Lau, MS, Maurizio Voi, MD, and Bijoyesh Mookerjee, MD, FACS (all Novartis) for their contribution to the study design and data analyses. The authors also thank Vijay Kadasi, MSc, Novartis Healthcare Pvt Ltd, for providing medical writing and editorial assistance support.
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