Cabozantinib plus Atezolizumab in Advanced, Progressive Endocrine Malignancies: A Multicohort, Basket, Phase II Trial (CABATEN/GETNE-T1914)
Jaume Capdevila1, Jorge Hernando1, Javier Molina-Cerrillo2, Marta Benavent Viñuales3, Rocio Garcia-Carbonero4, Alex Teulé5, Ana Custodio6, Paula Jimenez-Fonseca7, Carlos López8, Cinta Hierro9, Alberto Carmona-Bayonas1º, Vicente Alonso11, Marta Llanos12, Isabel Sevilla13, Alejandro García-Alvarez1, Teresa Alonso-Gordoa2, Inmaculada Gallego Jiménez3, Beatriz Antón-Pascual2, Andrea Modrego Sánchez4, and Enrique Grande14
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ABSTRACT
Purpose: Multikinase inhibitors have shown efficacy in en- docrine neoplasms, and synergism with immune checkpoint in- hibitors has been noted in other tumors.
Patients and Methods: This is a prospective, multicenter, open-label, Simon two-stage optimal design, phase II study in- cluding patients with advanced and refractory endocrine and neuroendocrine neoplasms in six cohorts: lung well-differentiated neuroendocrine tumors, anaplastic thyroid cancer (ATC), adre- nocortical carcinoma (ACC), pheochromocytoma/paraganglioma (PPGL), well-differentiated gastroenteropancreatic neuroendo- crine tumors (GEP-NET), and grade 3 extrapulmonary neuro- endocrine neoplasms. Patients received atezolizumab 1,200 mg intravenously every 3 weeks plus cabozantinib 40 mg/day orally until disease progression or unacceptable toxicity. The primary objective was the overall response rate (ORR) by RECIST 1.1.
Results: From October 2020 to December 2022, 93 patients were included. The ORR was 14.3% [95% confidence interval (CI), 1.8-42.8] in ATC (N = 14); 8.3% (95% CI, 1.0-27.0) in ACC (N = 24); 15.4% (95% CI, 1.9-45.5) in PPGL (N = 13), and 16.7% (95% CI, 4.7-37.4) in GEP-NET (N = 24). Lung well- differentiated neuroendocrine tumors and grade 3 extrapulmo- nary neuroendocrine neoplasms had no responses. The duration of response was 20.4 months in ATC, 13.1 months in ACC, 12.2 months in PPGL, and 15.8 months in GEP-NET. Survival rates at 12 months in ATC and ACC were 47.6% and 47.6%, respectively. No unexpected toxicity was observed.
Conclusions: Cabozantinib and atezolizumab were safely ad- ministered and showed promising ORR, and preliminary long- term survival rates were observed in aggressive and pretreated ACC and ATC, which warrants further investigation.
Introduction
Research in rare and heterogeneous cancers is a challenge. The lack of targetable alterations in the majority of these rare tumors prevents their inclusion in basket or umbrella trials. Furthermore, the difficulty in developing modern pharmacologic treatment strategies generates a complex scenario for clinical trial design and patient recruitment, ulti- mately hindering timely regulatory approval of new drugs.
Neuroendocrine neoplasms include pheochromocytomas and paragangliomas (PPGL), gastroenteropancreatic neuroendocrine tumors (GEP-NET), and lung neuroendocrine tumors (lungNET). High-grade (G3) extrapulmonary neuroendocrine neoplasms (EP- NEN) and aggressive endocrine tumors such as anaplastic thyroid cancer (ATC) and adrenocortical carcinomas (ACC) also exemplify these rare and complex-to-treat diseases. Such malignancies repre- sent a challenge in drug development (1-9). These heterogeneous
1Medical Oncology Department, Vall Hebron University Hospital, Vall Hebron Institute of Oncology (VHIO), Barcelona, Spain. 2Medical Oncology Depart- ment, Hospital Universitario Ramón y Cajal, Madrid, Spain. 3Medical Oncology Department, University Hospital Virgen del Rocío, Instituto de Biomedicina de Sevilla (IBIS), Seville, Spain. 4Medical Oncology Department, Hospital Uni- versitario 12 de Octubre, Imas12, Facultad de Medicina, UCM, Madrid, Spain. 5Medical Oncology Department, Institut Català d’Oncologia (ICO) - IDIBELL, L ‘Hospitalet de Llobregat, Barcelona, Spain. 6Medical Oncology Department, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain. 7Medical Oncology De- partment, Hospital Universitario Central de Asturias, ISPA, Oviedo, Spain. 8Medical Oncology Department, Hospital Universitario Marqués de Valdecilla, IDIVAL, UNICAN, Santander, Spain. 9Medical Oncology Department, Catalan Institute of Oncology (ICO)- Badalona, Badalona-Applied Research Group in Oncology (B-ARGO), Badalona, Spain. 1ºHematology and Medical Oncology Department, Hospital Universitario Morales Meseguer. UMI. IMIB, Murcia, Spain. “1Medical Oncology Department, Instituto Aragonés de Investigación Sanitaria, Hospital Universitario Miguel Servet, Zaragoza, Spain. 12Medical Oncology De- partment, Hospital Universitario de Canarias, San Cristóbal de la Laguna, Spain. 13Medical Oncology Department, Investigación Clínica y Traslacional en Cáncer, Instituto de Investigaciones Biomédicas de Málaga (IBIMA), Hospitales
Universitarios Regional y Virgen de la Victoria de Málaga, Málaga, Spain. 14Medical Oncology Department, MD Anderson Cancer Center Madrid, Madrid, Spain.
Prior presentation: The study design was first presented as a trial in progress at the 2021 European Society for Medical Oncology (ESMO) Congress. Pre- liminary results were subsequently presented as oral communications at the 2023 ESMO Congress, the 2024 American Society of Clinical Oncology (ASCO) Genitourinary Cancers Symposium, the 21st Annual European Neu- roendocrine Tumor Society Conference (ENETS 2024), and the 2024 ASCO Congress. This article reports the final results of the study.
Corresponding Author: Enrique Grande, Medical Oncology Department, MD Anderson Cancer Center Madrid, C. de Arturo Soria, 270, Cdad. Lineal, Madrid 28033, Spain. E-mail: egrande@mdanderson.es
Clin Cancer Res 2025;31:4655-63 doi: 10.1158/1078-0432.CCR-25-2143
This open access article is distributed under the Creative Commons Attribution- NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
@2025 The Authors; Published by the American Association for Cancer Research
AAGR
American Association for Cancer Research
Translational Relevance
CABATEN assesses initial signals of efficacy and the safety profile of the combination of cabozantinib and atezolizumab in six different cohorts of neuroendocrine and endocrine neo- plasms. The combination showed a response rate of 14.3% in anaplastic thyroid cancer (ATC), 8.3% in adrenocortical carci- noma (ACC), 15.4% in advanced/metastatic pheochromocytoma and paraganglioma, and 16.7% in digestive gastro- enteropancreatic neuroendocrine tumor. Lung typical and atypical carcinoids (lung well-differentiated neuroendocrine tu- mors) and grade 3 extrapulmonary neuroendocrine neoplasms had no responses. The duration of response was 20.4 months in ATC, 13.1 months in ACC, 12.2 months in pheochromocytoma and paraganglioma, and 15.8 months in digestive gastro- enteropancreatic neuroendocrine tumors. Atezolizumab and cabozantinib showed limited activity in terms of response rates but achieved prolonged disease control and survival rates in aggressive and pretreated ACC and ATC, warranting further investigation of predictive factors that will help select patients for this combination.
groups of neoplasms differ in prognosis and therapeutic scenario, from advanced GEP-NET that have life expectancies of 5 to 10 years and diverse systemic therapies approved to ATC or ACC, which are orphan diseases with median overall survivals (OS) in the range of 6 to 12 months, respectively (1-9).
The design of clinical trials in these complex settings should focus on increasing the treatment repertoire after progression to standard therapies in tumors with good prognosis, such as NET, but also on early treatment lines for highly aggressive neoplasms with still poor prognosis and lack of treatment opportunities, such as G3 EP-NEN, ATC, and ACC.
Targeting VEGF and other cellular signaling cascade components such as rearranged during transfection, mesenchymal-epithelial transi- tion factor, and tyrosine-protein kinase receptor UFO “anexelekto” with multikinase inhibitors (MKI) has shown significant activity in well- differentiated NET and thyroid cancers in several phase II/III studies (10-20). However, despite the rationale to use the same approach in more aggressive endocrine tumors, the data on MKI monotherapy in ATC and ACC are less promising (21-25). Alternatively, the use of immune checkpoint inhibitors (ICI) in low-grade endocrine and neu- roendocrine neoplasms has been disappointing and has shown potential utility in more aggressive tumors such as G3 EP-NEN, ATC, and ACC (21, 26-33). The combination of MKI and ICI has shown enhanced activity in many tumor types and may be the key to revert intrinsic or acquired resistance in neuroendocrine and endocrine neoplasms (34-39).
In this study, we report the final results of the proof-of-concept, multicohort study of cabozantinib plus atezolizumab in different neu- roendocrine and endocrine neoplasm scenarios with a dual objective: to explore the efficacy in late treatment lines for low-grade/well-differen- tiated tumors (reverting acquired resistance) or early treatment lines in more aggressive carcinomas (reverting intrinsic resistance).
Patients and Methods
Study design and patients
CABATEN (EudraCT:2019-002279-32/NCT04400474) is a pro- spective, open-label, multicohort, multicenter, phase II study that
includes patients with advanced and refractory endocrine and neuroendocrine neoplasms across 15 hospitals in Spain. Patients were enrolled in six cohorts: (i) well-differentiated lungNET [World Health Organization (WHO) grades 1 and 2, typical and atypical carcinoids] after progression of the disease (PD) to somatostatin analogs (SSA), MKI, peptide receptor radionuclide therapy (PRRT), and/or chemotherapy; (ii) ATC in first-line treatment or after PD to chemotherapy or investigational drugs; (iii) ACC after PD to che- motherapy and/or mitotane; (iv) malignant PPGL after PD to PRRT if indicated, prior chemotherapy, and/or SSA; (v) well-differentiated GEP-NET (WHO grades 1 and 2) after PD to SSA, MKI, PRRT, and/ or chemotherapy; (vi) G3 EP-NEN (WHO grade 3, including NET and NEC) of any origin, excluding small cell lung cancer, after PD to chemotherapy, MKI, or PRRT. The main inclusion criteria are as follows: age >18 years, Eastern Cooperative Oncology Group per- formance status of 0 or 1, and adequate organ and bone marrow function. For additional details on eligibility, see the protocol. See Supplementary Table S1 for the representativeness of the study population.
This study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was approved in 2020 by the competent authority in Spain and the Independent Ethics Committee from Vall d’Hebron Uni- versity Hospital. Written informed consent was obtained from all patients.
Procedures
Patients received intravenous atezolizumab at a fixed dose of 1,200 mg every 3 weeks (one cycle) plus oral cabozantinib at 40 mg/ day until confirmed PD, unacceptable toxicity, patient withdrawal, or death from any cause, whichever occurred first. The cabozantinib 40-mg dose was chosen based on the results from the COSMIC-021 trial showing coincident toxicity with higher doses when combined with atezolizumab (35). Cabozantinib dose reduction to 20 mg/day was allowed in the case of unacceptable toxicities (Supplementary Fig. S1). Temporary discontinuations to manage adverse events (AE) were allowed for both drugs.
Clinical assessments included medical history review; a complete physical examination, including vital signs, Eastern Cooperative Oncology Group performance status, electrocardiogram, and clini- cal laboratory tests (hematology, serum biochemistry, and urinaly- sis); a record of AE using NCI-Common Terminology Criteria for Adverse Events version 5.0; and treatment compliance. Tumor imaging assessments were performed by CT scans or MRI (RECIST 1.1; ref. 40) locally by the investigator at screening and every 12 weeks until objective PD, death, or the initiation of an alternative treatment. Confirmation of response was required at least 4 weeks after initial evidence of response.
Outcome measures
The primary endpoint for all cohorts was overall response rate (ORR), including patients with confirmed partial and complete re- sponses as the best response according to RECIST 1.1. The sec- ondary efficacy endpoints included the duration of response (DoR), progression-free survival (PFS) as per RECIST 1.1, OS, and quality of life using questionnaires EQ-5D-5L and European Organisation for Research and Treatment of Cancer QLQ-C30. Safety was assessed using AE frequency, clinical laboratory test results, vital signs, and physical examinations.
Molecular assessments
PD-L1 expression in archival formalin-fixed tumor samples was assessed at a central laboratory (VHIO’s Cancer Genomics Group, RRID: SCR_011755) using the VENTANA PD-L1 assay (SP263; Roche, cat. No. 790-4905, RRID: AB_2819099). A PD-L1 combined positive score (CPS) of 1 or greater was considered positive. Microsatellite instability was assessed by IHC. Microsatellite insta- bility was determined by loss of nuclear expression of at least one of the following genes: MLH1 (Roche, cat. No. 790-5091, RRID: AB_3669002), MSH6 (Roche, cat. No. 790-5092, RRID: AB_ 2936885), PMS2 (Roche, cat. No. 790-5094, RRID: AB_3669003), and MSH2 (Roche, cat. No. 760-5093, RRID: AB_2936886). Translational studies were limited to responders in order to opti- mize resources and to enable molecular characterization of this subgroup. This analysis was purely descriptive, as the lack of as- sessment of nonresponders precluded the identification of markers associated with response.
Statistical considerations
Sample size was estimated by Simon two-stage optimal design [R software, version 3.6.3 (2020-02-29), R Foundation for Statistical Computing, RRID: SCR_001905]. Establishing a null ORR in re- fractory settings from less than 5% from historic cohorts (1-9) to an alternate ORR of 20% (a one sided = 0.1 and ß= 80%), 24 patients per cohort were required. If ≥ 1 patient reports an objective re- sponse of the first nine patients within a cohort, the study will continue recruiting 15 additional patients in that cohort. A cohort will be considered positive if ≥ 3 of 24 patients achieve an objective response (Supplementary Fig. S1).
The efficacy analysis was based on the full analysis set, in- cluding all enrolled patients. Safety was assessed using a safety analysis set that included all patients who received at least one dose of study treatment. Continuous variables are summarized by the number of observations (n), median, SD, and/or range, whereas categorical variables are summarized by counts and percentages. Response rates were estimated using exact binomial (Clopper-Pearson) 95% confidence intervals (CI). Follow-up
time was calculated using the arithmetic median from the time between the first dose of study treatment and last status. Time- to-event endpoints were analyzed by Kaplan-Meier curves. Pa- tients without documented PD or death at the time of analysis were censored at the last date of tumor evaluation for PFS or the last date of follow-up for OS. Landmark analysis was performed as an ad hoc analysis using Kaplan-Meier curves, with 3- and 6- month threshold selected as clinically relevant landmarks for treatment adherence based on the expected prognosis and treatment duration of the diseases studied. Statistical test sig- nificance was set at P < 0.05 (two-tailed). All statistical analyses were performed using R version 4.2.1 statistical language (RRID: SCR_001905). Figures and tables were created using RStudio version 2022.02.3 + 492 (RRID: SCR_000432).
Results
Baseline patient characteristics
From October 2020 to December 2022, 93 patients were enrolled (Fig. 1): nine lungNET, 14 ATC, 24 ACC, 13 PPGL (six pheo- chromocytomas and seven paraganglioma), 24 G1 to G2 GEP-NET, and nine G3 EP-NEN. The cohorts for G3 EP-NEN and lungNET did not pass the futility threshold and were not expanded. The ATC and PPGL cohorts prematurely closed during the second stage be- cause of slow accrual. Table 1 and Supplementary Table S2 present the baseline characteristics.
Efficacy endpoints
The ORR was 14% (n = 2/14; 95% CI, 2-43) in ATC (both patients were PD-L1-positive and microsatellite-stable), 8% (n = 2/24; 95% CI, 1-27) in ACC, 15% (n = 2/13; 95% CI, 2-46) in PPGL, and 17% (n = 4/24; 95% CI, 5-37) in GEP-NET. The study achieved the primary endpoint only in GEP-NET. Patients with ACC and Cushing syndrome showed no responses. Patients with BRAF-mutated ATC had no responses, whereas BRAF wild- type (WT) ATC showed an ORR of 20%. Patients with lungNET and G3 EP-NEN had no responses (Fig. 2; Supplementary Tables S3 and S4).
Screened patients N = 116
8 No adequate organ and marrow function
2 Prohibited concomitant medication
1 Prior TKI treatment
1 No NEN histopathologically
CABATEN trial Enrolled patients N = 93
3 Withdrew consent
3 Death
2 Investigation decision
3 Not specified
Received atezolizumab 1,200 mg IV every 3 weeks cabozantinib 40 mg/daily treatment
LungNET
ATC
ACC
PPGL
G1-2 GEP-NET
G3 EP-NEN
1st Stage
N = 9
N = 9
N = 9
N = 9
N = 9
N = 9
0 PR
1 PR
1 PR
1 PR
1 PR
V
0 PR
2nd Stage
N = 5
N = 15
N = 4
N = 15
Total N
N = 9
N = 14
N = 24
N = 13
N = 24
N = 9
8 Discontinued C 8 Discontinued A
13 Discontinued C
24 Discontinued C 24 Discontinued A
10 Discontinued C
17 Discontinued C 18 Discontinued A
9 Discontinued C
11 Discontinued A
11 Discontinued A
9 Discontinued A
Treatment ongoing
N = 1
N = 3
N = 0
N= 3
N = 7
N = 0
| Characteristic | LungNET N = 9 | ATC N = 14 | ACC N = 24 | PPGLa N = 13 | G1-2 GEP-NET N = 24 | G3 EP-NEN N = 9 |
|---|---|---|---|---|---|---|
| Median age (range), years | 63 (31-81) | 62 (47-80) | 51 (23-75) | 48 (36-67) | 60 (31-77) | 62 (38-73) |
| Gender, n (%) | ||||||
| Male | 5 (56) | 5 (36) | 11 (46) | 10 (77) | 13 (54) | 6 (67) |
| Female | 4 (44) | 9 (64) | 13 (54) | 3 (23) | 11 (46) | 3 (33) |
| ECOG PS, n (%) | ||||||
| 0 | 2 (22) | 6 (43) | 13 (54) | 5 (39) | 14 (58) | 2 (22) |
| 1 | 7 (78) | 8 (57) | 11 (46) | 8 (60) | 10 (42) | 7 (78) |
| Histopathologic diagnosis, n (%) | ||||||
| Well differentiated | 7 (78) | 1 (7) | 6 (25) | 3 (23) | 22 (92) | 2 (22) |
| Moderately differentiated | 2 (22) | 0 (0) | 3 (1) | 0 (0) | 2 (8) | 0 (0) |
| Poorly differentiated | 0 (0) | 10 (71) | 6 (25) | 3 (23) | 0 (0) | 7 (78) |
| NA | 0 (0) | 3 (21) | 7 (29) | 3 (23) | 0 (0) | 0 (0) |
| UK | 0 (0) | 0 (0) | 2 (8) | 4 (31) | 0 (0) | 0 (0) |
| Clinical stage at initial diagnosis, n (%) | ||||||
| I | 1 (11) | 0 (0) | 0 (0) | 0 (0) | 0 (0) | 0 (0) |
| II | 0 (0) | 0 (0) | 3 (13) | 1 (8) | 1 (4) | 0 (0) |
| III | 2 (22) | 0 (0) | 2 (8) | 2 (15) | 1 (4) | 0 (0) |
| IV | 6 (67) | 14 (100) | 19 (79) | 10 (77) | 22 (92) | 9 (100) |
| Tumor grade, n (%)b | ||||||
| 1/Low grade | 0 (0) | — | 2 (8) | — | 7 (29) | 0 (0) |
| 2/High grade | 8 (89) | — | 14 (58) | — | 17 (71) | 0 (0) |
| 3 | 0 (0) | — | — | — | 0 (0) | 9 (100) |
| UK | 1 (11) | — | 8 (34) | — | 0 (0) | 0 (0) |
| Ki-67 index“ | ||||||
| <3% | 0 (0) | — | 0 (0) | — | 6 (25) | 0 (0) |
| 3%-20% | 8 (89) | — | 9 (38) | — | 17 (71) | 0 (0) |
| >20% | 0 (0) | — | 6 (25) | — | 0 (0) | 9 (100) |
| UK | 1 (11) | — | 9 (38) | — | 1 (4) | 0 (0) |
| Metastasis locations, n (%) | ||||||
| Liver | 6 (67) | 1 (7) | 15 (63) | 4 (31) | 20 (83) | 9 (100) |
| Lymph nodes | 5 (56) | 9 (64) | 6 (25) | 2 (15) | 11 (46) | 6 (67) |
| Lung | 3 (33) | 8 (57) | 14 (58) | 3 (23) | 2 (8) | 1 (11) |
| Bone | 2 (22) | 4 (29) | 3 (13) | 6 (46) | 6 (25) | 2 (22) |
| Previous treatment type, n (%) | ||||||
| SSA | 7 (78) | 0 (0) | 0 (0) | 4 (31) | 20 (83) | 0 (0) |
| Chemotherapy | 5 (56) | 6 (75) | 22 (92) | 7 (54) | 7 (29) | 9 (100) |
| TKI | 7 (78) | 2 (25) | 0 (0) | 2 (15) | 11 (46) | 0 (0) |
| PRRT | 1 (11) | 1 (13) | 0 (0) | 3 (23) | 4 (17) | 0 (0) |
| Mitotane | 0 (0) | 0 (0) | 11 (46)d | 1 (8) | 0 (0) | 0 (0) |
| Other | 1 (11) | 0 (0) | 1 (4) | 0 (0) | 0 (0) | 0 (0) |
Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status; EP, extrapulmonary; NA, not available; TKI, tyrosine kinase inhibitor; UK, unknown.
ªPPGL: six patients with pheochromocytoma and seven with paraganglioma.
bTumor grade uses the WHO classification for NET in patients with lungNET, G1-2 GEP-NET, and G3 EP-NET. Patients with ACC tumors were graded as low grade (Ki-67 < 10% or <20 mitoses/50 high-power field) and high grade (Ki-67 ≥ 10% or ≥20 mitoses/50 high-power field).
“Ki-67 index does not apply for ATC and PPGL cohorts. dMedian time from mitotane discontinuation to the start of study treatment was 3.6 months (range, 0.1-70.1).
The median DoR were 20.4 months (range, 11.5-29.4), 13.1 months (range, 5.4-20.9), 12.2 months (range, 5.5-19.0), and 15.8 months (range, 10.6-20.2) in ATC, ACC, PPGL, and GEP-NET, respectively (Fig. 2; Supplementary Fig. S2; Supple- mentary Table S3).
With a median follow-up of 17.0 (range, 0.5-36.4) months, the median PFS was 8.4 [95% CI, 7.7-not reached (NR)] months in the lungNET, 4.1 (95% CI, 2.7-NR) months in ATC, 2.9 (95% CI, 2.8- 5.7) months in ACC, 8.6 (95% CI, 5.7-NR) months in PPGL, 13 (95% CI, 11.2-NR) months in G1 to G2 GEP-NET, and 2.7 (95% CI, 2.6- NR) months in G3 EP-NEN (Fig. 3A). Subgroup analysis showed no
trends toward better outcomes based on BRAF-mutated status in ATCs, hypercortisolism, histologic differentiation in ACC, or primary pancreatic origin in GEP-NET (Supplementary Figs. S3-S6).
In total, 51 (55%) patients died; 43 (46%) because of PD, two (2%) because of toxicity related to the study treatment (see descrip- tion of events below), and six (7%) because of other medical condi- tions unrelated to the study drugs, including abdominal sepsis, COVID-19 infection, encephalitis infection, febrile neutropenia, heart failure, and intestinal perforation.
The median OS rates were 6.1 (95% CI, 4.4-NR), 13.5 (95% CI, 9.2-NR), 26.7 (95% CI, 9.7-NR), and 5.4 (95% CI, 3.6-NR)
Figure 2. ORR for each cohort: lungNET, ATC, ACC, PPGL, G1-2 GEP-NET, and G3 EP-NEN. CPS, combined positive score; MSI, microsatellite instability; MSS, microsatellite- stable; NA, not available; PR, partial response; TMB, tumor mutational burden. Molecular analyses were performed in the 10 patients who responded to treatment.
| LungNET | ATC | ACC | PPGL | G1-2 GEP-NET | G3 EP-NEN |
|---|---|---|---|---|---|
| 9 | 14 | 24 | 13 | 24 | 9 |
| 0 (0) | 2 (14.3) | 2 (8.3) | 2 (15.4) | 4 (16.7) | 0 (0) |
| NA | 20.4 (11.5-29.4) | 13.1 (5.4-20.9) | 12.2 (5.5-19.0) | 15.8 (10.6-20.2) | NA |
250
Maximum reduction from baseline (%)
200
n
ORR, n (%) DoR, median (range); m
150
100
50
0
-50
LungNET
ATC
-100
ACC
PPGL
PR (green)
G1-2 GEP-NET
PD-L1-positive (>1 CPS; red)/PD-L1-negative (blue)
G3 EP-NEN
MSS (orange)/MSI (green)
High TMB (≥10 mutations/megabase)
months for ATC, ACC, PPGL, and G3 EP-NEN, respectively (Fig. 3B). The median OS was not reached for lungNET and G1 to G2 GEP-NET. The 12-month OS rates were 67% (95% CI, 42-100), 62% (95% CI, 40-95), 92% (95% CI, 81-100), and 11% (95% CI, 2-71) in lungNET, PPGL, G1 to G2 GEP-NET, and G3 EP-NEN, respectively (Fig. 3B). ATC and ACC showed 12-month OS rates of 48% (95% CI, 27-84) and 58% (95% CI, 42-82), respectively.
Safety
The median duration of treatment was 6.2 (95% CI, 3.5-8.6) months and 6.8 (95% CI, 3.8-8.2) months for cabozantinib and atezolizumab, respectively. Patients with G1 to G2 GEP-NET remained in treatment longer, with a median of 11.6 (95% CI, 6.8- 31.5) months for atezolizumab and 12.4 (95% CI, 8.6-30.5) months for cabozantinib (Supplementary Fig. S7).
Cabozantinib and atezolizumab were temporarily interrupted to manage AE in 65% and 34% of patients, respectively. The dosage of cabozantinib was reduced to 20 mg/day in 45.2% of patients (data by cohort are presented in Supplementary Fig. S7). The most common toxicities leading to dose reductions were transaminitis (8%), fatigue (7%), neutropenia (5%), diarrhea (4%), and palmar-plantar erythrodysesthesia syndrome (3%). Efficacy landmark analysis showed no differences in PFS or OS among subgroups based on the reduction of dose intensity (Supplemen- tary Fig. S8).
Overall, 81 (87%) patients discontinued cabozantinib because of unacceptable toxicity in 12 (13%) patients. Atezolizumab was dis- continued in 81 (87%) patients because of unacceptable toxicity in 10 (11%) patients.
Most treatment-related AE were fatigue (60%), diarrhea (43%), increased aspartate aminotransferase levels (32%), increased alanine transaminase) levels (28%), oral mucositis (27%), nausea (26%), and hypertension (26%; Fig. 4). Serious AE occurred in 46% of patients. Grade ≥3 toxicities had low frequency, and the most common were fatigue (10%), increased alanine transaminase (9%), neutropenia (7%), and hypertension (5%; Fig. 4). Treatment-related cardiac grade 3 to 5 events consisted of only one patient with a grade 3 myocardial infarction. One patient died because of treatment-
related acute pancreatitis, and another patient with preexisting cardiac/vascular comorbidities died because of a treatment-related cerebral artery stroke. Both events occurred during the first week of administering cabozantinib at 40 mg/day plus atezolizumab. Patient self-reported quality of life was maintained throughout the study (Supplementary Fig. S9).
Discussion
CABATEN is the largest multicohort trial to evaluate the efficacy of the combination of MKI (cabozantinib) plus ICI (atezolizumab) in a broad repertoire of advanced, refractory, and heavily pretreated endocrine and neuroendocrine malignancies.
Cabozantinib plus atezolizumab showed encouraging activity in ATC with an ORR of 14%. One patient achieved a DoR of 29.4 months, and the 1-year OS rate was 47.6%, which compares fa- vorably with routinely used chemotherapy, particularly considering that most patients were pretreated or had poor prognostic features (41, 42). The combination achieved a higher ORR than MKI ad- ministered as a single agent. For instance, lenvatinib reported no responses and was halted for futility (21). Of note, lenvatinib and pembrolizumab administered as first-line treatment demonstrated a higher ORR compared with our study, which included 57% pre- treated patients. This probably emphasizes the importance of early intervention with this treatment modality (36). Moreover, all pa- tients were BRAF-WT (36), a patient subset with fewer treatment options that achieved a 20% ORR in our study. The use of ICI has also reported relevant activity in ATC but is potentially associated with PD-L1 expression and also BRAF-WT status (43, 44).
Cabozantinib and atezolizumab also showed potential activity in ACC, with an ORR of 8%, DoR of 13.1 months, and a median OS of 13.5 months in a chemotherapy-refractory population. This out- come is encouraging when compared with the outcomes of other second-line treatment options for ACC, including gemcitabine- based combinations or streptozotocin (45-47). The results of small trials with ICI in ACC were heterogeneous. Single ICI showed modest activity in ACC, which was also translated to poor survival outcomes with a median OS below 11 months (48-50). Only one study showed a potential benefit of pembrolizumab monotherapy, with a median OS of 24.9 months, which may be in part attributable
A
B
Survival probability (%)
100%
LungNET
Survival probability (%)
100%
ATC
75%
ACC
PPGL
75%
G1-2 GEP-NET
G3 EP-NEN
50%
50%
25%
25%
0%
0%
0
6
12
18
24
30
36
0
6
12
18
24
30
36
Number at risk
Time (months)
9
8
6
6
6
5
0
14
7
6
5
2
1
0
24
17
13
9
3
2
0
13
10
8
7
3
0
0
24
22
21
16
16
14
0
9
5
2
1
1
1
1
| Number | at risk | Time (months) | |||||||
|---|---|---|---|---|---|---|---|---|---|
| 9 | 7 | 3 | 3 | 3 | 2 | 0 | |||
| 14 | 4 | 4 | 1 | 1 | 1 | 0 | |||
| 24 | 5 | 4 | 2 | 2 | 0 | 0 | |||
| 13 | 9 | 5 | 5 | 1 | 0 | 0 | |||
| 24 | 20 | 14 | 8 | 8 | 6 | 0 | |||
| 9 | 2 | 1 | 0 | 0 | 0 | 0 | |||
| PFS | 12 m PFS rate % (95 % CI) | Median PFS month, m (95 % Cl) |
|---|---|---|
| LungNET | 33.3 (13.2-84) | 8.4 (7.7-NR) |
| ATC | 31.4 (14.2-70.4) | 4.1 (2.7-NR) |
| ACC | 16.7 (6.8-40.8) | 2.9 (2.8-5.7) |
| PPGL | 38.5 (19.3-76.5) | 8.6 (5.7-NR) |
| G1-2 GEP-NET | 58.3 (41.6-81.8) | 13 (11.3-NR) |
| G3 EP-NEN | 11.1 (1.8-70.5) | 2.7 (2.6-NR) |
| os | 12m OS rate % (95 % CI) | Median OS month, m (95 % CI) |
|---|---|---|
| LungNET | 66.7 (42-100) | NR |
| ATC | 47.6 (27.0-84.1) | 6.1 (4.4-NR) |
| ACC | 58.3 (41.6-81.8) | 13.5 (9.2-NR) |
| PPGL | 61.5 (40.0-94.6) | 26.7 (9.7-NR) |
| G1-2 GEP-NET | 91.7 (81.3-100) | NR |
| G3 EP-NEN | 11.1 (1.8-70.5) | 5.4 (3.6-NR) |
Figure 3. Survival endpoints. PFS for each cohort (A). OS for each cohort (B). m, month.
to earlier ICI administration after mitotane (51). In our cohort, most patients had two or more previous treatment lines, and up to 92% were previously exposed to platinum-based chemotherapy. Cushing syndrome was present in five patients and correlated with worse outcomes. Recently, new ICI/MKI combinations (camreli- zumab and apatinib) showed encouraging activity (ORR, 52%), with median PFS and OS of 12.6 and 20.9 months, respectively (52).
In patients with G1 to G2 GEP-NET, cabozantinib and atezo- lizumab surpassed the futility threshold, with an ORR of 17%, but because of the latest reports on cabozantinib monotherapy showing higher ORR than those initially hypothesized (10), the
interpretation is limited, and the relevance of this finding seems less relevant. In patients with PPGL, the ORR of cabozantinib combined with atezolizumab was 15%, not showing improvement compared with cabozantinib alone or single-agent antiangiogenic therapies (53-55). For instance, lenvatinib showed a higher ORR of up to 63% in a retrospective series of PPGL and an ORR of 29% in a prospective phase III trial including G1 to G2 GEP-NET (11, 55). Therefore, the addition of ICI seems to have limited effect on these cohorts.
In lungNET, the CABINET trial showed modest activity of cabozantinib (10), which might have constrained the detection of
Fatigue
9
56
Diarrhea
1
40
AST increased
6
30
ALT increased
8
26
Mucositis oral
25
Nausea
24
Hypertension
5
24
Anorexia
1
20
Vomiting
1
15
Neutropenia
6
14
PPE syndrome
1
13
SST disorders
12
Hypothyroidism
11
Arthralgia
1
10
Thrombocytopenia
10
Anemia
10
Dysgeusia
9
Peripheral sensory neuropathy
8
Investigations
8
Constipation
7
Serum amylase increased
1
7
Abdominal pain
2
6
Grade ≥ 3
Headache
6
GI disorders
6
Any grade
Hypomagnesemia
6
Lipase increased
1
6
Pruritus
5
Hyperthyroidism
5
BLS disorders
3
5
CPK increased
1
5
0
10
20
30
40
50
60
70
80
Patients (%)
potential benefit in such a small sample. The results were not sig- nificantly better than those previously reported for single cabo- zantinib treatment or immunotherapy, either ICI or dual ICI, which reported controversial results (10, 27, 28). For instance, spartalizu- mab achieved an ORR of 17%, which was not observed with dur- valumab plus tremelimumab (27, 28). In G3 EP-NEN, dual ICI showed ORR up to 44% and a survival benefit greater than that observed with the MKI combination in our study (27, 31). Con- versely, preliminary data from 19 patients with NEC treated with cabozantinib plus avelumab showed a promising ORR of 21% (56).
The selection of combination drug partners is also relevant for achieving synergy and optimal dosing. The combination of atezo- lizumab and bevacizumab showed ORR of 20% for pancreatic NET and 15% for extrapancreatic NET (57). Combined treatment with camrelizumab, a novel PD-1 inhibitor, and apatinib, a selective VEGF receptor-2 oral inhibitor, showed an ORR of 52% in 21 pa- tients with refractory ACC (52). Conversely, pembrolizumab plus lenvatinib in advanced well-differentiated NET showed limited efficacy (50).
The optimal cabozantinib dose remains debatable. In our study, 45% of patients required a dose reduction to 20 mg/day, in line with previous reports on such combinations (58, 59). Landmark analysis showed no effect of dose reduction on efficacy. However, this analysis was not statistically powered. Cabozantinib mono- therapy has been active in several NEN at doses of 60 mg/day, which is higher than the initial dose used in the CABATEN trial (40 mg/day) and three times higher than that for patients re- quiring dose reductions (10, 22, 53). In other NEN, such as medullary thyroid carcinoma, cabozantinib was administered at doses of 140 mg/day. (17) The toxicity profile of the combination limited the use of higher cabozantinib doses, and the impact of a potentially suboptimal cabozantinib dose on efficacy could not be excluded.
This safety profile was consistent with that observed in studies using VEGF inhibitors or ICI as single agents (10, 17, 22, 53, 60). Specific toxicities did not increase, and most were of low grade, which is in agreement with previous studies using this combination (35, 59). The incidence of transaminitis was within the range of atezolizumab monotherapy (60). Surprisingly, the frequency of cardiac toxicities was lower than that reported in previous studies on cabozantinib (35, 58, 59). Grade 3 to 4 hypertension was re- ported in 5.3% of patients. This result might be relevant for ACC and PPGL, which typically involve hypertensive crises.
The Simon two-stage optimal design allowed us to investigate multiple cohorts while minimizing the exposure to ineffective MKI/ ICI treatments but restricted the ability to identify modest im- provements. Nevertheless, a high level of antitumor activity is re- quired in phase II trials to justify embarking on further drug development in these rare tumors. The low incidence also limited accrual, leading to a premature end of recruitment for patients with ATC and PPGL.
In conclusion, cabozantinib plus atezolizumab showed limited efficacy in patients with PPGL, GEP-NEN, and lungNET but achieved promising responses and survival rates in ACC and ATC. These findings support further investigation in patients with these tumor types and highlight the need to identify predictive factors that may guide patient selection for this combination therapy.
Data Availability
The study protocol is available as a Supplementary Note in the Supplementary Information File. The clinical raw data are protected and are not available due to
data privacy laws. The data that support the findings of this study are available from the corresponding author upon reasonable request (for purposes consistent with the consent provided by the patients for use of their data). Data-sharing requests will be considered on a case-by-case basis in a timely manner. Response to access requests will be provided within 1 month, and data will be available for 6 months once access has been granted. Data will be provided anonymously, with no personal identifiable data.
Authors’ Disclosures
J. Capdevila reports grants from Ipsen and Roche during the conduct of the study; grants and personal fees from Ipsen, Exelixis, Eisai, and ITM Radiopharma; personal fees from Bayer, Eli Lilly and Company, Novartis, Incyte Corporation, Sanofi, Merck, Esteve, Pfizer, and Advanz; and grants from AstraZeneca and Gilead Sciences outside the submitted work. J. Molina-Cerrillo reports grants from Ipsen and Roche during the conduct of the study; grants, personal fees, and nonfinancial support from MSD; personal fees and nonfinancial support from Astellas Pharma, Adium Pharma, and Bristol Myers Squibb; personal fees from AAA Pharma and Pfizer; and grants from Exelisis and Recordati outside the submitted work. M. Benavent Viñuales reports other support from Pfizer, Ipsen, Gilead Sciences, Esteve, and Novartis outside the submitted work. R. Garcia- Carbonero reports personal fees from Ipsen during the conduct of the study, as well as personal fees from Advanz Pharma, Astellas Pharma, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Crinetics, Esteve, GSK, Hutchmed, ITM Radio- pharma, MSD, Novartis, Novocure, PharmaMar, Pierre Fabre, Sanofi, Servier, and Takeda outside the submitted work. A. Teulé reports other support from Advanced Accelerator Applications (ADACAP), Novartis, Esteve, Ipsen, Advanz Pharma, and AstraZeneca outside the submitted work. C. López reports grants, personal fees, and nonfinancial support from Ipsen, Eisai, and Roche; personal fees and nonfinancial support from Novartis/AAA Pharma; and grants from Pfizer during the conduct of the study. C. Hierro reports other support from Eli Lilly and Company, AstraZeneca, Bristol Myers Squibb, MSD, Jazz Pharmaceuticals, ALX Oncology, Amgen, and Roche and grants from Merck outside the submitted work. I. Sevilla reports grants from GETNE during the conduct of the study, as well as personal fees from Ipsen, AAA Pharma, Novartsi, PharmaMar, Esteve, Merck, Deciphera, and Boehringer Ingelheim outside the submitted work. A. García- Álvarez reports other support from Ipsen, personal fees and other support from Novartis, Elli Lilly and Company, and Eisai, and other support from Amgen and Advanz Pharma outside the submitted work. T. Alonso-Gordoa reports personal fees from Bayer, Astellas Pharma, Pfizer, Bristol Myers Squibb, MSD, Adacap, Novartis, Eisai, and Eli Lilly and Company; grants and personal fees from Johnson & Johnson; and personal fees and nonfinancial support from Ipsen during the conduct of the study. B. Antón-Pascual reports grants from NET España and personal fees from AAA Pharma, Novartis, Advanz Pharma, Merck, MSD, Persan Farma, Nutricia, and Servier outside the submitted work. E. Grande reports grants from Roche and Ipsen during the conduct of the study, as well as grants from Merck, Astellas Pharma, AstraZeneca, Novartis, and Merck outside the submitted work. No disclosures were reported by the other authors.
Authors’ Contributions
J. Capdevila: Conceptualization, resources, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing- original draft, project administration, writing-review and editing. J. Hernando: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. J. Molina-Cerrillo: Resources, formal analysis, supervision, validation, investiga- tion, visualization, writing-original draft, project administration, writing-review and editing. M. Benavent Viñuales: Resources, formal analysis, supervision, val- idation, investigation, visualization, writing-original draft, project administration, writing-review and editing. R. Garcia-Carbonero: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. A. Teulé: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. A. Custodio: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. P. Jimenez-Fonseca: Re- sources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. C. Lopez: Resources, formal analysis, supervision, validation, investigation, visu- alization, writing-original draft, project administration, writing-review and
editing. C. Hierro: Resources, formal analysis, supervision, validation, investiga- tion, visualization, writing-original draft, project administration, writing-review and editing. A. Carmona-Bayonas: Resources, formal analysis, supervision, vali- dation, investigation, visualization, writing-original draft, project administration, writing-review and editing. V. Alonso: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administra- tion, writing-review and editing. M. Llanos: Resources, formal analysis, supervi- sion, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. I. Sevilla: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. A. Garcia-Alvarez: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing-review and editing. T. Alonso-Gordoa: Resources, formal analysis, supervision, validation, investigation, visualization, writing- original draft, project administration, writing-review and editing. I. Gallego Jiménez: Resources, formal analysis, supervision, validation, investigation, visu- alization, writing-original draft, project administration, writing-review and edit- ing. B. Antón-Pascual: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administration, writing- review and editing. A. Modrego Sánchez: Resources, formal analysis, supervision, validation, investigation, visualization, writing-original draft, project administra- tion, writing-review and editing. E. Grande: Conceptualization, resources, formal analysis, supervision, funding acquisition, validation, investigation, visualization,
methodology, writing-original draft, project administration, writing-review and editing.
Acknowledgments
This work was supported by the Grupo Español de Tumores Neuroendocrinos y Endocrinos. Roche provided atezolizumab, whereas Ipsen supplied cabozantinib and awarded a grant to Grupo Español de Tumores Neuroendocrinos y Endo- crinos to cover the costs of the study. The funders have no role in the design, conduct, or analysis of the study. The authors thank all patients and families, investigators, and study staff involved in the CABATEN trial; special thanks to the MFAR Clinical Research team for their support in regulatory, monitoring, and quality assurance activities; Pau Doñate, Ph.D., and Fanny Rubio, Ph.D., for their assistance with manuscript and language editing; and Oriol Prat M.S. for his statistical support.
Note
Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
Received June 6, 2025; revised July 28, 2025; accepted September 10, 2025; posted first September 12, 2025.
References
1. Pavel M, Öberg K, Falconi M, Krenning EP, Sundin A, Perren A, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:844-60.
2. Panzuto F, Ramage J, Pritchard DM, van Velthuysen M-LF, Schrader J, Begum N, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastroduodenal neuroendocrine tumours (NETs) G1-G3. J Neuroendocrinol 2023; 35:e13306.
3. Rinke A, Ambrosini V, Dromain C, Garcia-Carbonero R, Haji A, Koumarianou A, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for colorectal neuroendocrine tumours. J Neuroendocrinol 2023;35: e13309.
4. Rindi G, Mete O, Uccella S, Basturk O, La Rosa S, Brosens LAA, et al. Overview of the 2022 WHO classification of neuroendocrine neoplasms. Endocr Pathol 2022;33:115-54.
5. Fassnacht M, Assie G, Baudin E, Eisenhofer G, de la Fouchardiere C, Haak HR, et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2020;31:1476-90.
6. Baudin E, Caplin M, Garcia-Carbonero R, Fazio N, Ferolla P, Filosso PL, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up *. Ann Oncol 2021;32:439-51.
7. Kos-Kudła B, Castaño JP, Denecke T, Grande E, Kjaer A, Koumarianou A, et al. European Neuroendocrine Tumour Society (ENETS) 2023 guidance paper for nonfunctioning pancreatic neuroendocrine tumours. J Neuroendocrinol 2023;35: e13343.
8. Hofland J, Falconi M, Christ E, Castaño JP, Faggiano A, Lamarca A, et al. European Neuroendocrine Tumor Society 2023 guidance paper for function- ing pancreatic neuroendocrine tumour syndromes. J Neuroendocrinol 2023; 35:e13318.
9. Sorbye H, Grande E, Pavel M, Tesselaar M, Fazio N, Reed NS, et al. European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for digestive neuroendocrine carcinoma. J Neuroendocrinol 2023;35:e13249.
10. Chan JA, Geyer S, Zemla T, Knopp MV, Behr S, Pulsipher S, et al. Phase 3 trial of cabozantinib to treat advanced neuroendocrine tumors. N Engl J Med 2025; 392:653-65.
11. Capdevila J, Fazio N, Lopez C, Teulé A, Valle JW, Tafuto S, et al. Lenvatinib in patients with advanced grade 1/2 pancreatic and gastrointestinal neuroendo- crine tumors: results of the phase II TALENT trial (GETNE1509). J Clin Oncol 2021;39:2304-12.
12. Brose MS, Robinson B, Sherman SI, Krajewska J, Lin C-C, Vaisman F, et al. Cabozantinib for radioiodine-refractory differentiated thyroid cancer (COS- MIC-311): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2021;22:1126-38.
13. Yao JC, Guthrie KA, Moran C, Strosberg JR, Kulke MH, Chan JA, et al. Phase III prospective randomized comparison trial of depot octreotide plus inter- feron alfa-2b versus depot octreotide plus bevacizumab in patients with ad- vanced carcinoid tumors: SWOG S0518. J Clin Oncol 2017;35:1695-703.
14. Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo- controlled, phase 3 study. Lancet 2016;387:968-77.
15. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621-30.
16. Mitry E, Walter T, Baudin E, Kurtz J-E, Ruszniewski P, Dominguez-Tinajero S, et al. Bevacizumab plus capecitabine in patients with progressive advanced well-differentiated neuroendocrine tumors of the gastro-intestinal (GI-NETs) tract (BETTER trial)-a phase II non-randomised trial. Eur J Cancer 2014;50: 3107-15.
17. Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 2013;31: 3639-46.
18. Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol 2012;30: 134-41.
19. Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501-13.
20. Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Ever- olimus for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011; 364:514-23.
21. Wirth LJ, Brose MS, Sherman EJ, Licitra L, Schlumberger M, Sherman SI, et al. Open-label, single-arm, multicenter, phase II trial of lenvatinib for the treat- ment of patients with anaplastic thyroid cancer. J Clin Oncol 2021;39:2359-66.
22. Campbell MT, Balderrama-Brondani V, Jimenez C, Tamsen G, Marcal LP, Varghese J, et al. Cabozantinib monotherapy for advanced adrenocortical carcinoma: a single-arm, phase 2 trial. Lancet Oncol 2024;25:649-57.
23. Tahara M, Kiyota N, Yamazaki T, Chayahara N, Nakano K, Inagaki L, et al. Lenvatinib for anaplastic thyroid cancer. Front Oncol 2017;7:25.
24. Fassnacht M, Berruti A, Baudin E, Demeure MJ, Gilbert J, Haak H, et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol 2015;16:426-35.
25. O’Sullivan C, Edgerly M, Velarde M, Wilkerson J, Venkatesan AM, Pittaluga S, et al. The VEGF inhibitor axitinib has limited effectiveness as a therapy for adrenocortical cancer. J Clin Endocrinol Metab 2014;99:1291-7.
26. Riesco-Martinez MC, Capdevila J, Alonso V, Jimenez-Fonseca P, Teule A, Grande E, et al. Nivolumab plus platinum-doublet chemotherapy in treatment-naive patients with advanced grade 3 Neuroendocrine Neoplasms of gastroenteropancreatic or unknown origin: the multicenter phase 2 NICE- NEC trial (GETNE-T1913). Nat Commun 2024;15:6753.
27. Capdevila J, Hernando J, Teule A, Lopez C, Garcia-Carbonero R, Benavent M, et al. Durvalumab plus tremelimumab for the treatment of advanced neuro- endocrine neoplasms of gastroenteropancreatic and lung origin. Nat Commun 2023;14:2973.
28. Yao JC, Strosberg J, Fazio N, Pavel ME, Bergsland E, Ruszniewski P, et al. Spartalizumab in metastatic, well/poorly-differentiated neuroendocrine neo- plasms. Endocr Relat Cancer 2021;28:161-72.
29. Girard N, Mazieres J, Otto J, Lena H, Lepage C, Egenod T, et al. LBA41 Nivolumab (nivo) ± ipilimumab (ipi) in pre-treated patients with advanced, refractory pulmonary or gastroenteropancreatic poorly differentiated neuro- endocrine tumors (NECs) (GCO-001 NIPINEC). Ann Oncol 2021;32(suppl 5): S1318.
30. Strosberg J, Mizuno N, Doi T, Grande E, Delord J-P, Shapira-Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced neuroendocrine tumors: results from the phase II KEYNOTE-158 study. Clin Cancer Res 2020;26:2124-30.
31. Patel SP, Othus M, Chae YK, Giles FJ, Hansel DE, Singh PP, et al. A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART SWOG 1609) in patients with nonpancreatic neuroendocrine tumors. Clin Cancer Res 2020;26:2290-6.
32. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929-39.
33. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220-9.
34. Rahma OE, Tyan K, Giobbie-Hurder A, Brohl AS, Bedard PL, Renouf DJ, et al. Phase IB study of ziv-aflibercept plus pembrolizumab in patients with ad- vanced solid tumors. J Immunother Cancer 2022;10:e003569.
35. Agarwal N, McGregor B, Maughan BL, Dorff TB, Kelly W, Fang B, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Lancet Oncol 2022;23: 899-909.
36. Dierks C, Seufert J, Aumann K, Ruf J, Klein C, Kiefer S, et al. Combination of lenvatinib and pembrolizumab is an effective treatment option for anaplastic and poorly differentiated thyroid carcinoma. Thyroid 2021;31: 1076-85.
37. Ren Z, Xu J, Bai Y, Xu A, Cang S, Du C, et al. Sintilimab plus a bevacizumab biosimilar (IBI305) versus sorafenib in unresectable hepatocellular carcinoma (ORIENT-32): a randomised, open-label, phase 2 to 3 study. Lancet Oncol 2021;22:977-90.
38. Finn RS, Ikeda M, Zhu AX, Sung MW, Baron AD, Kudo M, et al. Phase Ib study of lenvatinib plus pembrolizumab in patients with unresectable hepa- tocellular carcinoma. J Clin Oncol 2020;38:2960-70.
39. García-Aranda M, Redondo M. Targeting protein kinases to enhance the re- sponse to anti-PD-1/PD-L1 immunotherapy. Int J Mol Sci 2019;20:2296.
40. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-47.
41. Filetti S, Durante C, Hartl DM, Leboulleux S, Locati LD, Newbold K, et al. ESMO Clinical Practice Guideline update on the use of systemic therapy in advanced thyroid cancer. Ann Oncol 2022;33:674-84.
42. Haddad RI, Nasr C, Bischoff L, Busaidy NL, Byrd D, Callender G, et al. NCCN Guidelines insights: thyroid carcinoma, version 2.2018. J Natl Compr Cancer Netw 2018;16:1429-40.
43. Capdevila J, Wirth LJ, Ernst T, Ponce Aix S, Lin C-C, Ramlau R, et al. PD-1 blockade in anaplastic thyroid carcinoma. J Clin Oncol 2020;38:2620-7.
44. Capdevila J, Plana M, Castelo B, Iglesias L, Hernando J, Tur RY, et al. 1645O Durvalumab (D) plus tremelimumab (T) for the treatment of patients with progressive, refractory advanced thyroid carcinoma: The DUTHY (GETNE- T1812) trial. Ann Oncol 2022;33(suppl 7):S1294-5.
45. Fassnacht M, Terzolo M, Allolio B, Baudin E, Haak H, Berruti A, et al. Combination chemotherapy in advanced adrenocortical carcinoma. N Engl J Med 2012;366:2189-97.
46. Henning JEK, Deutschbein T, Altieri B, Steinhauer S, Kircher S, Sbiera S, et al. Gemcitabine-based chemotherapy in adrenocortical carcinoma: a multicenter study of efficacy and predictive factors. J Clin Endocrinol Metab 2017;102: 4323-32.
47. Sperone P, Ferrero A, Daffara F, Priola A, Zaggia B, Volante M, et al. Gem- citabine plus metronomic 5-fluorouracil or capecitabine as a second-/third- line chemotherapy in advanced adrenocortical carcinoma: a multicenter phase II study. Endocr Relat Cancer 2010;17:445-53.
48. Carneiro BA, Konda B, Costa RB, Costa RLB, Sagar V, Gursel DB, et al. Nivolumab in metastatic adrenocortical carcinoma: results of a phase 2 trial. J Clin Endocrinol Metab 2019;104:6193-200.
49. Le Tourneau C, Hoimes C, Zarwan C, Wong DJ, Bauer S, Claus R, et al. Avelumab in patients with previously treated metastatic adrenocortical car- cinoma: phase 1b results from the JAVELIN solid tumor trial. J Immunother Cancer 2018;6:111.
50. Habra MA, Stephen B, Campbell M, Hess K, Tapia C, Xu M, et al. Phase II clinical trial of pembrolizumab efficacy and safety in advanced adrenocortical carcinoma. J Immunother Cancer 2019;7:253.
51. Raj N, Zheng Y, Kelly V, Katz SS, Chou J, Do RKG, et al. PD-1 blockade in advanced adrenocortical carcinoma. J Clin Oncol 2020;38:71-80.
52. Zhu Y-C, Wei Z-G, Wang J-J, Pei Y-Y, Jin J, Li D, et al. Camrelizumab plus apatinib for previously treated advanced adrenocortical carcinoma: a single- arm phase 2 trial. Nat Commun 2024;15:10371.
53. Jimenez C, Habra MA, Campbell MT, Tamsen G, Cruz-Goldberg D, Long J, et al. Cabozantinib in patients with unresectable and progressive metastatic phaeochromocytoma or paraganglioma (the Natalie Trial): a single-arm, phase 2 trial. Lancet Oncol 2024;25:658-67.
54. Baudin E, Goichot B, Berruti A, Hadoux J, Moalla S, Laboureau S, et al. Sunitinib for metastatic progressive phaeochromocytomas and para- gangliomas: results from FIRSTMAPPP, an academic, multicentre, interna- tional, randomised, placebo-controlled, double-blind, phase 2 trial. Lancet Lond Engl 2024;403:1061-70.
55. Hassan Nelson L, Fuentes-Bayne H, Yin J, Asmus E, Ryder M, Morris JC, et al. Lenvatinib as a therapeutic option in unresectable metastatic pheochromo- cytoma and paragangliomas. J Endocr Soc 2022;6:bvac044.
56. Weber MMM, Apostolidis L, Krug S, Rinke A, Gruen B, Michl P, et al. 1185MO Activity and safety of avelumab alone or in combination with cabozantinib in patients with advanced high grade neuroendocrine neoplasias (NEN G3) progressing after chemotherapy. The phase II, open-label, multi- center AVENEC and CABOAVENEC trials. Ann Oncol 2023;34(suppl 2): S702.
57. Halperin DM, Liu S, Dasari A, Fogelman D, Bhosale P, Mahvash A, et al. Assessment of clinical response following atezolizumab and bevacizumab treatment in patients with neuroendocrine tumors: a nonrandomized clinical trial. JAMA Oncol 2022;8:904-9.
58. Neal J, Pavlakis N, Kim S-W, Goto Y, Lim SM, Mountzios G, et al. CON- TACT-01: a randomized phase III trial of atezolizumab + cabozantinib versus docetaxel for metastatic non-small cell lung cancer after a checkpoint inhib- itor and chemotherapy. J Clin Oncol 2024;42:2393-403.
59. Neal JW, Santoro A, Viteri S, Ponce Aix S, Fang B, Lim FL, et al. Cabozantinib (C) plus atezolizumab (A) or C alone in patients (pts) with advanced non- small cell lung cancer (aNSCLC) previously treated with an immune check- point inhibitor (ICI): results from Cohorts 7 and 20 of the COSMIC-021 study. J Clin Oncol 2022;40(suppl 16):9005.
60. Tabernero J, Andre F, Blay J-Y, Bustillos A, Fear S, Ganta S, et al. Phase II multicohort study of atezolizumab monotherapy in multiple advanced solid cancers. ESMO Open 2022;7:100419.