Neoplasms

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Rare Diseases

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Avelumab

Antineoplastic Agents, Immunological

800 mg Avelumab every 2 weeks and 40 mg Cabozantinib daily

Cabozantinib 40 mg daily PO in combination with Avelumab at a dose of 800 mg as a 1h intravenous (i.v.) infusion every two weeks (q2w) until disease progression (PD), unacceptable toxicity, or any criterion for treatment withdrawalis met, for a maximum of 12 months

combination of Avelumab and Cabozantinib

Matthias M Weber, MD

The purpose of the CaboAveNEC trial is to investigate the clinical activity and safety of Cabozantinib in combination with avelumab in patients refractory to standard chemotherapy with advanced neuroendocrine neoplasias G3 (NEN G3).

According to the WHO classification of 2010, Neuroendocrine neoplasms (NEN) are graded according to the Ki67 proliferation index and grouped into neuroendocrine Tumors (NET) Grade 1 (NET G1, Ki67 \<3%), NET G2 (Ki67 3-20%), and neuroendocrine Carcinomas (NEC) (G3, Ki67 \>20%). However, since the WHO 2017/2019 classification the group of gastrointestinal neuroendocrine tumors with a Ki67 ≥20% (NEN G3) is subdivided according to their morphology into highly proliferative differentiated NET G3 and poorly differentiated high grade neuroendocrine Carcinomas (NEC G3, Ki67 \> 20%), which - depending on their morphology - are subdivided into small cell as well as large cell NECs. The vast majority (60-90%) of patients with high grade NEC are metastasized at the time of diagnosis with distant metastases present in approximately two third of the patients.

The prognosis of patients with metastatic NEN G3 is poor, and median overall survival has been reported to be 5 months with a 2-year survival rate of 11 % in the SEER data base for gastrointestinal NEC. In two large series of GEP-NEC, median survival was 12-19 months for patients with best available therapy (mainly platinum based chemotherapy) and as short as 1 month for those receiving only best supportive therapy. In contrast to the "classical" undifferentiated NEC G3 with a poorly differentiated morphology and a Ki 67 \> 55%, NET G3 typically do not respond as well to a platinum based chemotherapy but a have a somewhat better prognosis with a 4-months longer median survival as compared to classical NEC G3. Therefore, according to current guidelines other treatment options like temozolomide based chemotherapy may be considered as a first line therapy in patients with differentiated "NET G3".

There is a strong and unmet medical need for a novel and effective second line treatment option for these highly aggressive and rapidly progressing tumors.

Considering the lack of any other established therapeutic option and the very limited efficacy of alternative second or third line chemotherapy in patients with NEN G3 who are progressive after a first-line chemotherapy, the availability of a novel therapeutic option with a significant clinical benefit (SD; PR; CR) in at least 40 % of the patients and with tolerable side effects would represent an important and clinical highly relevant break through in the treatment of these aggressive tumors.

Avelumab is a fully human antibody that binds PD-L1 and blocks the interaction between PD-L1 and PD-1. This removes the suppressive effect of PD-L1 on anti-tumor CD8+ T cells, resulting in restoration of cytotoxic T cell response.

In the ongoing phase II trial of the investigator (AveNEC, EudraCT No: 2016-004373-40), which is the largest immunotherapy trial in patients with NEN G3, the clinical activity and safety of the PD-L1 inhibitor avelumab is evaluated in 60 patients with advanced, metastatic NEN G3 progressive after chemotherapy. According to the interim analysis presented at ASCO 2019 a clinically meaningful response was seen in 27 % of patients with a significant longer progression free survival (mean PFS 33.5 vs 7.7 weeks) and overall survival (\> 60 weeks mean not reached vs 22.4 weeks) as compared to the non-responders.

Cabozantinib is a multikinase inhibitor of MET, VEGFR, AXL and RET which is currently being used very successfully in medullary thyroid carcinoma (MTC), which is a differentiated neuroendocrine neoplasia, in advanced renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC).

In addition to its TKI activity, there is strong evidence that Cabozantinib modulates the tumor immune microenvironment leading to a synergistic efficacy in combination with a checkpoint inhibitor therapy.

There is an especially strong rationale for a combination therapy of the potent antiangiogenic TKI Cabozantinib with the checkpoint inhibitor Avelumab in NEN G3. Both drugs have demonstrated efficacy and safety in combination therapy studies of a checkpoint inhibitor and an antiangiogenic TKI in a variety of tumors and both drugs in monotherapy have shown clinical relevant antitumor efficacy in NEN.

Cabozantinib in Combination With Avelumab in Patients Refractory to Standard Chemotherapy With Advanced Neuroendocrine Neoplasias G3 (NEN G3)

A Phase II, Open-label, Multicenter Trial to Investigate the Clinical Activity and Safety of Cabozantinib in Combination With Avelumab in Patients Refractory to Standard Chemotherapy With Advanced Neuroendocrine Neoplasias G3 (NEN G3).

Correlation of the primary and secondary endpoints with the differentiation of the NEN G3 (NET G3 vs NEC) and tumor immune microenvironment (e.g. PD-L1 expression, TIL)

Comparison of the efficacy and tolerability of the combination treatment with Cabozantinib and Avelumab to the monotherapy with Avelumab in the AveNEC trial (EudraCT No.: 2016-004373-40)

Evaluation of tumor growth rate (TGR): TGR is the percentage change in tumour volume over one month

Disease control rate (DCR: CR, PR, SD) according to iRECIST after 16 weeks from start of treatment until documented disease progression (PD)

Disease control rate (DCR: CR, PR, SD) according to iRECIST

Objective response rate (ORR) according to iRECIST

Best overall response (BOR) according to iRECIST

Duration of disease control (DDC) according to iRECIST

Time to response (TTR) according to iRECIST

Progression-free survival time (PFS) according to iRECIST

Evaluation of tumor response according to RECIST1.1

Quality of life (QoL) assessed by European Organisation for Research and Treatment of Cancer Quality of life questionnaire (EORTC QLQ-C30); Scale 0 - 100; higher levels indicate better quality of life

Number, severity, and duration of treatment-emergent AEs according to NCI-CTCAE v5.0

Treatment interruption or termination of study drugs due to adverse events

Spots Global Cancer Trial Database for combination of avelumab and cabozantinib