CLO20-054: A Phase 2 Trial of Nivolumab and Temozolomide in Advanced Neuroendocrine Tumors (NETs): Interim Efficacy Analysis

Owen, Dwight H.; Wei, Lai; Goyal, Ashima; Zhou, Ye; Suffren, Sheryl‐Ann; Jacob, Rajani; Pilcher, Carly; Verschraegen, Claire F.; Shah, Manisha H.; Konda, Bhavana

doi:10.6004/jnccn.2019.7460

Cited by 10 publications

(7 citation statements)

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“…The anti-PD-1 antibody nivolumab was tested in combination with temozolomide in a phase II multi-cohort study of patients with well-differentiated NETs and small-cell lung cancer. 64 The scientific basis behind this combination arises from the antigen-presenting cell priming capacity of temozolomide, in certain dose administrations. 65 Theoretically, this improved activation of antigen-presenting cells would synergize with anti-PD-1 checkpoint inhibitors which improve T-cell infiltration into the tumor microenvironment.…”

Section: Immunotherapy Agentsmentioning

confidence: 99%

Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors

Das

Dasari

2021

Ther Adv Med Oncol

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Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs) represent the most common subtype of NETs. The incidence of all NETs, and specifically GEP NETs, has risen exponentially over the last three decades. Only within the past several years have these tumors been appropriately classified, allowing for meaningful drug development. Broadly, some of the most exciting drug classes being developed for patients with well-differentiated GEP NETs include newer types of peptide receptor radionuclide therapy (PRRT) or combinations which increase the potency of lutetium-177 (177Lu)-Dotatate, novel multi-target receptor tyrosine kinase inhibitors (RTKIs) and immunotherapy modalities, beyond checkpoint inhibitors, which seek to unleash the immune system against NETs. Specifically looking at newer types of PRRT, somatostatin receptor antagonists and alpha-emitter radionuclides each have demonstrated the ability to elicit greater DNA damage than 177Lu-Dotatate in preclinical models. Early clinical experiences with each of these agents suggest they may be more cytotoxic than 177Lu-Dotatate. Other approaches seeking to build upon the DNA damage created by 177Lu-Dotatate include combinations of PRRT with radiosensitizers such as heat shock protein 90 inhibitors, hedgehog inhibitors, chemotherapy combinations, and triapine. Many of these combinations have just begun to be tested clinically. With regards to novel RTKIs, some of the ones which have demonstrated potent cytoreductive potential include cabozantinib and lenvatinib. Other RTKIs which are further along the clinical development spectrum and have demonstrated benefit in randomized trials include surufatinib and pazopanib. And though single-agent immune checkpoint inhibitors have not demonstrated significant anti-tumor activity in patients with GEP NETs, outside of certain biomarker selected subsets, somatostatin receptor-directed chimeric antigen receptor (CAR) T cells and vaccines such as SurVaxM, which targets survivin, represent two means through which NET-directed immunity may be modulated. The potential of these agents, if clinically realized, will likely improve outcomes for patients with well-differentiated GEP NETs.

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Section: Immunotherapy Agentsmentioning

confidence: 99%

Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors

Das

Dasari

2021

Ther Adv Med Oncol

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“…Four analyses report a clinical benefit rate (CBR) > 30% [51][52][53][54]. The first [51] is derived from NCT03043664, which investigates pembrolizumab plus SRLs in 22 patients with low/intermediate grade GEP-NETs.…”

Section: Future Perspective In Gep-nensmentioning

confidence: 99%

“…Relevant antitumor activity was also described for avelumab, tested in 29 patients [52] deriving from NCT03352934, with either NEC or NET (mostly GEP), that obtained a disease control rate (DCR) of 32%. Nivolumab combined with temozolomide showed promising results in an interim analysis [53] from NCT03728361: out of 12 patients (7 GEP-NETs and 5 pulmonary carcinoids) 25% showed partial response (PR), 67% SD and 8% progressive disease (PD), although the median follow-up was short (approximately 7 months) and the cohort very limited. Lastly, according to an interim analysis [54] from NCT03365791, spartalizumab, administered with LAG525 (an antibody to LAG-3), achieved an astounding 86% of clinical benefit rate at 24 weeks in a GEP-NET cohort.…”

Section: Future Perspective In Gep-nensmentioning

confidence: 99%

"Present and future of immunotherapy in Neuroendocrine Tumors"

Albertelli

Dotto

Nista

et al. 2021

Rev Endocr Metab Disord

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Immunotherapy, so promising in many neoplasms, still does not have a precise role in the treatment of neuroendocrine neoplasms (NENs). In this article, we provide an overview on the current knowledge about immunotherapy with immune checkpoint inhibitors (ICIs) applied to NENs, evaluating future perspectives in this setting of tumors.Evidence so far available for ICIs in gastroenteropancreatic (GEP)-NENs is definitively not as robust as for other tumors such as Small Cell Lung Cancer or Merkel Cell Carcinoma. In fact, with regard to the well-differentiated forms of NENs (NETs), the results obtained nowadays have been disappointing. However, the near future, might reserve interesting results for ICIs in GEP-NEN from a total of nine different ICI drugs, used throughout 19 randomised controlled trials. Such numbers highlight the growing attention gathering around NENs and ICIs, in response to the need of stronger evidences supporting such therapy.For the future, the most important aspect will be to study strategies that can make NETs more susceptible to response to ICI and, thus, enhance the effectiveness of these treatments. Therefore, the combination of conventional therapy, target therapy and immunotherapy deserve attention and warrant to be explored. A sequential chemotherapy, possibly inducing an increase in tumor mutational burden and tested before immunotherapy, could be a hypothesis deserving more consideration. A radiation treatment that increases tumor-infiltrating lymphocytes, could be another approach to explore before ICIs in NENs. Equally essential will be the identification of biomarkers useful for selecting patients potentially responsive to this type of treatment.

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“…A multi-cohort phase II trial explored the antitumor activity of the combination of temozolomide with the checkpoint inhibitor nivolumab [ 83 ]. The possible synergy between the agents stems from the ability of temozolomide to increase the activation of antigen-presenting cells.…”

Section: Combinatorial Approaches With Chemotherapymentioning

confidence: 99%

Chemotherapy in Neuroendocrine Tumors

Das

Al‐Toubah

Strosberg

2021

Cancers

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The role for cytotoxic chemotherapy in patients with well-differentiated neuroendocrine tumors (NETs) remains debated. Compared to patients with poorly differentiated neuroendocrine carcinomas (NECs) where chemotherapy is utilized ubiquitously, chemotherapy may play a more select role in patients with certain types of NETs (e.g., pancreatic tumors, higher grade tumors, and tumors possessing DNA damage repair defects). The primary types of chemotherapy that have been tested in patients with NETs include alkylating agent- and platinum agent-based combinations. Across regimens, chemotherapy appears to elicit greater antitumor activity in patients with pancreatic or grade 3 NETs. The role for chemotherapy in lower grade extra-pancreatic NETs remains undefined. Furthermore, while chemotherapy has demonstrated clinically meaningful benefit for patients in the systemic setting, its role in the adjuvant or neoadjuvant setting is as-of-yet undetermined. Finally, efforts to combine chemotherapy with targeted therapy and peptide receptor radionuclide therapy are ongoing, in hopes of improving the cytoreductive treatment options for patients with NETs.

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CLO20-054: A Phase 2 Trial of Nivolumab and Temozolomide in Advanced Neuroendocrine Tumors (NETs): Interim Efficacy Analysis

Cited by 10 publications

References 0 publications

Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors

Novel therapeutics for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors

"Present and future of immunotherapy in Neuroendocrine Tumors"

Chemotherapy in Neuroendocrine Tumors

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