2023 World Conference on Lung Cancer (Posters)-EP13.05. Temozolomide-associated Hypermutation and Response to Immunotherapy in Advanced Pulmonary Neuroendocrine Tumors.

EP13.05. Temozolomide-associated Hypermutation and Response to Immunotherapy in Advanced Pulmonary Neuroendocrine Tumors. - PDF(Abstract)

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This presentation at the WCLC 2023 conference discusses a study on the response to immunotherapy in patients with advanced pulmonary neuroendocrine tumors (PNET) who have been treated with temozolomide (TEM). It is well known that TEM has clinical activity in PNET, but the therapy for advanced well differentiated PNET remains ill defined. The cytotoxicity of TEM depends on an intact DNA mismatch repair pathway and low levels of O6-methylguanine DNA methyltransferase (MGMT). The absence of MGMT-mediated repair coupled with defective DNA mismatch repair (dMMR) can lead to a resistance mechanism called TEM-associated hypermutation, where there is an increase in tumor mutational burden (TMB) and a loss of TEM-induced cytotoxicity. However, this hypermutation may make the tumors sensitive to immunotherapy with checkpoint inhibitors. <br /><br />The study performed whole genome sequencing in a single center on five patients with atypical carcinoid PNET who were treated with a combination of capecitabine (CAP) and TEM. Four patients did not show a typical enrichment of C:G to A:T transition pattern, but one patient did exhibit TEM-associated hypermutation. This patient had a very high tumor mutational load and was treated with pembrolizumab, a checkpoint inhibitor, resulting in stable disease as the best response. The treatment is still ongoing and further exploration of the resistance mechanism will be conducted in these patients.<br /><br />The study aims to expand the series of patients to gain a better understanding of the occurrence of TEM-associated hypermutation and the effect of checkpoint inhibition in pulmonary neuroendocrine tumors. Overall, this study suggests that TEM-associated hypermutation may occur in a subset of PNET patients and that immunotherapy with checkpoint inhibitors can have a modest benefit in these cases. Further research is needed to fully understand and explore this resistance mechanism.

Asset Subtitle

Wieneke Buikhuisen

Meta Tag

Speaker Wieneke Buikhuisen

Topic SCLC & Neuroendocrine Tumors: NETs

Keywords

WCLC 2023 conference

immunotherapy response

advanced pulmonary neuroendocrine tumors

temozolomide treatment

well differentiated PNET

DNA mismatch repair pathway

O6-methylguanine DNA methyltransferase

TEM-associated hypermutation

tumor mutational burden

checkpoint inhibitors