Targeting genomic instability in extrapulmonary small cell neuroendocrine cancers: A phase II study with ATR inhibitor berzosertib and topotecan.

Abstract

8518 Background: Extra-pulmonary small cell neuroendocrine cancers (EP-SCNC) are rare cancers with no standard treatments at relapse that share molecular similarities with small cell lung cancer (SCLC). Concurrent inhibition of ataxia telangiectasia and Rad3 related (ATR) and topoisomerase 1, key enzymes for maintaining genomic stability, exacerbated replication stress in SCLC cells and produced durable antitumor responses in patients with relapsed SCLC (Cancer Cell 2021; PMID: 33848478). Methods: Combination of berzosertib and topotecan was evaluated in patients with relapsed EP-SCNC (NCT02487095). Berzosertib was administered at 210 mg/m2 on days 2 and 5 and topotecan 1.25 mg/m2 on days 1-5 in 21-day cycles. Whole exome sequencing (WES) and transcriptome analyses were performed to assess the genomic features associated with response. Results: Fifteen patients with EP-SCNC involving various primary sites were enrolled [three each: cervix, transformed SCLC; two each: bladder, breast, prostate; one each: gallbladder, ovary, rectum]. Two patients (13.3%: breast and rectum) achieved a confirmed partial response (PR; -72.2% and -48.5% tumor reduction in size) lasting 6.9 and 5.8 months. Responses occurred irrespective of platinum-sensitivity or prior treatment with topotecan or immunotherapy. Pre-treatment tumor gene expression profiles of EP-SCNC patients who achieved clinical benefit revealed enrichment of neuroendocrine differentiation (normalized enrichment score and p-value of a gene set enrichment analysis: 2.1 and 2.1 x 10-4). Principal component analysis showed convergent gene expression profiles of both SCLC and EP-SCNC patients who achieved PR. Pre-treatment tumor of a breast small cell cancer patient who achieved durable response revealed amplifications of multiple genes driving replication stress such as KRAS and CCND1. Longitudinal tumor sampling of the patient through treatment course revealed increasing intra-tumor heterogeneity as a potential resistant mechanism. Conclusions: Combination of berzosertib and topotecan is a novel therapeutic paradigm for patients with EP-SCNCs. Both SCLCs and EP-SCNCs responding to this approach show a similar transcriptional phenotype characterized by high replication stress. Clinical trial information: NCT02487095.