Targeting Replication Stress and Chemotherapy Resistance with a Combination of Sacituzumab Govitecan and Berzosertib: A Phase I Clinical Trial

Abstract

Purpose: Despite promising preclinical studies, toxicities have precluded combinations of chemotherapy and DNA damage response (DDR) inhibitors. We hypothesized that tumor-targeted chemotherapy delivery might enable clinical translation of such combinations.

Patients and methods: In a phase I trial, we combined sacituzumab govitecan, antibody-drug conjugate (ADC) that delivers topoisomerase-1 inhibitor SN-38 to tumors expressing Trop-2, with ataxia telangiectasia and Rad3-related (ATR) inhibitor berzosertib. Twelve patients were enrolled across three dose levels.

Results: Treatment was well tolerated, with improved safety over conventional chemotherapy-based combinations, allowing escalation to the highest dose. No dose-limiting toxicities or clinically relevant ≥grade 4 adverse events occurred. Tumor regressions were observed in 2 patients with neuroendocrine prostate cancer, and a patient with small cell lung cancer transformed from EGFR-mutant non-small cell lung cancer.

Conclusions: ADC-based delivery of cytotoxic payloads represents a new paradigm to increase efficacy of DDR inhibitors. See related commentary by Berg and Choudhury, p. 3557.

Figure 1.

Trial design and safety of sacituzumab govitecan and berzosertib combination. A: Trial design and dose escalation schema. B: Adverse events, labeled as red for grade 1–2 and dark red for grade 3–4[25]. C: Blood cell count trends for all patients across cycle 1, showing minimal hematologic toxicity related to treatment.

Figure 2.

Efficacy of sacituzumab govitecan and berzosertib combination. A: Tumor responses based on maximum change in tumor dimensions from baseline. Each bar represents a patient’s tumor response, corresponding with the assigned patient number. Patients who experienced a partial response per RECIST criteria are annotated in blue, and those with a metabolic response on PET imaging are annotated in red. B: Efficacy based on duration of response, including timing of partial responses, indicated with a yellow diamond, when applicable. C: Efficacy based on change in tumor dimensions from baseline over time. D. Patient 1 with NEPC experienced a partial response, with yellow arrows annotating target lesions. E: Patient 8 with SCLC transformed from EGFR-mutated NSCLC experienced a partial response with a decrease in size of multiple lung masses, as indicated by yellow arrows. F: Patient 11 with de novo NEPC had a metabolic response to therapy across many metastatic sites as shown on PET imaging. SLD: sum of the total diameter of target lesions PR: Partial Response per RECIST criteria PANC = pancreatic adenocarcinoma, COLON = colon adenocarcinoma, ACC = adrenocortical carcinoma, SCLC = small cell lung cancer, NSCLC = non-small cell lung cancer, t-SCLC = SCLC transformed from NSCLC, NEPC = neuroendocrine prostate cancer, HGNEC = high grade neuroendocrine carcinoma

Figure 3.

Predictors of benefit to sacituzumab govitecan and berzosertib combination A: RNA sequencing of tumors from patients with clinical benefit (n=2) and without clinical benefit (n=5). GSEA using the Hallmark signature showed that tumors with clinical benefit were enriched for genes associated with replication stress and proliferation and were de-enriched for immune and inflammatory pathways. B: GSEA using the Hallmarks of Cancers signature showing that tumors with clinical benefit were enriched for pathways associated with genome instability. C: Summary of whole exome sequencing results. Blue squares indicate presence of a gene mutation in tumor tissue, with germline mutations indicated by a yellow asterisk. D. Trop-2 IHC from Patient 8 with SCLC transformed from EGFR-mutated NSCLC showed minimal expression. Patients 11 (E) and 1 (F) with NEPC both had IHC with high Trop2 expression. GSEA: gene set enrichment analysis NES: normalized enrichment score SCLC: small cell lung cancer NSCLC: non-small cell lung cancer t-SCLC: transformed SCLC