Discussion
oesophageal cancer, toxicity, toxicities, tumours, rash, tumour, myelosuppression, ATM, oesophageal stricturing, Oesophageal cancer
ESOPHAGEAL CANCER, SOLID TUMOUR, OESOPHAGEAL CANCER, TUMOURS, DNA DAMAGE, ADVERSE EVENT, TUMOUR
The conventional chemoradiotherapy for oesophageal cancer can result in considerable treatment-related side effects, however, a complete clinical response is achieved only in a minority of patients (30%) [Recently, radiotherapy in combination with radiosensiters such as PARP inhibitors and immunotherapy have been investigated in oesophageal cancer, indicating a shift towards investigating novel drug-radiotherapy combinations [In this study, we evaluated two dose escalation cohorts, cohort A1, the combination of berzosertib with palliative radiotherapy in advanced oesophageal cancer and cohort A2, the combination of berzosertib with cisplatin and capecitabine in patients with any solid tumour as a preamble to testing in the definitive setting for chemoradiation in oesophageal cancer.Berzosertib has previously been shown to be safe and well tolerated alone and in combination with a variety of DNA-damaging cytotoxic drugs [Overall, the combination of berzosertib with radiotherapy was considered well tolerated as there were no exacerbations of lung, cardiac or oesophageal toxicities seen due to local thoracic treatment despite some subjects incurring large volumes of thorax being irradiated. A maculopapular rash was the only serious adverse event that was considered possibly related to berzosertib. This was transient and resolved following administration of topical medications.The majority of patients in A1 (81%) had received at least one line of prior systemic treatment, including checkpoint immunotherapy in two cases due to prior participation in a separate clinical trial. Median overall survival observed for first-line therapy in the treatment of advanced oesophageal cancer varies between 9 and 14 months [Cohort A2 evaluated the combination of cisplatin, capecitabine and berzosertib with a view to informing dosing for a future chemo-radiotherapy combination study with berzosertib in oesophageal cancer. Expected mechanism-based myelosuppression was the predominant toxicity and two patients experienced dose limiting toxicities. The recommended phase II dosing schedule was determined to be cisplatin 60 mg/mIdentifying biomarkers for selection of patients to target tumours harbouring ATM truncating mutations or ATM protein loss, TP53 mutations, BRCA1 or BRCA2 mutations, or other alterations conferring homologous recombination repair deficiency is key for treatment success. Oesophageal cancer is a top candidate as it has been shown that accumulated DNA Damage repair (positive staining for γH2AX and phospho-ATM) was evident within tumour tissue and significantly increased in non-malignant tissue surrounding the tumour cells although activation of p53 by phosphorylation at serine 15 was observed only in tumour tissue ([This study has several limitations. Firstly, the small number recruited and the absence of pharmacodynamic data makes it challenging to precisely understand the radiation dose-response relationship of berzosertib. As often in phase I studies the absence of comparative arms involving chemotherapy, ATR inhibition, or radiation therapy hinders our ability to make direct comparisons among these treatment modalities. Lastly, late toxicities due to chemoradiation such as oesophageal stricturing were not assessed beyond the 12-week follow-up.To address these limitations and refine the understanding of the optimal combination of systemic therapy, ATR inhibition, and radiation therapy in curative radiotherapy setting, further dose-finding investigations are warranted.In summary, this study is the first clinical trial to evaluate the combination of an ATR inhibitor with radiotherapy. Berzosertib is well tolerated when scheduled with radiotherapy and encouraging clinical activity was observed. We consider that further clinical study is warranted, including combination with chemo-radiotherapy.