Phase I clinical and translational evaluation of AZD6738 in combination with durvalumab in patients (pts) with lung or head and neck carcinoma

Krebs, Matthew; Lopez, Juanita; El-Khoueiry, Anthony B.; Bang, Yung‐Jue; Postel-Vinay, Sophie; Abidah, W.; Im, Seock‐Ah; Khoja, Leila; Standifer, Nathan; Jones, Gemma N.; Marco-Casanova, Paola; Frewer, Paul; Berges, Aliénor; Cheung, A.; Stephens, C.; Felicetti, B.; Dean, Emma; Pierce, Andrew J.; Hollingsworth, Simon J.

doi:10.1093/annonc/mdy279.401

Cited by 6 publications

(3 citation statements)

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“…Based on these data, in-vitro sensitivity was assessed using cell viability assays after a selection of PDCLs were treated with increasing doses of inhibitors of CHK1 (AZD7762), CDK4/6 (Palbociclib) and PLK4 (CFI-400945) demonstrating differential sensitivity ( Supplementary Figure 4). Based on promising early clinical trial results in other cancer types [37][38][39][40][41][42] , more extensive testing using inhibitors of ATR (AZD6738) and WEE1 (AZD1775) was performed on 15 PDCLs defined as high and low replication stress based on the replication stress signature score ( Figure 3a, Supplementary Figure 4). This demonstrated that PDCLs with high replication stress were more sensitive to both ATR and WEE1 inhibition (Figure 4c-f).…”

Section: Replication Stress Is Associated With Sensitivity To Cell Cymentioning

confidence: 99%

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Dreyer

Upstill-Goddard

Paulus-Hock³

et al. 2019

Preprint

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Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting the DNA damage response (DDR) and replication stress. We show that patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum and PARP inhibitor therapy in vitro and in vivo. We generated a novel signature of replication stress with potential clinical utility in predicting response to ATR and WEE1 inhibitor treatment. Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy.

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Section: Replication Stress Is Associated With Sensitivity To Cell Cymentioning

confidence: 99%

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Dreyer

Upstill-Goddard

Paulus-Hock³

et al. 2019

Preprint

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“…In an ongoing phase I study (NCT02264678), ATR inhibitor AZD6738 (ceralasertib) is being tested in combination with anti‐PD‐L1 antibody durvalumab for treatment‐refractory HNSCC. In an interim analysis reported at the 43rd ESMO Congress, investigators reported one response in a HNSCC patient 187 . A recently completed phase I biomarker study evaluated AZD6738 with the poly‐ADP ribose polymerase (PARP) inhibitor olaparib administered before surgery for HNSCC, but results have not yet been reported 188 .…”

Section: Clinical Trials Investigating Atr Inhibition In Hnsccmentioning

confidence: 99%

Pharmacologic inhibition of ataxia telangiectasia and Rad3‐related (ATR) in the treatment of head and neck squamous cell carcinoma

Karukonda

Odhiambo

Mowery

2021

Molecular Carcinogenesis

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Head and neck squamous cell carcinoma (HNSCC) poses significant treatment challenges, with high recurrence rates for locally advanced disease despite aggressive therapy typically involving a combination of surgery, radiation therapy, and/or chemotherapy. HNSCCs commonly exhibit reduced or absent TP53 function due to genomic alterations or human papillomavirus (HPV) infection, leading to dependence on the S‐ and G2/M checkpoints for cell cycle regulation. Both of these checkpoints are activated by Ataxia Telangiectasia and Rad3‐related (ATR), which tends to be overexpressed in HNSCC relative to adjacent normal tissues and represents a potentially promising therapeutic target, particularly in combination with other treatments. ATR is a DNA damage signaling kinase that is activated in response to replication stress and single‐stranded DNA breaks, such as those induced by radiation therapy and certain chemotherapies. ATR kinase inhibitors are currently being investigated in several clinical trials as part of the management of locally advanced, recurrent, or metastatic HNSCC, along with other malignancies. In this review article, we summarize the rationale and preclinical data supporting incorporation of ATR inhibition into therapeutic regimens for HNSCC.

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“…AZD6738 was combined with the PD-L1 inhibitor durvalumab in a multicohort trial. Twenty five patients with either nonsmall cell lung cancer or HNSCC were enrolled in the trial and 1 response was seen in a HNSCC patient [47]. A phase 1 trial of the ATR inhibitor VX970 also known as M6620 in combination with cisplatin and radiation is currently underway enrolling clinical stage III or IV HNSCC (NCT02567422).…”

Section: Dna Repair Inhibitorsmentioning

confidence: 99%

New and Promising Targeted Therapies in First and Second-Line Settings

Roden

Johnson

Szturz

et al. 2021

Critical Issues in Head and Neck Oncology

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Deeper understanding of the molecular pathogenesis of malignancies, including head and neck squamous cell carcinoma (HNSCC), has led to the investigation of several novel targeted therapies. These therapeutic approaches may eventually replace or complement existing treatment modalities, such as surgery, radiation therapy, and traditional cytotoxic chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors, and specifically cetuximab, are as of now the only class of targeted agents, excluding immune checkpoint inhibitors, with approval in the treatment of HNSCC. Beyond EGFR inhibition, novel therapies under evaluation are directed against vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), PI3K/AKT/mTOR pathway, cell cycle regulation (for example, cyclin dependent kinases 4 and 6), HRAS, DNA repair mechanisms, and others. Development of new therapies has to take into consideration the complexity of solid tumors and their heterogeneity. Multitargeted combination therapy approaches may be required in certain cases in order to maximize antitumor effect. Ways to individualize treatment using validated biomarkers are likely to improve outcomes. We review the most relevant molecular targets in HNSCC and provide updates on clinical trial data with promising new targeted agents.

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Phase I clinical and translational evaluation of AZD6738 in combination with durvalumab in patients (pts) with lung or head and neck carcinoma

Cited by 6 publications

References 0 publications

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Pharmacologic inhibition of ataxia telangiectasia and Rad3‐related (ATR) in the treatment of head and neck squamous cell carcinoma

New and Promising Targeted Therapies in First and Second-Line Settings

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