Search

Epidermal growth factor receptor exon 20 insertion mutations (EGFRexon20ins) are detected in approximately 2% of patients with non-small cell lung cancer (NSCLC). Due to a lack of effective therapy, the prognosis of these patients is typically poor. Sunvozertinib (DZD9008) was designed as an oral, potent, irreversible, and selective EGFR tyrosine kinase inhibitor, showing activity against EGFRexon20ins and other mutations. In both cell lines and xenograft models, sunvozertinib shows potent antitumor activity. In the two ongoing phase I clinical studies, sunvozertinib was tolerated up to 400 mg once daily. The most common drug-related adverse events included diarrhea and skin rash. Antitumor efficacy was observed at the doses of 100 mg and above in patients with EGFRexon20ins NSCLC across different subtypes, with prior amivantamab treatment as well as with baseline brain metastasis. The median duration of response has not been reached.SignificanceWe report the discovery and early clinical development of sunvozertinib, a potential treatment option for the unmet medical need of EGFRexon20ins NSCLC. This article is highlighted in the In This Issue feature, p. 1599.

The prognosis for metastatic gastric adenocarcinoma (mGAC) remains poor. Gene alterations in receptor tyrosine kinases (RTKs) such as epidermal growth factor receptor (EGFR) and their downstream effectors including catalytic subunit alpha of the phosphatidylinositol 3-kinase (PIK3CA) are common in mGAC. Targeted RTK and phosphatidylinositol-3-kinase (PI3K) treatments have demonstrated clinical benefits in other solid tumours and are key potential targets for clinical development against mGAC given the presence of recurrent alterations in these pathways. Furthermore, combination RTK/PI3K treatments may overcome compensatory mechanisms that arise using monotherapies, leading to improved patient outcomes. Herein, we investigated RTK/PI3K single and combination drug responses against our unique human mGAC-derived PIK3CA gain-of-function mutant, human epidermal growth factor receptor 2 (HER2)-negative, EGFR-expressing circulating tumour cell line, UWG02CTC, under two- and three-dimensional culture conditions to model different stages of metastasis. UWG02CTCs were highly responsive to the PI3K p110α-subunit targeted drugs PIK-75 (IC50 = 37.0 ± 11.1 nM) or alpelisib (7.05 ± 3.7 µM). Drug sensitivities were significantly increased in 3D conditions. Compensatory MAPK/ERK pathway upregulation by PI3K/Akt suppression was overcome by combination treatment with the EGFR inhibitor gefitinib, which was strongly synergistic. PIK-75 plus gefitinib significantly impaired UWG02CTC invasion in an organotypic assay. In conclusion, UWG02CTCs are a powerful ex vivo mGAC drug responsiveness model revealing EGFR/PI3K-targeted drugs as a promising combination treatment option for HER2-negative, RAS wild-type mGAC patients. [ABSTRACT FROM AUTHOR]

The ectonucleotidases CD39 and CD73 are present on immune cells and play important roles in cancer progression by suppressing antitumour immunity. As such, CD39 and CD73 on peripheral blood mononuclear cells (PBMCs) are emerging as potential biomarkers to predict disease outcomes and treatment responses in cancer patients. This study aimed to examine T and B cells, including CD39 and CD73 expressing subsets, by flow cytometry in PBMCs from 28 patients with head and neck squamous cell carcinoma (HNSCC) and to assess the correlation with the treatment modality, human papillomavirus (HPV) status, and relapse-free survival (RFS). The PBMCs were examined pre-, mid-, and post-radiotherapy with concurrent cisplatin chemotherapy or anti-epidermal growth factor receptor antibody (cetuximab) therapy. Combination radiotherapy caused changes to T and B cell populations, including CD39 and CD73 expressing subsets, but no such differences were observed between concurrent chemotherapy and cetuximab. Pretreatment PBMCs from HPV+ patients contained increased proportions of CD39−CD73−CD4+ T cells and reduced proportions of CD39−/+CD73+CD4+ T cells compared to the equivalent cells from HPV− patients. Notably, the pretreatment CD4+:CD8+ T cell ratios and CD39+CD73+CD19+ B cell proportions below the respective cohort medians corresponded with an improved RFS. Collectively, this study supports the notion that CD39 and CD73 may contribute to disease outcomes in HNSCC patients and may assist as biomarkers, either alone or as part of immune signatures, in HNSCC. Further studies of CD39 and CD73 on PBMCs from larger cohorts of HNSCC patients are warranted. [ABSTRACT FROM AUTHOR]

Introduction: The number and complexity of early phase cancer clinical trials has increased significantly globally over the past decade. Australia is an attractive location for the conduct of first-in-human early phase trials due to efficient start-up timelines, favorable regulatory landscape, and a well-established health system with trained clinical investigators. However, access to clinical trials can be challenging for patients from regional areas, and those with rare biomarkers. To improve the efficiency and access of early phase trials for patients and attract international sponsors, the NSW Early Phase Clinical Trials Alliance (NECTA) was established in 2016. We aimed to document the activities and achievements of NECTA over the past eight years to provide a framework by which clinical research trial centers can cooperate to support the quality of trials, efficacy of patient access and investigator training and expertise. Methods: The NECTA network commenced with three large trials units in metropolitan NSW in 2016, which has grown to ten early phase units (including two rural and two regional sites), with a memorandum of understanding between trial sites and the Garvan Institute, and central NECTA manager funded by the Cancer Institute (NSW Government). Three pillars to foster collaboration involving 1) centralized referral pathways, 2) multi-site investigator-led research, and 3) annual drug-development meeting and fortnightly education podcast with sponsor engagement / funding have fostered the growth of NECTA-facilitated trial activation and enrolment. An investigator-led study utilizing liquid biopsy to facilitate early phase trial selection and enrolment for patients (PANNA-COTA) seeking early phase trials was activated in 2022. Results: NECTA's centralized referral pathway has facilitated ten new enquiries/month from overseas sponsors searching for clinical trial sites, to better align trial portfolios between neighboring trial units to prevent population overlap, and to open trials for patients with rare cancers/biomarkers. NECTA's fortnightly MDTs have facilitated molecular tumor board discussion of 24 patients seeking Phase 1 trials with liquid biopsy results from the investigator-led PANNA-COTA study. An average of 20 patients (range 14-24) per month have been referred to NECTA utilizing the central phone number and email. The annual drug development meeting held 7 times since 2017, has attracted approximately 2,100 attendees and 77 sponsors to date, resulting in growth in the diversity and quality of biotechnology and pharmaceutical sponsored studies in NSW. Ongoing initiatives includes growth of decentralized trial models utilizing telehealth reviews and increasing social media activity of NECTA with the ongoing fortnightly education podcast with sponsor engagement / funding have fostered the growth of NECTA-facilitated trial activation and enrolment. An investigator-led study utilizing liquid biopsy to facilitate early phase trial selection and enrolment for patients (PANNA-COTA) seeking early phase trials was activated in 2022. Results: NECTA's centralized referral pathway has facilitated ten new enquiries/month from overseas sponsors searching for clinical trial sites, to better align trial portfolios between neighboring trial units to prevent population overlap, and to open trials for patients with rare cancers/biomarkers. NECTA's fortnightly MDTs have facilitated molecular tumor board discussion of 24 patients seeking Phase 1 trials with liquid biopsy results from the investigator-led PANNA-COTA study. An average of 20 patients (range 14-24) per month have been referred to NECTA utilizing the central phone number and email. The annual drug development meeting held 7 times since 2017, has attracted approximately 2,100 attendees and 77 sponsors to date, resulting in growth in the diversity and quality of biotechnology and pharmaceutical sponsored studies in NSW. Ongoing initiatives includes growth of decentralized trial models utilizing telehealth reviews and increasing social media activity of NECTA with the ongoing 'Dangerous Ideas in Drug Development" Podcast. Conclusion: A patient-centric early phase trials consortium as modelled by NECTA has the potential to facilitate improvement in patient access to trials, efficiency of trial site selection/start-up and education and training of investigators. [ABSTRACT FROM AUTHOR]

Background: Advanced biliary tract cancer (ABTC) is a highly aggressive malignancy, with a 5‐year overall survival of < 10%. Although preliminary evidence suggests a role of targeted treatments or immunotherapy in a subset of patients, chemotherapy remains the standard second‐line treatment in the majority. We conducted a pilot study of second‐line chemotherapy with capecitabine and nab‐paclitaxel after failure of gemcitabine and platinum. Methods: Eligible patients had histologically proven, unresectable biliary tract cancer, which had progressed on a gemcitabine/platinum doublet. In this single‐arm, multicenter trial, all patients received capecitabine (825 mg/m2 bd PO D1‐14 q21d) and nab‐paclitaxel (125 mg/m2 IV D1,8 q21d) until progression or unacceptable toxicity. The primary objective was feasibility of delivering the proposed regimen, with secondary objectives of disease control measures and QOL outcomes. Results: Ten patients were enrolled between 2015 and 2016 from four cancer centers in NSW. Treatment was generally well tolerated with grade III toxicities in five patients (including infection, cholangitis, obstruction, and intestinal perforation) and no grade IV toxicity. Median treatment duration was 4.3 months, with a disease control rate of 80% (8/10), and median progression‐free and overall survival of 5.7 and 12.1 months, respectively. Quality of life data and specimens for translational research have been collected. Conclusions: Our pilot study demonstrates that combination of capecitabine and nab‐paclitaxel is feasible as a second‐line treatment in ABTC. Adequate safety and promising early efficacy signals make further assessment of the combination in a formal phase II or III trial reasonable. Clinical trial information: ACTRN12615000504516. [ABSTRACT FROM AUTHOR]