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Drugs targeting the VEGF (vascular endothelial growth factor) signaling pathway are approved for several malignancies. Unfortunately, VEGF inhibitors lead to hypertension in 30% to 80% patients. Reduced nitric oxide synthase activity, microvascular rarefaction, and increased vascular resistance have been proposed as potential mechanisms. We aimed to assess these mechanisms in patients receiving the VEGF inhibitor, pazopanib, for cancer. Twenty-seven normotensive patients with advanced solid malignancies received pazopanib 800 mg od. Endothelial function was assessed using forearm plethysmography with intraarterial infusions of acetylcholine. Detailed hemodynamic measurements were taken. Density and diameter of the conjunctival and episcleral microvasculature were evaluated using hemoglobin video imaging. Measurements were taken at baseline, 2, and 12 weeks after initiation of pazopanib or earlier if patients became hypertensive. By the end of the trial, systolic blood pressure increased by 12 mm Hg (95% CI, 4–19 mm Hg; P =0.003), diastolic by 10 mm Hg (95% CI, 5–15 mm Hg; P 5 (95% CI, 616–1168 dynes×s/cm 5 ; P P P =0.003) and diameter by −2.09 µm (95% CI, −3.95 to −0.19 µm; P =0.03). A post hoc colorimetric assay revealed that pazopanib inhibited acetylcholinesterase activity by −56% (95% CI, −62% to −52%; P Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01392352.

Background Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure for patients with brain tumors. For most patients who don't respond to treatment, it is not known whether this is due to inadequate drug concentrations in the tumor, or due to drug resistance. Preliminary data suggest that low-dose radiotherapy may disrupt the BBB, and could facilitate increased drug delivery into brain tumors. Afatinib is a potent, irreversible inhibitor of EGFR / HER2 / HER4 and takes approximately 8 days to achieve steady-state concentrations in cancer patients. Aims CamBMT1 has been designed to investigate the delivery of afatinib into brain metastases and whether this might be enhanced by low dose-radiotherapy. Patient Population Key eligibility criteria Patients with operable brain metastases from breast or lung primaries for whom neurosurgical resection would be standard of care, as determined by the local multi-disciplinary team. ECOG PS 0, 1 or 2. Trial design After a phase 1b safety run- in, the phase 2 part of the trial randomises patients (n=60) into 3 pre-operative arms: Arm 1afatinib alone for 11 days, then neurosurgery on day 12Arm 2afatinib for 11 days plus a single 2 Gy fraction on day 10, then neurosurgery on day 12Arm 3afatinib for 11 days plus a single 4 Gy fraction on day 10, then neurosurgery on day 12 Primary endpoint: to compare steady-state afatinib concentration in resected brain metastases, following afatinib administered alone, or in combination with radiotherapy (2 Gy or 4 Gy). Afatinib concentrations are measured in the resected brain metastases and in plasma. Secondary endpoints: safety of afatinib administration in combination with radiotherapy; and multi-sequence MRI (optional) to detect changes in perfusion, vascular density, blood-brain-barrier permeability and interstitial pressure. Exploratory endpoints: molecular profiling of resected brain metastases, for comparison with paired primary lung and breast cancers; the establishment and study of patient-derived xenografts. Statistical methods With 20 patients randomised in each of 3 arms in the phase 2 part of CamBMT1, the trial has a power of 84% at a significance level of 20% (one-sided) to detect an increase in afatinib concentrations with targeted radiotherapy, measured as a Cohen's D (standardised mean difference) ≥0.5. Accrual By the end of q2 2016, phase 1b had nearly completed enrolment. The randomised phase 2 part of CamBMT1 is due to open by q4 2016 at additional Experimental Cancer Medicine Centres. Acknowledgments CamBMT1 is funded by Cancer Research UK, the Brain Tumour Charity and Boehringer-Ingelheim. Citation Format: Baird RD, Ramenatte N, Watts C, Jonson A, Jones L, Biggs H, Harrison E, Oberg I, Bullen G, Williams M, Qian W, Gilbert F, Jodrell D, Caldas C, Karabatsou K, Dunn L, Jena R, Whitfield G, Chalmers A, Jefferies S, Price S. Cambridge brain mets trial 1 (CamBMT1): A proof-of-principle phase 1b / randomised phase 2 study of afatinib penetration into brain metastases for patients undergoing neurosurgical resection, both with and without prior low-dose, targeted radiotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-04-01.

Introduction: Drugs targeting Vascular Endothelial Growth Factor (VEGF) signaling pathway are approved therapies for cancer. Unfortunately, VEGF inhibitors lead to hypertension in 30-80% patients. Reduced nitric oxide synthase activity and increased vascular resistance have been proposed as potential mechanisms. We aimed to assess these mechanisms in oncology patients receiving VEGF inhibitor, pazopanib (NCT01392352). Methods: 27 normotensive patients received pazopanib 800mg od. Endothelial function was assessed using forearm plethysmography with intra-arterial infusion of Acetylcholine (ACh), Sodium Nitroprusside (SNP) and L-N-monomethyl-arginine (L-NMMA). Also, Blood Pressure (BP), Pulse Wave Velocity (PWV), Cardiac Output (CO), and Peripheral Vascular Resistance (PVR) and capillary density in the eye were assessed. All measurements were taken at baseline, 2 and 12 weeks after initiation of the treatment. Results: Following 12 weeks of treatment, systolic BP rose by 12 (95% CI:4–19) mmHg; P = 0.003, diastolic by 10 (95% CI:5–15) mmHg; P < 0.001, PWV by 1.3 (95% CI:0.3–2.2) m/s; P = 0.01, PVR by 11.1 (95% CI:7.7–14.6) mmHg*L/min; P < 0.001. Capillary density in the sclera reduced by 12 ± 18%; P = 0.02. Forearm blood flow response to ACh improved (P < 0.001), whereas SNP and L-NMMA responses were unchanged. A post-hoc colorimetric assay revealed in whole blood from healthy volunteers that pazopanib inhibited acetylcholinesterase activity by 35%. Conclusion: Unexpectedly, pazopanib led to an increase in ACh response, but this is most likely due to the inhibition of acetylcholinesterase activity by pazopanib. Interestingly, we found that PVR was increased and capillary density reduced by the treatment, suggesting that capillary rarefaction could be one of the mechanisms behind VEGF inhibition induced hypertension.

Overall survival of non-small-cell lung cancer (NSCLC) patients remains poor as patients are frequently diagnosed at a late stage. The evaluation of circulating tumour DNA (ctDNA) has been shown to offer a non-invasive method for detection of cancer. However, detection rates of ctDNA in patients with early stage cancers, including NSCLC, have been limited due to sampling and sensitivity issues. We developed a novel algorithm for INtegration of VAriant Reads (INVAR), which uses sequencing data across hundreds to thousands of tumour-mutated loci to detect ctDNA in plasma samples at high sensitivity. We applied this to a cohort of stage I-III NSCLC patients recruited in the LUCID study. LUCID is a prospective and observational study of 100 stage I-IIIB NSCLC who are planning to undergo radical treatment (surgery or radiotherapy +/- chemotherapy) with curative intent. Plasma samples were collected before and after treatment with curative intent. We analysed a total of 50 patients using patient specific-sequencing panels and detected ctDNA in 78% of cases before treatment, at ctDNA fractions as low as 1.7x10-5. For 17 of those patients staging information was available. Here, we detected ctDNA in 50% of stage I patients (split evenly between stages IA and B) and 100% of stage II and III patients. We also applied INVAR to whole exome and shallow whole genome sequencing data from plasma samples, and showed that this algorithm can be used to detect low ctDNA fractions in such data. Our findings highlight an opportunity to improve ctDNA detection in early stage NSCLC by using patient specific sequencing information. Additionally, our algorithm has the potential to aid in longitudinal cancer monitoring and is applicable to a variety of sequencing data types. We aim to apply this approach to serial samples obtained through the LUCID study to investigate its application in the treatment management. Citation Format: Katrin Heider, Jonathan C. Wan, Davina Gale, Florent C. Mouliere, Wendi Qian, Angels Kateb, Gail Doughton, Nicola Ramenatte, Ruth Tysoe, Christopher G. Smith, Doris M. Rassl, Susan Harden, Robert C. Rintoul, Charles Massie, Nitzan Rosenfeld. Improved ctDNA detection in early stage non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1377.

2008 Background: Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure in pts with brain tumours. Preliminary data suggest that low-dose RT may disrupt the BBB, and could facilitate increased drug delivery into brain tumours. CamBMT1 is a phase 1b/2 pre-operative window-of-opportunity trial designed to test if the delivery of afatinib into brain mets might be enhanced by targeted, low dose-RT. Methods: Pts with operable brain mets from breast or lung origin were treated with afatinib for 11 days prior to surgery on day 12. Pts also received a single fraction of targeted RT on day 10 (pts in either 2Gy or 4Gy arm). In phase 1b, afatinib dose (20, 30, or 40mg QD) was escalated in each arm using an accelerated titration design. Primary endpoint: steady-state afatinib concentration in resected brain mets, compared with plasma. Secondary endpoints: safety and tolerability. Results: 10 pts were treated (4 breast, 6 lung), with no dose-limiting toxicities seen, thus completing recruitment to phase 1b. Treatment was generally well tolerated. Median afatinib concentrations on day 12 were: plasma 22.7ng/mL (range 9.94-179); and tumour 405ng/g (range 120-1129). Conclusions: It was feasible to conduct a window-of-opportunity study of afatinib plus RT in pts with operable brain mets. The recommended phase 2 dose of afatinib was 40mg QD for both 2Gy and 4Gy arms. Afatinib concentrations in resected tumour were on average >15-fold higher than those in plasma. Phase 2 of CamBMT1 is now underway in multiple UK sites, and randomises patients into 3 treatment arms (n=20 per arm): 1. afatinib 40mg QD; 2. afatinib 40mg QD + 2Gy# RT; 3. afatinib 40mg QD + 4Gy# RT. Clinical trial information: NCT02768337. [Table: see text]

Vascular endothelial growth factor (VEGF) promotes nitric oxide activity. VEGF inhibitors are anti-cancer drugs that often cause hypertension but mechanisms are unclear. We hypothesised that VEGF inhibition leads to endothelial dysfunction, thus increasing blood pressure. 27 normotensive cancer