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Neurotrophic tyrosine receptor kinase genes (NTRK1/2/3) act as oncogenic drivers across a range of tumors. NTRK fusions occur at low frequency (90% of secretory breast carcinomas. Furthermore, up to 30% of patients (pts) with breast cancer will develop central nervous system (CNS) metastases (mets). Entrectinib is a potent, oral TRKA/B/C, ROS1 and ALK inhibitor, specifically selected for its CNS penetration properties. Entrectinib was evaluated in 3 global phase 1/2 clinical trials (ALKA-372-001 [EudraCT 2012-000148-88], STARTRK-1 [NCT02097810], and STARTRK-2 [NCT02568267]), where it demonstrated strong and durable systemic and intracranial efficacy in pts with NTRK-fp solid tumors, including those with breast cancer. We present updated data from this integrated analysis (data cut-off: 31 October 2018) focusing on pts with breast cancer. The entrectinib trials were conducted at >150 sites in 15 countries, and enrolled pts with locally advanced/metastatic NTRK-fp tumors (with or without baseline CNS mets) confirmed by nucleic acid-based methods. Tumor assessments were performed at the end of cycle 1 (4 weeks) and every 8 weeks thereafter, and evaluated by blinded independent central review (BICR) using RECIST v1.1. Primary endpoints were objective response rate (ORR) and duration of response (DoR) by BICR. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and safety. At clinical cut-off, the overall efficacy-evaluable population included 74 adults from the 3 trials, with 12 different NTRK-fp tumor types and >25 histopathologies. In these pts, ORR by BICR was 63.5% (95% CI 51.5-74.4), including five complete responses (CR) and 42 partial responses (PR). Median (95% CI) DoR, PFS and OS were 12.9 (9.3-not estimable [NE]), 11.2 (8.0-15.7) and 23.9 (16.0-NE) months, respectively. The efficacy-evaluable NTRK-fp breast cancer cohort included 6 pts with a median age of 63 (range 36-67) years; most had an Eastern Cooperative Oncology Group performance status of 0 (3/6; 50%) or 1 (1/6; 17%). Breast cancer tumors were classified as secretory (4/6; 67%; all NTRK3-fp) or non-secretory (2/6; 33%; all NTRK1-fp). Pts had received 0 (3/6; 50%), 1 (1/6; 17%) or ≥4 (2/6; 33%) lines of prior therapy for metastatic disease. At data cut off, the median survival follow-up was 17.4 (range 1.7-23.9) months. ORR was 100% (2 CR, 2 PR; 95% CI 39.8-100.0) in pts with secretory and 50% (1 PR, 1 missing/unevaluable; 95% CI 1.3-98.7) in pts with non-secretory histology. Median (95% CI) DoR, PFS, and OS were 12.9 (4.2-NE), 10.1 (5.1-NE), and 23.9 (5.1-23.9) months, respectively. At baseline, 2 pts had CNS mets per investigator assessment; 1 of these pts had missing response data. CNS mets were confirmed by BICR in the other pt (non-secretory); this pt had received whole brain radiotherapy 2-6 months before starting entrectinib treatment, and had systemic PR and intracranial non-CR/non-progressive disease (non-measurable CNS lesion). The overall integrated safety-evaluable population comprised 504 pts with any gene fusion who received ≥1 dose of entrectinib. Most treatment-related adverse events (TRAEs) were Grade ≤3 (96.1%); the most frequently reported TRAEs were dysgeusia (39.7%) and fatigue (31.5%). Seven breast cancer pts were evaluated for safety, of whom six (85.7%) reported TRAEs; all were Grade ≤3. The most frequently reported TRAEs (each occurring in 3/7 pts; 42.9%) were nausea, anemia, and increased alanine or aspartate aminotransferase. Dose reductions and interruptions due to TRAEs were each reported in 3/7 pts (42.9%); no discontinuations or deaths due to TRAEs were recorded. In this updated integrated analysis, entrectinib induced objective responses in all pts with NTRK-fp breast cancer who had data available, and was generally well tolerated with no discontinuations due to TRAEs. Citation Format: Janice Lu, Collin M. Blakely, Christophe Le Tourneau, Saiama N. Waqar, Todd M. Bauer, Filippo de Braud, David S. Hong, Alexander Spira, Tira Tan, Samuel McCallum, Stuart Osborne, Brian Simmons, Minal Barve. Efficacy and safety of entrectinib in NTRK fusion-positive (NTRK-fp) breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-28.

Advances in adjuvant therapy have led to increased survival rates after cancer prognosis. Herceptin, a targeted therapy, had first been introduced to Singapore in 2006. We aimed to assess whether subsidies for Herceptin from 2012 will lead to changes in uptake among Human Epidermal Growth Factor Receptor 2 (HER2) positive patients by socio-economic groups. Two-level random-intercept logistic regression was used to model diagnostic test and Herceptin uptake using the Singapore Breast Cancer Cohort from 2006 to 2018, adjusting for covariates such as education, housing type and marital status before and after subsidies. Interrupted time series (ITS) analysis was used to evaluate the impact of Herceptin subsidy on treatment uptake. The concentration index was also computed to measure inequality in uptake by ethnicity and education. We found that the odds of diagnostic testing were not associated with socioeconomic factors. However, before subsidies, the highest education attained (OR = 4.57, 95% CI= (1.90, 11.02), P< 0.01) significantly increased the odds of Herceptin uptake. These odds were levelled after the introduction of subsidies to Herceptin treatment in 2012. After subsidy, we also found that Herceptin uptake increased significantly by 11.4% (95% CI= (3.47%, 19.4%), P=0.016). Also, inequality of Herceptin use decreased especially amongst the Indians, where at least 40% were used in the higher educated group prior to the subsidy. Subsidies have lowered the barriers to Herceptin uptake for marginalized individuals. Having targeted subsidies for socio-economically disadvantaged groups may work more efficiently in providing ease of access than a blanket subsidy in Herceptin.

THOR-707 (SAR444245) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, THOR-707 improved the anti-tumor benefits of aldesleukin, but without its severe side effects, both as single agent and combined with anti-PD1. Here we report safety, PK/PD, and preliminary anti-tumor activity for THOR-707 as monotherapy and combined with pembrolizumab in the ongoing HAMMER Phase 1/2 trial. THOR-707 was administered via IV infusion as monotherapy Q2W (Cohort A), Q3W (Cohort B), or combined with pembrolizumab 200 mg IV Q3W (Cohort C); escalation follows a 3 + 3 schema to identify the maximum tolerated dose and/or the recommended Phase 2 dose. As of 16 November 2020, 28 pts were enrolled: ECOG 0-1; median age 62 (37-76) yrs; median lines of prior therapies were 3 (1-9; 11 pts had prior anti-PD1). Most common tumor types: colorectal (n=5), melanoma (n=4). Cohort enrollment was A: 8 µg/kg (n=4); B: 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=7); C: 8 µg/kg (n=4), 16 µg/kg (n=3). No dose-limiting toxicity (DLT) or vascular leak syndrome (VLS) was observed. Most common treatment-emergent adverse events (TEAEs) were flu-like symptoms (46.4%), fever (46.4%), vomiting/nausea (35.7%), chills (32.1%), following the first dose and resolved with standard supportive care. No cumulative toxicity, end organ toxicity, QTc prolongation, or other cardiac toxicity was observed. Grade (G) 3-4 related toxicities in B: 1 G3 rash (8 µg/kg); 1 G4 AST increase, 2 G3 increase in AST/ALT & 1 G4 decrease in lymphocytes (16 µg/kg); 2 G4 decrease in lymphocytes, 1 G4 CRS with G3 hypertension (led to discontinuation), and 1 G3 acute kidney injury (24 µg/kg); C: 1 G3 & 1G4 decrease in lymphocytes (16 µg/kg). CD8 cells (effector & memory) and NK cells increased in Cycle 1 by a median (range) respectively of 3.1 (1.04 - 5.91) and 7.93 (1.71 - 26.85) fold and were sustained until next cycle. There was no meaningful increase in CD4 Tregs or eosinophil counts (a marker of potential VLS), 1.89 (0.86- 5.36) and 1.77 (0.47- 3.65) fold. No anti-drug antibodies (IL-2 or PEG) and no meaningful IL-5 elevations were found. One IL-6 increase at 24 hrs (to 1,000 pg/mL) was observed. Half-life is ~ 10 hours. Three pts have confirmed partial responses: 1 PD-1-naïve basal cell carcinoma; 1 head & neck squamous cell carcinoma with progression after a prior anti-PD-1, ongoing for 9+ mos in C (8 µg/kg); 1 squamous cellular carcinoma of unknown origin, unresponsive to prior anti-PD-1, ongoing for 3+ mos in B (24 µg/kg). Two pts had stable disease for 9 and 6 mos, respectively, with pancreatic (in A, 8 µg/kg) and prostate cancer (in B, 16 µg/kg); 11 pts remained on treatment for ≥5 cycles. Preliminary encouraging results with THOR-707 monotherapy and in combination with pembrolizumab support IL-2 not-alpha preferential activity, validating preclinical models, with initial efficacy and a tolerable safety profile. Dose escalation continues. NCT04009681 Citation Format: Filip Janku, Raghad Abdul-Karim, Arun Azad, Johanna Bendell, Gerald Falchook, Hui K. Gan, Tira Tan, Judy S. Wang, Cheng Ean CHEE, Lina Ma, Jill Mooney, Neyssa Marina, Giovanni Abbadessa, Marcos Milla, Tarek Meniawy. THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1/2 Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB041.

Triple-negative breast cancer (TNBC) is clinically defined as lacking expression of the estrogen receptor (ER), progesterone receptor (ER), and HER2. Historically, TNBC has been characterized by an aggressive natural history and worse disease-specific outcomes compared with other breast cancer subtypes. The advent of next-generation sequencing (NGS) has allowed for the dissection of TNBC into molecular subtypes (i.e., basal-like, claudin-low). Within TNBC, several subtypes have emerged as “immune-activated,” consistently illustrating better disease outcome. In addition, NGS has revealed a host of molecular features characteristic of TNBC, including high rates of TP53 mutations, PI3K and MEK pathway activation, and genetic similarities to serous ovarian cancers, including inactivation of the BRCA pathway. Identified genetic vulnerabilities of TNBC have led to promising therapeutic approaches, including DNA-damaging agents (i.e., platinum salts and PARP inhibitors), as well as immunotherapy. Platinum salts are routinely incorporated into the treatment of metastatic TNBC; however, best outcomes are observed among those with deficiencies in the BRCA pathway. Although the incorporation of platinum in the neoadjuvant care of patients with TNBC yields higher pathologic complete response (pCR) rates, the impact on longer-term outcome is less clear. The presence of immune infiltrate in TNBC has shown both a predictive and prognostic role. Checkpoint inhibitors, including PD-1 and PD-L1 inhibitors, are under investigation in the setting of metastatic TNBC and have shown responses in initial clinical trials. Finally, matching emerging therapeutic strategies to optimal subtype of TNBC is of utmost importance as we design future research strategies to improve patient outcome.

Separation of lipoproteins by traditional sequential salt density floatation is a prolonged process ( approximately 72 h) with variable recovery, whereas iodixanol-based, self-generating density gradients provide a rapid ( approximately 4 h) alternative. A novel, three-layered iodixanol gradient was evaluated for its ability to separate lipoprotein fractions in 63 subjects with varying degrees of dyslipidemia. Lipoprotein cholesterol, triglycerides, and apolipoproteins were measured in 21 successive iodixanol density fractions. Iodixanol fractionation was compared with sequential floatation ultracentrifugation. Iodixanol gradient formation showed a coefficient of variation of 0.29% and total lipid recovery from the gradient of 95.4% for cholesterol and 84.7% for triglyceride. Recoveries for VLDL-, LDL-, and HDL-cholesterol, triglycerides, and apolipoproteins were approximately 10% higher with iodixanol compared with sequential floatation. The iodixanol gradient effectively discriminated classic lipoproteins and their subfractions, and there was evidence for improved resolution of lipoproteins with the iodixanol gradient. LDL particles subfractionated by the gradient showed good correlation between density and particle size with small, dense LDL (25.5 nm) separated in fractions with density1.028 g/dl. The new iodixanol density gradient enabled rapid separation with improved resolution and recovery of all lipoproteins and their subfractions, providing important information with regard to LDL phenotype from a single centrifugation step with minimal in-vitro modification of lipoproteins.

Background: Recombinant compound interferon (rSIFN-co) is a new class of interferon derived from altering the spatial structure and configuration of the basic interferon protein. rSIFN-co displayed greater anti-tumor activity in solid tumors compared to interferon α-2b in pre-clinical studies. Methods: Patients with advanced malignancies were enrolled to determine the safety, tolerability, recommended phase II dose (RP2D), pharmacodynamics (PD) and preliminary anti-tumor activities in a 3+3 dose escalation design. Two pre-defined dose levels were planned. rSIFN-co was dosed 3 times a week via subcutaneous injection for 21 days followed by 7 days rest. This was preceded by a lead in phase. PD studies comprised of FDG-PET, pre- and post treatment changes in plasma cytokine profile and tumor repressive/ enhancing genes as well as 2'5'-oligoadenylate synthetase levels. Results: Results presented are based on preliminary data collected as of Jan. 27, 2015. 22 patients (median age 65.5 years, 14 male and 8 female) have been enrolled with 21 evaluable for safety and 15 amenable to efficacy analysis. 10 hepatocellular carcinoma (HCC), 6 non-small cell lung cancer (NSCLC), 4 colorectal cancer (CRC), 1 melanoma and 1 nasopharyngeal carcinoma patients (pts) were dosed at 2 dose levels. The RP2D was 24μg 3x/week for 21days followed by 7 days rest. No dose limiting toxicities were encountered. Most adverse events (92%) were CTCAE grade 1 and 2. The most frequent grade 1/2 treatment related adverse events (trAEs) were flu-like symptoms (90%), anorexia (33%), fatigue (33%), weight loss (33%), nausea (29%), thrombocytopenia (29%), and diarrhea (24%). Grade 3/4 trAEs were fever (2 pts), leucopenia (2 pts), transaminitis (2 pts), weight loss (1 pt), fatigue (1 pt), afebrile neutropenia (1 pt) and syncope (1 pt). 11 patients had stable disease (SD) and 4 patients had progressive disease (PD). 4 patients (2 HCC, 1 NSCLC and 1 CRC) had prolonged stable disease (>16 weeks). Detailed PD data will be presented for all cohorts. Conclusion: The RP2D was 24μg three times a week for 21days followed by 7 days rest with a lead in phase. Modest activity was seen in heavily pre-treated advanced solid tumor patients. Citation Format: Su Pin Choo, Wai Meng Tai, Maria Macapagal, Aziah Ahmad, Greg Li, Mui Leng Goh, Matthew Ng, Tira Tan, Shao Weng Tan, Wan Teck Lim. A phase I open-label, non-randomized study of recombinant compound interferon (rSIFN-co) in patients with advanced solid tumors. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A027.

Background Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. The prevalence of IBS in Asian countries varies from 2.9% to 15.6%. IBS does not result in increased mortality, but is associated with psychological distress and disruption of work and sleep. Consequently, the evaluation of health-related quality of life (HRQoL) is an important outcome measure for patients with IBS since it provides a holistic assessment of the patient's emotional, social and physical function. However, some HRQoL tools can be time-consuming to apply. EQ-5D is a brief HRQoL tool which has been validated in the Western IBS population but has thus far not been used in Asia. This study was conducted to determine whether persons with self-reported symptoms that met the Rome III criteria for IBS had a poorer quality of life than those without these symptoms. We also aimed to determine which specific aspects of quality of life were most affected and whether any risk factors distinguished those with and without IBS. Methods Self-administered questionnaires which included the Rome III diagnostic questionnaire modules for IBS and the EQ-5D questionnaire were obtained from participants of a health symposium in Singapore on 31th October 2010. IBS was diagnosed based on the Rome III Criteria. The main outcome measure was the EQ-5D index score. The relationship between the presence of IBS and the EQ-5D index score, individual dimensions of EQ-5D and demographic risk factors were examined. Results 449 completed questionnaires were analyzed. The mean EQ-5D index score for IBS was 0.739 which was a significant reduction compared to non-IBS participants [−0.11 (95% CI: -0.15 to −0.07), p Conclusion IBS sufferers have significantly poorer quality of life. Assessment of HRQoL in IBS using the EQ-5D should be considered in further studies and routine clinical practice.