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Purpose:RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer.Patients and Methods:Patients with advanced ER+/HER2− breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion.Results:Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0–11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index.Conclusions:Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.

Supplementary Table from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Supplementary Data from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Supplementary Figure from Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer

Purpose: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer. Patients and Methods: Patients with advanced ER+/HER2− breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion. Results: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0–11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index. Conclusions: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.

Purpose Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can “normalize” the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients. Methods This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2. Results In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004). Conclusion Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery. Trial registry ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Background: Atypical response patterns have been a topic of increasing relevance since the advent of immune checkpoint inhibitors (ICIs), challenging the traditional RECIST (Response Evaluation Criteria in Solid Tumors) method of tumor response assessment. Newer immune-related response criteria can allow for the evolution of radiologic pseudoprogression, but still fail to capture the full range of atypical response patterns encountered in clinical reporting. Methods: We did a detailed lesion-by-lesion analysis of the serial imaging of 46 renal cell carcinoma (RCC) patients treated with ICIs with the aim of capturing the full range of radiologic behaviour. Results: Atypical response patterns observed included pseudoprogression (n = 15, 32.6%), serial pseudoprogression (n = 4, 8.7%), dissociated response (n = 22, 47.8%), abscopal response (n = 9, 19.6%), late response (n = 5, 10.9%), and durable response after cessation of immunotherapy (n = 2, 4.3%). Twenty-four of 46 patients (52.2%) had at least one atypical response pattern and 18 patients (39.1%) had multiple atypical response patterns. Conclusions: There is a high incidence of atypical response patterns in RCC patients receiving ICIs and the study contributes to the growing literature on the abscopal effect. The recognition of these interesting and overlapping radiologic patterns challenges the oncologist to tweak treatment options such that the clinical benefits of ICIs are potentially maximized.

Background: The approved doses of the single agent nivolumab – an anti-programmed cell death protein 1 (PD-1) monoclonal antibody – for renal cell carcinoma (RCC) are 3 mg/kg and a 240-mg flat dose, despite efficacy shown at lower doses in earlier CheckMate trials. In view of financial constraints, the minimum dose of nivolumab required for efficacy remains a critical area of inquiry. Methods: A retrospective review of RCC patients receiving single-agent anti-PD-1 treatment was conducted. Using the median cutoff of the maximum dose per body weight received, we investigated the effect of lower dosages on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and immune-related adverse event-free survival (irAE-FS). Survival analysis was made by Kaplan-Meier, by uni- and multivariable Cox models, and by modeling the statistical interaction between dosages and survival. Results: 32 patients were recruited: 8 patients (25%) receiving first-line treatment and 24 (75%) receiving second-line treatment and beyond. A median split at 2.15 mg/kg yielded 16 patients in both the lower-dose (LD) and the higher-dose (HD) cohort. Hazard ratios (HRs) demonstrated no difference in OS after adjustment for gender (HR = 0.22, 95% CI 0.05–1.05, p = 0.054; favoring LD), as well as in PFS after adjustment for gender and concurrent radiation therapy (HR = 0.58, 95% CI 0.25–1.34, p = 0.210; favoring LD). No differences in ORR were observed (50.0 vs. 43.8%, p = 1.00, in the LD and the HD cohort, respectively). Immune-related phenomena were observed in the LD group, including pseudoprogression and increased all-grade immune-related toxicities (irAE-FS: HR = 1.72, 95% CI 0.48–6.14, p = 0.293; favoring HD). Iterative dichotomization of dosages showed no dose-OS or dose-irAE-FS relationship. Conclusion: Our study suggests no apparent reduction in efficacy when using a low-dosage nivolumab regimen.

Purpose of Review Colorectal cancer liver metastasis is a major clinical problem, and surgical resection is the only potentially curative treatment. We seek to discuss various liver-directed therapy modalities and explore their roles in the evolving realm of treatment strategies for metastatic colorectal cancer. Recent Findings Clinical outcomes for patients with colorectal cancer liver metastases have improved as more patients undergo potentially curative resection and as the armamentarium of systemic treatment and liver-directed therapies continues to expand. Liver-directed therapies have been developed as adjuncts to improve resectability, employed in the adjuvant setting to potentially reduce local recurrence rates, and utilized in the palliative setting with the aim to improve overall survival. Summary Ongoing research is expected to validate the role of these evolving therapeutic options, and determine how best to sequence and when to apply these therapies.

165 Background: The addition of intraperitoneal (IP) paclitaxel (PTX) to systemic chemotherapy comprising taxane/fluoropyrimidine doublet has shown promising results for patients with gastric cancer (GC) and peritoneal metastases (PM). However, this has not been studied in combination with platinum/fluoropyrimidine doublet which is the current standard-of-care for metastatic GC. We conducted a prospective phase 2 trial of IP PTX with capecitabine and oxaliplatin (XELOX) in patients with GCPM. Methods: The trial enrolled 44 patients with GCPM who received treatment comprising IP PTX (40mg/m2 on day 1,8), PO capecitabine (1000mg/m2 twice daily from day 1-14) and IV oxaliplatin (100mg/m2 on day 1) in 21-day cycles. Patients with synchronous GCPM were eligible for conversion surgery comprising radical gastrectomy if they had good response after chemotherapy, negative cytology on 2 consecutive peritoneal fluid assessments, no extraperitoneal metastasis and no peritoneal disease during surgery. The primary endpoint was overall survival and secondary endpoints were progression-free survival and safety. Outcomes from the trial were also compared with a retrospective cohort of 39 patients with GCPM who received identical systemic chemotherapy (SC) comprising platinum/fluoropyrimidine agents alone. Results: The median OS for the IP and SC groups was 14.6 and 10.6 months (HR 0.44; 95% CI, 0.26-0.74; P=0.002). The 1-year OS was 67.8% in the IP group and 32.3% in the SC group (Logrank p

e24095 Background: The chemo-brain effect associated with systemic chemotherapy results in cognitive disturbances impacting the capacity to engage in tasks and quality of life (QOL). Patients with colorectal cancer (CRC) who receive adjuvant chemotherapy generally have long survival times. The long-term effect of chemotherapy on cognition is uncertain. We aimed to ascertain the frequency of long-term cognitive impairment using neuropsychological assessments and correlating with neuroimaging. Methods: In this prospective pilot study, patients (n=22) with stage II to III CRC between 45 to 75 years old, who were planned to receive adjuvant chemotherapy, were recruited. 3 visits were scheduled for each subject – pre-chemotherapy (V1), at 1 month post chemotherapy (V2), and at 6 months post chemotherapy (V3). Serial tests were performed – the Cambridge Neuropsychological Test Automated Battery (CANTAB), QOL questionnaires (Hospital Anxiety and Depression Scale (HADS), Perceived Deficits Questionnaire (PDQ), EORTC QLQ-C30, FACT-ES), 3 item pocket smell test, functional PET/MRI brain imaging, and blood biomarker studies. Results: 18/22 subjects (13 male, 5 female) had completed tests at all 3 visits; the median age was 62 years (range 51 – 69). 9/18 had an initial decline (median -0.033) of Rapid Visual Information processing (RVP) at V2; 3/9 showed improvement to baseline at V3. 8/18 had a persistent decline in RVP scores at V3 (median -0.054). This was associated with increased HADS depression scores (mean 3.63 at V2 vs 4.63 at V1), worsening attention scores (mean 4.38 at V3 and 3.63 at V1), prospective memory scores (mean 3.75 at V3 vs 3.38 at V1), and total scores (mean 14.63 at V3 vs 13.75 at V1) on the PDQ. 7/18 had an increase in Paired Associates Learning (PAL) errors (median +6) at V2. 3/7 improved to baseline at V3, while 4/7 continued to have a persistent decline. PAL scores were not associated with worsening retrospective or prospective PDQ memory scores, changes in HADS depression or EORTC QLQ-C30 scores. There was no difference in baseline CANTAB scores for patients reporting declining vs stable QLQ-C30 scores. Conclusions: Only half of patients with initial RVP A and PAL decline improved at 6 months post chemotherapy. Further efforts should be placed to identify those at risk of poor recovery, and develop strategies to manage the chemo-brain effect. The correlation of cognitive decline with neuroimaging will be presented in the final analysis.

1019 Background: Preclinical studies show cross talk between RET and estrogen receptor, with at least additive treatment (Tx) effect of Len, a RET inhibitor, with Let. Our previous work concluded a recommended phase 2 dose (RP2D) of Len 14mg daily and Let 2.5mg daily (Lim, ASCO 2019). We present efficacy data from dose escalation and expansion cohorts. Methods: Safety, tolerability and efficacy data of MBC patients in both dose escalation (Len dose level 1 [DL]:20mg, DL -1:16mg and DL -2:14mg) and expansion (Len 14mg) cohort of this phase Ib/II study of combination Len+Let study was analysed. Patients were treated with single-agent Len for 2 weeks, followed by Len+Let until disease progression (PD). Serial tumor biopsies at baseline, after Len alone, 4 weeks post Len+Let, and upon PD, were sequenced for 440 genes with the ACTOnco+ platform. Results: A total of 33 pts (DL1 6pts, DL-1 6pts, DL-2 + expansion 21pts) with median 5 lines of prior Tx (range 0-11) were enrolled; 87.9%, 75.8%, and 75.8% had prior endocrine therapy (ET), ET+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. Objective response rate (ORR), disease control rate (DCR) ≥6 months (m), median duration of response (DOR), and percentage progression-free (PPF) at 12m were 33.3%, 45.5%, 11.5m (range 6.3-22.4), and 27.2% respectively. Among patients who previously progressed on CDK4/6i (n = 25), ORR, DCR ≥6m, median DOR, and PPF at 12m were 24.0%, 40.0%, 13.7m (range 6.3-18.2), and 12.0% respectively. Of note, 3/25 (12%) patients had durable response to Len+Let lasting ≥12m, despite having only modest PFS on ET+CDK4/6i (3, 7, and 12 months respectively). Most frequent all-grade toxicities (tox) were HTN (n = 15, G3:15), hypothyroidism (n = 20, G3:0) and fatigue (n = 13, G3:2), with no G4/5 tox. No new toxicity signals were observed compared to dose escalation phase. Pre-treatment tumor molecular profiling showed responders to be more likely to harbor NEFH, USH2A and PTCH1 mutations, while non-responders were more likely to carry PIK3R1, APC and PALB2 mutations. Sequencing of serial biopsies showed downregulation of BRD4, PTCH1, KIT, NTRK1 and CREBBP after Len treatment. Conclusions: Len+Let showed significant anti-tumor activity with meaningful duration of response, even in pts who failed prior CT or ET+CDK4/6i. The results support further investigation in randomized studies. Tumor profiling identified mutations associated with response and insights on molecular effects of lenvatinib. Clinical trial information: NCT02562118 .

e19385 Background: Pembrolizumab has dramatically improved the survival of patients with non-small cell lung cancer (NSCLC) and is considered the standard of care for first line treatment of NSCLC who do not harbour oncogenic drivers. The fixed dose of 200mg was approved by the US Food and Drug Administration. The dose of 200mg was based on pharmacokinetic analysis. Studies have demonstrated equivalent efficacy with weight-based dosing 2mg/kg. An average Asian weighs 50-60kg. We aimed to look at the efficacy of pembrolizumab at a low fixed dose compared to the standard dosing. Methods: A review of all consecutive patients receiving pembrolizumab for advanced NSCLC from January 2016 to December 2019 in a large, high-volume academic medical centre, the National University Hospital, Singapore was conducted. Data fields collected include patient’s demographics, treatment doses and clinical characteristics. Time on treatment and overall survival were analysed using the Kaplan Meier method. Results: In total, 92 ECOG 0-2 patients with advanced NSCLC were treated with pembrolizumab. Median age was 69 years (Range, 29-92). Most were males (76%) and Chinese race (68%). Of the 92 patients, 46 (50%) and 46 (50%) received 100mg (Pem100) and 200mg (Pem200) of pembrolizumab respectively. Pembrolizumab was prescribed as first line in 73 (79%) and second line in 19 patients (21%). The average dose of pembrolizumab received in the low dose group was 1.87mg/kg (Range, 1.24mg/kg – 2.70mg/kg). 88 patients were included in the survival analysis. 4 were excluded due to the presence of an oncogenic driver. Patients were followed up for a median of 13.2 months. There was no difference in progression free survival between Pem100 and Pem200 for first-line single agent and when combined with chemotherapy (PFS: NR versus 5.3months, HR 2.17, 95% CI 0.76-6.16, p = 0.15 and NR vs 16.9 months, HR 2.89, 95% CI 0.35-25.16, p = 0.33 respectively). For patients who received pembrolizumab in the first line setting, the response rate was 56% vs 20% (p = 0.07), 67% vs 52% (p = 0.69) for Pem100 and Pem200 as a single agent and when combined with chemotherapy respectively. The median number of cycles received was 8.9 (Range, 1-60 cycles), translating to estimated cost savings of SGD 45 395 (~ USD 32 664) per patient who received Pem100. Conclusions: A lower fixed dose of pembrolizumab at 100mg showed no difference in progression free survival and response rate in an Asian cohort with significant cost savings. A further randomised controlled trial in an Asian population should be carried out.

The 3-weekly regimen of carboplatin and paclitaxel is the backbone of first line adjuvant chemotherapy for advanced ovarian cancer. The landmark Japanese Gynaecologic Oncology Group (JGOG) 3016 study demonstrated significant improvements in progression-free survival and overall survival with dose dense weekly administration of paclitaxel in combination with 3-weekly carboplatin. However, efforts to replicate these benefits have failed in subsequent phase III trials. Weekly paclitaxel is purported to have enhanced antitumor activity, with stronger anti-angiogenic effects, and yet is better tolerated. In this review, we explore the rationale for dose dense weekly paclitaxel, and compare the relevant trials as well as quality of life considerations. Possible reasons for the difference in outcomes between the JGOG 3016 and other studies are reviewed, with a focus on how the addition of bevacizumab, the variations between histological and molecular subtypes of epithelial ovarian cancers, and ethnic pharmacogenetic differences may potentially affect the efficacy of dose dense paclitaxel.

Drug resistance invariably limits the response of oncogene-addicted cancer cells to targeted therapy. The upregulation of signal transducer and activator of transcription 3 (STAT3) has been implicated as a mechanism of drug resistance in a range of oncogene-addicted cancers. However, the development of inhibitors against STAT3 has been fraught with challenges such as poor delivery or lack of specificity. Clinical experience with small molecule STAT3 inhibitors has seen efficacy signals, but this success has been tempered by drug limiting toxicities from off-target adverse events. It has emerged in recent years that, contrary to the Warburg theory, certain tumor types undergo metabolic reprogramming towards oxidative phosphorylation (OXPHOS) to satisfy their energy production. In particular, certain drug-resistant oncogene-addicted tumors have been found to rely on OXPHOS as a mechanism of survival. Multiple cellular signaling pathways converge on STAT3, hence the localization of STAT3 to the mitochondria may provide the link between oncogene-induced signaling pathways and cancer cell metabolism. In this article, we review the role of STAT3 and OXPHOS as targets of novel therapeutic strategies aimed at restoring drug sensitivity in treatment-resistant oncogene-addicted tumor types. Apart from drugs which have been re-purposed as OXPHOS inhibitors for-anti-cancer therapy (e.g., metformin and phenformin), several novel compounds in the drug-development pipeline have demonstrated promising pre-clinical and clinical activity. However, the clinical development of OXPHOS inhibitors remains in its infancy. The further identification of compounds with acceptable toxicity profiles, alongside the discovery of robust companion biomarkers of OXPHOS inhibition, would represent tangible early steps in transforming the therapeutic landscape of cancer cell metabolism., Highlights • Metabolic reprogramming of cancer cells is one of the hallmarks of cancer. • STAT3 and OXPHOS upregulation are resistance mechanisms in oncogene-addicted tumors. • mSTAT3 has a role in the direct, non-transcriptional regulation of OXPHOS. • Combining OXPHOS inhibitors with TKIs reverses resistance to targeted therapy.

A 2-week-old female Thoroughbred foal was born with a firm, expansile, progressively enlarging mass involving the left hemimandible. Grossly, the mass was composed of variably sized cavernous spaces containing clotted blood and serofibrinous exudate, separated by fibrous and fibroosseous septa. Histologically, the spaces were lined by flattened to plump spindle cells and contained hemorrhage, fibrin, and multinucleated osteoclast-like cells. The septa separating adjacent cavernous spaces contained interlacing bundles and streams of spindle cells, multinucleated giant cells, hemosiderophages, mineral deposits, and spicules and trabeculae of reactive and poorly mineralized bone. A diagnosis of congenital aneurysmal bone cyst was made based on histologic features. The pathogenesis for the development of aneurysmal bone cysts is still undetermined, although spindle cells lining cavernous spaces in the foal exhibited negative immunolabeling for factor-VIII (F8) and positive immunolabeling for smooth muscle actin, suggesting vascular smooth muscle origin and possible blood flow disturbance.

2588Background: Varlitinib (V) is a reversible inhibitor of HER1/HER2/HER4. This is a phase 1b dose confirmation study to determine safety and early efficacy signals of V ± T combined with weekly P...

Background Hospital in-patient laboratory testing is steadily rising, contributing to increasing healthcare costs, errors, and unnecessary treatments. Strategies to reduce over-utilization of laboratory tests have been tried with mixed results. Objectives To reduce the volume of the most frequently ordered laboratory tests by 10% over 6 months. Methods The most commonly ordered tests in medical wards were determined and a survey was conducted among residents and faculty to determine the perceived causes of over-testing. A resident-led multilevel collaborative campaign was launched. This comprised of education sessions (intern and resident teaching), cost awareness information (mini cards, computer screensavers), publicity (reminders to on-call teams), regular audits and feedback. The focus was on changing test ordering behavior and culture. Monthly average test numbers were compared with those in the preceding year. Results The campaign was launched in 8 medical wards from the period of September 2014 to February 2015. The top 6 laboratory tests/panels (full blood count, renal panel, calcium panel, liver panel, C-reactive protein and acute coronary screen) were selected based on order-volume. There was a 9.4% reduction in tests ordered during the study period, resulting in costs savings estimated at $34,235 per month. Results were sustained over the 6-month study period. Reduced testing had no effect on in-hospital mortality (3.17% post-intervention vs. 3.02% pre-intervention, p=0.47). Conclusions The development of a multilevel collaborative initiative resulted in reduction in test-ordering and significant and sustained costs savings. Approaches targeting culture change may be a feasible method of maintaining a lean health care system.