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Background We evaluated the relevance of PD-1+CD8+ T-cells in gastric cancer (GC) including prognostic significance, association with chemotherapy and immunotherapy sensitivity and correlations with the tumor microenvironment (TME). Methods Discovery cohort: GC samples were evaluated for AE1/3, CD8, PD-1, Ki-67 and Granzyme-B expression with fluorescence-based multiplex immunohistochemistry (mIHC). Validation cohorts: we analyzed bulk RNAseq GC datasets from TCGA, the “3G” chemotherapy trial and an immunotherapy phase 2 trial. The cox proportional hazards model was used to identify factors that influenced overall survival (OS). To study the TME, we analyzed single-cell RNAseq performed on GCs. Results In the discovery cohort of 350 GCs, increased PD-1 expression of CD8 T-cells was prognostic for OS (HR 0.822, p = 0.042). PD-1 expression in CD8 T-cells highly correlated with cytolytic [Granzyme-B+] (r = 0.714, p +] (r = 0.798, p PD-1 and CD8A expression levels had improved OS when treated with immunotherapy (HR 0.117, p = 0.036) and chemotherapy (HR 0.475, p = 0.017). Analysis of an scRNAseq dataset of 152,423 cells from 40 GCs revealed that T-cell and NK-cell proportions were higher (24% vs 18% and 19% vs 15%, p p high compared to CD8PD-1low tumors. Conclusion This is one of the largest GC cohorts of mIHC combined with analysis of multiple datasets providing orthogonal validation of the clinical relevance of PD-1+CD8+ T-cells being associated with improved OS. CD8PD-1high tumors have distinct features of an immunologically active, T-cell inflamed TME.

Purpose:Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies.Patients and Methods:In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy.Results:In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91–603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0–12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment.Conclusions:NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.

Purpose:Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability.Patients and Methods:We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2.Results:This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively.Conclusions:The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases.See related commentary by de Jong et al., p. 1830

Mean concentration-time profiles of pressurized intraperitoneal aerosol chemotherapy (PIPAC) oxaliplatin (n = 14) in plasmatot (A) and ultrafiltrate (B)

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

The area under the curve(AUC) ratio (Ultrafiltrate(UF) vs Plasmatot) at different dose levels

Supplementary Materials, Figures

Study timeline

Supplementary tables and figures

Introduction Peritoneal carcinomatosis is difficult to treat. Pressurized Intra-Peritoneal Aerosolised Chemotherapy (PIPAC) is a novel method of delivering chemotherapy to the peritoneal cavity, aiming for homogenous and deeper drug distribution. To date, limited chemotherapeutics have been used with promising results. Here, we evaluate the pharmacokinetics, peritoneal tissue drug concentration, penetration, and short-term safety of PIPAC using solvent-based paclitaxel in swine to guide clinical trials. Materials and methods PIPAC solvent-based paclitaxel was administered at 60, 30, and 15mg/m2 for 3 cohorts. Each PIPAC procedure was followed by intravenous (IV) administration of the same dose of solvent-based paclitaxel on Day 7, serving as control for pharmacokinetic comparison in the same pig. Safety and toxicity were evaluated by clinical assessment, blood counts and biochemistry. Blood samples were taken for pharmacokinetic analysis. Peritoneal biopsies were taken to measure tissue paclitaxel concentrations and distribution. Results 12 Yorkshire x Landrace pigs underwent trial procedures. With PIPAC, there was linear pharmacokinetics and lower systemic exposure to paclitaxel compared to IV administration. MALDI-MSI demonstrated concentration of paclitaxel at the peritoneal surface, with estimated 2 mm penetration. PIPAC paclitaxel had favorable toxicity profile. The most significant adverse event was neutropenia which was dose dependent, with absolute neutrophil count Conclusion PIPAC paclitaxel at 15mg/m2 may be considered for a Phase I study.

Breast cancers are heterogeneous with variable clinical courses and treatment responses.We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents.Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOncoThirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029).Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy.ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).

Purpose: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel laparoscopic, intraperitoneal chemotherapy delivery technique aiming to improve drug distribution and tissue penetration to treat peritoneal metastases. Thus far, PIPAC oxaliplatin is conducted at an arbitrary dose of 92 mg/m2. We conducted a phase I study to establish safety and tolerability. Patients and Methods: We used a 3+3 dose-escalation design of PIPAC oxaliplatin for patients with peritoneal metastases from gastrointestinal tumors, after failure of at least first-line chemotherapy. Dose levels were planned at 45, 60, 90, and 120 mg/m2. Results: This study included 16 patients with 24 PIPAC procedures (8 gastric; 5 colorectal; and 1 gallbladder, pancreas, and appendix cancer each). Median age and peritoneal cancer index (PCI) score were 62 years and 17, respectively. Two patients developed pancreatitis (grade 2 and 3) at 45 mg/m2, necessitating cohort expansion. Another patient developed grade 2 pancreatitis at 90 mg/m2. There were no other dose-limiting toxicities, and the highest-dose cohort (120 mg/m2) tolerated PIPAC well. Pharmacokinetic analyses demonstrated good linearity between dose and maximum concentration (r2 = 0.95) and AUC (r2 = 0.99). On the basis of RECIST, 62.5% and 50% had stable disease after one and two PIPAC procedures, respectively. A total of 8 patients underwent two PIPAC procedures, with improvement of median PCI and peritoneal regression grade score from 15 to 12 and 2.5 to 2.0, respectively. Conclusions: The recommended phase II dose is 120 mg/m2. Future studies should further delineate the efficacy and role of PIPAC oxaliplatin for peritoneal metastases. See related commentary by de Jong et al., p. 1830

Adding intraperitoneal paclitaxel (IP-PTX) to paclitaxel/5-fluoropyrimidine has shown promising results in patients with gastric cancer peritoneal metastases (GCPM) but has not been studied with standard-of-care platinum/fluoropyrimidine combinations. Our goal to was evaluate IP-PTX with capecitabine/oxaliplatin (XELOX) in GCPM.Forty-four patients with GCPM received IP PTX (40 mg/mThe median OS for the IP and SC groups was 14.6 and 10.6 months (hazard ratio [HR] 0.44; 95% confidence interval [CI], 0.26-0.74; p = 0.002). The median PFS for the IP and SC group was 9.5 and 4.4 months respectively (HR 0.39; 95% CI 0.25-0.66; p 0.001). Patients in the SC group were younger (IP vs. SC, 61 vs. 56 years, p = 0.021) and had better performance status (ECOG 0, IP vs. SC, 47.7% vs. 76.9%, p = 0.007) compared with the IP cohort. In IP group, conversion surgery was performed in 36.1% (13/36) of patients, with a median OS of 24.2 (95% CI 13.1-35.3) months and 1-year OS of 84.6%.IP PTX with XELOX is a promising treatment option for GCPM patients. In patients with good response, conversion surgery was feasible with favourable outcomes.

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).

3584 Background: Trifluridine/tipiracil (TAS-102) is currently approved as third-line treatment in metastatic colorectal cancer (mCRC). However, there is paucity of real-world data on the tolerability and efficacy with biweekly dosing as monotherapy or in combination with bevacizumab. In this study, we present our center’s experience with biweekly TAS-102 with or without bevacizumab in mCRC patients (pts). Methods: We performed a single center retrospective observational study of pts receiving TAS-102 between 2018 and 2021. Results: A total of 83 pts were included (53 men, 30 women), with a median age of 64 years. Majority of pts were treated with TAS-102 in the 3rd-line (48.2%) and 4th-line (28.9%) setting. Almost all (94.0%) were of ECOG ≤ 1 at the initiation of treatment. The mean number of cycles administered was 3.8 and bevacizumab (5mg/kg on Day 1, every 2 weeks) was used in combination with TAS-102 in 18 pts (21.7%). Majority of pts (84.3%) were given TAS-102 using the biweekly regimen (35mg/m2 BD, on Day 1-5 and 15-19, q28 days) rather than standard regimen (35mg/m2 BD, on Day 1-5 and 8-12, q28 days) following a change in institutional practice. Fifteen pts (18.1%) had their initial dose reduced to 30mg/m2 BD at prescriber's discretion. Median PFS and OS were 2.37 and 10.15 months, respectively. In terms of tolerability, fatigue (any grade, 42.2%) and neutropenia (any grade, 44.6%) were the two most common adverse events reported. Grade 3 or higher neutropenia and febrile neutropenia were 16.9% and 3.6%, respectively. Dose reduction during treatment was required in 15 pts (18.1%), dose delay in 31 pts (37.3%) and six pts (7.2%) discontinued treatment due to toxicity. More than half (54.2%) had at least an additional line of therapy (regorafenib, clinical trials or re-challenge previous chemotherapy agents) following disease progression with TAS-102. Conclusions: We report the largest real-world experience with biweekly TAS-102. Our pts treated with TAS-102 had comparable median PFS to the RECOURSE cohort but with significantly better OS as more than half continued to receive treatment. Biweekly dosing of TAS-102 with or without bevacizumab is well tolerated with significantly lower rates of Grade 3 neutropenia compared to the published data in the literature.

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: Natural killer (NK) cells exert antibody-dependent cell cytotoxicity (ADCC). We infused expanded, activated autologous NK cells to potentiate trastuzumab-mediated ADCC in patients with HER2-positive malignancies. Patients and Methods: In a phase I trial, patients with treatment-refractory HER2-positive solid tumors received trastuzumab, with or without bevacizumab, and autologous NK cells expanded by 10-day coculture with K562-mb15-41BBL cells. Primary objectives included safety and recommended phase II dose determination; secondary objectives included monitoring NK-cell activity and RECIST antitumor efficacy. Results: In 60 cultures with cells from 31 subjects, median NK-cell expansion from peripheral blood was 340-fold (range, 91–603). NK cells expressed high levels of CD16, the mediator of ADCC, and exerted powerful killing of trastuzumab-targeted cells. In the 22 subjects enrolled in phase I dose escalation, trastuzumab plus NK cells were well tolerated; MTD was not reached. Phase IB (n = 9) included multiple cycles of NK cells (1 × 107/kg) and addition of bevacizumab. Although no objective response was observed, 6 of 19 subjects who received at least 1 × 107/kg NK cells at cycle 1 had stable disease for ≥6 months (median, 8.8 months; range 6.0–12.0). One patient, the only one with the high-affinity F158V CD16 variant, had a partial response. Peripheral blood NK cells progressively downregulated CD16 postinfusion; paired tumor biopsies showed increased NK cells, lymphocytic infiltrates, and apoptosis posttreatment. Conclusions: NK-cell therapy in combination with trastuzumab was well tolerated, with target engagement and preliminary antitumor activity, supporting continued assessment of this approach in phase II trials.

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.

// Ross A. Soo 1, 2, 5 , Zhaojin Chen 3 , Rebecca Siew Yan Teng 4 , Hon-Lyn Tan 1 , Barry Iacopetta 5 , Bee Choo Tai 3, 6 and Richie Soong 2, 7 1 Department of Haematology-Oncology, National University Health System, Singapore 2 Cancer Science Institute of Singapore, National University of Singapore, Singapore 3 Investigational Medicine Unit, National University Health System, Singapore 4 Yong Loo Lin School of Medicine, National University of Singapore, Singapore 5 School of Surgery, The University of Western Australia, Perth, Australia 6 Saw Swee Hock School of Public Health, National University of Singapore, Singapore 7 Department of Pathology, National University Health System, Singapore Correspondence to: Ross A. Soo, email: ross_soo@nuhs.edu.sg Keywords: non-small cell lung cancer; immune cells; dendritic cells; tumor associated macrophages; mast cells Received: December 29, 2017 Accepted: March 06, 2018 Published: May 15, 2018 ABSTRACT Background: Tumor-associated immune cells are prognostic in non-small cell lung cancer (NSCLC) but findings have been conflicting. Objectives: To determine the prognostic role of immune cells according to localization in NSCLC patients. Methods: A systematic literature review and meta-analysis was performed on dendritic cell (DC), tumor associated macrophages (TAM), mast cells (MC), natural killer (NK) cells, T and B cells and tumor CTLA-4 and PD-L1 studies. Results: We analysed 96 articles ( n = 21,752 patients). Improved outcomes were seen with increased tumor DCs (overall survival (OS) hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.44–0.68), NK cells (OS HR 0.45; 0.31–0.65), TAMs (OS HR 0.33; 0.17–0.62), M1 TAMs (OS HR 0.10; 0.05–0.21), CD3+ T cells (disease specific survival (DSS) HR 0.64; 0.48–0.86), CD8+ T cells (OS HR 0.78; 0.66–0.93), B cells (OS HR 0.65; 0.42–0.99) and with increased stroma DC (DSS HR 0.62; 0.47–0.83), NK cells (DSS HR 0.51; 0.32–0.82), M1 TAMs (OS HR 0.63; 0.42–0.94), CD4+ T cells (OS HR 0.45; 0.21–0.94), CD8+ T cells (OS HR 0.77; 0.69–0.86) and B cells (OS HR 0.74;0.56–0.99). Poor outcomes were seen with stromal M2 TAMs (OS HR 1.44; 1.06–1.96) and Tregs (relapse free survival (RFS) HR 1.80; 1.34–2.43). Tumor PD-L1 was associated with worse OS (1.40; 1.20–1.69), RFS (1.67) and DFS (1.24). Conclusion: Tumor and stroma DC, NK cells, M1 TAMs, CD8+ T cells and B cells were associated with improved prognosis and tumor PD-L1, stromal M2 TAMs and Treg cells had poorer prognosis. Higher quality studies are required for confirmation.

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.

360 Background: PIPAC is a novel, laparoscopic intraperitoneal chemotherapy delivery technique which aims to improve on hyperthermic intraperitoneal chemotherapy (HIPEC), ameliorating drug distribution and tissue penetration. Thus far, PIPAC has been conducted with oxaliplatin chemotherapy in Europe, at an arbitrary dose of 92mg/m2; 150mg/m2 was found to be intolerable. We conducted a dose-escalation phase 1 study to establish the safety, tolerability and recommended phase 2 dose (RP2D) for PIPAC in Asian patients. Methods: This phase 1 study of oxaliplatin administered via PIPAC was designed as a traditional 3+3 dose escalation study for patients with predominant peritoneal metastasis from a gastrointestinal primary tumor, after failure of standard therapies. Dose levels were planned at 45, 60, 90 and 120mg/m2. Repeat doses of PIPAC were permitted, 6 weeks apart. Dose limiting toxicities (DLT) were defined as any clinically relevant grade 3 adverse events occurring within 28 days after PIPAC. Results: This study included 16 patients (25 PIPAC procedures; 8 gastric, 4 colorectal and 1 gallbladder, pancreas and appendix cancer each). Median age was 62 years, with a median peritoneal carcinomatosis index (PCI) score of 17 (range 1 - 39). Two patients developed pancreatitis (grade 2 and 3) on day 6 and day 9 after PIPAC administration at the dose cohort of 45mg/m2, necessitating cohort expansion to 6 patients. One patient was noted to have asymptomatic grade 3 hyperamylasemia (90mg/m2 cohort). There were no other DLTs and all 3 patients in the highest dose cohort (120mg/m2) tolerated PIPAC well. Nine patients who underwent a 2nd PIPAC procedure had a decrease in PCI score from 18.4 to 15.5; one patient at 120mg/m2 had an improvement in PCI from 30 to 12. Conclusions: The RP2D of PIPAC with oxaliplatin is 120mg/m2. Single agent PIPAC is well tolerated, and future studies with PIPAC must consider a bi-directional approach with the incorporation of systemic therapy, with either chemotherapy or immunotherapy to improve efficacy. Clinical trial information: NCT03172416.

BackgroundPressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel laparoscopic intraperitoneal chemotherapy technique, with advantages such as homogeneous distribution of aerosol and deeper tissue penetration. Thus far, PIPAC oxaliplatin has been administered at an arbitrary dose of 92 mg/m2.AimWe aim to determine the dose-related safety profile and tolerability of PIPAC oxaliplatin using an evidence-based approach. The secondary aim is to evaluate clinic-pathologic response and the pharmacokinetic profile.MethodsThis is a phase I 3+3 dose escalation study for gastric and colorectal cancer with predominant peritoneal metastasis starting at a dose of 45 mg/m2. Safety is assessed according to Clavien-Dindo Classification and Common Terminology Criteria for Adverse Events (version 4.0). Clinico-pathologic response is assessed using the Peritoneal Regression Grading Score, Peritoneal Cancer Index, and Response Evaluation Criteria In Solid Tumour criteria (version 1.1). Pharmacokinetic analysis is performed using Inductively Coupled Plasma-Mass Spectrometry assay. This trial is registered on ClinicalTrials.gov (NCT03172416).ConclusionsThis phase I study can provide the scientific basis to identify the optimal dose for PIPAC with oxaliplatin such that the benefits of this novel and promising intraperitoneal chemotherapy delivery technique can be maximized.

SUMMARY The management of advanced-stage NSCLC has been dramatically transformed by the recognition of histology-based treatment and the use of targeted therapy for molecular selected patients with adenocarcinoma. While outcomes have improved with adenocarcinoma, treatment options and outcomes are still limited in patients with advanced-stage squamous cell lung cancer. Through advances in the molecular characterization of squamous cell cancers, exciting novel targets have identified. In this paper, we will review the importance of histology in the treatment of NSCLC, existing chemotherapy and targeted therapies, the new molecular subsets and novel inhibitors in squamous cell lung carcinoma and the emerging role of immune checkpoint inhibitors.

The management of advanced stage nonsmall cell lung cancer (NSCLC) has been altered by the recognition of histology-based treatment and the use of targeted therapy. Whilst outcomes have improved with adenocarcinoma, treatment options are still limited in advanced stage squamous cell lung cancer. With advances in the molecular characterization of squamous cell cancers (SCCs), new potential targets have been identified. In this review, we discuss the role of histology in the treatment of NSCLC, cytotoxic chemotherapy, existing targeted therapies, the new molecular subsets and novel inhibitors in squamous cell lung carcinoma, and the emerging role of immune checkpoint inhibitors. Based on the results of two recent studies, nivolumab, a programmed death 1 (PD-1) immune checkpoint inhibitor, has been approved by the US Food and Drug Administration (FDA) in the treatment of squamous cell NSCLC in the second-line setting. Well-designed biomarker driven studies are needed to accelerate the development and approval of novel therapies for patients with lung SCC.