A phase 1b study of OXIRI in pancreatic adenocarcinoma patients and its immunomodulatory effects.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and debilitating disease with limited therapeutic options. The aim of this clinical study was to evaluate the safety, efficacy and pharmacokinetics of a novel regimen comprised of metronomic oxaliplatin (O), chronomodulated capecitabine (X) and UGT1A1 genotype-guided dosing of irinotecan (IRI) [OXIRI] as well as its immunomodulatory effects. Thirty-six patients were enrolled into either dose-escalation or expansion cohorts. In the dose escalation phase, capecitabine doses (2000, 2650, 3500 and 4500 mg/day) were administered at midnight on days 1 to 14 while oxaliplatin and irinotecan were intravenously infused at fixed doses of 50 and 75 mg/m2 respectively on days 1, 8 in a 21-day cycle. The maximum tolerated dose of capecitabine was 2650 mg/day and the most common grade 3 adverse events were neutropenia (30.6%) and diarrhea (13.9%). No grade 4 toxicity was observed. UGT1A1-genotype directed dosing resulted in similar exposure levels of irinotecan, SN-38 and SN-38G in all patients. Objective response rate was 22.2%. Median overall survival and progression-free survival were 8.1 and 5.2 months, respectively. Exploratory immunoprofiling by flow cytometry and quantitative spatial localization analysis of infiltrated immune cells performed on biopsy and plasma samples revealed significant declines in CCL22, CCL2 and TNFα levels at end of first cycle and an active host immune response. Our study showed that OXIRI was well-tolerated and exhibited good efficacy, with immunomodulatory effects. It may be considered as an alternative to FOLFIRINOX in patients intolerant to the latter.

Real-world outcomes of pemetrexed-platinum chemotherapy plus osimertinib after progression on first-line osimertinib in advanced EGFR-mutated NSCLC.

OBJECTIVES: First-line pemetrexed-platinum chemotherapy + osimertinib(Pem-Plat-Osi) improves progression-free survival as compared to osimertinib alone in advanced epidermal growth factor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, many patients are hesitant to commence chemotherapy upfront. We describe outcomes to Pem-Plat-Osi after first-line osimertinib failure. MATERIALS AND METHODS: Patients with advanced EGFR-mutated (ex19del/L858R) NSCLC who had Pem-Plat-Osi between 1/7/2018-30/9/2023 after progression on first-line osimertinib at National Cancer Centre Singapore, Prince of Wales Hospital and Chinese University of Hong Kong were identified. Key endpoints were time to treatment failure (TTF) and overall survival (OS). RESULTS: A total of 60 patients were included. Median age at diagnosis was 62, 53.3 % (32/60) were male and 76.7 % (46/60) were never smokers. Ex19del comprised 56.7 % (34/60) and L858R 43.3 % (26/60). Baseline central nervous system (CNS) metastases were present in 66.7 % (40/60). Median TTF on osimertinib (TTF1) was 14.4 months(m) and median time to initiation of Pem-Plat-Osi was 41 days(d) (range 0-652) after progression on osimertinib. Partial response (PR) or stable disease to Pem-Plat-Osi was achieved in 81.7 %(49/60). Intracranial disease control was achieved in 90.6 % (29/32) of patients with measurable CNS metastases, including those who did not undergo brain radiotherapy. At median follow up of 31.2 m, median TTF on Pem-Plat-Osi (TTF2) was 6.6 m. Median TTF1 + TTF2 was 23.4 m and median OS was 34.2 m. Survival outcomes were similar comparing ex19del and L858R (median TTF1 + TTF2 21.8 m vs 23.5 m, p = 0.90; median OS 34.2 m vs 36.8 m, p = 0.37) and in patients without/with baseline CNS metastases (median TTF1 + TTF2 21.8 m vs 23.4 m, p = 0.44; median OS 36.2 m vs 31.9 m, p = 0.65). TTF1 duration was not significantly associated with TTF2 (p = 0.76). Patients who started Pem-Plat-Osi within 20d of progression on osimertinib had significantly longer TTF2 as compared to patients who started after 20d (median 8.4 m versus 6.0 months, p = 0.03), which remained statistically significant on multivariable analysis. CONCLUSIONS: Our real-world data supports the efficacy of Pem-Plat-Osi after progression on first-line osimertinib, including L858R and baseline CNS metastases. Chemotherapy initiation within 20d of Osi progression was predictive of superior TTF2.

A phase I study of an adenoviral vector delivering a MUC1/CD40-ligand fusion protein in patients with advanced adenocarcinoma.

Cancer vaccines as immunotherapy for solid tumours are currently in development with promising results. We report a phase 1 study of Ad-sig-hMUC1/ecdCD40L (NCT02140996), an adenoviral-vector vaccine encoding the tumour-associated antigen MUC1 linked to CD40 ligand, in patients with advanced adenocarcinoma. The primary objective of this study is safety and tolerability. We also study the immunome in vaccinated patients as a secondary outcome. This trial, while not designed to determine clinical efficacy, reports an exploratory endpoint of overall response rate. The study meets its pre-specified primary endpoint demonstrating safety and tolerability in a cohort of 21 patients with advanced adenocarcinomas (breast, lung and ovary). The maximal dose of the vaccine is 1 ×1011 viral particles, with no dose limiting toxicities. All drug related adverse events are of low grades, most commonly injection site reactions in 15 (71%) patients. Using exploratory high-dimensional analyses, we find both quantitative and relational changes in the cancer immunome after vaccination. Our data highlights the utility of high-dimensional analyses in understanding and predicting effective immunotherapy, underscoring the importance of immune competency in cancer prognosis.

Individualized Molecular Profiling for Allocation to Clinical Trials Singapore Study-An Asian Tertiary Cancer Center Experience.

PURPOSE: Precision oncology has transformed the management of advanced cancers through implementation of advanced molecular profiling technologies to identify increasingly defined subsets of patients and match them to appropriate therapy. We report outcomes of a prospective molecular profiling study in a high-volume Asian tertiary cancer center. PATIENTS AND METHODS: Patients with advanced cancer were enrolled onto a prospective protocol for genomic profiling, the Individualized Molecular Profiling for Allocation to Clinical Trials Singapore study, at the National Cancer Center Singapore. Primary objective was to identify molecular biomarkers in patient's tumors for allocation to clinical trials. The study commenced in February 2012 and is ongoing, with the results of all patients who underwent multiplex next-generation sequencing (NGS) testing until December 2018 presented here. The results were discussed at a molecular tumor board where recommendations for allocation to biomarker-directed trials or targeted therapies were made. RESULTS: One thousand fifteen patients were enrolled with a median age of 58 years (range 20-83 years). Most common tumor types were lung adenocarcinoma (26%), colorectal cancer (15%), and breast cancer (12%). A total of 1,064 NGS assays were performed, on fresh tumor tissue for 369 (35%) and archival tumor tissue for 687 (65%) assays. TP53 (39%) alterations were most common, followed by EGFR (21%), KRAS (14%), and PIK3CA (10%). Of 405 NGS assays with potentially actionable alterations, 111 (27%) were allocated to a clinical trial after molecular tumor board and 20 (4.9%) were enrolled on a molecularly matched clinical trial. Gene fusions were detected in 23 of 311 (7%) patients tested, including rare fusions in new tumor types and known fusions in rare tumors. CONCLUSION: Individualized Molecular Profiling for Allocation to Clinical Trials Singapore demonstrates the feasibility of a prospective broad molecular profiling program in an Asian tertiary cancer center, with the ability to develop and adapt to a dynamic landscape of precision oncology.

Multiplex immunohistochemistry/immunofluorescence (mIHC/IF) for PD-L1 testing in triple-negative breast cancer: a translational assay compared with conventional IHC.

BACKGROUND: Programmed death-ligand 1 (PD-L1) monoclonal antibody therapy has recently gained approval for treating metastatic triple-negative breast cancer (TNBC) -, in particular in the PD-L1+ patient subgroup of the recent IMpassion130 trial. The SP142 PD-L1 antibody clone was used as a predictive assay in this trial, but this clone was found to be an outlier in previous harmonisation studies in lung cancer. AIMS: To address the comparability of PD-L1 clones in TNBC, we evaluated the concordance between conventional immunohistochemistry (IHC) and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) that allowed simultaneous quantification of three different PD-L1 antibodies (22C3, SP142 and SP263). METHODS: Our cohort comprised 25 TNBC cases, 12 non-small-cell lung carcinomas and 8 other cancers. EpCAM labelling was used to distinguish tumour cells from immune cells. RESULTS: Moderate-to-strong correlations in PD-L1 positivity were found between results obtained through mIHC/IF and IHC. Individual concordance rates in the study ranged from 67% to 100%, with Spearman's rank correlation coefficient values up to 0.88. CONCLUSIONS: mIHC/IF represents a promising tool in the era of cancer immunotherapy, as it can simultaneously detect and quantify PD-L1 labelling with multiple antibody clones, and allow accurate evaluation of tumour and immune cells. Clinicians and pathologists require this information to predict patient response to anti-PD-1/PD-L1 therapy. The adoption of this assay may represent a significant advance in the management of therapeutically challenging cancers. Further analysis and assay harmonisation are essential for translation to a routine diagnostic setting.

Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC.

INTRODUCTION: RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes. METHODS: This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected. RESULTS: A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009). CONCLUSIONS: In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance.