Recent Progress in the Systemic Treatment of Advanced/Metastatic Cholangiocarcinoma

Cholangiocarcinomas (CCAs) comprise of a heterogeneous group of cancers arising in the biliary tract (intrahepatic or iCCA, perihilar or pCCA and distal or dCCA; the latter are known under the collective term of eCCA), each subtype having its own particularities in carcinogenesis, management and prognosis. The increasing incidence in recent decades, limited treatment options and high mortality rates, even in the early stages, have led to an imperious need for more in-depth understanding and development of tailored treatments for this type of aggressive tumour. The wide use of molecular profiling has increased the understanding of biology and identified key molecular drivers, for example, IDH1 mutations or FGFR2 fusions for iCCA, or BRAF mutations in eCCA. Most recently, the FDA approved pemigatinib, an FGFR inhibitor and ivosidenib, an IDH1 inhibitor, but even though progress has been made to better understand the mechanisms of tumorigenesis, genetic make-up, and tumour resistance to standard chemotherapy and targeted therapies, cholangiocarcinomas still represent an important challenge in the daily clinical practice of oncology. The purpose of this review is to highlight the recent progress in the systemic treatment of advanced/metastatic CCAs with a focus on targeted drugs and their biomarkers currently evaluated in early-phase clinical trials

Dynamics of neutrophils to lymphocyte ratio (NLR) predict outcomes of PD-1/PD-L1 blockade

Introduction. Baseline neutrophil-to-lymphocyte ratio (NLR) has been repeatedly reported as a significant prognostic factor in advanced cancer patients. We explored whether changes in NLR may predict outcome of advanced cancer patients enrolled into phase 1 trials and treated with PD-1/PD-L1 inhibitors. Patients and Methods. Advanced cancer patients enrolled into phase 1 trials between September 2013 and May 2016 and treated with anti-PD-1/PD-L1 agents were included in this retrospective study. NLR was calculated at baseline and after 2 cycles of treatment. Royal Marsden Hospital (RMH) prognostic score and Eastern Cooperative Group (ECOG) performance status (PS) were determined at baseline. Kaplan-Meier estimation and Cox regression analyses were used to assess the impact of NLR dynamics on PFS. Results. Among the 55 patients eligible, 26 (47%) were treated with anti-PD-L1 monotherapy, 22 (40%) received single agent anti-PD-1, and 7 (13%) were given a tyrosine kinase inhibitor (TKI) plus a PD-1 inhibitor. Neither ECOG PS nor RMH prognostic score was significantly associated with PFS in our cohort, whereas changes in NLR significantly impacted on PFS. Conclusion. Changes in the NLR may be a useful predicting factor in advanced cancer patients treated with anti-PD-1/PD-L1 agents. Further prospective trials are needed to verify these findings

Dabrafenib and trametinib activity in a patient with BRAF V600E mutated and microsatellite instability high (MSI-H) metastatic endometrial cancer

BACKGROUND: Targeting BRAF V600E mutation has been proven effective in the treatment of several types of cancer. In endometrial adenocarcinoma, the BRAF V600E mutation has been rarely reported. Whether targeting BRAF oncogene may represent a plausible therapeutic strategy for the rare patients with BRAF-mutated endometrial cancer remains to be ascertained in prospective studies. CASE PRESENTATION: We report herein the case of a heavily pre-treated patient with recurrent microsatellite instability high (MSI-H) BRAF V600E mutated endometrial adenocarcinoma, which was successfully treated with the V600E targeting agent dabrafenib. After developing resistance to this agent, the MEK targeting agent trametinib was added to dabrafenib achieving again a therapeutic response. CONCLUSIONS: This case shows that dabrafenib both as monotherapy and when combined with trametinib may exert significant therapeutic activity in heavily pretreated BRAF V600E mutated endometrial adenocarcinoma, and highlight potential benefits of personalized treatment in this disease

Early mortality and overall survival in oncology phase I trial participants: can we improve patient selection?

<p>Abstract</p> <p>Background</p> <p>Patient selection for phase I trials (PIT) in oncology is challenging. A typical inclusion criterion for PIT is 'life expectancy > 3 months', however the 90 day mortality (90DM) and overall survival (OS) of patients with advanced solid malignancies are difficult to predict.</p> <p>Methods</p> <p>We analyzed 233 patients who were enrolled in PIT at Princess Margaret Hospital. We assessed the relationship between 17 clinical characteristics and 90DM using univariate and multivariate logistic regression analyses to create a risk score (PMHI). We also applied the Royal Marsden Hospital risk score (RMI), which consists of 3 markers (albumin < 35g/L, > 2 metastatic sites, LDH > ULN).</p> <p>Results</p> <p>Median age was 57 years (range 21-88). The 90DM rate was 14%; median OS was 320 days. Predictors of 90DM were albumin < 35g/L (OR = 8.2, p = 0.01), > 2 metastatic sites (OR = 2.6, p = 0.02), and ECOG > 0 (OR = 6.3, p = 0.001); all 3 factors constitute the PMHI. To predict 90DM, the PMHI performed better than the RMI (AUC = 0.78 vs 0.69). To predict OS, the RMI performed slightly better (RMI ≥ 2, HR = 2.2, p = 0.002 vs PMHI ≥ 2, HR = 1.6, p = 0.05).</p> <p>Conclusions</p> <p>To predict 90DM, the PMHI is helpful. To predict OS, risk models should include ECOG > 0, > 2 metastatic sites, and LDH > ULN. Prospective validation of the PMHI is warranted.</p

Pharmacokinetics and safety of capmatinib with food in patients with MET-dysregulated advanced solid tumors

Purpose: In the Phase II GEOMETRY mono-1 study, the potent and selective mesenchymal-epithelial transition (MET) inhibitor capmatinib exhibited considerable efficacy in MET exon 14 skipping (METex14)–mutated metastatic non–small cell lung cancer at a dose of 400 mg BID. The current recommended dose is 400 mg BID in tablet formulation, with or without food. This article reports the pharmacokinetic (PK) profile, safety, and tolerability of capmatinib 300 and 400 mg BID given with food in MET-dysregulated advanced solid tumors. Methods: This multicenter, open-label, Phase I study enrolled adult patients with MET-dysregulated advanced solid tumors. In the dose escalation phase, capmatinib tablets were orally administered at a dose of 300 mg BID with food; if tolerated, the dose escalation cohort of 400 mg BID was to be opened to enrollment. In the expansion phase, patients were to be enrolled at the higher of the tolerated doses. Tablets were taken within 30 minutes of an unrestricted meal type, except on cycle 1 day 1 (C1D1) and cycle 1 day 7 (C1D7), when they were given with a high-fat meal. The primary objectives were to determine the higher of the tolerated study doses and assess PK variables, with a secondary objective of safety. Findings: Overall, 35 patients (300 mg BID, n = 8; 400 mg BID, n = 27) with MET-dysregulated advanced solid tumors were enrolled; all patients had received prior antineoplastic therapy, and the most common primary site was lung (45.7%). Among PK-evaluable patients, the median T for capmatinib after administration with a high-fat meal (on C1D1/C1D7) was 4.0 to 5.6 hours across doses. At steady state (C1D7), capmatinib accumulation was low across dose levels (geometric mean of accumulation ratios, 1.29–1.69), with an increase in exposure (AUC and C ) from 300 to 400 mg BID. There were no occurrences of dose-limiting toxicity. All patients experienced at least 1 adverse event, and treatment-related adverse events occurred in 28 patients (80%; 300 mg BID, n = 6; 400 mg BID, n = 22), the most frequent of which were fatigue (37.1%) and nausea (34.3%). Implications: Capmatinib tablet formulation at a dose of up to 400 mg BID with food is well tolerated in patients with MET-dysregulated advanced solid tumors, with safety observations consistent with the existing profile under fasted conditions. These findings support the capmatinib dosing recommendation of 400 mg BID with or without food. ClinicalTrials.gov identifier: NCT02925104

A retrospective analysis of clinical outcome of patients with chemo-refractory metastatic breast cancer treated in a single institution phase I unit

BACKGROUND AND METHODS: Novel approaches to treat chemo-refractory metastatic breast cancer (MBC) are currently under investigation. This retrospective series reviews the outcome of 70 MBC patients who have participated in 30 phase I trials at the Royal Marsden Hospital from 2002 to 2009. RESULTS: The median treatment lines before phase I trial entry for MBC was 5 (range: 1-12 lines). The overall response rate was 11.4% (95% CI: 4.0-18.9%) and the clinical benefit rate at 4 months was 20% (95% CI: 10.6-29.3). The median time to progression was 7.0 weeks (95% CI: 6.4-7.5) and median overall survival was 8.7 months (95% CI: 7.6-9.8) from start of first phase I treatment. No patients discontinued trial because of treatment-related toxicities. Abnormal lactate dehydrogenase, serum albumin <35 mg per 100 ml, >or=5 previous treatment lines, liver metastases and Eastern Cooperative Group performance status >or=2 at study entry were significantly associated with poor overall survival in multivariate analysis. CONCLUSION: This retrospective analysis provides evidence that patients with MBC tolerate phase I clinical trials and a significant proportion of patients with chemo-refractory disease, particularly those with triple-negative or Her2-positive breast cancer, may benefit from treatment

A phase 1b study evaluating the safety and preliminary efficacy of berzosertib in combination with gemcitabine in patients with advanced non-small cell lung cancer

OBJECTIVES: Berzosertib (formerly M6620, VX-970) is an intravenous, highly potent and selective, first-in-class ataxia telangiectasia and Rad3-related (ATR) protein kinase inhibitor. We assessed the safety, tolerability, preliminary efficacy, and pharmacokinetics (PK) of berzosertib plus gemcitabine in an expansion cohort of patients with advanced non-small cell lung cancer (NSCLC). The association of efficacy with TP53 status and other tumor markers was also explored. MATERIALS AND METHODS: Adult patients with advanced histologically confirmed NSCLC received berzosertib 210 mg/m2 (days 2 and 9) and gemcitabine 1000 mg/m2 (days 1 and 8) at the recommended phase 2 dose established in the dose escalation part of the study. RESULTS: Thirty-eight patients received at least one dose of study treatment. The most common treatment-emergent adverse events were fatigue (55.3%), anemia (52.6%), and nausea (39.5%). Gemcitabine had no apparent effect on the PK of berzosertib. The objective response rate (ORR) was 10.5% (4/38, 90% confidence interval [CI]: 3.7–22.5%). In the exploratory analysis, the ORR was 30.0% (3/10, 90% CI: 9.0–61.0%) in patients with high loss of heterozygosity (LOH) and 11.0% (1/9, 90% CI: 1.0–43.0%) in patients with low LOH. The ORR was 33.0% (2/6, 90% CI: 6.0–73.0%) in patients with high tumor mutational burden (TMB), 12.5% (2/16, 90% CI: 2.0–34.0%) in patients with intermediate TMB, and 0% (0/3, 90% CI: 0.0–53.6%) in patients with low TMB. CONCLUSIONS: Berzosertib plus gemcitabine was well tolerated in patients with advanced, pre-treated NSCLC. Based on the observed clinical efficacy, future clinical trials should involve genomically selected patients

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC

INTRODUCTION: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)-positive NSCLC (cohort E) are reported (NCT02443324). METHODS: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell-inflamed, Gajewski, and effector T cells) and CD274 gene expression. RESULTS: Cohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%-49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry. CONCLUSIONS: First-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression