A drug safety evaluation of pemigatinib for advanced cholangiocarcinoma.

INTRODUCTION: Pemigatinib is a selective small-molecule inhibitor of the fibroblast growth factor receptor (FGFR) 1-3. FGFR is associated with increased cell division, proliferation, and survival. Inhibition of this receptor is an effective treatment against tumors driven by activated fusions in FGFR2. AREAS COVERED: The drug was first evaluated in patients with advanced solid tumors and demonstrated a manageable safety profile, with the most common adverse events being oscillations in blood phosphate levels, fatigue, gastrointestinal symptoms, and skin and ocular toxicities. Pemigatinib was further evaluated in a phase II cohort study of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 genomic alterations. After a median follow-up of 17.8 months, the objective response rate in patients with tumors harboring FGFR2 fusions or rearrangements was 35.5% (95% CI, 26.5-45.4). Based on these results, the FDA granted accelerated approval on 17 April 2020, to pemigatinib, for the treatment of adults with previously treated, unresectable locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or another rearrangement. Articles selected for this review were based on reported studies indexed in PubMed (2010-2023). EXPERT OPINION: Future perspectives in the treatment of FGFR2 fused cholangiocarcinoma include the evaluation of pemigatinib in previously untreated patients and possible active combinations or sequencing strategies with other drugs.

Characterization of Morreton virus as an oncolytic virotherapy platform for liver cancers.

BACKGROUND: Morreton virus (MORV) is an oncolytic Vesiculovirus , genetically distinct from vesicular stomatitis virus (VSV). AIM: To report that MORV induced potent cytopathic effects (CPEs) in cholangiocarcinoma (CCA) and hepatocellular carcinoma (HCC) in vitro models. APPROACH AND RESULTS: In preliminary safety analyses, high intranasal doses (up to 10 10 50% tissue culture infectious dose [TCID 50 ]) of MORV were not associated with significant adverse effects in immune competent, non-tumor-bearing mice. MORV was shown to be efficacious in a Hep3B hepatocellular cancer xenograft model but not in a CCA xenograft HuCCT1 model. In an immune competent, syngeneic murine CCA model, single intratumoral treatments with MORV (1 × 10 7 TCID 50 ) triggered a robust antitumor immune response leading to substantial tumor regression and disease control at a dose 10-fold lower than VSV (1 × 10 8 TCID 50 ). MORV led to increased CD8 + cytotoxic T cells without compensatory increases in tumor-associated macrophages and granulocytic or monocytic myeloid-derived suppressor cells. CONCLUSIONS: Our findings indicate that wild-type MORV is safe and can induce potent tumor regression via immune-mediated and immune-independent mechanisms in HCC and CCA animal models without dose limiting adverse events. These data warrant further development and clinical translation of MORV as an oncolytic virotherapy platform.

The Role of Systemic Therapy in Resectable Colorectal Liver Metastases: Systematic Review and Network Meta-Analysis.

BACKGROUND: Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. METHODS: We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). RESULTS: Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. CONCLUSIONS: This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.

Evaluation of NUC-1031: a first-in-class ProTide in biliary tract cancer.

PURPOSE: NUC1031 is a first-in-class ProTide, that is a gemcitabine pro-drug designed to overcome putative mechanisms of resistance, including decreased expression of hENT/hCNT transporters, absence of activating enzymes such as deoxycytidine kinase (dCK) and presence of degrading enzymes such as cytidine deaminase (CDA). We undertook comprehensive pre-clinical evaluation of NUC1031 in biliary tract cancer (BTC) models, given that gemcitabine/cisplatin is a standard first-line therapy in advanced BTC. METHODS: Here, we compared the in vitro activity of NUC1031 in comparison to gemcitabine, validate putative mechanism(s) of action, assessed potential biomarkers of sensitivity or resistance, and performed combination studies with cisplatin. We also evaluated the in vivo efficacy of NUC1031 and gemcitabine using a CDA-high cholangiocarcinoma patient-derived xenograft (PDX) model. RESULTS: In a panel of BTC cell lines (N = 10), NUC1031 had less potency than gemcitabine in multiple cellular assays. NUC1031 did not demonstrate evidence of greater synergy over gemcitabine in combination with cisplatin. Surprisingly, efficacy of both gemcitabine and NUC1031 was not found to be correlated with hENT/hCTN, dCK or CDA transcript levels. Gemcitabine and NUC1031 showed equivalent efficacy in a CDA-high PDX model in vivo contradicting the primary rationale of NUC1031 design. CONCLUSION: NUC1031 did not exhibit evidence of superior activity over gemcitabine, as a single-agent, or in combination with cisplatin, in either our in vivo or in vitro BTC models. Given that the largest Phase 3 study (ClinicalTrials.gov: NCT0314666) to date in BTC is underway (N = 828) comparing NUC1031/cisplatin to gemcitabine/cisplatin, our results suggest that a more conservative clinical evaluation path would be more appropriate.

The impact of metastatic sites in advanced pancreatic adenocarcinoma, systematic review and meta-analysis of prospective randomized studies.

The real impact of specific sites of metastasis on prognosis of metastatic pancreatic cancer (MPC) is unknown. To evaluate the association of specific metastatic sites and survival outcomes in MPC a systematic literature review was performed including prospective randomized trials of systemic treatments in metastatic pancreatic cancer indexed in PubMed, Embase and Web of Science. Data regarding systemic treatment regimens, progression free survival and overall survival were extracted. The outcomes were compared using a random effects model. The index I2 and the graphs of funnel plot were used for the interpretation of the data. Of 1,052 abstracts, 7 randomized trials were considered eligible with a combined sample size of 2,975 MPC patients. Combining the studies with meta-analysis, we could see that patients with liver metastasis had a HR for death of 1.53 with 95% CI of 1.15 to 2.02 (p-value 0.003) and HR for risk of progression of 1.96 with 95% CI of 1.28 to 2.99 (p-value 0.002), without significant heterogeneity. Having two or more sites of metastasis comparing to one site did not have impact on overall survival; RR of 1.05 with 95% CI 0.91 to 1.23 (p-value 0.493). In conclusion, liver metastasis confers worse outcomes among patients with MPC. Apparently, multiple metastatic sites do not present worse prognosis when compared with only one organ involved, therefore, demonstrating the severity of this disease. Prospective studies evaluating other treatments are necessary to address the impact of local treatments in liver metastasis in MPC.

Impact of Pathology Review for Decision Therapy in Localized Prostate Cancer.

BACKGROUND: The Gleason score is an essential tool in the decision to treat localized prostate cancer. However, experienced pathologists can classify Gleason score differently than do low-volume pathologists, and this may affect the treatment decision. This study sought to assess the impact of pathology review of external biopsy specimens from 23 men with a recent diagnosis of localized prostate cancer. METHODS: All external biopsy specimens were reviewed at our pathology department. Data were retrospectively collected from scanned charts. RESULTS: The median patient age was 63 years (range: 46-74 years). All patients had a Karnofsky performance score of 90% to 100%. The median prostate-specific antigen level was 23.6 ng/dL (range: 1.04-13.6 ng/dL). Among the 23 reviews, the Gleason score changed for 8 (35%) patients: 7 upgraded and 1 downgraded. The new Gleason score affected the treatment decision in 5 of 8 cases (62.5%). CONCLUSIONS: This study demonstrates the need for pathology review in patients with localized prostate cancer before treatment because Gleason score can change in more than one-third of patients and can affect treatment decision in almost two-thirds of recategorized patients.

Does Time-to-Chemotherapy Impact the Outcomes of Resected Ovarian Cancer? Meta-analysis of Randomized and Observational Data.

OBJECTIVES: This study is a meta-analysis of prior publications evaluating the impact of time-to-chemotherapy (TTC) on disease recurrence and survival 3 years after the original surgery. METHODS: We performed a meta-analysis of studies published in PubMed (1950-2016) as of April 2016. Inclusion criteria were as follows: randomized controlled trials and prospective or retrospective cohorts that included patients with ovarian cancer who had undergone surgery with curative intent and use of adjuvant chemotherapy. We compared rates of disease recurrence and death according to the TTC ("early" vs "delayed") using a random-effects model and performed a metaregression to evaluate the impact of covariates on these outcomes. RESULTS: Of 239 abstracts in the original search, 12 were considered eligible. The cutoffs used for TTC were between 20 and 40 days. All studies used a platinum-based chemotherapy, and the rates of patients with suboptimal resection varied from 33% to 70%. A longer TTC was not associated with higher rates of disease recurrence (odds ratio, 0.89; 95% confidence interval, 0.63-1.24) or death at 3 years (odds ratio, 1.06; 95% confidence interval, 0.9-1.24). There was no evidence of significant publication bias (Egger test P = 0.472), but data were heterogeneous (I = 64.3%). Metaregression showed that the percentage of patients with suboptimal surgery and values used as cutoff to define "delayed" chemotherapy combined were a significant source of bias (residual I = 0%). CONCLUSIONS: In our analysis, TTC after surgery for ovarian cancer with curative intent was not associated with higher risk of disease recurrence or death. However, this association was influenced by the rate of optimal debulking and definition of "late" initiation of chemotherapy, so we must be careful when applying these data to patients with complete resection.