Systemic chemotherapy is the main treatment option for patients with advanced intrahepatic cholangiocarcinoma (iCCA), however, its efficacy is limited. Herein, we report a young patient with NRAS-mutated chemoresistant metastatic iCCA, who received second-line therapy with a combination of trametinib (MEK1/2 inhibitor), hydroxychloroquine (autophagy inhibitor), and bevacizumab (angiogenesis inhibitor). A significant response was achieved during therapy, resulting in a 25% decrease in the size of tumor lesions after 2 months of treatment and an improvement in the patient\'s condition. The duration of this response was 4 months, but the patient died 10 months after the initiation of this triple therapy. This case report and the analysis of other available studies warrant further investigations on combined MEK and autophagy inhibition in RAS-mutated tumors.

BACKGROUND: Lenvatinib (LEN) and atezolizumab + bevacizumab (A + B) have drastically changed the treatment paradigm for advanced hepatocellular carcinoma (HCC). Before these landmark trials, sorafenib (SOR) served as the standard first-line treatment for a decade. Our study aimed to assess the outcomes of HCC patients treated during the SOR era (2008-2018) in contrast to those in the post-SOR era (2018-2021), of which the predominant first-line treatments were LEN or A + B.
METHODS: Inclusion criteria of the study were all HCC patients in the Canadian province of Alberta who started first-line systemic therapy at cancer centers between 1 January 2008 and 31 December 2021. Survival outcomes, including overall survival (OS) and progression-free survival (PFS), along with clinician-assessed response rate (RR), were subject to retrospective analysis.
RESULTS: Of 372 total patients, 230 received treatment in the SOR era and 142 in the post-SOR era. The demographic and clinical characteristics for the SOR era and post-SOR era groups are as follows, respectively: the median age was 63 and 64 years, 80% and 81% were male, and 24% and 11% were of East Asian ethnicity. Before receiving systemic treatment, 40% and 33% received TACE, 7% and 9% received TARE, and 3% and 14% received SBRT in the two eras, respectively. In the post-SOR era, patients received A + B (23%), LEN (51%), and SOR (23%) as first-line treatment. There was a statistically significant improvement in RR (15% vs. 26%; p = 0.02), median PFS (3.8 months vs. 7.9 months; p < 0.0001), and median OS (9.8 months vs. 17.0 months; p < 0.0001).
CONCLUSIONS: In this retrospective multicenter real-world study, HCC patients treated in the post-SOR era, where LEN and A + B were commonly used first-line treatments, exhibited superior OS, PFS, and RR compared to patients treated in the SOR era. The findings of this study affirm the tangible progress achieved in the real world in enhancing outcomes for HCC patients through advancements in treatments over the past 15 years.

Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that treated patients have a high risk of disease recurrence. Moreover, ovarian cancer is very diverse in terms of molecular, histological features and mutations. Many patients may also develop platinum resistance, resulting in poor response to subsequent lines of treatment. To improve the prognosis of patients with ovarian cancer, it is expected to make better existing and implement new, promising treatment methods. Targeted therapies seem very promising. Currently, bevacizumab - a VEGF inhibitor and therapy with olaparib - a polyADP-ribose polymerase inhibitor are approved. Other methods worth considering in the future include: folate receptor α, immune checkpoints or other immunotherapy methods. To improve the treatment of ovarian cancer, it is also important to ameliorate the determination of molecular features to describe and understand which group of patients will benefit most from a given treatment method. This is important because a larger group of patients treated for ovarian cancer can have a greater chance of surviving longer without recurrence.

Both atezolizumab (a PD-L1 inhibitor) plus bevacizumab (A+B) and sintilimab (a PD-1 inhibitor) plus bevacizumab (S+B) are recommended as the first-line regimen for advanced hepatocellular carcinoma (HCC) in China. Different efficacy between the two regimens combined with transvascular intervention for unresectable HCC (uHCC) remain unknown. We retrospectively analyzed uHCC patients treated in three centers by simultaneous combination of A+B or S+B with transarterial chemoembolization (TACE) and FOLFOX-based hepatic arterial infusion chemotherapy (HAIC). Objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAEs) were compared. Totally 188 patients were included, with 92 and 96 administered A+B+TACE-HAIC (ABTH) and S+B+TACE-HAIC (SBTH), respectively. ORRs (62.0 vs. 70.8%, respectively; P = 0.257) and disease control rates (88.0 vs. 93.8%, P = 0.267) were similar between groups by the mRECIST criteria. ABTH showed no survival advantage over SBTH, with median PFS times of 11.7 months and 13.0 months, respectively (HR = 0.81, 95% CI, 0.52-1.26, P = 0.35) and similar OS times (HR = 1.19, 95% CI, 0.32-4.39, P = 0.8). No significant differences were observed in grade 3-4 TRAEs between groups. Either PD-L1 or PD-1 inhibitor plus bevacizumab combined with TACE-HAIC have similarly excellent therapeutic efficacy with manageable adverse events, representing promising treatment options for uHCC.

OBJECTIVE: The landscape of treatments for hepatocellular carcinoma (HCC), including immune checkpoint inhibitors, has expanded significantly. However, unresectable HCC patients with portal vein tumor thrombus (PVTT) continue to face a poor prognosis. This investigation examined the survival outcomes and determinants influencing survival rates in advanced HCC patients with PVTT undergoing treatment with atezolizumab plus bevacizumab (ATZ+BEV) or hepatic arterial infusion chemotherapy (HAIC).
METHODS: Between December 2003 and June 2023, 48 advanced HCC with PVTT underwent treatment with either ATZ+BEV (16 patients) or HAIC (32 patients).
RESULTS: The analysis revealed no significant disparities in overall survival (OS) or treatment efficacy between the ATZ+BEV and HAIC groups (ATZ+BEV: 10.0 months, HAIC: 15.3 months). Treatment with either ATZ+BEV or HAIC resulted in minimal alterations in the ALBI score and preserved hepatic function. Independent prognostic factors for OS, identified via multivariate logistic regression, included serum α-fetoprotein levels >400 ng/ml [hazard ratio (HR)=1.94; p=0.001], the existence of more than five tumors (HR=1.55; p=0.043), and the Child-Pugh score (HR=2.53; p=0.002).
CONCLUSIONS: This investigation revealed no significant variance in OS and response rates between patients receiving ATZ+BEV and those treated with HAIC. The survival of advanced HCC patients with PVTT is intricately linked to the preservation of liver function, emphasizing the necessity for additional research to enhance treatment approaches for this patient population.

Lung cancer is one of the most common and deadliest cancers. Preclinical models are essential to study new therapies and combinations taking tumor genetics into account. We have established cell lines expressing the luciferase gene from lines with varied genetic backgrounds, commonly encountered in patients with pulmonary adenocarcinoma. We have characterized these lines by testing their response to multiple drugs. Thus, we have developed orthotopic preclinical mouse models of NSCLC with very high engraftment efficiency. These models allow the easy monitoring of tumor growth, particularly in response to treatment, and of tumor cells dissemination in the body. We show that concomitant treatment with osimertinib (3rd generation tyrosine kinase inhibitor targeting mutated EGFR) and bevacizumab (anti-angiogenic targeting VEGF) can have a beneficial therapeutic effect on EGFR-mutated tumors. We also show that the addition of afatinib to osimertinib-treated tumors in escape leads to tumor growth inhibition. No such effect is observed with selumetinib or simvastatin. These preclinical mouse models therefore make it possible to test innovative therapeutic combinations and are also a tool of choice for studying resistance mechanisms.

BACKGROUND: Ovarian cancer (OC) is a significant cause of cancer-related mortality in women globally, with a five-year survival rate of approximately 49%. Standard therapy involves cytoreductive surgery followed by chemotherapy. Its poor prognosis has driven interest in alternative therapies such as targeted molecular agents like bevacizumab and poly (ADP-ribose) polymerase inhibitors (PARPi).
METHODS: This review systematically searched PubMed from January 2018 to December 2023 for studies on PARPi in OC. Emphasis was on identifying relevant Phase III trials, extracting data on study design, patient demographics, and outcomes. Special focus was on assessing PARPi efficacy, safety, impact on quality of life, and ongoing trials, including those on Clinicaltrials.gov.
RESULTS: The efficacy of PARPi in first-line therapy for OC has been extensively studied. Trials like SOLO-1, PRIMA, and ATHENA-MONO have demonstrated significant improvements in progression-free survival (PFS) and overall survival (OS), particularly in patients with BRCA mutations. Additionally, the combination of PARPi with other agents like bevacizumab has shown promising results in extending PFS. However, PARPi treatment is associated with various adverse effects, including hematologic toxicities like anemia, thrombocytopenia, and neutropenia. While most adverse events are manageable, some patients may require dose adjustments or discontinuation of treatment. Importantly, PARPi maintenance therapy has not adversely affected health-related quality of life (HRQoL), with studies reporting similar HRQoL scores between PARPi-treated and placebo-treated patients.
CONCLUSIONS: PARPi offer effective treatment with manageable side effects, suitable even for medically fragile patients. Individualized dosing can optimize benefits while minimizing adverse events. Exploring diverse treatment approaches, particularly in patients with limited life expectancy or high disease burden, could improve outcomes. Ongoing research is investigating alternative therapies and combinations to broaden treatment options. Combining bevacizumab with PARPi may be justified for first-line and recurrent maintenance therapy. Regardless of mutational status, PARPi should be considered for maintenance therapy in newly diagnosed advanced OC. Platinum sensitivity remains crucial for treatment decisions and predicting survival outcomes.

OBJECTIVE: Atezolizumab and bevacizumab (Atezo/Bev) combination immunotherapy regimens and direct oral anticoagulants (DOACs) are both associated with bleeding. Therefore, combining Atezo/Bev regimens with DOACs may exacerbate the bleeding risk. This study investigated the feasibility of the Atezo/Bev regimen in patients taking DOACs.
METHODS: This retrospective study included 141 patients with unresectable hepatocellular carcinoma (HCC) or advanced lung cancer (LC) treated with Atezo/Bev regimens. Patients who used antithrombotic agents other than DOACs were excluded. Bleeding events during the Atezo/Bev regimen were analyzed.
RESULTS: The incidence rates of bleeding of any grade in the DOAC (n = 11) and no antithrombotic agent (NAA) (n = 130) groups were 9.1% and 10.8%, respectively, with no significant differences. Moreover, no significant difference was found in the frequency of bleeding of grade ≥3 between the DOAC and NAA groups. No patients in the DOAC group discontinued the Atezo/Bev regimen because of severe bleeding. Although serum albumin levels, with a hazard ratio (HR) of 0.298 (95% confidence interval [CI]: 0.105-0.847), independently contributed to bleeding events (p = 0.023), DOAC administration did not (HR: 1.357; 95% CI: 0.157-10.54; p = 0.770). Among only patients with HCC (n = 59), none of the five patients taking DOACs experienced bleeding events. A high albumin-bilirubin score (HR: 9.083, 95% CI: 1.118-73.76) was associated with bleeding events (p = 0.039).
CONCLUSIONS: DOACs did not have a considerable effect on bleeding events in the Atezo/Bev regimens for HCC or LC. Under careful surveillance for bleeding, Atezo/Bev regimens may be feasible in patients receiving DOACs.

OBJECTIVE: HER2 is an infrequently mutated driver gene in non-small cell lung cancer (NSCLC). At present, there has been no comprehensive large-scale clinical study to establish the optimal first-line treatment strategy for advanced lung adenocarcinoma (LUAD) with HER2-Mutant. Besides that, the effectiveness and safety of pyrotinib, a pan-HER inhibitor, in the context of NSCLC are still undergoing investigation.
METHODS: In this study, we conducted a retrospective data collection of HER2-Mutated advanced LUAD who received first-line treatment and pyrotinib between May 2014 and June 2023. Patients treated with chemotherapy, chemotherapy + immune checkpoint inhibitors (ICIs), chemotherapy + bevacizumab and pyrotinib in first-line treatment. Furthermore, we collected data on the efficacy and safety of pyrotinib in these patients after disease progression. The main endpoint of the study was progression-free survival (PFS).
RESULTS: In the final analysis, 89 patients were included in the first-line cohort and 30 patients were included in the pyrotinib cohort. In the first-line treatment cohort, chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib exhibited notable survival benefits compared to chemotherapy (median PFS: 9.87 vs. 7.77 vs. 7.10 vs. 5.40 months, p-value < 0.05). Furthermore, patients with a first-line treatment PFS of less than 6 months may potentially benefit from subsequent treatment with pyrotinib (median PFS: 7.467 vs. 3.000, p-value = 0.0490).
CONCLUSIONS: In the first-line treatment of HER2-Mutant LUAD, regimens involving combinations like chemotherapy + ICIs, chemotherapy + bevacizumab, and pyrotinib may confer enhanced survival advantages compared to chemotherapy. Nevertheless, no significant distinctions were observed among these three treatment strategies, underscoring the imperative to identify biomarkers for the discerning selection of suitable therapeutic modalities. Moreover, patients with suboptimal response to first-line treatment may potentially derive more benefit from pyrotinib.

Bevacizumab plus platinum-based chemotherapy provides modest benefits in non-squamous non-small cell lung cancer (NSCLC), while its application as a neoadjuvant regimen has yet to be validated. The present study aimed to assess the efficacy of neoadjuvant bevacizumab plus platinum-based chemotherapy in patients with stage-IIIA non-squamous NSCLC. Data from 110 patients with stage-IIIA non-squamous NSCLC with negative driver genes, who received neoadjuvant bevacizumab plus platinum-based chemotherapy (n=50) or neoadjuvant platinum-based chemotherapy alone (n=60), and tumor resection, were retrospectively reviewed in the current study. In addition, the data on pathological response, disease-free survival (DFS), overall survival (OS) and adverse events were obtained. The results demonstrated that neoadjuvant bevacizumab plus chemotherapy did not significantly increase the pathological complete response (pCR) rate in comparison with neoadjuvant chemotherapy alone (18.0 vs. 8.3%; P=0.130). However, neoadjuvant bevacizumab plus chemotherapy significantly increased the rates of DFS (P=0.007) and OS (P=0.049) compared with neoadjuvant chemotherapy alone. Adjustments were then performed using multivariate logistic or Cox regression analyses, which demonstrated that neoadjuvant bevacizumab plus chemotherapy in comparison with neoadjuvant chemotherapy alone only significantly independently prolonged DFS [hazard ratio (HR)=0.251; P=0.042], but did not significantly affect pCR (odds ratio=2.897; P=0.117) or OS (HR=0.297; P=0.158). Furthermore, no significant differences were demonstrated between the number of adverse events in patients receiving neoadjuvant bevacizumab plus chemotherapy in comparison with those receiving neoadjuvant chemotherapy alone (all P>0.05). In conclusion, neoadjuvant bevacizumab plus platinum-based chemotherapy was only associated with a significant improvement in the rate of DFS, but showed limited efficacy in improving pCR and OS rates in comparison with neoadjuvant chemotherapy alone in patients with stage-IIIA non-squamous NSCLC. Therefore, a larger sample size and randomized controlled studies are needed for further validation of the findings of the present study.