Second-line Patients Research Articles

Efficacy and safety of antiangiogenic therapy (bevacizumab or apatinib) plus chemotherapy in patients with platinum‑resistant recurrent ovarian cancer: A retrospective study.

The majority of patients with ovarian cancer will relapse and subsequently develop platinum-resistant recurrent ovarian cancer (PRROC). Antiangiogenic therapy plus chemotherapy may be a potential treatment option in patients with PRROC. However, further evidence is required to facilitate clinical application. The present study aimed to investigate the efficacy and safety of antiangiogenic therapy (bevacizumab or apatinib) plus chemotherapy in patients with PRROC. Data from 86 patients with PRROC receiving antiangiogenic therapy (bevacizumab or apatinib) plus chemotherapy (pegylated liposomal doxorubicin, weekly-paclitaxel or gemcitabine) were reviewed retrospectively. Data for treatment response, progression-free survival (PFS), overall survival (OS) and adverse events were obtained. Complete response, partial response, stable disease and progressive disease rates were 0.0, 33.7, 44.2 and 22.1%, respectively. Objective response and disease control rates were 33.7 and 77.9%, respectively. Median (and 95% confidence intervals) PFS and OS values were 6.5 (4.7-8.2) and 20.3 (14.1-26.5) months, respectively. PFS (P=0.016) and OS (P=0.005) durations were longer in patients that received the antiangiogenic plus chemotherapy regimen as a second-line treatment vs. patients that received it as a third-line or above treatment. Ascites (yes vs. no) and current treatment lines (third or above vs. second) were independently associated with shorter PFS and OS (all P<0.05). The most frequent treatment-induced adverse events were leukopenia (34.9%), hypertension (30.2%) and fatigue (30.2%). All adverse events were considered acceptable and only previously reported adverse events were observed. The findings of the present study may provide further clinical evidence for the application of antiangiogenic therapy plus chemotherapy in patients with PRROC.

Clinical efficacy and safety of immune checkpoint inhibitors plus anlotinib as secondline or subsequent therapy in extensive stage small cell lung cancer: a retrospective study.

Treatments are limited for extensive stage small cell lung cancer (ES-SCLC) patients in secondline or subsequent setting. This study aimed to explore the clinical efficacy and safety of immune checkpoint inhibitors (ICIs) plus anlotinib as secondline or subsequent therapy in ES-SCLC. We retrospectively analyzed 116 patients with ES-SCLC at Shandong Provincial Qianfoshan Hospital between January 2019 and March 2024. According to the different therapy regimes, they were divided into three groups, ICI plus anlotinib as secondline or subsequent therapy group (ICI + anlotinib group), single ICI as secondline or subsequent therapy group (single ICI therapy group), single chemotherapy as secondline therapy group (single chemotherapy group). Kaplan-Meier method was used to compare the progression-free survival (PFS) and the overall survival time (OS) among these three groups. Cox regression analysis was used to analyze different factors which correlated to PFS and OS. The adverse events were assessed according to the Common Terminology Criteria for Adverse Events version 5.0. Kaplan-Meier analysis showed that patients in ICI + anlotinib group had a longer PFS and OS compared to patients in single ICI therapy group (median PFS [mPFS]: 6.7months vs. 4.6months, P = 0.007; median OS [mOS]:12.4months vs. 8.4months, P = 0.041) and single chemotherapy group (mPFS: 6.7months vs. 3.0months, P < 0.001; mOS: 12.4months vs. 7.2months, P = 0.002). The Cox regression analysis showed that the Eastern Cooperative Oncology Group performance status (ECOG PS), liver metastasis, brain metastasis and treatment regimes were independent predictors that affecting the PFS and OS of all the enrolled patients. The common adverse events (AEs) were wleukopenia and fatigue. There was no significant statistical difference in other AEs among the three groups except for leukopenia. ICI + anlotinib as secondline or subsequent therapy has better efficacy than single ICI group and single chemotherapy group and with tolerable toxicities for patients with ES-SCLC.

Efficacy and safety of camrelizumab, apatinib, and capecitabine combination therapy in advanced biliary tract cancer: a phase 2, nonrandomized, prospective study.

Biliary tract cancer (BTC) is a highly malignant tumor, with limited therapy regimens and short response duration. In this study, we aim to assess the efficacy and safety of the combination of camrelizumab, apatinib, and capecitabine as the first- or second-line treatment in patients with advanced BTC. In this phase 2, nonrandomized, prospective study, eligible patients received camrelizumab (200 mg, d1, Q3W), apatinib (250 mg, qd, d1-d21, Q3W), and capecitabine (1000 mg/m², bid, d1-d14, Q3W) until trial discontinued. The primary endpoint was the objective response rate (ORR). The secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and safety. From July 2019 to April 2023, we enrolled a total of 28 patients, of whom 14 patients were in the first-line treatment setting and 14 patients were in the second-line setting. At the data cutoff (April 30, 2023), the median follow-up duration was 18.03 months. Eight of 28 patients reached objective response (ORR: 28.57%), with an ORR of 50% and 7.1% for first-line and second-line treatment patients (P = .033). The median PFS was 6.30 months and the median OS was 12.80 months. Grade 3 or 4 adverse events (AEs) occurred in 9 (32.14%) patients, including elevated transaminase, thrombocytopenia, etc. No serious treatment-related AEs or treatment-related deaths occurred. In this trial, the combination of camrelizumab, apatinib, and capecitabine showed promising antitumor activity and manageable toxicity in patients with advanced BTC, especially in the first-line setting. NCT04720131.

A phase II trial of anlotinib combined chemotherapy as second-line and above therapy in HER2-negative advanced breast cancer.

e13140 Background: The group of HER2-negative accounts for about 75% of breast cancer and has limited response to chemotherapy. Anlotinib is a novel multitarget tyrosine kinase inhibitor targeting VEGFR, PDGFR, FGFR, and c-Kit. In this study, we assessed the efficacy and safety of anlotinib plus chemotherapy in second-line and above treatment of HER-2 negative advanced breast cancer. Methods: This open-label, single-arm, phase II study enrolled women aged 18-75 years with HER2-negative breast cancer who underwent at least one-line chemotherapy. All patients were treated with anlotinib (12mg, qd, administered orally on Days 1-14 of each 21 day cycle) in combination with investigator-selected chemotherapy. The primary endpoint evaluated in this study was the median progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety. Results: From August 2022 to August 2023, 33 patients were enrolled in this study including 22(66.7%) HR+/HER2- patients and 11(33.3%) TNBC patients. After a median follow-up time of 11 months (95% CI, 5.8-16.2), the median PFS (mPFS) of the all patients was 8.6 months (95% CI 7.3-NA). In the HR+ and HR- populations, mPFS was 7.6 months versus 9.5 months (HR,0.376 [95%CI 0.12-1.13], p=0.072), respectively. All the patients had the confirmed best overall response assessments, no patient achieved complete response (CR); 11(33.3%) patients got partial response (PR) and 19(57.6%) patients achieved stable disease (SD). ORR was 33.3% (95% CI 18.0-51.8), DCR was 90.9% (95% CI 75.7-98.1) and CBR was 60.6% (95% CI 42.1-77.1). The most frequently observed adverse events were elevated triglycerides (78.8%), elevated blood sugar (63.6%), anemia (60.6%), elevated cholesterol (51.5%), elevated alanine aminotransferase (48.5%), and leukopenia (48.5%). Dose reductions due to adverse events occurred in 7 (21.2%) patients. Conclusions: Anlotinib combined with chemotherapy showed a promising efficacy with an acceptable safety profile for second-line and above patients with HER2-negative metastatic breast cancer. Further studies enrolling more patients are still needed.

Statistical analysis on the incidence and predictors of death among second-line ART patients in public hospitals of North Wollo and Waghemira Zones, Ethiopia, 2021

Acquired immune deficiency virus, caused by the human immunodeficiency virus, is a significant global health concern. Sub-Saharan Africa particularly Ethiopia faces a high prevalence of human immunodeficiency virus. In low-income settings like Ethiopia, early mortality rates are elevated due to severe opportunistic infections and advanced disease at Anti-retroviral treatment initiation. Despite available treatments, delayed treatment initiation among Human Immunodeficiency Virus -infected individuals in Africa, including Ethiopia, leads to disease progression and increased mortality risk. This study aimed to identify the factors contributing to the death of HIV patients under treatment at second line regimen in public hospitals of North Wollo and Waghemira Zones. A retrospective cohort study with 474 patients was conducted in selected hospitals of North Wollo and Waghemira Zones. A parametric Weibull regression model was employed, and the adjusted hazard ratio served as the measure of association. Variables significantly affected the outcome of the study was determined at a p-value < 0.05, along with a 95% confidence interval for the variables. The patients were within the average age of 38.6(standard deviation ± 12.5) years and majority (45.57%) had no formal education. The overall death incidence rate among second-line anti-retroviral treatment patients was 1.98 per 100-person years [95% CI 1.4—2.9%]. Poor adherence to antiretroviral treatment, male gender, and being underweight significantly increased the hazard of death. Conversely, increased anti-retroviral treatment duration had a significant and negative impact, reducing the hazard of death among patients. The study reveals a high incidence of death among second line anti-retroviral treatment users. Independent predictors include poor adherence, male gender, and underweight status, all significantly increasing the risk of death. On the positive side, the hazard of death decreases with longer anti-retroviral treatment duration. A critical concern and counseling should be given for better ART adherence, to change their nutritional status and for males.

Abstract PO2-17-01: Impact of the introduction of CDK4/6 inhibitors on treatment duration in patients with HR+, HER2– advanced breast cancer: Final analysis of TreatER+ight, a Canadian prospective, real-world, observational study

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) are the established first-line targeted therapy (TT) for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2–) advanced breast cancer (ABC). TreatER+ight, the first prospective, real-world study evaluating the treatment patterns, safety and effectiveness of ET alone or ET + TT in Canadian patients with HR+, HER2– ABC (2016 to 2020) recorded ET as the standard of care (SOC) in the first interim analysis report. However, treatment with CDK4/6i combined with ET have rapidly evolved as the SOC in the metastatic setting. Methods: This prospective, multicenter, observational study (NCT02753686) enrolled patients with HR+, HER2‒ ABC with or without prior exposure to ET and up to one line of prior CT in the advanced setting. The patients were enrolled by the line of their therapy (first-line, second-line or third-line) and grouped into 2 cohorts (ET and ET + TT). Duration of therapy, and overall survival (OS) are estimated using Kaplan–Meier method. Here, we report the final outcome with CDK4/6i treatment evolution with sequencing strategy and duration in routine clinical practice. Results: At data cutoff (December 1, 2022), a total of 439 enrolled patients (ET, n=104; ET + TT, n=335) from 25 centers in Canada, constituted the full analysis set. The median age (range) was 71.5 (37.0–96.0) years in ET cohort and 65.0 (23.0-87.0) years in ET + TT cohort. About 84.6% and 66.4% were postmenopausal patients in the ET and ET + TT cohorts, respectively. Patients with ECOG PS scores 0 to 1 composed of 82.0% and 93.5% in the ET and ET + TT cohorts, respectively. In the overall population, ET alone and ET + CDK4/6i were the most common treatment received by patients in first-line (43.5% and 43.3%) and second-line (36.3% and 24.6%) treatment settings. In third-line treatment setting, CT was the most common treatment received by patients (38.4%). Conclusions: Data from final analysis of TreatER+ight have further confirmed the evolution to primary use of CDK4/6i-based combination therapy in the first-line setting for Canadian patients with HR+, HER2– ABC. Additional details on duration of therapy by CDK4/6i agents, overall survival data and age subgroup analysis will be presented at SABCS 2023 Table 1_Baseline characteristics, treatment patterns, and duration of treatment Citation Format: Catherine Doyle, Ana Elisa Lohmann, Nayyer Iqbal, Jan-Willem Henning, Swati Kulkarni, Nadia Califaretti, John Hilton, Cristiano Ferrario, Nathaniel Bouganim, Mihaela Mates, Stephanie Guillemette, Ricardo Leite, Stephen Chia. Impact of the introduction of CDK4/6 inhibitors on treatment duration in patients with HR+, HER2– advanced breast cancer: Final analysis of TreatER+ight, a Canadian prospective, real-world, observational study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-01.

Study design and rationale for IFCT- 2203 TAXIO: A study that aims to evaluate the effectiveness of a first-line chemotherapy regimen without etoposide, combined with durvalumab, for patients with extensive disease small cell lung cancer

BackgroundStudies have shown improvement in overall survival with anti-PD1/PD-L1 molecules in combination with cisplatin/carboplatin and etoposide as a first-line treatment for Small Cell Lung Cancer (SCLC). However, first-line efficacy remains limited and well below that observed in Non-Small Cell Lung Cancer (NSCLC). Etoposide may have a detrimental effect on lymphocyte activation, which could explain the limited benefit of immunotherapy in the first line and the lack of benefit in the second line for patients previously exposed to high levels of etoposide. MethodsWe initiated a multicenter, single-arm, open-label phase II study of a chemotherapy regimen with durvalumab, combined with carboplatin and paclitaxel for extensive disease SCLC. Eligible patients will receive durvalumab plus carboplatin and paclitaxel every 3 weeks for up to 4 cycles, followed by durvalumab every 4 weeks until progression or unacceptable toxicity. A total of 67 patients will be enrolled in this study, with a 12-month enrollment period and 36-month follow-up. The primary endpoint is Overall Survival (OS) rate at 12 months. Secondary endpoints are best response rate, OS, OS at 24- and 36 months, progression free survival (PFS), duration of response, quality of life and safety. ResultsThis study aims to establish the efficacy of durvalumab combined with carboplatin and paclitaxel in patients with extensive disease Small Cell Lung Cancer. Clinical trial registrationEU CT: 2023-504670-38-00.

Real-world prevalence of microsatellite instability testing and related status in women with advanced endometrial cancer in Europe

PurposeTo assess the real-world prevalence of microsatellite instability (MSI)/mismatch repair (MMR) testing and related tumor status in recurrent/advanced endometrial cancer patients in Europe.MethodsData were from two multi-center, retrospective patient chart review studies conducted in the United Kingdom, Germany, Italy, France and Spain: The Endometrial Cancer Health Outcomes-Europe-First-Line (ECHO-EU-1L) study and the ECHO-EU-Second-Line (ECHO-EU-2L) study. ECHO-EU-1L included recurrent/advanced endometrial cancer patients who received first-line systemic therapy between 1/JUN/2016 and 31/MAR/2020 after recurrent/advanced diagnosis. ECHO-EU-2L included patients with recurrent/advanced endometrial cancer who progressed between 1/JUN/2016 and 30/JUN/2019 following prior first-line systemic therapy. Data collected included patient demographics, MSI/MMR tumor testing and results, and clinical/treatment characteristics.ResultsECHO-EU-1L included 242 first-line patients and ECHO-EU-2L included 475 s-line patients. For all patients, median age at recurrent/advanced diagnosis was 69 years, roughly half had endometrioid carcinoma histology and over 75% had Stage IIIB-IV disease at initial diagnosis. The prevalence of MSI/MMR testing in the first-line and second-line cohorts was similar (36.4 and 34.9%, respectively). Among those tested, a majority had non-MSI-high/MMR proficient tumors (80.7 and 74.7% among first- and second-line patients, respectively). About 15% had MSI-high/MMR deficient tumors in both cohorts, and a few patients had discordant results (3.4 and 10.8% among first- and second-line patients, respectively).ConclusionPrior to the approvals of biomarker-directed therapies for recurrent/advanced endometrial cancer patients in Europe, there were low MSI/MMR testing rates for these patients of just over one-third. Given the availability of biomarker-directed therapies, increased MSI/MMR testing may help inform treatment decisions for recurrent/advanced endometrial cancer patients in Europe.

Applying Next-Generation Sequencing to Track HIV-1 Drug Resistance Mutations Circulating in Portugal.

The global scale-up of antiretroviral treatment (ART) offers significant health benefits by suppressing HIV-1 replication and increasing CD4 cell counts. However, incomplete viral suppression poses a potential threat for the emergence of drug resistance mutations (DRMs), limiting ART options, and increasing HIV transmission. We investigated the patterns of transmitted drug resistance (TDR) and acquired drug resistance (ADR) among HIV-1 patients in Portugal. Data were obtained from 1050 HIV-1 patient samples submitted for HIV drug resistance (HIVDR) testing from January 2022 to June 2023. Evaluation of DRM affecting viral susceptibility to nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) was performed using an NGS technology, the Vela Diagnostics Sentosa SQ HIV-1 Genotyping Assay. About 71% of patients were ART naïve and 29% were experienced. Overall, 20% presented with any DRM. The prevalence of TDR and ADR was 12.6% and 41.1%, respectively. M184V, T215S, and M41L mutations for NRTI, K103N for NNRTI, and M46I/L for PIs were frequent in naïve and treated patients. E138K and R263K mutations against INSTIs were more frequent in naïve than treated patients. TDR and ADR to INSTIs were 0.3% and 7%, respectively. Patients aged 50 or over (OR: 1.81, p = 0.015), originating from Portuguese-speaking African countries (PALOPs) (OR: 1.55, p = 0.050), HIV-1 subtype G (OR: 1.78, p = 0.010), and with CD4 < 200 cells/mm3 (OR: 1.70, p = 0.043) were more likely to present with DRMs, while the males (OR: 0.63, p = 0.003) with a viral load between 4.1 to 5.0 Log10 (OR: 0.55, p = 0.003) or greater than 5.0 Log10 (OR: 0.52, p < 0.001), had lower chances of presenting with DRMs. We present the first evidence on TDR and ADR to INSTI regimens in followed up patients presenting for healthcare in Portugal. We observed low levels of TDR to INSTIs among ART-naïve and moderate levels in ART-exposed patients. Regimens containing PIs could be an alternative second line in patients with intermediate or high-level drug resistance, especially against second-generation INSTIs (dolutegravir, bictegravir, and cabotegravir).

Active tuberculosis incidence among treatment failure experienced patients in North Wollow Zone: A multicenter historical cohort.

In Ethiopia, tuberculosis (TB) is a significant cause of death among individuals living with HIV, especially in resource-limited areas and those who have experienced treatment failure. However, there is the paucity of data regarding TB among treatment failures experienced people living with HIV. This study aimed to estimate the rate and identify predictors of tuberculosis among patients who received second-line treatment in North Wollo, Northeast Ethiopia. A retrospective follow-up study was conducted on 474 HIV-infected patients who experienced treatment failure. The study period ranged from January 2015 to September 30, 2021. The incidence of TB was assessed using a Cox proportional hazard regression model, after ensuring that all assumptions were met. Factors associated with active TB were determined by analyzing adjusted hazard ratios and 95% confidence intervals. In a study of 474 HIV-positive patients on second-line antiretroviral treatment, we found an incidence rate of 3.6% with 17 new cases of TB observed over 4412.4 persons per year (PPY). The overall incidence density rate was estimated to be 0.39 cases per 100 PPY (95% CI: 0.239-0.618). Regarding the occurrence of active TB in second-line patients, WHO clinical treatment stage (T3 and T4), missed isoniazid preventive therapy had a significantly higher risk (AHR: 13.225, 95% CI: 2.894-60.434, p = 0.001), while being married was associated with a lower risk (AHR: 0.203, 95% CI: 0.045-0.907, p = 0.001). A high incidence of active TB was observed shortly after initiating second-line antiretroviral treatment. Factors such as being in the WHO clinical treatment stage (T3 and T4) and marital status were determinants for active TB. To improve overall survival rates, it is vital to enhance early TB screening and implement effective isoniazid preventive therapy.

Efficacy and safety of anti-programmed death-1 antibody-based combination therapy in advanced or metastatic gastric or gastroesophageal junction cancer in Chinese patients: A real-world study.

Programmed death-1 antibody plus chemotherapy has gained approval for the treatment for (human epidermal growth factor receptor 2 negative locally advanced or metastatic gastric or gastroesophageal junction cancer. This study aims to analyze the efficacy and safety of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis therapy in Chinese patients with advanced or metastatic gastric or gastroesophageal junction cancer in a real-world setting. In total, 122 patients treated with anti-programmed death-1 antibody-based combination therapy between April 2019 and December 2021 were encompassed. Clinical outcomes and safety profile were measured and analyzed. In the whole cohort, median overall survival was 17.2 months, median progression-free survival was 10.9 months, and median duration of response was 9.4 months. Notably, in the first-line patients, the median overall survival was not reached, median progression-free survival was 14.8 months, objective response rate was 68.4%. In the second-line group, median overall survival, median progression-free survival, median duration of response, and objective response rate were 10.9 months, 5.9 months, 4.5 months, and 41.5%, respectively. Treatment-related adverse events of any grade were observed in 28.2% of the overall cohort, primarily affecting the hematological and liver function. Grade 3 or 4 adverse events were mainly characterized by increased levels of aspartate aminotransferase, alanine aminotransferase, along with decreased lymphocyte and white blood cells, as well as anemia. Patients in our cohort experienced a clinical benefit from anti-programmed death-1 antibody-combined treatment in first-line treatment settings, with acceptable treatment-related adverse events. The benefit of anti-programmed death-1 antibody combined with chemo- or anti-angiogenesis treatment to the second-line patients should be further confirmed by large multi-center randomized, controlled clinical trials.

Efficacy and safety of fruquintinib with nab-paclitaxel in advanced G/GEJ cancer after exposure to immune checkpoint inhibitors: A single-center prospective clinical trial.

327 Background: Immune checkpoint inhibitors (ICIs) expanded choices of early-line therapies in advanced gastric (G)/gastro-esophageal junction (GEJ) cancer. In addition, it’s observed that early-line ICI therapy, compared to chemotherapy, could enhance the efficacy of VEGFR inhibitors with chemotherapy in late lines. This single-center prospective clinical trial was aimed to explore the efficacy and safety of fruquintinib with nab-paclitaxel as second-line in patients (pts) with G/GEJ cancer exposed to ICIs in early lines. Methods: This is a single-center, prospective, open-label clinical trial. Pts with advanced G/GEJ cancer who had been exposed to ICIs before the second line were eligible. 42 pts would receive 100g/m2 nab-paclitaxel on day 1 and day 8 every 3 weeks, and 4mg fruquintinib from day 1 to day 14 every 3 weeks. Progression-free survival (PFS) was set as the primary endpoint. The Kaplan–Meier method would be used to evaluate time-to-event outcomes. Results: Up to Aug 10, 2023, 25 pts had been enrolled, 23 of whom were evaluable. 14 (60.9%) pts in evaluable set were male. All these pts was with stage Ⅳ of TNM staging. The median age was 58 (range: 33-74), and 6 (26.1%) pts were elder than 65 yr. 12 (63.2%) pts were with PD-L1 CPS greater than 1, 9 (47.4%) pts greater than 5, and 4 (17.4%) pts greater than 10. PD-L1 CPS of 4 pts was unknown. The pts had received a median of 5 (range: 1-20) cycles in early-line ICI therapy. 17 (73.9%) pts suffered metastasis in retroperitoneal lymph node and 7 (30.4%) pts in liver. With a median follow up time of 5.6 (range: 2.1-16.6) mo, the PFS achieved 4.8 (95% CI: 4.6-NA) mo. Despite the immatureness of overall survival (OS), the 1-year OS rate was 56.25% (95% CI: 17.27%-95.23%). The ORR was 47.8% (n=11), and DCR was 100% (n=23). As to safety, the most common (≥20%) AEs of all grades were white blood cell decrease, peripheral sensory neuropathy, and neutrophil count decrease, while that of grade≥3 was white blood cell decrease. Conclusions: Fruquintinib with nab-paclitaxel as second-line therapy demonstrated good efficacy and safety in advanced G/GEJ cancer after exposure to ICIs. ICIs might increase benefit from this therapy, which warrants further investigations in a large cohort. Clinical trial information: ChiCTR2200059976 .

Efficacy of immune checkpoint inhibitors for metastatic colorectal cancer with microsatellite instability in second or latter line using synthetic control arms: A non-randomised evaluation

PurposeImmune checkpoint inhibitors (ICIs) appeared active in single-arm trials for patients with chemoresistant metastatic colorectal cancer (mCRC) harboring microsatellite instability (MSI). Given the paucity of randomised controlled trials (RCTs) in this setting, we evaluated the effect size of ICIs using intra-patients comparison and ARCAD database as historical controls. Patients and methodsIndividual-patient data from NIPICOL and CheckMate 142 phase II trials that evaluated a combination of ICIs for MSI mCRC patients (N = 176) and from five non-ICI mCRC historical RCTs in second-line or latter (N = 4026) were analyzed. Firstly, promising of ICIs was identified using intra-patient comparison based on growth modulation index (GMI) defined the ratio of progression-free survivals (PFS) on ICIs and previous line of therapy. Survival outcomes of ICIs-treated patients were then compared with those matched non-ICIs treated from ARCAD database historical RCTs. ResultsAmong ICIs-treated patients, median PFS on ICIs was 32.66 (range 0.10–74.25) versus 4.07 months (range 0.7–49.87) on prior therapy, resulting on median GMI of 4.97 (range 0.07–59.51; hazard-ratio (HR)= 0.16 (95 %CI=0.11–0.22, P < 0.001)). Compared to matched non-ICI patients, in third-line, median overall survival (OS) was not reached with ICIs versus 3.52 months with placebo (HR=0.20, 95 %CI=0.10–0.41, P < 0.001), and 6.51 months with active drugs (HR=0.30, 95 %CI=0.15–0.60, P = 0.001). In second-line, median OS was not reached with ICIs versus 11.7 months with chemotherapy+placebo (HR=0.12, 95 %CI=0.07–0.22, P < 0.001), and 16.3 months with chemotherapy+targeted therapy (HR=0.10, 95 %CI=0.05–0.19, P < 0.001). ConclusionICIs demonstrates high effect size for MSI mCRC patients in second-line and later. This work might be useful as an example of methodology to avoid RCTs when benefit from experimental therapy is likely to be high.

An updated cost-effectiveness analysis of axicabtagene ciloleucel in second-line large B-cell lymphoma patients in the United States

Aims This economic evaluation of axicabtagene ciloleucel (axi-cel) versus previous standard of care (SOC; salvage chemotherapy followed by high-dose therapy with autologous stem cell rescue) in the second line (2L) large B-cell lymphoma population is an update of previous economic models that contained immature survival data. Methods This analysis is based on primary overall survival (OS) ZUMA-7 clinical trial data (median follow-up of 47.2 months), from a United States (US) payer perspective, with a model time horizon of 50 years. Mixture cure models were used to extrapolate updated survival data; subsequent treatment data and costs were updated. Patients who remained in the event-free survival state by 5 years were assumed to have achieved long-term remission and not require subsequent treatment. Results Substantial survival and quality of life benefits were observed despite 57% of patients in the SOC arm receiving subsequent cellular therapy: median model-projected (ZUMA-7 trial Kaplan–Meier estimated) OS was 78 months (median not reached) for axi-cel versus 25 months (31 months) for SOC, resulting in incremental quality-adjusted life year (QALY) difference of 1.63 in favor of axi-cel. Incrementally higher subsequent treatment costs were observed in the SOC arm due to substantial crossover to cellular therapies, thus, when considering the generally accepted willingness to pay threshold of $150,000 per QALY in the US, axi-cel was cost-effective with an incremental cost-effectiveness ratio of $98,040 per QALY. Conclusions Results remained consistent across a wide range of sensitivity and scenario analysis, including a crossover adjusted analysis, suggesting that the mature OS data has significantly reduced the uncertainty of axi-cel’s cost-effectiveness in the 2L setting in the US. Deferring treatment with CAR T therapies after attempting a path to transplant may result in excess mortality, lower quality of life and would be an inefficient use of resources relative to 2L axi-cel.

Autologous Stem Cell Transplantation Remains a Curative Option As Second Line Treatment for Patients with Relapsed/Refractory Large B Cell Lymphoma: Spanish Multicenter Geth-TC/Geltamo Study

Introduction: High dose therapy and Autologous Stem Cell Transplantation (ASCT) has remained the treatment of choice for transplant-eligible patients with relapsed/refractory (R/R) large B cell lymphoma (LBCL) and chemosensitive disease. Recently, CART therapy has been approved in second line for patients with primary refractory disease or early relapse (&amp;lt;1 year of first-line therapy) and the current role of ASCT has been questioned. However, several studies have shown that despite early failure of first line, patients with chemosensitive disease after salvage therapy can be cured with ASCT consolidation. Our objective was to analyze the efficacy of ASCT in patients with R/R LBCL after a long-term follow up and try to define the optimal role of ASCT. Patients and methods: We performed a retrospective multicenter study based on GETH-TC database of ASCT. We included patients from centers of GETH-TC/GELTAMO with R/R LBCL who underwent ASCT from January 2010 to December 2021. All the patients received rituximab and anthracycline-based frontline therapy. Diffuse LBCL NOS, high-grade B-cell lymphoma double/triple hit and NOS, primary mediastinal, transformed follicular lymphoma (tFL) and other less frequent LBCL subtypes were included. Plasmablastic and primary central nervous system lymphoma were excluded. Patients who underwent ASCT in first CR were also excluded except patients with tFL who had received previous anthracycline-based frontline therapy for the indolent lymphoma. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in the overall series and according to different prognostic factors, including disease status at ASCT. Disease status was defined as complete remission (CR), partial response (PR) and refractory disease (stable disease or progression) assessed by PET/CT. Results: Seven-hundred and ninety-one patients fulfilled the inclusion criteria. Patients characteristics are summarized in Table 1. After a median follow-up of 74 months (95%CI 68-81), 65% of the patients were alive and 84% of them free of disease. Six-year-PFS and OS were 51% (95%CI 47-54) and 63% (95%CI 60-67), respectively. Non-relapse mortality at 1 year was 9% (95%CI 7-11). The main causes of death were progression in 161 (58%), ASCT-related toxicity in 18 (6%) and other causes in 98 (35%). PFS was significantly influenced by age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p&amp;lt;0.01). OS was influenced by age at diagnosis, R-IPI at diagnosis, age at ASCT, treatment lines prior to ASCT and disease status at ASCT (p&amp;lt;0.01). In the multivariate analysis, age &amp;gt;60 years at ASCT [HR 1.31 (95%IC: 1.06-1.62), p=0.011], ASCT as ≥3 th line [HR 1.81 (95%IC: 1.42-2.31), p&amp;lt;0.001] and PR versus CR at ASCT [HR 1.46 (95%IC: 1.18-1.81), p&amp;lt;0.001] were the only independent variables influencing PFS, Figure 1. Age &amp;gt;60 years at ASCT [HR 1.62 (95%IC: 1.24-2.12), p&amp;lt;0.001], ASCT as ≥3 th line [HR 1.77 (95%IC: 1.32-2.37), p&amp;lt;0.001] and PR versus CR at ASCT [HR 1.58 (95%IC: 1.22-2.05), p&amp;lt;0.001] were the only independent variables for OS. From 307 (39%) patients who relapsed after ASCT, 59 received CART therapy (median PFS 8.9 months) and 69 allo-SCT (median PFS 10.8 months). Refractory disease or early relapse did not significantly influenced survival. Analyzing this population separately (n=477), disease status at ASCT (PR versus CR) and ASCT as ≥3 th line were the only independent variables for both PFS [HR 1.46 (95%IC: 1.11-1.92), p=0.007; HR 1.79 (95%IC: 1.32-2.43), p&amp;lt;0.001, respectively] and OS [HR 1.92 (95%IC: 1.38-2.67), p&amp;lt;0.001; HR 1.91 (95%IC: 1.35-2.69), p&amp;lt;0.001, respectively]. Conclusions: To our knowledge, this is the largest series analyzing the efficacy of ASCT in patients with R/R LBCL after rituximab-containing frontline therapy. Our results indicate that ASCT is a curative option for patients with chemosensitive disease (especially in CR after salvage), regardless of the timing of relapse after frontline treatment. These data support that ASCT could be considered in patients with primary refractory or early relapse, provided the disease is sensitive to salvage therapy.

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study

The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy. In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort. Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required. Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma. Merck Sharp & Dohme.

Niraparib and Advanced Ovarian Cancer: A Beacon in the Non-BRCA Mutated Setting.

Ovarian cancer (OC) is the eighth most common cancer among the female population and the most lethal of all the female reproductive system malignancies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have reshaped the treatment scenario of metastatic OC in the maintenance setting post platinum-based chemotherapy. Niraparib is the first Food and Drug Administration (FDA)- and European Medical Agency (EMA)-approved PARPi as maintenance therapy for platinum-sensitive OC, regardless of BReast CAncer gene (BRCA) status, in first-line patients, with a recent restriction to germline BRCA mutations in second-line patients. In this review, we comprehensively summarized the pharmacological properties of niraparib, alongside the efficacy and safety data of the main trials leading to the current approvals, and discussed the future development of this agent.

Updated overall survival from the MONALEESA-3 trial in postmenopausal women with HR+/HER2− advanced breast cancer receiving first-line ribociclib plus fulvestrant

BackgroundThe phase III MONALEESA-3 trial included first- (1L) and second-line (2L) patients and demonstrated a significant overall survival (OS) benefit for ribociclib + fulvestrant in patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative (HR+/HER2−) advanced breast cancer (ABC) in the final protocol-specified and exploratory (longer follow-up) OS analyses. At the time of these analyses, the full OS benefit of 1L ribociclib was not completely characterized because the median OS (mOS) was not reached. As CDK4/6 inhibitor (CDK4/6i) + endocrine therapy (ET) is now a preferred option for 1L HR+/HER2− ABC, we report an exploratory analysis (median follow-up, 70.8 months; 14.5 months longer than the prior analysis) to fully elucidate the OS benefit in the MONALEESA-3 1L population.MethodsPostmenopausal patients with HR+/HER2− ABC were randomized 2:1 to 1L/2L fulvestrant + ribociclib or placebo. OS in 1L patients (de novo disease or relapse > 12 months from completion of [neo]adjuvant ET) was assessed by Cox proportional hazards model and Kaplan–Meier methods. Progression-free survival 2 (PFS2) and chemotherapy-free survival (CFS) were analyzed. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615).ResultsAt data cutoff (January 12, 2022; median follow-up time, 70.8 months), mOS was 67.6 versus 51.8 months with 1L ribociclib versus placebo (hazard ratio (HR) 0.67; 95% CI 0.50–0.90); 16.5% and 8.6% of ribociclib and placebo patients, respectively, were still receiving treatment. PFS2 (HR 0.64) and CFS (HR 0.62) favored ribociclib versus placebo. Among those who discontinued treatment, 16.7% and 35.0% on ribociclib or placebo, respectively, received a subsequent CDK4/6i. No new safety signals were observed.ConclusionsThis analysis of MONALEESA-3 reports the longest mOS thus far (67.6 months) for 1L patients in a phase III ABC trial. These results in a 1L population show that the OS benefit of ribociclib was maintained through extended follow-up, further supporting its use in HR+/HER2− ABC.

Eustachian tube balloon dilation

Eustachian tube dysfunction is a frequent pathology of middle-ear ventilation, leading to many more or less disabling otologic symptoms. Severity varies from simple otitis media with effusion to aggressive chronic otitis or cholesteatoma. First-line treatment is medical, but surgery can also be proposed. It consists in balloon dilation of the Eustachian tube, in order to increase ventilation and improve symptoms. It is performed in second-line in patients with Eustachian tube dysfunction confirmed by tubomanometry, after failure of local drug treatment. It can be performed under general or local anesthesia but it is mandatory to use a medical device with market authorization for this indication. The main aim of this surgical note is to describe the technique of balloon dilation in the treatment of Eustachian tube dysfunction and the three balloon models with CE label and market authorization currently available in France and in Europe. Balloon dilation of the Eustachian tube appears to be a promising option to restore natural middle-ear ventilation in patients with chronic obstructive Eustachian tube dysfunction.

Treatment outcomes of multidrug-resistant tuberculosis patients receiving ambulatory treatment in Shenzhen, China: a retrospective cohort study.

WHO recommended multidrug-resistant tuberculosis (MDR-TB) should be treated mainly under ambulatory model, but outcome of ambulatory treatment of MDR-TB in China was little known. The clinical data of 261 MDR-TB patients treated as outpatients in Shenzhen, China during 2010-2015 were collected and analyzed retrospectively. Of 261 MDR-TB patients receiving ambulatory treatment, 71.1% (186/261) achieved treatment success (cured or completed treatment), 0.4% (1/261) died during treatment, 11.5% (30/261) had treatment failure or relapse, 8.0% (21/261) were lost to follow-up, and 8.8% (23/261) were transferred out. The culture conversion rate at 6 months was 85.0%. Although 91.6% (239/261) of patients experienced at least one adverse event (AE), only 2% of AEs caused permanent discontinuation of one or more drugs. Multivariate analysis showed that previous TB treatment, regimens containing capreomycin and resistance to FQs were associated with poor outcomes, while experiencing three or more AEs was associated with good outcomes. Good treatment success rates and early culture conversions were achieved with entirely ambulatory treatment of MDR-TB patients in Shenzhen, supporting WHO recommendations. Advantageous aspects of the local TB control program, including accessible and affordable second-line drugs, patient support, active monitoring and proper management of AEs and well-implemented DOT likely contributed to treatment success rates.