Third-line Therapy In Patients Research Articles

Efficacy and safety of RS plus bevacizumab versus RS plus fruquintinib as the third-line therapy in patients with refractory metastatic colorectal cancer: A real-world propensity score matching study.

This study aims to compare the effectiveness and safety of the combination of raltitrexed, S-1 (RS), and fruquintinib with the combination of RS and bevacizumab in patients with refractory metastatic colorectal cancer (mCRC). This retrospective cohort included mCRC patients who received the RS plus fruquintinib or regorafenib as the third-line therapy from May 2019 to April 2023. A propensity score matching (PSM) analysis was used to balance the baseline characteristics of all patients. Overall survival (OS), progression-free survival (PFS), tumor response, and safety of the two regimens were evaluated. Of the 153 patients enrolled, 123 patients received the RS plus bevacizumab and 30 patients received the RS plus fruquintinib. After PSM, 30 pairs were analyzed. Patients treated with RS plus fruquintinib had a longer PFS than those treated with RS plus bevacizumab before PSM (5.0 months vs. 4.3 months, p=0.008) and after PSM (5.0 months vs. 4.4 months, p=0.012). A longer OS was also observed in RS plus fruquintinib group before PSM and after PSM, but there was no statistic difference between two groups after PSM. Both objective response rate and disease control rate were higher in the RS plus fruquintinib cohort than those in the RS plus bevacizumab cohort before PSM, and the difference in values between the two groups reduced after PSM. The adverse effects (AEs) of both groups were well tolerated. In patients with refractory mCRC, RS plus fruquintinib demonstrated a superior OS, PFS than RS plus bevacizumab and had manageable AEs.

Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer

BackgroundRecurrent cervical cancer is a life-threatening disease, with limited treatment options available when disease progression occurs after first-line combination therapy.MethodsWe conducted a phase 3, multinational, open-label trial of tisotumab vedotin as second- or third-line therapy in patients with recurrent or metastatic cervical cancer. Patients were randomly assigned, in a 1:1 ratio, to receive tisotumab vedotin monotherapy (2.0 mg per kilogram of body weight every 3 weeks) or the investigator’s choice of chemotherapy (topotecan, vinorelbine, gemcitabine, irinotecan, or pemetrexed). The primary end point was overall survival.ResultsA total of 502 patients underwent randomization (253 were assigned to the tisotumab vedotin group and 249 to the chemotherapy group); the groups were similar with respect to demographic and disease characteristics. The median overall survival was significantly longer in the tisotumab vedotin group than in the chemotherapy group (11.5 months [95% confidence interval {CI}, 9.8 to 14.9] vs. 9.5 months [95% CI, 7.9 to 10.7]), results that represented a 30% lower risk of death with tisotumab vedotin than with chemotherapy (hazard ratio, 0.70; 95% CI, 0.54 to 0.89; two-sided P=0.004). The median progression-free survival was 4.2 months (95% CI, 4.0 to 4.4) with tisotumab vedotin and 2.9 months (95% CI, 2.6 to 3.1) with chemotherapy (hazard ratio, 0.67; 95% CI, 0.54 to 0.82; two-sided P<0.001). The confirmed objective response rate was 17.8% in the tisotumab vedotin group and 5.2% in the chemotherapy group (odds ratio, 4.0; 95% CI, 2.1 to 7.6; two-sided P<0.001). A total of 98.4% of patients in the tisotumab vedotin group and 99.2% in the chemotherapy group had at least one adverse event that occurred during the treatment period (defined as the period from day 1 of dose 1 until 30 days after the last dose); grade 3 or greater events occurred in 52.0% and 62.3%, respectively. A total of 14.8% of patients stopped tisotumab vedotin treatment because of toxic effects.ConclusionsIn patients with recurrent cervical cancer, second- or third-line treatment with tisotumab vedotin resulted in significantly greater efficacy than chemotherapy. (Funded by Genmab and Seagen [acquired by Pfizer]; innovaTV 301 ClinicalTrials.gov number, NCT04697628.)

Panitumumab plus trifluridine/tipiracil as anti-EGFR rechallenge therapy in patients with refractory RAS wild-type metastatic colorectal cancer: Overall survival and subgroup analysis of the randomized phase II VELO trial.

The randomized phase II VELO trial showed that the addition of panitumumab to trifluridine/tipiracil significantly improves progression-free survival (PFS) as compared to trifluridine/tipiracil in third-line therapy in patients with refractory RAS wild-type (WT) metastatic colorectal cancer (mCRC). With longer follow-up, final overall survival results and posttreatment subgroup analysis are presented. Sixty-two patients with refractory RAS WT mCRC were randomly assigned to receive, as third-line therapy, trifluridine/tipiracil alone (arm A) or in combination with panitumumab (arm B). Primary endpoint was PFS; secondary endpoints included overall survival (OS) and overall response rate (ORR). Median OS was 13.1 months (95% CI 9.5-16.7) in arm A compared to 11.6 months (95% CI 6.3-17.0) in arm B (HR: 0.96, 95% CI 0.54-1.71, P = .9). To evaluate the impact of subsequent lines of treatment, subgroup analysis was performed for the 24/30 patients in arm A, that received fourth-line therapy after disease progression. Median PFS was 4.1 months (95% CI 1.44-6.83) for 17 patients treated with anti-EGFR rechallenge as compared to 3.0 months (95% CI 1.61-4.31) for seven patients that received other therapies (HR: 0.29, 95% CI 0.10-0.85, P = .024). Median OS from the start of fourth-line treatment was 13.6 months (95% CI 7.2-20), and 5.1 months (95% CI 1.8-8.3) for patients treated with anti-EGFR rechallenge vs other therapies, respectively (HR: 0.30, 95% CI 0.11-0.81, P = .019). Final results of the VELO trial support the role of anti-EGFR rechallenge in the continuum of care of patients with RAS/BRAF WT mCRC.

CD4-T Cells as a Predictor of Immune Status and Its Outcomes Following Second-Line Combination Antiretroviral Therapy in Adult HIV-1 Infected Patients Attending Apin/Juth HIV Clinic in Jos, Plateau State, Nigeria

Deficiency in immune cell number or activity is a cardinal feature of HIV. Second line antiretroviral therapy is geared towards improving immune cell activity and improving treatment outcomes. More people are now accessing free combination antiretroviral therapy through public health programmes in resource limited settings. There is currently no third line therapy for patients failing second line therapy in most of these programmes and data on effectiveness of second line antiretroviral therapy are limited. To adequately address and prepare for this scenario, critical assessments of the outcomes of second-line cART are needed. This is a retrospective cohort study of patients accessing second line cART at the APIN/ JUTH, Jos adult HIV clinic from 2004 to 2018, to determine the proportion of patients failing second line cART, to evaluate time to immunologic failure, time to lost to follow up and time to death using Kaplan Meier estimates. Immunological failure occurs when there is a fall of CD4 counts to pre-therapy baseline (or below) or 50% fall from the on-treatment peak value (if known) or persistent CD4 levels below 100 cells/mm 3 6 months after ART initiation. A total of 285 patients were included in the study, with a mean age of 45±9.5 years. Females where 194 (68.1%) All the patients were on boosted protease inhibitor, the predominant combination antiretroviral therapy for second line regimen was Lopinavir boosted with ritonavir in combination with Tenofovir, Lamivudine and Zidovudine (43.9%). The baseline CD4 count was 134 (IQR 54-272). The CD4 count increased to 339 (IQR213-498) at 72 weeks. In conclusion, Second line cART immunologic failure rates are low in our cohort and patient stay longer on cART before failure. Keywords: CD4 cells, Immunologic failure, Antiretroviral therapy DOI: 10.7176/JHMN/107-02 Publication date: April 30 th 2023

Management of patients with immune thrombocytopenia in the Moscow region

Background. Idiopathic thrombocytopenic purpura (ITp) is an autoimmune disease characterized by antibody-mediated platelets destruction and impairment of their production, which manifests itself as: isolated thrombocytopenia, risk of spontaneous hemorrhage and bleeding of varying severity. ITp is a hematological, orphan disease with an incidence of 1–4 cases per 100,000 population. In modern literature, primary and secondary immune thrombocytopenias are distinguished. primary immune thrombocytopenia is a diagnosis of exclusion. To verify it, a certain diagnostic search is required.Aim. To evaluate clinical characteristics and treatment efficacy in patients with a confirmed primary immune thrombocytopenia in the Moscow region.Materials and methods. This article presents the results of an analysis of more than 2,400 outpatient records of patients diagnosed with thrombocytopenia (for the period from 2010 to 2022). Of these, about 400 confirmed clinical cases of various ITp forms were included in the ITp registry of the Moscow Region. All patients live in the Moscow region, receive treatment and are observed at the Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute.Results. There are 415 patients with a verified diagnosis of ITp in the register of the Moscow Region Center for Orphan diseases of the M.f. vladimirskiy Moscow Regional Research Clinical Institute (71 % (n = 294) are female). In 69.8 % (n = 290) of patients at the time of disease manifestation, hemorrhagic syndrome was recorded. As a first-line therapy, 92.8 % (n = 385) of patients received corticosteroids (prednisolone, methylprednisolone, dexamethasone), in the second-line therapy, 82 % (n = 340) of patients were recommended therapy with thrombopoietin receptor agonists (romiplostim, eltrombopag). The options for third-line therapy in patients with ITp are rituximab monotherapy, splenectomy, and intravenous immunoglobulin. Splenectomy was performed in 3.37 % (n = 14) of patients.Conclusion. when evaluating this register, the highest efficiency of thrombopoietin receptor agonists (romiplostim, eltrombopag) is observed – 84.1 % of the objective response.

The third-line therapy for patients with metastatic colorectal cancer: regorafenib or repeated administration of drugs? A review

To this date, the treatment of metastatic colorectal cancer involves continuous drug therapy, the so-called "continuum of care" approach in order to control of tumor growth and try to increase life expectancy for patients. The characteristic is the limited availability and insufficient number of third- and subsequent-line therapy. The main options for the treatment of resistant forms of metastatic colorectal cancer in real practice are the alternation of chemotherapy regimens, targeted drugs and the application of regorafenib. The choice of the treatment tactics is influenced by the patient's condition, the previous treatment and the efficacy, the molecular status of the tumor. The correct sequence of use of such approaches is currently not clearly defined and is the subject of many discussions and retrospective studies. The article discusses the main trends in the application of targeted antiangiogenic therapy for this category of patients.

Abstract CT558: Capmatinib vs docetaxel as second- or third-line therapy in patients with locally advanced or metastatic METex14-mutated NSCLC: The GeoMETry-III trial

Abstract Background: MET dysregulation is a poor prognostic factor in advanced non-small cell lung cancer (NSCLC). MET exon 14 skipping (METex14) mutations occur in ~3% of patients with NSCLC. There is limited evidence of the efficacy of standard therapies, such as chemotherapy or immunotherapy, in patients with METex14-mutated advanced NSCLC. Capmatinib, a MET inhibitor (METi), is approved for the treatment of adult patients with metastatic METex14-mutated NSCLC, based on the results of the phase 2 GEOMETRY mono-1 study. Results (data cutoff: September 18, 2020) of this study in patients with METex14-mutated NSCLC treated with capmatinib showed an overall response rate (ORR) of 66.7% in first line (N=60), 51.6% in second line (N=31) and 40.6% in second- or third-line (2/3L; N=69). GeoMETry-III (NCT04427072) is a multicenter, open-label, randomized, controlled, global, phase 3 trial that is further evaluating the efficacy and safety of capmatinib vs docetaxel in the 2/3L setting in patients with METex14-mutated NSCLC. Methods: This study began enrollment in September 2020 and is currently recruiting adult patients with EGFR wild-type, ALK-negative, stage IIIB/IIIC/IV METex14-mutated NSCLC, who have progressed on 1 or 2 prior lines of systemic therapy for advanced/metastatic disease and are candidates for single-agent docetaxel. Other eligibility criteria include ≥1 measurable lesion per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), an Eastern Cooperative Oncology Group performance status of ≤1 and no prior treatment with any METi or hepatocyte growth factor-targeting therapies. Patients with neurologically unstable, symptomatic central nervous system (CNS) metastases or those requiring increasing doses of steroids ≤2 weeks prior to study entry to manage CNS symptoms are excluded. Around 90 patients will be randomized 2:1 to receive either oral capmatinib 400 mg twice daily or intravenous docetaxel 75 mg/m2 every 21 days. Randomization is stratified by number of prior lines (1 or 2) of systemic therapy. Patients meeting protocol-specified eligibility criteria can cross over from the docetaxel to the capmatinib arm after blinded independent review committee (BIRC)-confirmed progressive disease as per RECIST 1.1.The primary endpoint is progression-free survival (PFS) by BIRC per RECIST 1.1. The key secondary endpoint is ORR by BIRC per RECIST 1.1. Other secondary endpoints include investigator-assessed ORR and PFS; duration of response, time to response and disease control rate (DCR) by BIRC and investigator; overall survival; safety; pharmacokinetics; patient-reported outcomes; overall intracranial response rate, intracranial DCR, duration of- and time to- intracranial response by BIRC per the Response Assessment in Neuro-Oncology Brain Metastases criteria in patients with baseline CNS lesions. Citation Format: Pierre Jean Souquet, Sang-We Kim, Johan F. Vansteenkiste, Anna Robeva, Aline Jary, Sabine Glaser, Alejandro Yovine, Juergen Wolf. Capmatinib vs docetaxel as second- or third-line therapy in patients with locally advanced or metastatic METex14-mutated NSCLC: The GeoMETry-III trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT558.

Immunotherapy in Hispanic patients with advanced non-small cell lung cancer: A real-world data.

e21094 Background: Nivolumab is a human programmed death receptor-1 (PD-1) blocking antibody, used as treatment option in patients with advanced non-small cell lung cancer (NSCLC). We assessed the nivolumab efficacy in terms of survival and response to treatment as second- or third-line therapy in patients with advanced NSCLC. Methods: This is a multicentric observational study. Data of patients with advanced NSCLC who received nivolumab as second (2L) or third-line (3L) treatment were analyzed retrospectively. Information regarding patient demographics and clinical backgrounds, treatment patterns from diagnosis to post-nivolumab treatment, effectiveness, and safety of nivolumab treatment were collected. The outcomes evaluated were overall survival (OS), progression-free survival (PFS), and objective reponse rate to treatment (ORR). OS and PFS were estimated with the Kaplan-Meier method. Statistical analysis was carried out using SPSS version 21.0. Results: Eleven centers distributed across the country (Colombia) participated. Data from 178 patients were included. The median follow-up was 26.8 months (IQR 20.3 - 40.4). Women represented 51.7% of the population, and the median age was 63 years (IQR 56-72 years). Nivolumab was commonly used as a 2L treatment. The ORR with nivolumab as 2L treatment was 21.0%. The median PFS and OS were 5.5 months (95%CI: 4.5 – 6.5) and 12.4 months (95%CI: 10.8 – 14.0), respectively. In 3L the ORR with nivolumab was 15.0%. The overall incidence of adverse events was 1.7%. Conclusions: Nivolumab effectiveness and safety in this scenario was consistent with than reported by previous trials and other real world data.

Efficacy of anlotinib for advanced SCLC patients: A real-world study.

e20621 Background: Anlotinib is a novel small molecule multi-target tyrosine kinase inhibitor, which has been approved as a third-line therapy for patients with advanced small cell lung cancer (SCLC) by NMPA in Aug 2019. ALTER 1202 trial has demonstrated that anlotinib significantly prolonged progress-free survival (PFS) and improved disease control rate (DCR) of advanced SCLC patients. Since the efficacy of patients in real clinical practice is affected by many factors, the objective of this study was to assess the efficacy of anlotinib for patients with advanced SCLC in real world. Methods: This is a multi-center, non-interventional, prospective real-world study and all registered data are collected from real clinical practice cases. Patients diagnosed as advanced SCLC and treated with anlotinib were included. The primary endpoint was PFS, and secondary endpoints included overall survival (OS), objective response rate (ORR), DCR and safety. Results: Until Dec 2021, a total of 44 eligible patients were included, with a median age of 62 years, including 34 males (77.3%) and 10 females (22.7%). Among them, 38 patients (86.4%) were diagnosed as a limited stage SCLC and 6 patients (13.6%) diagnosed extensive stage. All patients have not received other targeted therapies before. The median PFS was 6.0 months (95%CI 2.4-5.8), and the median OS was 15.9 months (95%CI 9.1-18.83). At the data cut-off date, 1 patient was assessed as CR, 22 patients were assessed as PR, 15 patients were assessed as SD and 4 patients were assessed as PD. The ORR was 52.3% and the DCR was 86.4%. Conclusions: Significant improvement in OS and PFS were found for advanced SCLC patients in this real-world study. This exhibited that anlotinib has a potential efficacy over previous treatment models. Of course, safety must be further observed subsequently.

The efficacy of anlotinib as third-line treatment for non-small cell lung cancer by EGFR mutation status: a subgroup analysis of the ALTER0303 randomized phase 3 study.

BackgroundAnlotinib demonstrated improved overall survival (OS) and progression-free survival (PFS) compared with placebo as a third-line or subsequent therapy in patients with non-small cell lung cancer (NSCLC) in the ALTER0303 trial. The status of epidermal growth factor receptor (EGFR) mutation, different previous treatment may affect the efficacy of subsequent therapy, and we did this subgroup analysis to characterize the efficacy of anlotinib in patients with and without EGFR mutation.MethodsThe ALTER0303 trial was a randomized, double-blind, phase 3 study of anlotinib in patients with NSCLC who failed at least 2 lines of treatment. In the study, 138 of 437 randomized patients were EGFR mutation positive. A Cox model was used to examine the influence of previous treatment on the efficacy of anlotinib according to EGFR mutation status.ResultsFor patients with EGFR mutation, the OS was 10.7 and 6.3 months (HR 0.59; 95% CI: 0.38–0.94, P=0.025) in the anlotinib and placebo group, respectively. The PFS was 5.6 and 0.8 months (HR 0.21; 95% CI: 0.13–0.32, P<0.0001) in the anlotinib and placebo group, respectively. For patients without EGFR mutation, the OS was 8.9 months for anlotinib and 6.5 months for placebo (HR 0.73; 95% CI: 0.55–0.97, P=0.029), and the PFS was 5.4 months for anlotinib and 1.6 months for placebo (HR 0.29; 95% CI: 0.22–0.39, P<0.0001). In the anlotinib group, the OS and PFS for patients with and without EGFR mutation was 10.7 and 8.9 months (HR 0.69; 95% CI: 0.50–0.95, P=0.021), 5.6 and 5.4 months (HR 1.00; 95% CI: 0.75–1.34, P=1.000), respectively. The incidence of adverse events was similar in subgroups.ConclusionsThis analysis demonstrated that the benefit of anlotinib as a third-line therapy for patients with NSCLC was independent of EGFR mutation status.

Feasibility and Tolerance of Apatinib plus PD-1 Inhibitors for Previously Treated Advanced Gastric Cancer: A Real-World Exploratory Study.

Background Apatinib is established to be the standard of care as third-line therapy for patients with previously treated advanced gastric cancer (GC). Programmed cell death protein 1 (PD-1) blockades also exhibited promising efficacy and safety for patients with treatment-refractory advanced GC. Objective This study was to explore the feasibility and tolerance of apatinib plus PD-1 inhibitors for patients with previously treated advanced GC. Methods This study was performed as a real-world study; patients with advanced GC who were treated with previous systemic chemotherapy were screened retrospectively. Eligible patients were administered with apatinib combined with PD-1 blockade treatment. Efficacy of the patients was assessed with the change of target lesion using radiological evidence according to RECIST 1.1 criteria, and follow-up was carried out regularly. A safety profile was collected and documented during the combination treatment. Univariate analysis based on baseline characteristic subgroup was implemented in univariate analysis to identify the potential factor that might contribute to progression-free survival (PFS). Results Between August 2018 and October 2021, a total of 39 patients with advanced GC or gastroesophageal junction adenocarcinoma participated in this study consecutively and all the patients were available for efficacy and safety assessment. The best overall response during apatinib plus PD-1 blockade administration exhibited that PR was observed in 8 patients, SD was noted in 19 patients, and PD was found in 12 patients, which yielded an ORR of 20.5% (95% CI: 9.3%-36.5%), and DCR was 69.2% (95% CI: 52.4%-83.0%). Furthermore, the relatively enough follow-up had resulted in the mature PFS and overall survival (OS) data, suggesting that the median PFS of the 39 patients with advanced GC was 3.9 months (95% CI: 2.74-5.06). Additionally, the median OS of the 39 patients with advanced GC was 7.8 months (95% CI: 4.82-10.78). Furthermore, the most common adverse reactions of the 39 patients who received apatinib plus PD-1 blockades treatment were fatigue (61.5%), nausea and vomiting (56.4%), diarrhea (48.7%), hypertension (46.2%), hand-foot syndrome (38.5%), and rash (28.2%). Furthermore, performance status was independently associated with PFS of apatinib plus PD-1 inhibitor combination administration in baseline characteristic subgroup analysis. Conclusion Apatinib plus PD-1 inhibitors exhibited promising effectiveness and acceptable tolerance for previously treated advanced GC preliminarily. And this conclusion should be confirmed in clinical trials in the future.

67 - Efficacy, safety, and health-related quality of life from a global phase 3 study of tislelizumab as second- or third-line therapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC): RATIONALE 303

67 - Efficacy, safety, and health-related quality of life from a global phase 3 study of tislelizumab as second- or third-line therapy for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC): RATIONALE 303

P345 The Effectiveness of Ustekinumab and Vedolizumab as Third-line Therapy in Patients with Refractory Crohn’s Disease

Abstract Background There is no head-to-head trial comparing ustekinumab (UST) and vedolizumab (VDZ) in Crohn’s disease (CD). Recently, real-world studies evaluated the two biologics in patients refractory to anti-TNF therapy, i.e. as second-line agents. Conversely, no study specifically focused on the effectiveness of UST and VDZ as third-line agents, i.e. after failure with at least one TNF-α inhibitor plus failure with VDZ or UST. We performed a multicentre, real-world assessment of the effectiveness of UST and VDZ in these highly-refractory patients with CD. Methods Data of consecutive patients with CD treated with UST and VDZ as third-line therapy until October, 2021 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease (SN-IBD). The effectiveness was evaluated at, 8, 26, and, 52 weeks, and as treatment persistence at the end of follow up. The clinical outcomes were steroid-free clinical remission (SFCR - Harvey-Bradshaw Index &amp;lt;, 5 without steroid use) and clinical response (CR - reduction of the Harvey-Bradshaw Index ≥, 3 points with a concomitant decrease of steroid dosage compared with baseline). Multiple logistic regression models were build to find independent predictors of effectiveness, including the use of UST and VDZ as candidate predictors. Results 143 patients (UST: n=113; VDZ: n=30) were included. After, 8 weeks, SFCR was reported in, 38.1% of patients treated with UST and in, 43.3% of patients treated with VDZ (p=0.75), while CR was reported in, 61.9% of patients treated with UST and in, 60.0% patients treated with VDZ (p=1.00). After, 26 weeks, the rates of SFCR and CR were, 41.6% for UST and, 50.0% for VDZ (p=0.60), and, 61.4% for UST and, 66.7% for VDZ (p=0.81), respectively. After, 52 weeks, the rates of SFCR and CR were, 51.8% for UST and, 57.1% for VDZ (p=0.78), and, 65.9% for UST and, 71.4% for VDZ (p=0.77), respectively. Lack of difference in effectiveness between the two drugs at any time point was confirmed by multiple logistic regression models. After, 26 weeks, 88.7% of patients treated with UST and, 81.4% of patients treated with VDZ were still on treatment. Univariable Cox survival analysis showed a higher probability of treatment discontinuation for VDZ compared with UST (HR for VDZ:, 2.66; p=0.008), even if such difference was not confirmed at the multiple Cox proportional hazard regression model (HR for VDZ:, 1.94; p=0.08), where only age (HR, 0.98; p=0.04) and use of systemic steroids at baseline (HR, 3.29; p=0.003) were found to be independent predictors of treatment discontinuation. Conclusion This is the first real-world study assessing VDZ and UST as third-line therapy in patients with CD. Both drugs showed surprisingly high effectiveness, without significant differences between them.

A phase I study of the tyrosine kinase inhibitor anlotinib combined with platinum/pemetrexed-based chemotherapy in untreated nonsquamous non-small-cell lung cancer

SummaryBackground. Anlotinib hydrochloride is an oral small molecule inhibitor of multiple tyrosine kinases, and it has been approved as a third-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) in China. This dose-exploration study was designed to investigate the feasibility of anlotinib in combination with other chemotherapy regimens in patients with nonsquamous NSCLC. Methods. This phase I study followed a 3 + 3 dose reduction design with three doses of anlotinib (12 mg, 10 mg, and 8 mg). Anlotinib was given at an initial dose of 12 mg with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC = 5) on 21-day cycles for 4 cycles. The primary goal of the study was to identify the maximum tolerated dose (MTD), and secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results. A total of eight participants were enrolled. Dose-limiting toxicities (DLTs) were observed in two patients (pts) at anlotinib 12 mg (grade 3 hand-foot syndrome and grade 3 appetite loss). No DLTs occurred with 10 mg anlotinib, and the MTD was 10 mg. Among seven evaluable pts, four achieved a confirmed partial response (PR), and three had stable disease (SD). With a median follow-up of 10.05 months, the median PFS was 7.00 months (95% CI: 2.76 to NE). Grade 3 treatment-related adverse events (TRAEs) included appetite loss (n = 2), hypertension (n = 2), thrombocytopenia (n = 1), diarrhea (n = 1) and hand-foot syndrome (n = 1). No grade 4 or grade 5 TRAEs were observed during the treatment. Conclusion. The feasible dose of anlotinib in combination with platinum/pemetrexed-based chemotherapy as a first-line regimen was 10 mg, which was well tolerated and showed promising antitumor activity in advanced nonsquamous NSCLC.

P40.06 A Real-World Study: Efficacy and Safety of Anlotinib for Advanced Non-Small Cell Lung Cancer

Anlotinib is an oral novel receptor tyrosine kinase (RTK) inhibitor and targets multiple RTKs including VEGFR, PDGFR, FGFR, and c-kit, which has been approved as a third-line therapy for patients with advanced NSCLC by CFDA in May 2018 due to its high efficacy and low side effects in ALTER 0303 trail. Phased data from multiple studies of anlotinib report its clinical efficacy and safety, but its real-world data are scarce, and the efficacy of patients in real clinical practice is affected by many factors.

PD-1/PD-L1 Inhibitors versus Chemotherapy for Previously Treated Advanced Gastroesophageal Cancer: A Meta-Analysis of Randomized Controlled Trials.

Patients with advanced gastroesophageal cancer refractory to the previous regimen of chemotherapy suffered from poor prognosis without many effective treatment options. Immune checkpoint inhibitors (ICIs) provide promising efficacy, but the relevant clinical trials have offered controversial data. We performed this meta-analysis to compare the efficacy and safety of inhibitors against programmed cell death receptor 1 (PD-1) and its ligand PD-L1 versus chemotherapy as second or third-line therapy in patients with advanced gastroesophageal cancer. Six randomized controlled trials (RCTs) including 2,648 patients were included. The meta-analysis results indicated that both ORR (RR = 1.39, 95% CI: 0.85∼2.25, P = 0.188) and PFS (HR = 1.14, 95% CI: 0.88∼1.46, P = 0.316) were not significantly improved by ICIs compared with chemotherapy. However, the OS was significantly prolonged (HR = 0.85, 95% CI: 0.75–0.97, P = 0.018) in the ICIs group compared with chemotherapy. Subgroup analysis showed that ICIs provide statistically significant OS benefits over chemotherapy in PD-L1-positive, squamous cell carcinoma, Asia origin, esophageal cancer, second-line treatment, male, and aged 65 or older patients. Compared with chemotherapy, the TRAEs risk of ICIs was reduced by 33% (RR = 0.67, 95% CI: 0.62–0.73, P ≤ 0.001). And the risk of grades 3–5 of TRAEs was reduced by 60% (RR = 0.40, 95% CI: 0.33–0.49, P ≤ 0.001). Compared to chemotherapy, ICIs appeared to improve OS and were better tolerated in previously treated patients with advanced esophageal cancer. We recommend PD-1/PD-L1 inhibitors as an optimal treatment option for positive PD-L1 expression, squamous cell carcinoma, Asia origin, esophageal cancer, second-line treatment, male, and ≥65 years of age patients.

Abstract CT039: Results from RATIONALE 303: A global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC

Abstract Results From RATIONALE 303: A Global Phase 3 Study of Tislelizumab (TIS) vs Docetaxel (TAX) as Second- or Third-Line Therapy for Patients With Locally Advanced or Metastatic NSCLC Background: Anti-PD-1/L1 therapies have improved OS by 2-4 mo vs TAX in patients (pts) with advanced NSCLC who progressed after platinum regimens. TIS is an anti-PD-1 antibody engineered to minimize FcγR binding on macrophages, a mechanism of T-cell clearance and potential anti-PD-1 resistance. Methods: RATIONALE 303 (BGB-A317-303; NCT03358875) compared efficacy and safety of TIS vs TAX as 2 or 3L therapy for pts with advanced NSCLC. Patients without oncogenic driver mutation who failed at least 1 prior systemic therapy including a platinum regimen were randomized 2:1 to receive TIS 200 mg IV Q3W (Arm A) or TAX 75 mg/m2 IV Q3W (Arm B). Dual primary endpoints were OS in the ITT analysis set and OS in the PD-L1 high (≥25% TC) analysis set. A prespecified interim analysis (IA) was conducted after ≈426 deaths (76% of planned events); in the IA, formal OS superiority testing was conducted only in the ITT. The IA results are presented. Results: Overall, 805 pts were randomized (n=535, TIS; n=270, TAX); demographics were generally balanced between arms. With a 19-mo median follow-up (441 OS events), median OSITT was significantly longer in Arm A vs B (17.2 vs 11.9 mo; HR=0.64 [95% CI: 0.53, 0.78]; P&amp;lt;.0001). OS benefit was also observed in the PD-L1 high analysis set (19.1 vs 11.9 mo; HR=0.52 [95% CI: 0.38, 0.71]) and across most subgroups including histology. In the ITT analysis set, PFS, ORR, and DoR were also improved in Arm A vs B (Table). Anemia (TIS) and alopecia (TAX) were the most commonly reported AEs (Table); pneumonia (TIS) and neutropenia (TAX) were the most common grade ≥3 AEs. AEs leading to death were 6.0% (TIS) and 4.3% (TAX); treatment-related AEs leading to death were 1.5% (TIS) and 1.6% (TAX). Conclusions: RATIONALE 303 demonstrated that, as 2 or 3L therapy in pts with advanced NSCLC, TIS was tolerable and prolonged OS by 5-7 mo with improved PFS and ORR vs TAX regardless of histology or PD-L1 expression. ITT Analysis Set (N=805)Arm A Tislelizumab (n=535)Arm B Docetaxel (n=270)EfficacyMedian OS, mo17.211.9OS difference, mo5.3HR (95% CI)a0.64 (0.53, 0.78)P-valuea,b&amp;lt;0.0001Median PFS, mo4.12.6PFS difference, mo1.5HR (95% CI)a0.64 (0.53, 0.76)P-valuea,b&amp;lt;0.0001cORR, n (%)117 (21.9)19 (7.0)ORR difference, %14.9OR (95% CI)3.71 (2.24, 6.14)P-valued&amp;lt;0.0001cMedian DoR, mo (95% CI)13.5 (8.5, 21.8)6.2 (2.1, 7.2)Adverse event profileAEs occurring in ≥15% of patients in either arm, n (%)All gradeGrade ≥3All gradeGrade ≥3Anemia152 (28.5)18 (3.4)112 (43.4)16 (6.2)Alanine aminotransferase increased106 (19.9)4 (0.7)38 (14.7)0Cough104 (19.5)5 (0.9)40 (15.5)1 (0.4)Aspartate aminotransferase increased101 (18.9)5 (0.9)31 (12.0)1 (0.4)Appetite decreased82 (15.4)5 (0.9)59 (22.9)3 (1.2)Weight decreased81 (15.2)4 (0.7)26 (10.1)0Alopecia5 (0.9)0122 (47.3)2 (0.8)Neutrophil count decreased15 (2.8)3 (0.6)95 (36.8)71 (27.5)Neutropenia9 (1.7)3 (0.6)81 (31.4)72 (27.9)White blood cell count decreased20 (3.7)1 (0.2)74 (28.7)47 (18.2)Leukopenia15 (2.8)1 (0.2)69 (26.7)41 (15.9)Asthenia67 (12.5)6 (1.1)56 (21.7)14 (5.4)Constipation65 (12.2)042 (16.3)0Hypoalbuminemia70 (13.1)041 (15.9)1 (0.4)Nausea59 (11.0)041 (15.9)1 (0.4)Abbreviations: AE, adverse event; DoR, duration of response; HR, hazard ratio; ITT, intent-to-treat; mo, months; NA, not available; OR, odds ratio; ORR, objective response rate; PFS, progression-free survival.aStratified.bOne-sided log-rank test.cDescriptive P-value.dCochran-Mantel-Haenszel. Citation Format: Caicun Zhou, Dingzhi Huang, Xinmin Yu, Yunpeng Liu, Yun Fan, Yongqian Shu, Zhiyong Ma, Ziping Wang, Ying Cheng, Jie Wang, Sheng Hu, Zhihua Liu, Mikhail Dvorkin, Elena Poddubskaya, Umut Disel, Andrey Akopov, Yiyuan Ma, Yan Wang, Zhenyu Pan, Cunjing Yu, Gareth Rivalland. Results from RATIONALE 303: A global phase 3 study of tislelizumab (TIS) vs docetaxel (TAX) as second- or third-line therapy for patients with locally advanced or metastatic NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT039.

Safety and Efficacy of Pomalidomide (POM) + Low-Dose Dexamethasone (LoDEX) + Daratumumab (DARA) As Second- or Third-Line Therapy in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) after Lenalidomide (LEN)-Based Treatment (Tx) Failure

Safety and Efficacy of Pomalidomide (POM) + Low-Dose Dexamethasone (LoDEX) + Daratumumab (DARA) As Second- or Third-Line Therapy in Patients with Relapsed and/or Refractory Multiple Myeloma (RRMM) after Lenalidomide (LEN)-Based Treatment (Tx) Failure

PD-1 antibody (Camrelizumab) for metastatic EBV positive gastric cancer: A prospective single-arm, open-label, phase 2 trial.

e16014 Background: Programmed cell death 1 (PD-1) inhibitors have been approved as third line therapy for patients with metastatic gastric cancer (mGC). Epstein–Barr virus (EBV)-positive is a potential predictor to response of PD-1 inhibitors. The aim of this study was to assess the efficacy and safety of camrelizumab as salvage treatment in metastatic EBV positive GC patients and explored the potential biomarkers associated with response (NCT03755440). Methods: In this prospective single-arm, phase II study, stage IV EBV positive GC patients received 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR), which were based on RECIST V.1.1. Secondary endpoints were progression free survival (PFS), overall survival (OS), disease control rate (DCR), durationn of response (DoR), and toxicity. Exploratory analysis included association between response and tumor mutational burden (TMB) and cell death ligand-1 (PD-L1) expression. Results: According to Simon’s optimum two-stage design with α = 0.05 and β = 0.20. P0 = 15% (null hypothesis), the presence of at least 1 success in the 6 patients enrolled in the first stage allowed the trial to proceed to the second stage in which 13 more patients were needed to be enrolled for the minimum total of 20 patients (5% lost to follow-up calculated). Six eligible patients were enrolled at the first stage. All the patients were HER2 negative and pMMR. None of the patients had an objective response. The DCR was 66.7%. The median PFS was 2.2 months (95% CI: 1.5 months-not reached (NR)) and median OS was 6.8 months (95% CI: 1.7 months-NR). The most common treatment-related adverse event (TRAE) was reactive cutaneous capillary endothelial proliferation. No grade 3 or worse TRAEs were found. Only one patient had PD-L1 combined positive score (CPS) ≥1 but got disease progression. Three patients were TMB &gt; 10Mb and two of them got stable disease while one got disease progression. Conclusions: EBV positive is not a good predictor for response to PD-1 inhibitors. Potential biomarkers are needed to identify EBVaGC patients who might respond to PD-1 inhibitors. Clinical trial information: NCT03755440.

Skuteczność terapii pomalidomidem u pacjenta ze szpiczakiem plazmocytowym opornym na inne leki immunomodulujące

Treatment of patients with refractory or relapse multiple myeloma (MM) is a major therapeutic challenge. The introduction to the therapy of new active drugs, such as immunomodulating drugs (IMiDs) or proteasome inhibitors contributed to a significant increase in the percentage and quality of the obtained responses and, most importantly, to the prolongation of patients’ life. However, MM is a disease with frequent progressions, and choosing the right treatment strategy is much more difficult with each subsequent relapse. The drugs used in the treatment of such patients include pomalidomide — an IMiD, registered in Poland as the third-line therapy for patients with relapsed and refractory MM. The paper presents a case report of a 66-year-old patient diagnosed with IgG lambda MM, who since January 2016 had received 5 lines of treatment with IMiDs, bortezomib and daratumumab, nevertheless she had not met the criteria of response to treatment. In May 2019, the patient was qualified for further treatment with pomalidomide in combination with low doses of oral dexamethasone (POM-DEX). During the treatment, a significant reduction in the level of the monoclonal IgG lambda protein was observed. After receiving two treatment cycles, the patient met the criteria for partial remission, and after 12 cycles the level of monoclonal protein decreased by 78% compared to the period before treatment. The therapy was quite well tolerated. The only side effects observed during treatment were: worse tolerance of physical effort, weight gain and slight edema of lower limbs. Due to the POM-DEX therapy, the patient achieved a durable response to the treatment, despite the rapid relapses of the disease during the previous lines of treatment.