Third-line Therapy Research Articles

SUCCESSFUL TREATMENT OF METASTATIC LUNG ADENOCARCINOMA WITH LAZERTINIB: A CASE REPORT

Lung cancer is one of the most common social diseases affecting the quality and length of life. A feature of lung cancer is the high frequency of genetic mutations. EGFR mutation is the most common among them. The prognosis for patients, especially with advanced stages, remains unfavorable since this type of tumor is resistant to chemotherapy. Tyrosine kinase inhibitors (TKIs) are considered the promising direction of targeted therapy. Gefitinib, afatinib, and erlotinib are TKIs widely used to treat patients. However, the significant problem remains the acquired resistance, which is most often associated with the additional mutation T790M. Lazertinib is a new and most promising third-generation EGFR-TKI.The study aimed to investigate the indications for lazertinib and to report the results of the successful treatment of a patient with metastatic lung adenocarcinoma with a follow-up period of 35 months.Case report and discussion. Lazertinib is used to treat patients with single (L858R, Ex19del, or T790M) or combined mutations (L858R and T790M, Ex19del and T790). This drug is effective for the first, second, and third lines of therapy, as it can block the T790M mutation, penetrate the blood-brain barrier, and counteract the emergence of acquired resistance. Lazertinib is used as monotherapy, but treatment effectiveness increases if combined with chemotherapy and/or amivantamab (a bispecific antibody against EGFR and MET). Our case report demonstrates that progression-free survival in patients receiving lazertinib can be very high. In patients taking tyrosine kinase inhibitors of the first generation, disease progression occurs after about 12 months. In our case, the patient has no progression within 35 months of treatment. Skin dryness and grade 1 thrombocytopenia have been reported as side effects. The high efficiency of lazertinib in the presented case report can be explained by the presence of the most sensitive to EGFR-TKI mutation - Ex19del, and the absence of uncommon mutations such as Ex20ins, G719X, L861Q, S768I, and T790M.Conclusions. Lazertinib is a highly effective EGFR-TKI with a low toxicity profile that may significantly improve the treatment outcomes of EGFR-mutated patients.

Predicting Survival of Metastatic Clear Cell Renal Cell Cancer Treated with VEGFR-TKI-Based Sequential Therapy.

(1) Objective: To develop a clinically useful nomogram that may provide a more individualized and accurate estimation of cancer-specific survival (CSS) for patients with clear-cell (CC) metastatic renal cell carcinoma (mRCC) treated with nephrectomy and vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFR-TKI)-based sequential therapy. (2) Methods: A prospectively maintained database of 145 patients with mRCC treated between 2008 and 2018 was analyzed to predict the CSS of patients receiving sunitinib and second- and third-line therapies according to current standards of practice. A nomogram based on four independent clinical predictors (Eastern Cooperative Oncology Group status, International Metastatic RCC Database Consortium score, the Morphology, Attenuation, Size and Structure criteria and Response Evaluation Criteria in Solid Tumors response criteria) was calculated. The corresponding 1- to 10-year CSS probabilities were then determined from the nomogram. (3) Results: The median age was 60 years (95% CI 57.9-61.4). The disease was metastatic at diagnosis in 59 (40.7%), and 86 (59.3%) developed metastasis during follow-up. Patients were followed for a median 48 (IQR 72; 95% CI 56-75.7) months after first-line VEGFR-TKI initiation. The concordance probability estimator value for the nomogram is 0.778 ± 0.02 (mean ± SE). (4) Conclusions: A nomogram to predict CSS in patients with CC mRCC that incorporates patient status, clinical risk classification and response criteria to first-line VEGFR-TKI at 3 months is presented. This new tool may be useful to clinicians assessing the risk and prognosis of patients with mRCC.

Design of 225Ac-PSMA for targeted alpha therapy in prostate cancer.

The first alpha emitting radiopharmaceutical, 223RaCl2, radium dichloride, was approved 10 years ago into the clinical armament of treating bone metastases in metastatic castration-resistant prostate cancer (mCRPC). In addition to this, the first beta-emitting radionuclide Lu-177 chelated with a prostate-specific membrane antigen (PSMA) compound, got last year its marketing approval for the third line treatment of mCRPC. Therefore, there is great excitement about combining alpha-emitters and prostate cancer targeting PSMA compounds. This review describes the clinical history of alpha-emitting PSMA in treating mCRPC. Here, we present the potential, current status, and opportunities for 225Ac-PSMA therapy. The work reviews the basic concepts, current treatment outcome, and toxicity, and areas requiring further investigations such as dosimetric aspects in clinical studies covering more than 400 patients. In general, approximately two-thirds of the patients benefit from this third-line therapy. There is also successful evidence of using 225Ac-PSMA in the second-line of prostate cancer management. The future potential of 225Ac-PSMA therapy and targeted alpha therapy (TAT) of cancer in general is enormous. According to our overview the clinical experience with 225Ac-PSMA therapy to date has shown great benefit and physicians dedicated to theragnostics are anxiously waiting for new applications. Hopefully, this review helps in deeper understanding of the strengths and limitations of TAT and may help in creating effective therapy protocols.

Real-world anti-seizure treatment and adverse events among individuals living with drug-resistant focal epilepsy in the United States.

This study aimed to understand how people living with drug-resistant focal epilepsy (DRE) navigate through lines of antiseizure medications (ASM) and experience adverse events (AEs) in the real-world setting in the United States. A retrospective study was conducted with medical chart data from clinical practices in the United States. Eligible adults had a confirmed diagnosis of DRE and initiated a third-line ASM therapy between January 2013 and January 2020 (i.e., the index date). Subjects must have medical history data available for ≥1 year prior to (the baseline) and ≥2 years after the index date (the follow-up). Treatment patterns were captured from first to fourth lines. After the emergence of drug resistance, time to ASM discontinuation, reasons for discontinuation, AE experience and AE management were reported separately during third and fourth lines of treatment and beyond. The study included a total of 345 individuals, with an average (standard deviation) age of 23.9 (11.9) years at first diagnosis. All individuals had at least three lines of ASMs with first and second lines during baseline, and third line during follow-up. The first line for most individuals was monotherapy. As individuals progressed through additional lines of ASM therapy, they were more likely to receive polytherapy. The regimens were more individualized after meeting drug resistance criteria. The top reasons for discontinuing were uncontrolled seizure and/or intolerance/AEs for both third and subsequent lines. More than a third of individuals experienced at least one AE. Among those with at least one AE, many individuals had to manage these AEs with dose adjustment (39.4%), discontinuation of offending ASM (37.9%), de novo pharmacotherapy (25.8%), emergency room visit (13.6%), and hospitalization (12.1%). This study demonstrated that individuals living with DRE experience significant AEs, and many of these AEs lead to treatment disruption and significant healthcare resource utilization. This study examined how individuals with focal epilepsy are treated across various clinics in United States and reported the adverse events these individuals experienced during treatment, along with the consequence associated with these adverse events. We found that as individuals progressed through additional treatments, they were more and more likely to receive more than one antiseizure medication, and a significant portion of individuals experienced at least one adverse event, often manifested as headache, somnolence, dizziness, and fatigue.

HIV-1 subtype-specific drug resistance on dolutegravir-based antiretroviral therapy: protocol for a multicentre study (DTG RESIST)

IntroductionHIV drug resistance poses a challenge to the United Nation’s goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was...

A non-comparative, randomized, phase II trial of atezolizumab or atezolizumab plus tiragolumab for programmed death-ligand 1-positive recurrent cervical cancer (SKYSCRAPER-04)

ObjectiveTo evaluate tiragolumab (anti-TIGIT) and atezolizumab (anti-PD-L1) as second- or third-line therapy for PD-L1-positive persistent/recurrent cervical cancer.MethodsIn the open-label, non-comparative, randomized phase II SKYSCRAPER-04 trial (NCT04300647), patients with PD-L1-positive (SP263...

The treatment pattern of advanced HR-positive and HER2-negative breast cancer in central southern China: a hospital-based cross-sectional study

AimsThis investigation aims to elucidate the treatment status of advanced HR+/HER2- breast cancer patients in Hunan Province of Central Southern China from November 2021 to December 2022.MethodsData from 301 patients with advanced HR+/HER2- breast cancer were collected from the breast cancer investigation project in Hunan under the guidance of the Chinese Society of Clinical Oncolfogy (CSCO). The data included the clinical characteristics of patients and the status of first-line and second-line rescue treatment.ResultsFirst-line chemotherapy and endocrine therapy for mBC accounted for 40% (121/301) and 60% (180/301) of treatments, respectively. AI (21%), AI plus CDK4/6 inhibitor (28%), and fulvestrant (24%) or fulvestrant plus CDK4/6 inhibitor (18%) were the most common first-line endocrine therapies. Taxane-based chemotherapy was the most common first-line chemotherapy (59%). Second-line chemotherapy and endocrine therapy for mBC accounted for 43% (72/166) and 57% (94/166) of treatments, respectively. Fulvestrant (23%) or fulvestrant plus CDK4/6 inhibitor (29%) were the most common second-line endocrine therapies. The prevalences of AI and AI plus CDK4/6 inhibitor decreased to 19% and 11%, respectively. T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Third-line chemotherapy was more prevalent than endocrine therapy (57% vs. 41%). T (taxane)-based chemotherapy was still the most common chemotherapy regimen (46%). Fulvestrant plus CDK4/6 inhibitor was the most common endocrine therapy (33%). AI, AI plus CDK4/6 inhibitor, and fulvestrant accounted for 21%, 12% and 18% of third-line endocrine therapies, respectively.ConclusionsCompared to chemotherapy, endocrine therapy was a more favorable choice for first-line and second-line treatment for HR+/HER2- advanced breast cancer patients in Hunan Province.

Current status of palliative care for patients with unresectable metastatic colorectal cancer in China: a questionnaire-based survey

Objective: To analyze the current adoption of palliative care by patients with unresectable metastatic colorectal cancer (mCRC) in China. Methods: From 1 March 2023 to 30 June 2023, a questionnaire survey was conducted by random sampling. An exclusive research platform for the Blue Book on Clinical Diagnosis and Treatment of Metastatic Colorectal Cancer. An online questionnaire was sent to medical oncologists (including chief physicians, associate chief physicians, attending physicians and residents) in general hospitals and oncology hospitals in four major regions of East, Central, South and Northeast China. The questionnaire contained 28 questions requesting basic information about doctors, the number of patients with mCRC, the status of treatment from first to fourth line and beyond, points concerning treatment of pain in patients with mCRC, and expectations for the future. A medical team was responsible for the quality control of data collected, whereas statisticians performed the data cleaning and sorting and statistical analysis. Results: A total of 300 clinical questionnaires were collected, including 217 (72%) from doctors in general hospitals and 83 (28%) from doctors in oncology hospitals. Senior physicians (including associate chief physicians and chief physicians) accounted for 65% of the respondents, attending physicians 30%, and residents 5%. Within 3 months (average for each month), 46.4±26.6% patients were diagnosed with recurrent or unresectable mCRC by each physician, 51.6±26.8% of the patients being in cancer hospitals and 44.4±26.3% in general hospitals. One hundred percent of patients receiving first-line treatment received palliative care, as did 80.3% of those receiving second-line treatment, 58.2% of those receiving third-line treatment, and 35.1% of those receiving ≥fourth-line treatment. The primary factor governing selection of first-line treatment was guideline recommendations, whereas comorbidities and the patients' physical status dictated second line to fourth line treatment. Standard first-line treatment was administered to 93.8% of eligible patients, standard second-line treatment to 94.3%; and standard third-line treatment to 73.5%. First-line therapy included targeted therapy in 63.6% of patients and immunotherapy in 2.8%; second-line therapy included targeted therapy in 63.0% of patients and immunotherapy in 2.0%; third-line therapy included targeted therapy in 59.2% of patients and immunotherapy in 2.2%; and fourth-line therapy included targeted therapy in 48.7% of patients and immunotherapy in 3.1%. First-line treatment lasted an average of 9.6 months, second-line treatment 6.7 months, third-line treatment 4.9 months, and fourth-line treatment 3.7 months. More than 70% of the patients maintained a good quality of life after receiving first and second-line treatment and more than 60% of them had ECOG performance scores of 0-1. After receiving third- and fourth-line treatment, 50%-60% of patients maintained a good quality of life and 40%-50% of them maintained ECOG performance scores of 0-1. The survey also revealed that the main deficiencies in treatment were limited effectiveness of third-line treatment, insufficient availability and opportunity for clinical research, popularity of new drugs or new drug combination strategies, and limited channels for participation in multidisciplinary diagnosis and treatment. Clinicians reported looking forward to participating in more clinical research on new drugs, hearing about the experience of experts in the field, and discovery of new targets and new drugs that increased the options for posterior line treatment of colorectal cancer. Conclusions: This report objectively summarizes the current situation, treatment difficulties, and expectations of frontline physicians concerning management of mCRC, thus providing a basis for decision-making and future direction for the diagnosis and research on treatment of mCRC.

Study Protocol: Predicting the Quality of Response to Specific Treatments (PQRST) in Chronic Graft-versus-Host Disease

BackgroundChronic graft-versus-host disease (GVHD) is a leading cause of late morbidity and mortality after allogeneic hematopoietic cell transplantation. Despite significant progress in chronic GVHD therapies, challenges remain in understanding pleomorphic phenotypes and varying response to treatment. The goal of the Predicting the Quality of Response to Specific Treatments (PQRST) in chronic GVHD study is to identify predictors of treatment response. This report describing the study design seeks to raise awareness and invite collaborations with investigators who wish to access clinical data and research samples from this study. MethodsThis is a prospective, observational cohort study involving data collection from patients who are beginning first-, second-, or third-line systemic therapy for chronic GVHD with defined agents. Evaluable participants will have baseline assessments and research samples prior to starting the index therapy, and 1 month after starting treatment. Response assessments occur at 3 and 6 months after start of treatment, or if a new systemic therapy is started before 6 months. Target enrollment is approximately 200 patients at 8 institutions, with at least 6 months of follow up to determine response to index therapy. ResultsEnrollment started in July 2020 and was delayed due to the COVID-19 pandemic; as of 3/1/2024, 137 evaluable participants have been enrolled. DiscussionThe Chronic GVHD Consortium “PQRST” is a large longitudinal cohort study that aims to investigate predictors of treatment response by identifying biologically and clinically defined patient subgroups. We welcome investigators to collaborate in the use of these data.Trial registration: NCT04431479

Real-world cost-effectiveness of panel-based genomic testing to inform therapeutic decisions for metastatic colorectal cancer

BackgroundMutations in KRAS and NRAS are associated with a lack of response to cetuximab and panitumumab, two biologics used for third-line therapy of metastatic colorectal cancer (mCRC). In British Columbia, Canada, eligibility for cetuximab or panitumumab was first based on single-gene KRAS testing. OncoPanel, a multi-gene next-generation sequencing panel with both KRAS and NRAS, was introduced in 2016. Our objective was to estimate the real-world cost-effectiveness of OncoPanel versus to single-gene KRAS testing to inform eligibility for cetuximab or panitumumab in mCRC. MethodsUsing population-based administrative health data, we identified a cohort of mCRC patients who had received a KRAS or OncoPanel test, and completed prior chemotherapy in 2010–2019. We matched KRAS- and OncoPanel-tested patients (1:1) using genetic matching to balance baseline covariates. Mean and incremental 3-year costs, survival, and quality-adjusted survival were estimated using inverse-probability-of-censoring weighting and bootstrapping. We conducted scenario-based sensitivity analysis for key costs and assumptions. FindingsAll OncoPanel-tested cases (n=371) were matched to a KRAS-tested comparator. In the KRAS and OncoPanel groups, respectively, 55·8 % and 41·2 % of patients were potentially eligible for cetuximab or panitumumab based on mutation status. Incremental cost and effectiveness of OncoPanel were $72 (95 % CI: −6387, 6107), −0·004 life-years (95 % CI: −0·119, 0·113), and −0·011 quality-adjusted life-years (95 % CI: −0·094, 0·075). Reductions in systemic therapy costs were offset by increased costs in other resources. Results were moderately sensitive to time horizon and changes in testing or treatment cost. InterpretationThe use of OncoPanel resulted in more precise targeting of cetuximab and panitumumab, but there was no change in incremental cost or quality-adjusted survival. Understanding the balance of costs achieved in practice can provide insight into the effect of future changes in testing policy, test cost, treatment eligibility, or drug prices in this setting.

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.)

Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation

Treatment-free remission after third-line therapy with asciminib in chronic myeloid leukemia with an atypical e19a2 BCR::ABL1 transcript and T315I mutation

Clinical Effectiveness of Targeted Therapies Following Nivolumab Therapy in Patients with Metastatic Renal Cell Carcinoma: A Real-World Study.

Background: The treatment and escape for metastatic renal cell carcinoma (RCC) has rapidly evolved, particularly with the integration of immune therapies into first-line regimens. However, optimal strategies following progression in first-line immunotherapy remain uncertain. This study aims to evaluate the efficacy and safety of axitinib and cabozantinib as third-line therapies after progression on nivolumab following first-line VEGF-TKI therapy. Methods: Patients with metastatic RCC who progressed on prior nivolumab treatment after receiving first-line VEGF-TKI therapy were included. Data on patient characteristics, treatment regimens, response rates, progression-free survival (PFS), and overall survival (OS) were collected. Statistical analyses were conducted to assess the prognostic factors and treatment outcomes. Results: A total of 46 patients were included who were predominantly male (83%) with clear-cell histology (89%). The median PFS on first-line TKI therapy was 10.2 months. All the patients received nivolumab as a second-line therapy, with a median of 12 cycles. The median second-line PFS was seven months. Third-line therapies included axitinib (24 patients) and cabozantinib (20 patients). The median PFS for axitinib and cabozantinib was six months, with comparable survival outcomes. The IMDC risk group and treatment tolerability were significant predictors of survival in multivariate analysis. Adverse events were manageable, with hypertension, fatigue, and diarrhea being the most common. Conclusion: Axitinib and cabozantinib show promise as third-line therapies post-nivolumab progression in metastatic RCC, though prospective validation is warranted. This study underscores the need for further research to establish treatment standards in this evolving landscape.

Sequential therapy of refractory metastatic pancreatic cancer with 5-FU/LV/irinotecan (FOLFIRI) vs. 5-FU/LV/oxaliplatin (OFF). The PANTHEON trial (AIO PAK 0116)

PurposeIn patients with metastatic pancreatic cancer, after failure of gemcitabine/nab-paclitaxel, this trial compares the efficacy of second-line therapy with FOLFIRI vs. OFF (1:1 randomisation) with cross-over to the vice-versa regimen as third-line therapy.Patients and MethodsThe primary endpoint was PFS (progression-free survival: time from randomization until progression or death) of second-line therapy. The trial aimed to demonstrate non-inferiority of FOLFIRI vs OFF (non-inferiority margin of a hazard ratio (HR) of 1.5, power of 80% and a significance level of 5%, 196 events needed). Secondary endpoints included overall survival (OS), progression-free survival of third-line therapy and safety. The trial is registered with EudraCT Nr. 2016–004640-11.ResultsThe trial was terminated with 60 evaluable (37 with FOLFIRI, 23 with OFF) patients due to insufficient recruitment. PFS of second-line therapy was 2.4 (95% CI 2.3–2.6) months with FOLFIRI vs 2.4 (95% CI 2.2–2.7) months with OFF (HR: 0.80, 95% CI 0.45–1.42, P = 0.43). OS was comparable between the arms (HR: 0.95, 95% CI 0.54–1.66), P = 0.84). Only 4 out of 28 (14%) patients receiving third-line therapy achieved a disease control (partial remission or stable disease). Both second-line regimens were well tolerated without new or unexpected safety signals being observed.ConclusionThe exploratory analysis of this early terminated trial suggests that FOLFIRI and OFF have similar efficacy ant toxicity as second-line therapy of PDAC after failure of gemcitabine/nab-paclitaxel. Third-line therapy regardless of regimen does not provide satisfactory efficacy in this sequential treatment algorithm.

Update on Overactive Bladder Therapeutic Options.

Millions of Americans are burdened by overactive bladder (OAB) syndrome and the psychogenic and economic hardships that accompany it. Several theories attempt to explain OAB as a neurogenic dysfunction, myogenic dysfunction, urothelial dysfunction, or decreased expression of a channel protein secondary to bladder outlet obstruction. Given that the etiology of OAB is a working theory, the management of OAB is also an evolving subject matter in medicine. There are uncertainties surrounding the pathophysiology of OAB, the strength of a clinical diagnosis, and accurate reporting because of the disease's stigma and decreased use of health care. This is a narrative review that used PubMed, Google Scholar, Medline, and ScienceDirect to review literature on current and future OAB therapies. Currently, first-line treatment for OAB is behavioral therapy that uses lifestyle modifications, bladder-control techniques, and psychotherapy. Second-line therapy includes antimuscarinic agents or beta 3 adrenergic agonists, and studies have shown that combination therapy with antimuscarinics and beta 3 adrenergic agonists provides even greater efficacy than monotherapy. Third-line therapies discussed include onabotulinumtoxinA, posterior tibial nerve stimulation, and sacral neuromodulation. OnabotulinumtoxinA has been FDA-approved as a nonpharmaceutical treatment option for refractory OAB with minimal side effects restricted to the urinary tract. Posterior tibial nerve modulation and sacral neuromodulation are successful in treating refractory OAB, but the costs and complication rates make them high-risk procedures. Therefore, surgical intervention should be a last resort. Estrogen therapy is effective in alleviating urinary incontinence in postmenopausal women, consistent with the association between estrogen deficiency and genitourinary syndrome. Potassium channel activators, voltage-gated calcium channel blockers, and phosphodiesterase inhibitors look to be promising options for the future of OAB management. As new therapies are developed, individuals with OAB can better personalize their treatment to maximize their quality of life and cost-effective care.

The prognostic role of albumin levels in lung cancer patients receiving third-line or advanced immunotherapy: a retrospective study.

Immunotherapy functions by leveraging immunoregulation drugs to bolster the immune system's capacity to identify and eliminate cancerous cells. In contrast to radiotherapy and chemotherapy, immunotherapy exhibits diminished side effects, heightened efficacy, and prolonged survival rates. Nevertheless, meticulous exploration into the determinants governing the advantageous effects of immunotherapy among patients who have previously undergone multiple prior therapies has yet to be conducted. Albumin (ALB) as a nutritional indicator has not been thoroughly studied for its prognostic effect on efficacy or survival. This study aims to identify factors that influence treatment outcomes among patients undergoing third-line or later immunological therapies. A cohort of 250 lung cancer patients undergoing toripalimab or tislelizumab immunotherapy was the focal point of data collection. The determination of the median value facilitated the establishment of a cut-off point, enabling the categorization of continuous variables. After data collection, a series of statistical analyses of various clinical factors at baseline were performed, including nonparametric tests, logistic regression, and Cox proportional risk modeling. The last follow-up was in May 2022. The primary study endpoint was overall survival (OS). A total of 250 patients were enrolled in the study, of which 129 patients received first- or second-line immunotherapy and 121 patients received third-line or subsequent immunotherapy. According to Cox multifactor regression analysis, in patients receiving either first- or second-line therapy, the ALB level exhibited negligible prognostic relevance (P>0.05). However, in patients subjected to immunotherapy beyond the second line, the ALB level manifested significant prognostic importance (P=0.039). Notably, patients demonstrating elevated ALB levels achieved a higher disease control rate (DCR) (70.0% vs. 52.5%, P=0.05) and displayed a tendency towards a heightened objective response rate (ORR) (20.0% vs. 16.4%, P=0.61) in comparison to those with lower ALB levels. Among patients undergoing immunotherapy in the third line or subsequent treatment phases, elevated ALB levels in baseline correlated with DCR and OS. Thus, the pre-immunotherapy ALB level emerges as an autonomous predictor of OS in patients subjected to third- or later line immunotherapy interventions.

Efficacy and safety of regorafenib in the treatment of metastatic colorectal cancer: a retrospective cohort study.

The majority of studies of regorafenib now were small-sample and single-arm, which potentially limits the strength of evidence. We conduct the study to identify the efficacy and safety of regorafenib for patients with metastatic colorectal cancer (mCRC) in real-world applications. mCRC patients who underwent regorafenib second line or post-second line treatment with at least one assessable lesion were analyzed. Patients received different doses of regorafenib and different combination regimens. The patients were followed up with laboratory tests and imaging examinations every 3 months to evaluate the efficacy and adverse events (AEs). The primary endpoint of this study was median overall survival (mOS), and the secondary endpoints were median progression-free survival (mPFS), the objective response rate (ORR), the disease control rate (DCR), and AEs. A total of 77 patients (45 males and 32 females, aged 58.80±11.65 years) were enrolled in the study. Most primary tumors were located in the rectum (59.74%), and the vast majority of tumors (89.62%) had an adenocarcinoma histological type. The 77 patients had an mOS of 17.8 months, a progression-free survival (PFS) of 4.63 months, an ORR of 6.76%, and a DCR of 55.41%. Patients underwent regorafenib third-line therapy had significantly higher overall survival (OS) than those underwent regorafenib post- third-line treatment (P=0.03). The neutrophil to lymphocyte ratio (NLR) was an independent factor affecting the OS of the mCRC patients [hazard ratio (HR) =1.12, P=0.03]. In both univariate and multivariate analyses, discontinued use of regorafenib after progression reduced patients' PFS (HR =3.07, P<0.001; HR =2.78, P=0.007). In terms of the tolerated dose, patients receiving 120 mg regorafenib had the longest OS numbers, but there was no statistical difference. We analyzed the effect of the baseline NLR on the OS of patients receiving regorafenib combined with immunotherapy, and found that the NLR ratio cut-off value was 4.4, and patients with a NLR ratio ≤4.4 benefited significantly in terms of OS (P=0.03). The AEs included 21 (27.27%) cases of hand and foot skin reaction, 15 (19.48%) cases of fatigue, 9 (11.69%) cases of pain, 9 (11.69%) cases of nausea, 9 (11.69%) cases of fever, 9 (11.69%) cases of cough, and so on. Regorafenib is relatively effective and safe as a third-line and posterior treatment of mCRC. Patients underwent regorafenib third-line therapy had longer OS than those underwent regorafenib post- third-line treatment. Moreover, PFS benefits can still be obtained by continuing regorafenib treatment after progression. Grade 1-2 AEs were common, but these were usually tolerated by most patients.

Ramucirumab Beyond Disease Progression After Paclitaxel Plus Ramucirumab in Gastric Cancer: A Phase II Trial.

Irinotecan monotherapy was the most widely used third-line chemotherapy for unresectable advanced or recurrent gastric cancer in Japan until the approval of nivolumab in September 2017 and trifluridine/tipiracil in August 2019. The benefit of continuing ramucirumab with irinotecan, an anti-VEGFR-2 monoclonal antibody, after the failure of paclitaxel plus ramucirumab (PTX+RAM) as second-line chemotherapy, has been under debate. A single-center phase II study was conducted in patients with unresectable advanced or recurrent gastric cancer previously treated with fluoropyrimidines and platinum, who received PTX+RAM as second-line therapy and irinotecan plus ramucirumab (IRI+RAM) as third-line therapy after treatment failure (UMIN000022956). Eleven patients were enrolled from July 2016 to July 2018. Enrolment was discontinued due to difficulties in case ascertainment because of expanded third-line treatment options (originally planned for 53 patients). The median progression-free survival (the primary endpoint) of the IRI+RAM was 3.98 months [95% confidence interval (CI)=1.78-NA]. Among secondary endpoints, the transition rate to IRI+RAM was 45%, the rate of 8-week treatment continuation for IRI+RAM was 100%, the response rate for IRI+RAM was 0%, the median overall survival (OS) for PTX+RAM was 13.53 months (95%CI=1.61-24.36), and the median OS for IRI+RAM was 9.99 months (95CI=4.5-NA). The transition rate from PTX+RAM to IRI+RAM was reasonable. Ramucirumab beyond progressive disease may be beneficial for patients who are able to transition to IRI+RAM.

First- vs second-line CDK 4/6 inhibitor use for patients with hormone receptor positive, human epidermal growth-factor receptor-2 negative, metastatic breast cancer in the real world setting

PurposeTo compare CDK4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) in the first- versus second-line setting for treatment of hormone receptor positive (HR+), HER2 negative, metastatic breast cancer (MBC) using real-world evidence.MethodsPatients with HR+, HER2 negative MBC, diagnosed between 2/3/2015 and 11/2/2021 and having ≥ 3 months follow-up were identified from the nationwide electronic health record-derived Flatiron Health de-identified database. Treatment cohorts included: (1) first-line ET with a CDK 4/6i (1st-line CDK4/6i) versus (2) first-line ET alone followed by second-line ET with a CDK4/6i (2nd-line CDK4/6i). Differences in baseline characteristics were tested using chi-square tests and two-sample t-tests. Time to third-line therapy, time to start of chemotherapy, and overall survival were compared using Kaplan-Maier method.ResultsThe analysis included 2771 patients (2170 1st-line CDK4/6i and 601 2nd-line CDK4/6i). Patients receiving 1st-line CDK4/6i were younger (75% vs 68% < 75 years old, p = 0.0001), less likely uninsured or not having insurance status documented (10% vs. 13%, p = 0.04), of better performance status (50% vs 43% with ECOG 0, p = 0.03), and more likely to have de novo MBC (36% vs. 24%, p < 0.001). Time to third-line therapy (49 vs 22 months, p < 0.001) and time to chemotherapy (68 vs 41 months, p < 0.001) were longer in those receiving first-line CDK4/6i. Overall survival (54 vs 49 months, p = 0.33) was similar between groups.ConclusionUse of CDK4/6i with first-, vs second-, line ET was associated with longer time to receipt of 3rd-line therapy and longer time to receipt of chemotherapy.

Successful R0 resection after chemotherapy, including nivolumab, for gastric cancer with liver metastases: three case reports

BackgroundAdvances in chemotherapy have increased clinical experience with conversion surgery for inoperable advanced gastric cancer. This report describes three patients with unresectable gastric cancer accompanied by multiple liver metastases. In all three patients, nivolumab resolved the liver metastases and subsequent conversion surgery achieved a pathological complete response.Case presentationIn Case 1, a 68-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX plus nivolumab. The patient completed 13 cycles; however, only nivolumab was continued for 3 cycles because of adverse events. Distal gastrectomy and partial hepatic resection were performed because of a significant reduction in the size of the liver metastases as observed on magnetic resonance imaging (MRI). In Case 2, a 72-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX. Because of the subsequent emergence of new liver metastases, the patient transitioned to ramucirumab plus paclitaxel as second-line therapy. Third-line therapy with nivolumab was initiated because of side effects. MRI revealed necrosis within the liver metastasis, and the patient underwent proximal gastrectomy and partial hepatectomy. In Case 3, a 51-year-old woman with clinical Stage IVB gastric cancer accompanied by multiple metastases of the liver and para-aortic lymph nodes began first-line therapy with SOX plus nivolumab. The patient completed 10 cycles; however, only nivolumab was continued for 5 cycles because of adverse events. Computed tomography showed a significant decrease in the size of the para-aortic lymph nodes, while MRI indicated the presence of a singular liver metastasis. Distal gastrectomy and partial hepatic resection were subsequently performed. In all three cases, MRI revealed the presence of liver metastases; however, pathological examination showed no viable tumor cells.ConclusionsWe herein present three cases in which chemotherapy, including nivolumab, elicited a response in patients with multiple unresectable liver metastases, ultimately culminating in R0 resection through conversion surgery. Although MRI showed liver metastases, pathological analysis revealed no cancer, underscoring the beneficial impact of chemotherapy.