Similar Response Rates Research Articles

Successful Treatment of a Relapsed, Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) Patient and Newly Diagnosed Meningeosis Lymphomatosa with CD19 CAR-T Cell Therapy and Intrathecal Chemotherapy: A Case Report

CD19 chimeric antigen receptor-modified (CAR)-T cell therapy can achieve similar response rates in Secondary central nervous system lymphoma (SCNSL) as in patients without central nervous system (CNS) involvement. However, the therapeutic success differs significantly when a distinction is made between parenchymal and meningeal involvement. A 42-year-old female patient with r/r DLBCL was treated with CD19 CAR-T cell therapy. The patient was diagnosed with meningeosis lymphomatosa six days after the administration of the CAR-T cells. The lumbar puncture was performed because of severe therapy refractory headaches. We additionally administered intrathecal chemotherapy after reaching a Partial Remission (PR) with CAR T cells with Methotrexate, Cytarabine and Dexamethasone. At the time of the report the patient has been in Complete Remission (CR) in the CNS and regarding the peripheral DLBCL manifestations for two months. To the authors' knowledge, this patient's case is the first case in which intrathecal chemotherapy was used in addition to CAR-T cells to treat clinically progressive meningeosis first diagnosed under CAR-T cell therapy. The follow-up progress so far appears promising, but the long-term course remains to be seen.

Outcomes After Stereotactic Body Radiation for Hepatocellular Carcinoma in Patients With Child-Pugh A Versus Child-Pugh B/C Cirrhosis

For patients with hepatocellular carcinoma (HCC), stereotactic body radiation therapy (SBRT) has emerged as a locoregional treatment. Our purpose was to report outcomes in patients with HCC with Child-Pugh A (CP A) versus Child-Pugh B or C (CP B/C) liver dysfunction treated with SBRT. A retrospective analysis of 80 patients with HCC, with a total of 94 tumors treated with SBRT, was conducted at a single institution. Outcomes were compared between patients with CP A (n = 51) and CP B/C (n = 29) liver dysfunction. Outcomes of interest included local control, overall survival (OS), and toxicity. Median tumor size was 3.2 cm. There were 59 tumors included in the CP A cohort and 35 tumors in the CP B/C cohort. Median radiation dose was 50 Gy in 5 fractions for the CP A cohort and 40 Gy in 5 fractions for the CP B/C cohort. The rates of pathologic complete response were similar between the 2 groups at 63% for the CP A group and 61% for the CP B/C group. The estimated 1-year local control rates were similar between the 2 groups at 93% for the CP A group and 91% for the CP B/C group (P = .59). The 1-year OS for the CP A group was 85%, whereas the 1-year OS for the CP B/C group was 61% (P = .19). There was a 5.9% rate of grade 3+ toxicity in the CP A group and a 20.7% rate of grade 3+ toxicity in the CPB/C group. Our findings suggest that SBRT is feasible and effective in patients with both CP A and CP B/C liver dysfunction with similar rates of local control and pathologic complete response despite lower radiation doses in the CP B/C cohort. In patients with more advanced CP B/C cirrhosis, toxicities were higher and must be weighed against possible treatment benefits. Further studies characterizing the optimal role of SBRT in patients with advanced cirrhosis are warranted.

Nodular Vasculitis: Retrospective Study of an Uncommon Disease in a Non-Tuberculosis Endemic Country with Focus on Treatment Modalities and Efficacy

Introduction: Nodular vasculitis (NV) is a rare form of panniculitis primarily affecting middle-aged females, presenting as painful, sometimes ulcerated nodules on the dorsal lower legs. Erythema induratum of Bazin (EIB) is a form of NV and is considered a manifestation of cutaneous tuberculin hypersensitivity. This retrospective study aims to analyze demographics, clinicopathological findings, laboratory results, and treatment outcomes of NV in a non-TB endemic country. Methods: Data of NV patients were extracted from the electronic hospital database of the University Hospital Zurich. Patients were included only if histopathologically confirmed diagnosis of NV and sufficient information on demographics, treatment, and follow-up were available. Results: We conducted a 20-year retrospective study, including 62 patients with NV. The most common site of involvement was the lower extremities. Disease duration varied from several months to over 20 years. Histopathological examination revealed lobular panniculitis, with or without vasculitis, and granuloma formation. Tuberculosis association was assessed through the QuantiFERON test and mycobacteria PCR, showing positive results in 22 or 37 (59%) tested cases and in 2 out of 27 cases (7.4%), respectively. Comorbidities were found in over half of the patients. Treatment modalities included topical corticosteroids, antitubercular therapy, systemic steroids, and potassium iodide. Almost 50% of all patients experienced relapses despite treatment. Conclusion: Topical steroids, antitubercular therapy, systemic steroids, and potassium iodide showed similar response rates. Tuberculostatic therapy upon detecting latent TB is recommended. Considering the high recurrence rate and potential side effects of systemic therapies, we recommend first-line treatment with potent topical steroids and compression stockings.

Effectiveness and Toxicity Profile of Reduced Dose Sorafenib for the Treatment of Hepatocellular Carcinoma: A Retrospective, Single Institutional Experience.

Background The treatment with sorafenib in hepatocellular carcinoma (HCC)is affected by toxicity and discontinuation rates. There is limited data on whether ensuring compliance by reducing the dose of sorafenib can influence outcomes. Methods In this retrospective study, we used hospital records to retrieve data on patients treated with low-dose sorafenib (400 mg /day) from July 2017 to June 2022 at the Malabar Cancer Centre, Thalassery. Results During the study period, 80 patients received low-dose sorafenib for HCC. Sixty-eight (85%) patients were males with median age being 62 years, ranging from 17 to 79 years. More than three-fourths (76.2%) of the patients had Barcelona stage C and nearly one-third (31.2%) had Child-Pugh B status. Alcohol consumption and obesity were seen in 36 (45%) and 24 (30%) patients respectively. Clinical benefit rate (at least stable disease) at three months was seen for 45 (56.25%) patients. The median follow-up was six months. The median progression-free survival (PFS) and overall survival (OS) were 3.68 (CI 2.89-4.46) and 5.26 (CI 3.26-7.27) months respectively. Nine patients (11.25%) had grade 3 toxicity, and six (7.5%) patients stopped sorafenib due to toxicity despite dose reduction. Conclusion In comparison to other published landmark studies, our study demonstrates that reduced dose sorafenib in advanced hepatocellular carcinoma has a similar response rate and progression-free survival with lesser toxicity.In the real world, a reduced dose of sorafenib is nevertheless effective when tolerance and cost are concerns. Additionally, since a third of the study cohort has Child-Pugh B, a reduced dose of sorafenib may be a choice for these patients.

Efficacy and safety of upadacitinib in patients with active ankylosing spondylitis refractory to biologic therapy: 2-year clinical and radiographic results from the open-label extension of the SELECT-AXIS 2 study

BackgroundThe efficacy and safety of upadacitinib in patients with ankylosing spondylitis (AS) and inadequate response/intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR) were evaluated through 1 year in the SELECT-AXIS 2 study. Here, we assess 2-year efficacy, safety, and imaging outcomes in SELECT-AXIS 2.MethodsPatients who received continuous upadacitinib, and those who switched from placebo to upadacitinib at week 14, could enter the open-label extension (OLE). Efficacy endpoints included Assessment of SpondyloArthritis international Society (ASAS) and Axial Spondyloarthritis Disease Activity Score (ASDAS) responses, and changes from baseline in measures of disease activity, back pain, function, and quality of life. Radiographic progression was evaluated using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). As observed (AO) and AO with non-responder imputation (AO-NRI) analyses were used for binary endpoints; AO with mixed-effects model for repeated measures (AO-MMRM) for continuous endpoints; and AO-analysis of covariance for mSASSS. Treatment-emergent adverse events (TEAEs) in patients receiving ≥ 1 upadacitinib dose through week 104 are presented as events (E)/100 patient-years (PY). Subgroup analyses were performed by prior tumor necrosis factor/interleukin-17 inhibitor exposure and bDMARD lack of efficacy/intolerance.ResultsOf 420 patients who entered the bDMARD-IR AS study, 409 entered the OLE, and 331 (continuous upadacitinib, n = 163; placebo to upadacitinib, n = 168) completed week 104. Improvements in efficacy measures were sustained through the OLE, with similar response rates between the continuous upadacitinib and placebo to upadacitinib groups at week 104. At week 104, 64.9% and 61.7% of patients, respectively, had achieved ASAS 40% response (AO-NRI). Mean changes from baseline were similar between the two groups at week 104 across measures (ASDAS: -2.1 and -2.0; total back pain: -4.9 and -4.6, respectively; AO-MMRM). Over 93.0% of patients showed no radiographic progression (mSASSS mean change from baseline < 2) at week 104. The overall TEAE rate was 165.2 E/100 PY, with low rates of major adverse cardiovascular and venous thromboembolic events (0.3 E/100 PY each).ConclusionsUpadacitinib efficacy, including very low rates of radiographic progression, was demonstrated through 104 weeks in treatment-refractory patients with active AS. Treatment was well tolerated, with no newly identified safety signals.Trial registrationNCT04169373.

Demographic Characteristics of Locally Advanced Laryngeal Cancer with Concurrent Chemo Radiotherapy along with Weekly Paclitaxel versus Weekly Cisplatin in Rajshahi Medical College

Modern multi-modality approaches using definitive concurrent chemoradiation has shown promising results in the treatment of locally advanced laryngeal cancer with intact cartilage and functional larynx. The aim of this study to estimate demographic Characteristics of Locally Advanced Laryngeal Cancer with Concurrent Chemo Radiotherapy along with Weekly Paclitaxel versus Weekly Cisplatin. This quasi-experimental study was conducted at the Department of Radiotherapy, Rajshahi Medical College Hospital, from January 2021 – June 2022 following ethical approval. Total 60 patients with locally advanced squamous cell carcinoma of larynx were included and divided into Arm-A (n=30) and Arm-B (n=30). After taking informed written consent, patients were given injection paclitaxel 30mg/m2 (Arm-A) or injection cisplatin 40mg/m2 (Arm-B) along with radiotherapy 66Gy in 33 fractions over 6.5 weeks. In this study, mean age of all study patients was 56.03±8.88 (SD) years with male predominance (88.3%). Demographic characteristics were similar across the two arms regarding age, gender, and tobacco history (p&gt;0.05). Treatment response was evaluated at 6, 12 and 24 weeks after the completion of treatment. In Arm- A 80.00% showed complete response whereas in Arm- B showed 70.00%. Partial response was 20.00% and 30.00% in Arm-A and Arm-B respectively. Both Arm-A and Arm-B had similar rate of treatment response at each follow up (p&gt;0.05).

Integrated Germline and Somatic Features Reveal Divergent Immune Pathways Driving Response to Immune Checkpoint Blockade.

Immune checkpoint blockade (ICB) has revolutionized cancer treatment; however, the mechanisms determining patient response remain poorly understood. Here, we used machine learning to predict ICB response from germline and somatic biomarkers and interpreted the learned model to uncover putative mechanisms driving superior outcomes. Patients with higher infiltration of T-follicular helper cells had responses even in the presence of defects in the MHC class-I (MHC-I). Further investigation uncovered different ICB responses in tumors when responses were reliant on MHC-I versus MHC-II neoantigens. Despite similar response rates, MHC II-reliant responses were associated with significantly longer durable clinical benefits (discovery: median overall survival of 63.6 vs. 34.5 months; P = 0.0074; validation: median overall survival of 37.5 vs. 33.1 months; P = 0.040). Characteristics of the tumor immune microenvironment reflected MHC neoantigen reliance, and analysis of immune checkpoints revealed LAG3 as a potential target in MHC II-reliant but not MHC I-reliant responses. This study highlights the value of interpretable machine learning models in elucidating the biological basis of therapy responses.

Assessment of the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer: A systematic review and meta-analysis.

Radioligand therapy (RLT) with 177Lu-labelled prostate specific membrane antigen ([177Lu]Lu-PSMA-X, referring with "PSMA-X" to a generic PSMA chemical compound) inhibitors has emerged as a viable treatment option in metastatic castration resistant prostate cancer patients having previously progressed on taxane and androgen receptor inhibitors. The aim of this study was to perform a systematic review and meta-analysis to assess the therapeutic efficacy of [177Lu]Lu-PSMA-X compared to taxane chemotherapy in taxane-chemo-naïve patients with metastatic castration-resistant prostate cancer. Searches in several bibliographic databases were made using relevant key words, and articles published up to March 2024 were included. The endpoints included prostate specific antigen (PSA) response rate (RR), progression-free survival, and overall survival. Individual patient data were pooled when feasible. PSA50 was defined as the median proportion of patients achieving at least a 50% decline in serum PSA from baseline. A meta-analysis of the PSA50 response rate (proportion meta-analysis) was performed, generating pooled estimates and 95% confidence intervals (95% CI). From the initially selected 8,414 studies published between 2019 and 2023, 24 were included in the [177Lu]Lu-PSMA-X treated group and 17 in the taxane treated group. Our findings show that [177Lu]Lu-PSMA-X RLT yielded comparable PSA50 responses in taxane-naïve patients versus those receiving taxane chemotherapy, despite considerable study heterogeneity. Notably, the taxane-naïve group had more extensive pretreatment. This meta-analysis combines the largest cohorts of taxane-naïve mCRPC patients treated with [177Lu]Lu-PSMA-X RLT and taxane-treated mCRPC. It underscores similar PSA50 response rates in both groups, suggesting a potential role for [177Lu]Lu-PSMA-X RLT in taxane-naïve patients who cannot or choose not to undergo chemotherapy.

Efficacy and Safety of Advanced Therapies in Moderately-to-Severely Active Ulcerative Colitis: a Systematic Review and Network Meta-analysis.

This study aimed to compare the efficacy and safety of biologics and small molecules for treatment of adults with moderately-to-severely active ulcerative colitis (UC). A systematic literature review was conducted to identify randomised controlled trials evaluating approved and emerging targeted therapies for patients with UC. A Bayesian network meta-analysis (NMA) approach was applied. Outcomes assessed included clinical response and remission, endoscopic mucosal healing, and safety. Thirty studies were included in the NMA following a feasibility assessment comparing approved induction dosing regimens and 22 studies comparing approved maintenance dosing regimens. In the biologic/Janus kinase inhibitor (JAKi)-naïve population, induction studies showed similar clinical response and remission rates across most interventions, with upadacitinib demonstrating significant improvements versus most other interventions. For maintenance studies, mirikizumab demonstrated significant improvements in clinical response and remission versus most other interventions. In the biologic/JAKi-experienced population, no significant differences were observed between most interventions in induction studies, except for significantly improved clinical response and remission for mirikizumab versus adalimumab, and upadacitinib demonstrated significant improvement versus all other interventions. Few differences between active treatments were observed in maintenance studies. In both populations, all active interventions had similar efficacy in terms of endoscopic mucosal healing in both induction and maintenance studies. Regardless of prior treatment exposure, similar rates of serious adverse events were seen across all active interventions in the induction period. Among the available interventions, owing to its favourable efficacy and safety profile, mirikizumab has a relevant role in the long-term treatment of UC.

Perioperative chemoimmunotherapy induces strong immune responses and long-term survival in patients with HLA class I-deficient non-small cell lung cancer

BackgroundLoss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy....

Letrozole Low Dose versus High Dose for Ovulation Induction with Timed versus Spontanous Intercourse in PCO

Abstract Objective to compare the effect of low dose and high dose of letrozole in ovulation induction in PCOS. Effect of (HCG) administration in ovulation rate and pregnancy rate. Effect of timed Versus spontaneous intercourse in pregnancy rate. Study Setting This study was carried out at. Ain Shams Maternity Hospital Infertility Clinic and Qena General Hospital Infertility Clinic. Study Design Four arm clinical randomized trial. Study Time Start from 4-October 2021 ended 10- Jan. 2023. Results The objective of this study was to investigate the effect of low dose and high dose of letrozole on ovulation induction and effect of spontaneous &amp; timed intercourse with (HCG) on pregnancy rate in one treatment cycle. This four arm clinical randomized trial study was carried out at Ain Shams Maternity Hospital Infertility Clinic and Qena General Hospital Infertility Clinic. The current study was conducted on 136 women. They were divided into 4 equal groups: A = letrozole 2.5 mg (Femra 2.5 mg NOVARTIS) (one tablet) without HCG. B = letrozole 2.5 mg+ HCG 10.000 IU. C = letrozole 10 mg (Femra 2.5 mg NOVARTIS) (four tablets) without HCG. D = lertozole 10 mg + HCG 10.000 IU. The study started 4-October 2021.ended 10-Jan 2023. Conclusion Conclusion, the present study revealed that, applying low dose or high dose of letrozole on ovulation induction and effect of spontaneous &amp; timed intercourse with (HCG) had similar follicular response and pregnancy rates. Recommendations Good selection of PCO patients acording to Rotirdam critaria. Start mangement of PCO patients by wieght reduction for obes patients. Start induction ovulation by letrozole as first choice. Start by smallest dose of letrozole 2.5mg &amp; can be titrated dose for not responding patient to high dose.

Assessment of prolonged safety and tolerability of erenumab in migraine patients in a long-term open-label study (APOLLON)

BackgroundEfficacy and safety of human monoclonal antibody erenumab used for migraine prophylaxis have been shown in clinical studies. APOLLON is an open-label, multi-center, single arm study, which permits dose adjustments of erenumab and includes an option for a drug holiday. The findings contribute to the accumulating long-term evidence regarding erenumab’s tolerability and safety profile in individuals experiencing episodic and chronic migraines.MethodsThe study population consisted of adult patients with episodic or chronic migraine, who had successfully completed the HER-MES study (NCT03828539). Patients were treated with erenumab for 128 weeks at a flexible dose of either 70 mg or 140 mg. Treatment discontinuation attempts were allowed as voluntary single treatment interruption (‘drug holiday’) of up to 24 weeks.Results701 patients were enrolled in APOLLON. The exposure associated incidence rate (EAIR) of adverse events (AEs) (N = 601) per 100 subject years was 101.71 (95% CI [92.28; 111.14]) meaning a patient could expect having about one adverse event per each year of treatment. EAIR was higher in females (n = 524, EAIR: 104.40, 95% CI [93.93; 114.86]) than in males (n = 77, EAIR: 86.55, 95% CI [65.39; 107.71]) and increased with initial monthly migraine days (MMD) and prior prophylactic treatment failures. A total of 155 patients discontinued erenumab treatment during open-label treatment phase. Of these, 29 were due to AEs (4.1% of total cohort) and out of these 65.5% (N = 19) were considered treatment-related. Safety parameters were in line with HER-MES data and did not reveal new safety signals. Drug holidays were realized by 108 patients (15.4%), of which 64.8% (N = 70) returned to treatment. The mean number of monthly headache days (MHDs), MMDs, and days with acute headache medication significantly increased during drug holiday. After resumption of erenumab treatment, a rapid reduction of the migraine parameters was observed.ConclusionsAPOLLON provides long-term safety and tolerability data confirming the beneficial safety profile of erenumab over a period of 128 weeks. In addition, reversibility of migraine deterioration during drug holiday was shown and most patients returned to their treatment with similar response rates compared to initial treatment.Trial registrationClinicalTrials.gov ID: NCT04084314 (https://clinicaltrials.gov/study/NCT04084314), First submitted: 2019-09-06.

Organ preservation after neoadjuvant long-course chemoradiotherapy versus short-course radiotherapy

Potential differences in organ preservation between total neoadjuvant therapy (TNT) regimens integrating long-course chemoradiotherapy (LCCRT) and short-course radiotherapy (SCRT) in rectal cancer remain undefined. This natural experiment arose from a policy change in response to the COVID-19 pandemic during which our institution switched from uniformly treating patients with LCCRT to mandating that all patients be treated with SCRT. Our study includes 323 locally advanced rectal adenocarcinoma patients treated with LCCRT-based or SCRT-based TNT from January 2018 to January 2021. Patients who achieved clinical complete response were offered organ preservation with watch-and-wait (WW) management. The primary outcome was 2-year organ preservation. Additional outcomes included local regrowth, distant recurrence, disease-free survival (DFS), and overall survival (OS). Patient and tumor characteristics were similar between LCCRT (n= 247) and SCRT (n= 76) cohorts. Median follow-up was 31 months. Similar clinical complete response rates were observed following LCCRT and SCRT (44.5% versus 43.4%). Two-year organ preservation was 40% [95% confidence interval (CI) 34% to 46%] and 31% (95% CI 22% to 44%) among all patients treated with LCCRT and SCRT, respectively. In patients managed with WW, LCCRT resulted in higher 2-year organ preservation (89% LCCRT, 95% CI 83% to 95% versus 70% SCRT, 95% CI 55% to 90%; P= 0.005) and lower 2-year local regrowth (19% LCCRT, 95% CI 11% to 26% versus 36% SCRT, 95% CI 16% to 52%; P= 0.072) compared with SCRT. The 2-year distant recurrence (10% versus 6%), DFS (90% versus 90%), and OS (99% versus 100%) were similar between WW patients treated with LCCRT and SCRT, respectively. While WW eligibility was similar between cohorts, WW patients treated with LCCRT had higher 2-year organ preservation and lower local regrowth than those treated with SCRT, yet similar DFS and OS. These data support induction LCCRT followed by consolidation chemotherapy as the preferred TNT regimen for patients with locally advanced rectal cancer pursuing organ preservation.

Modest survival benefits of autologous stem cell transplantation in multiple myeloma with renal impairment: a critical appraisal of the pre-antibody era

The benefit of high-dose melphalan followed by autologous hematopoietic stem cell transplantation (HDM-ASCT) for multiple myeloma (MM) patients with renal insufficiency (RI) is debated. A systematic review and meta-analysis were conducted to assess the safety and efficacy of HDM-ASCT in MM patients with RIs, and the findings were compared with real-world data. The study included 26 articles, 13 of which were pooled for meta-analysis. We compared three different types of MM patients with RI against MM patients with normal renal function (NRF). These patients were: MM patients with RI at the time of transplantation; MM patients with RI at the time of diagnosis; MM patients with RI at diagnosis but with NRF at transplantation. The meta-analysis indicated that MM patients with RIs conditioned with melphalan ≤ 140 mg/m2 followed by ASCT had transplant-related mortality rates comparable to those without RIs. The complete response rates post-ASCT were similar between MM patients with RIs and those with NRF. Although progression-free survival (PFS) was statistically similar between the groups, MM patients with RIs had significantly poorer overall survival (OS) than those with NRF. The real-world data supported these findings. With a reduced dose of melphalan, ASCT is safe and effective for MM patients with RI. MM patients with RI have similar complete response rates and PFS after ASCT compared to MM patients with NRF. The lower OS in MM patients with RI indicates the need for further research to improve OS in these patients.

Response of the intravenous versus oral antibiotic regimen in brucellosis bacteremia.

BACKGROUND AND OBJECTIVE: More than 500,000 new cases are reported globally annually. The World Health Organization recommends doxycycline with rifampicin or an aminoglycoside for brucellosis bacteremia. Some experts prefer to use doxycycline and rifampicin. We aimed to observe the response rate of intravenous versus oral anti-brucella therapy regimens in brucellosis bacteremia patients and compare the frequency of side effects and complications in both groups. METHODOLOGY: This observational study included adult brucellosis bacteremia patients treated in a hospital in Makkah, KSA for four years. According to the method of treatment (oral versus IV antibiotics), patients were grouped into two categories. Following the treatment, all these patients’ records were evaluated. The negative blood culture was the primary endpoint whereas complications and all-cause mortality were secondary endpoints. The chi-square test, Fisher's exact test, and Mann-Whitney U test were applied accordingly to analyze the two groups’ characteristics. RESULTS: A total of 93 cases were enrolled, the majority were males i.e., 64 (68.8%); with a mean age group (44.33 ±19.22 years). In total, 37 (39.8%) of patients were given IV regimens and the remaining 56 (60.2%) of patients were given oral regimens. Follow-up negative blood culture after 4 weeks was 90.3% (n = 84). The recovery rate was 93.5% (n = 87). No death was reported over this period. No difference was observed (P-value 0.309) between the oral and IV treatment regimens regarding the blood culture negativity. CONCLUSION: Oral doxycycline-rifampicin (DR) and IV gentamicin-doxycycline-rifampicin (GDR) regimens have similar response rates in bacteremia brucellosis.

Pembrolizumab plus epacadostat in patients with recurrent/metastatic head and neck squamous cell carcinoma (KEYNOTE-669/ECHO-304): a phase 3, randomized, open-label study

BackgroundAdvanced head and neck squamous cell carcinoma (HNSCC) has a poor prognosis, and new treatment options are needed. Combining immunotherapies with differing mechanisms of action may enhance clinical benefits compared with single-agent immunotherapy. Epacadostat, an indoleamine 2,3 dioxygenase 1 inhibitor, plus pembrolizumab, a PD-1 inhibitor, showed promising activity in advanced HNSCC in the phase 1/2 KEYNOTE-037/ECHO-202 trial.MethodsKEYNOTE-669/ECHO-304 is a randomized, open-label, phase 3 study evaluating the efficacy and safety of pembrolizumab plus epacadostat, pembrolizumab monotherapy, and the EXTREME regimen (cetuximab with a platinum [carboplatin or cisplatin] and 5-fluorouracil) in recurrent/metastatic (R/M) HNSCC. Participants had no prior systemic therapy for R/M HNSCC and were randomly assigned (2:1:2) to pembrolizumab 200 mg intravenously every 3 weeks plus epacadostat 100 mg orally twice daily, pembrolizumab monotherapy, or EXTREME. The primary endpoint was objective response rate (ORR; investigator assessment). Secondary endpoints were safety and tolerability. Change in serum kynurenine was an exploratory endpoint. Study enrollment was discontinued early as a strategic decision on May 2, 2018, and response assessment was discontinued after first on-study imaging assessment at week 9. Data cut-off was January 17, 2019.ResultsBetween December 1, 2017, and May 2, 2018, 89 patients were randomly allocated to pembrolizumab plus epacadostat (n = 35), pembrolizumab monotherapy (n = 19), or EXTREME (n = 35). ORR (95% CI) was 31% (17%–49%) for pembrolizumab plus epacadostat, 21% (6%–46%) for pembrolizumab monotherapy, and 34% (19%–52%) for EXTREME. Treatment-related adverse events (TRAEs) occurred in 82% (n = 28) of patients receiving pembrolizumab plus epacadostat, 63% (n = 12) receiving pembrolizumab monotherapy, and 100% (n = 34) receiving EXTREME. Grade 3–4 TRAEs occurred in 24% (n = 8) of patients receiving pembrolizumab plus epacadostat, 16% (n = 3) receiving pembrolizumab monotherapy, and 82% (n = 28) receiving EXTREME. No deaths occurred due to AEs. Pembrolizumab plus epacadostat treatment reduced kynurenine levels but not to that of healthy subjects.ConclusionsPembrolizumab plus epacadostat and pembrolizumab monotherapy provided a similar response rate to EXTREME and demonstrated a manageable safety profile in patients with R/M HNSCC.Trial registrationNCT03358472. Date of trial registration: November 30, 2017.

Efficacy and Safety of mFOLFOX-6 in Advanced Gastric Cancer: A Prospective Observational Study

Background The widespread use of oxaliplatin plus infusional 5-fluorouracil (5-FU) and folinic acid (FOLFOX) in advanced gastric cancers is mainly based on clinical trials conducted at Western/European countries. The prospective data on efficacy and safety of FOLFOX in advanced gastric cancer is lacking from the developing countries. In this prospective observational study, we evaluated the efficacy and toxicity of mFOLFOX-6 in patients with advanced gastric or gastroesophageal junction (GEJ) adenocarcinomas, as first-line palliative chemotherapy. Methods Patients with previously untreated metastatic adenocarcinoma of stomach/GEJ, received mFOLFOX-6 (2 hours infusion of oxaliplatin [85 mg/m2] and folinic acid [400 mg/m2], followed by fluorouracil 400 mg/m2 intravenous push, then a 46-hour continuous infusion of 5-FU [2,400 mg/m2]). Cycles were repeated every 2 weeks. The patients were prospectively followed up for response rates and toxicity. Results Sixty-six patients were included in the study with a median age of 57 years. Sixty-two patients were evaluable for response. The overall response rate was 53%, with a disease control rate (overall response and stable disease) of 81.8%. The median progression-free survival was 6 months (95% confidence interval [CI] 5.2–6.7 months) and the median overall survival was 11.5 months (95% CI 9.0–13.9 months). Ascites at presentation and more than one site of metastasis are associated with significantly lower survival on the log-rank test. Gastrointestinal and hematological toxicities were predominant, with rates of grade 3 to 4 nausea/vomiting (13.6%), anemia (15.1%), and neutropenia (13.6%). Among other toxicities, neurosensory toxicities were common. Four (6%) patients had grade 3 peripheral neuropathy. Conclusion mFOLFOX-6 is an active and well-tolerated chemotherapy regimen in advanced adenocarcinoma of stomach/GEJ. This regimen has similar response rates and treatment outcomes with lesser grade 3 or 4 toxicities than that of triplet regimens compared to historical studies.

Alectinib vs. Lorlatinib in the Front-Line Setting for ALK-Rearranged Non-Small-Cell Lung Cancer (NSCLC): A Deep Dive into the Main Differences across ALEX and CROWN Phase 3 Trials.

Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, 'non-comparative' assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile.

Sclerotherapy vs. surgical excision for lymphatic malformations of the head and neck: a systematic review and meta-analysis.

Lymphatic malformations (LMs) are abnormal lymphatic vessels with cystic characteristics, categorized as macrocystic, microcystic, or a combination of both. They represent the second most common vascular malformations, and their management involves multidisciplinary approaches based on clinical assessments and imaging studies. LMs manifest as a challenge to medical professionals in the head and neck, posing functional and aesthetic concerns. Our systematic review aims to compare the efficacy of sclerotherapy and surgery for LMs, identifying optimal treatment modalities for each scenario. We searched four electronic databases for related studies. Data were extracted from the included studies. We calculated the pooled rate ratios with 95% confidence intervals (CIs). The I2 test was used to detect heterogeneity. The inclusion of the studies required the following prerequisites: 1- Studies focusing on any lymphatic malformations in the head and neck, whether microcystic, macrocystic, or a mix of both; 2- Studies performed on more than ten patients; 3- All interventions used as surgery, sclerotherapy, or both. We included 58 studies in our systematic review, of which 45 were eligible for the meta-analysis. For macrocystic LMs, sodium tetradecyl sulfate (STS) mixed with ethanol and excision achieved the highest complete response rates at (92.9%) and (92.5%), respectively. Surgical excision showed the lowest poor response rate. Polidocanol microfoam had the highest poor response rate (11.1%). In microcystic LMs, combining sclerotherapy with excision showed the highest complete response rate (70.3%) and the lowest poor response rate (1.3%). Picibanil had the lowest complete response rate (9.1%) and the highest rate of poor response (61.4%). In mixed LMs, surgical excision had the highest complete response rate (70.3%). Both surgical excision and STS combined with ethanol are highly effective for treating macrocystic LMs, achieving similar complete response rates. The combination of sclerotherapy and surgical excision demonstrated the best outcomes in microcystic LMs. Surgical excision demonstrates superior efficacy over sclerotherapy for mixed LMs. These findings suggest that excision is generally more effective in achieving complete and excellent responses across all LM subtypes. Further high-quality studies are necessary to standardize and optimize treatment protocols.

Utility of bioselection with neoadjuvant chemotherapy for organ preservation in patients with T4 laryngeal cancer

BackgroundNeoadjuvant chemotherapy for induction selection of definitive treatment (IS) protocols have shown excellent outcomes for organ preservation and survival in patients with T3 laryngeal squamous cell carcinoma (LSCC). We seek to evaluate survival and organ preservation outcomes in T4 LSCC patients treated with IS protocols. MethodsRetrospective cohort of advanced T3 and T4 LSCC patients who underwent IS protocols based upon potential for preserving a functional larynx. Patients received one neoadjuvant cycle of platinum-based chemotherapy with either 5-fluorouracil or docetaxel or with two cycles of platinum-based chemotherapy with docetaxel and a Bcl-2 inhibitor. Patients who achieved ≥ 50 % response as determined by radiographic review and/or endoscopic evaluation received definitive chemoradiation. Patients who had < 50 % response after IS underwent total laryngectomy (TL) followed by post-operative radiation +/- chemotherapy. ResultsAmongst T4 patients, 114 met inclusion criteria including 89 who underwent IS protocols and 25 who received an upfront TL. In total, 76.0 % of T3 patients and 71.9 % of T4 patients responded to IS and underwent definitive chemoradiation. There was no significant difference in hazard of death between T4 IS and T4 TL patients (HR: 0.9, p = 0.86). Among responders, there was no significant difference in 5-year laryngectomy-free survival (T3 – 59.6 %, T4 44.3 %, p = 0.15) or laryngeal preservation by T stage (T3 – 72.8 %, T4 – 73.0 %, p = 0.84). ConclusionsSelect T4 patients may benefit from organ preservation using IS protocols with similar response rates to patients with T3 tumors, without compromising survival when compared to upfront TL.