Second-line Treatment Research Articles

Treatment of refractory diffuse large B-cell lymphoma involving the central nervous system with polatuzumab vedotin-based regimen: a case report and literature review

Polatuzumab vedotin (Pola) is a novel antibody-drug conjugate targeting CD79b, which has been shown to be effective in treating newly diagnosed and relapsed/refractory diffuse large B cell lymphoma (DLBCL) during clinical trials. This study aims to conduct a retrospective analysis of the clinical characteristics, diagnosis, and treatment of a patient with refractory secondary central nervous system lymphoma at Beijing Hospital, alongside a review of relevant literature. This study included a 79-year-old female patient who was diagnosed with DLBCL affecting the ilium, sacrum, spinal cord, and nerve roots and had an IPI score of 5 and a high-risk score according to MSKCC. She showed a geriatric comprehensive assessment (IACA) score of 2, which was categorized under the unfit group. Her initial treatment comprised chemo-free therapy and radiotherapy, followed by progression. In the second-line treatment, a Pola-based regimen was applied, and the patient achieved a complete response, suggesting that this regimen may be a therapeutic option for patients with DLBCL involving the central nervous system.

Assessing the Use of BotulinumtoxinA for Hyperactive Urinary Tract Dysfunction a Decade after Approval: A Single-Blind Study to Evaluate the Reduction in Pain in OnabotulinumtoxinA Detrusor Injection Using Different Injection Needles.

Overactive bladder (OAB) has a significant impact on the quality of life; thus, it requires treatment that can be adhered to over a long period without undue side effects. The current treatment which uses an anticholinergic or β-3 agonist may fail to improve symptoms and has side effects, leading to high discontinuation rates. OnabotulinumtoxinA (OnabotA) detrusor injection has been approved for idiopathic OAB as a second-line treatment with good effectiveness and tolerability. This study used a visual analog scale (VAS) to assess the impact of the type of needle used for OnabotA detrusor injections under local anesthesia on the pain levels after each injection. This study included 68 female patients. We used three different needles with thicknesses ranging from 22 to 27 gauge, lengths between 4 and 5 mm, and different cuts. The sensation of pain was rated at each standardized injection location. Regardless of the needle used, the patients' perceptions of pain at the beginning of the procedure were rated as being less than the subsequent injections. Most pain sensations were rated as low to moderate. The mean pain sensation on the VAS was 2.5 ± 0.3 overall, i.e., for all patients and needles used. Statistically significant differences in pain sensation were rated only at some locations of the bladder (on the back wall and the right side of the bladder). The single needles averaged the following pain scores: 2.8 ± 0.3 for needle A (20 G, 4 mm), 2.1 ± 0.3 for needle B (27 G, 5 mm), and 2.6 ± 0.4 for needle C (20 G, 4 mm, sharp cut 15°). The 27-gauge needle caused significantly less pain, and it had no negative impact due to its length, which was 1 mm longer than the other needles. Thus, the needle thickness was a decisive factor in the patients' perceptions of pain.

Thrombopoietin Receptor Agonists as Second-Line Treatment in Children With Ongoing Immune Thrombocytopenia

What Is the Issue? Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelets and an increase in bleeding risk; in the pediatric population, the reported incidence rate varies between 2 and 5 per 100,000 children per year. Spontaneous remission may be observed in up to 70% of patients, while 20% of patients may experience severe bleeding symptoms. In children whose ITP does not respond to first-line corticosteroids, IV immunoglobulin (IVIG), or anti-D immunoglobulin, guidelines recommend the use of thrombopoietin receptor agonists (TPO-RAs), i.e., eltrombopag or romiplostim (avatrombopag did not have a marketing authorization and Notice of Compliance at the time that the review was initiated). Rituximab is considered a subsequent-line of therapy. Splenectomy is not usually considered an appropriate treatment option in children. The goal of therapy in pediatric patients with ITP is to reduce bleeding and improve quality of life. Platelet response is considered a valid and appropriate surrogate end point in studies and routine assessment in clinical practice. Children whose ITP does not respond to available first-line drugs may require subsequent treatment with off-label drugs because they do not have access to TPO-RAs. What Did We Do? We searched key resources, including journal citation databases, and conducted a focused internet search for relevant evidence. A systematic review of the literature identified 5 studies (4 randomized controlled trials [RCTs] and 1 observational study), which were synthesized narratively. The review addressed the following policy questions: In children with ongoing, active ITP, what is the overall body of evidence supporting the use of TPO-RAs and rituximab after failure of first-line therapies? Based on the level and quality of clinical evidence, should TPO-RAs be reimbursed for use earlier in the treatment sequencing for children with ongoing, active ITP, instead of being reimbursed only after a course of rituximab? What Did We Find? Evidence from 2 RCTs (n = 159) suggests that eltrombopag likely increases and maintains platelet response over time, in addition to decreasing the use of rescue medication and clinically significant bleeding compared to placebo, which were considered clinically meaningful outcomes for pediatric patients with ITP. There was a low risk of bias in the studies, but uncertainty was introduced due to the small sample sizes. Evidence from 1 RCT (n = 62) suggests that romiplostim may also increase and maintain platelet response, as well as reduce clinically significant bleeding compared to placebo. However, there was some concern due to a high risk of bias in the studies and uncertainty due to the small sample size, which suggests a need for caution in the interpretation of the findings. The effectiveness of rituximab was inconclusive due to the lack of evidence, as no comparative RCTs could be identified, while the observational study included presented only descriptive comparisons. No evidence was identified in support of trying rituximab before accessing TPO-RAs. What Does This Mean? Given that ITP is rare in children, there is a gap in available relevant evidence, and robust evidence from large RCTs in this patient population are unlikely to be conducted. Jurisdictions may consider requesting an implementation advice panel for use of eltrombopag and romiplostim after failure of first-line therapies in children with ongoing, active ITP.

Effectiveness of treatment with budesonide orodispersible tablets in 76 patients with eosinophilic oesophagitis – real-life experience from the population-based DanEoE cohort

Background Eosinophilic oesophagitis (EoE) is a chronic immune-mediated disease. In Denmark, the budesonide orodispersible tablet (BOT) is recommended as a second-line treatment for proton pump inhibitor-refractory EoE patients. Aims To evaluate the effectiveness of treatment with BOT in adult EoE patients in a population-based setting in Denmark. Methods This was a retrospective, registry-based, DanEoE cohort study of all 76 adult EoE patients treated with BOT and diagnosed between 2007 and 2021 in the North Denmark Region. After medical record revision, the EoE diagnosis was defined according to the AGREE consensus. Symptomatic response was based on the information found in the patients’ medical reports and histologic remission was defined as <15 eosinophils per high-power field (eos/hpf). Results Histologic remission was achieved in 89% of the patients treated with BOT who underwent histologic evaluation. Clinicohistologic remission was achieved in 71% of the patients who underwent both symptomatic and histologic evaluation. Despite histologic remission, 18% of patients still experienced symptoms. Non-responders were found in 7% of the patients. Complications were rare, with dilation of strictures performed in 7% and food bolus obstruction (FBO) occurring in 3%. Discontinuation of the treatment due to unacceptable side effects was observed in 11% of the treated patients. Conclusions Treatment with BOT effectively induced histologic remission in most of the EoE patients. Despite achieving histologic remission, approximately 1/5 of the patients were still symptomatic. Complications were rare. In non-responders and those with unacceptable side effects, alternative treatment options such as biologic agents might be needed.

Belantamab mafodotin, pomalidomide, and dexamethasone for triple class exposed/refractory relapsed multiple myeloma: a subgroup analysis of the ALGONQUIN trial

Given the early use of triplet and quadruplet regimens, most patients with multiple myeloma (MM) will be exposed and/or refractory to PIs, IMiDs, and anti-CD38 mAbs after first- or second-line treatment. Effective treatment for this group of triple class exposed/refractory (TCE/R) patients is crucial. Here we present a post-hoc subgroup analysis of TCE/R patients treated on the ALGONQUIN study of belantamab mafodotin plus pomalidomide-dexamethasone (belamaf-Pd) for relapsed MM. Of the 99 patients treated on the ALGONQUIN study, 69 were TCE and 56 were TCR and were included in this analysis. Patients had a median of three prior lines of therapy. The ORR was 86.4% in TCE patients and 84.9% in TCR patients, with ≥ very good partial response rates of 64% and 68% respectively. The median progression free survival was 18.3 months in TCE patients and 19.6 months in TCR patients, with overall survival not yet reached and 34.4 months, respectively for TCE and TCR patients. No new safety signals were identified. The most common Grade ≥ 3 AEs were keratopathy (48%), decreased visual acuity (42%), neutropenia (36%), thrombocytopenia (27%), and infection (25%). In this subgroup analysis of the ALGONQUIN study, patients with TCE/TCR disease treated with belamaf-Pd achieved high clinical response rates with durable remissions, comparable to other novel therapeutics in this space.

The Trend of the Treatment of Advanced Hepatocellular Carcinoma: Combination of Immunotherapy and Targeted Therapy.

Hepatocellular carcinoma (HCC) is a common type of tumor worldwide. The development of systemic treatment of advanced HCC has remained stagnant for a considerable period. During the last years, a series of new treatment regimens based on the combination of immunotherapeutic drugs and targeted drugs have been gradually developed, increased the objective response rate (ORR), overall survival (OS), and progression free survival (PFS) of HCC patients. Among the different combination therapy groups, atezolizumab plus bevacizumab and sintilimab plus IBI-305 seem to have unique advantages, while head-to-head comparisons are still needed. A comprehensive understanding of the developments, the ongoing clinical trials and the mechanisms of combination of immunotherapy and targeted therapy might lead to the development of new combination strategies and solving current challenges such as the molecular biomarkers, the clinical administration order of drugs and the second-line treatments after combination therapy.

Artificial Intelligence-Powered Spatial Analysis of Tumor-Infiltrating Lymphocytes as a Potential Biomarker for Immune Checkpoint Inhibitors in Patients with Biliary Tract Cancer.

Recently, anti-programmed cell death-1/anti-programmed cell death ligand-1 (anti-PD1/L1) immunotherapy has been demonstrated for its efficacy when combined with cytotoxic chemotherapy in randomized phase 3 trials for advanced biliary tract cancer (BTC). However, no biomarker predictive of benefit has been established for anti-PD1/L1 in BTC. Here, we evaluated tumor-infiltrating lymphocytes (TIL) using artificial intelligence-powered immune phenotype (AI-IP) analysis in advanced BTC treated with anti-PD1. Pretreatment hematoxylin and eosin (H&E)-stained whole-slide images from 339 patients with advanced BTC who received anti-PD1 as second-line treatment or beyond, were employed for AI-IP analysis and correlative analysis between AI-IP and efficacy outcomes with anti-PD1. Next, data and images of the BTC cohort from The Cancer Genome Atlas (TCGA) were additionally analyzed to evaluate the transcriptomic and mutational characteristics of various AI-IP in BTC. Overall, AI-IP were classified as inflamed [high intratumoral TIL (iTIL)] in 40 patients (11.8%), immune-excluded (low iTIL and high stromal TIL) in 167 patients (49.3%), and immune-desert (low TIL overall) in 132 patients (38.9%). The inflamed IP group showed a substantially higher overall response rate compared with the noninflamed IP groups (27.5% vs. 7.7%, P < 0.001). Median overall survival and progression-free survival were significantly longer in the inflamed IP group than in the noninflamed IP group (OS, 12.6 vs. 5.1 months; P = 0.002; PFS, 4.5 vs. 1.9 months; P < 0.001). In the TCGA cohort analysis, the inflamed IP showed increased cytolytic activity scores and IFNγ signature compared with the noninflamed IP. AI-IP based on spatial TIL analysis was effective in predicting the efficacy outcomes in patients with BTC treated with anti-PD1 therapy. Further validation is necessary in the context of anti-PD1/L1 plus gemcitabine-cisplatin.

Efficacy of a new vacuum erection device (Vigor 2020) for erectile dysfunction: A retrospective study in Japan.

The vacuum erection device (VED) is a second-line treatment tool recommended in erectile dysfunction (ED) guidelines but has long been unavailable in Japan. A new VED, Vigor 2020® (A & HB Company Limited, Tokyo, Japan), has now been manufactured and received medical approval from the Pharmaceuticals and Medical Devices Agency in Japan. We conducted a retrospective observational study of ED patients who used Vigor 2020 in clinical practice. We analyzed male ED patients aged ≥20 years treated with Vigor 2020 in our outpatient clinics. The primary endpoint was improvement of erection as evaluated by an Erection Hardness Score (EHS) of ≥1 point. Secondary endpoints were improvement of sexual function and adverse events as evaluated by the International Index of Erectile Function (IIEF) and Male Sexual Health Questionnaire for assessing ejaculatory dysfunction (MSHQ-EjD). Thirty-three patients (mean age, 57.21 [27-86] years) could be evaluated before and after using Vigor 2020. Among the 16 patients with baseline EHS ≤2, 14 (93.33%) improved by ≥1 point, and 10 of these 16 patients (62.50%) improved to EHS ≥3 and could insert vaginally. Significant improvement was observed for IIEF total score and for the MSHQ-EjD in patients with an EHS of ≥3 after use of Vigor 2020. No patient experienced significant adverse events. The Vigor 2020 may be an efficacious treatment tool for ED. Patients with significant ED experienced not only significant improvement of erection but also improvement of ejaculation with its use.

Paclitaxel, Ifosfamide, and Cisplatin as Initial Salvage Chemotherapy for Germ Cell Tumors: Long-Term Follow-Up and Outcomes for Favorable- and Unfavorable-Risk Disease.

Paclitaxel, ifosfamide, and cisplatin (TIP) is an established salvage regimen for germ cell tumors (GCT) on the basis of a phase II trial, but efficacy on a large patient cohort including patients with unfavorable risk features and long-term outcomes has not been reported. Herein, we report updated treatment efficacy and long-term follow-up with TIP. Patients with GCT who received TIP after cisplatin-based chemotherapy were eligible. Favorable response (complete response or partial response with negative tumor markers), overall survival (OS) and progression-free survival (PFS) rates, relapse, and toxicity were determined. Disease was reclassified according to the International Prognostic Factor Study Group (IPFSG) score. Of the 104 patients, 87 had favorable risk factors and 17 had at least one unfavorable factor by Memorial Sloan Kettering Cancer Center (MSKCC) criteria. Ten patients were treated for a second gonadal primary GCT. With a median follow-up of 8.9 years, the 5-year PFS and OS rates were 66% (95% CI, 55 to 74) and 69% (95% CI, 59 to 77), respectively. Among 87 patients with favorable-risk disease, 69 (79%) achieved a favorable response with 5-year PFS and OS rates of 67% (95% CI, 56 to 76) and 72% (95% CI, 61 to 80), respectively. Among 17 patients with MSKCC unfavorable-risk disease, 13 (76%) achieved a favorable response with 5-year PFS and OS rates of 59% (95% CI, 33 to 78) and 56% (95% CI, 28 to 76), respectively. After IPFSG reclassification, 5-year PFS and OS rates for patients with ≤intermediate-risk disease were 75% (95% CI, 50 to 89) and 73% (95% CI, 55 to 85), respectively. TIP is an effective second-line regimen for patients with GCT. Similar outcomes were observed in patients with favorable- and unfavorable-risk disease. The randomized TIGER trial (ClinicalTrials.gov identifier: NCT02375204) comparing TIP with high-dose chemotherapy will determine the optimal second-line treatment approach.

Plinabulin plus docetaxel versus docetaxel in patients with non-small-cell lung cancer after disease progression on platinum-based regimen (DUBLIN-3): a phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial

There is an unmet need for second-line and third-line treatments that are effective and tolerable for advanced or metastatic non-small-cell lung cancer (NSCLC) with no driver mutations. In this phase 3, international, multicentre, single-blind, parallel group, randomised controlled trial, we enrolled patients from 58 medical centres in Australia, China, and the USA. Eligible patients were adults with epidermal growth factor receptor (EGFR) wild-type NSCLC who had progressed after first-line platinum-based therapy. Patients were randomly assigned (1:1) using an independent stratified randomisation schedule with a block size of four to receive intravenous docetaxel 75 mg/m2 on day 1 and either plinabulin (30 mg/m2) or placebo on days 1 and 8 in 21-day cycles until progression, unacceptable toxic effects, withdrawal, or death. The primary endpoint was overall survival (OS) in the intention-to-treat (ITT) population. Safety was analysed in all patients who had received at least one dose of study drug or placebo. This trial is registered with ClinicalTrials.gov (NCT02504489) and is now closed. Between Nov 30, 2015, and Jan 6, 2021, 919 patients were screened for inclusion. 360 patients were excluded, and 559 were enrolled and randomly assigned to receive either docetaxel and plinabulin (n=278) or docetaxel and placebo (n=281). 406 (73%) of 559 patients were male, 153 (27%) were female, and 488 (87%) were Asian. Median OS was 10·5 months (95% CI 9·34-11·87) in the plinabulin group compared with 9·4 months (8·38-10·68) in the control group (stratified HR 0·82, 95% CI 0·68-0·99; p=0·0399). Mean OS was 15·08 months (13·42-16·74) in the plinabulin group compared with 12·77 months (11·45-14·10) in the placebo group using restricted mean survival time analysis (difference 2·31 months, 95% CI 0·18-4·44; p=0·0332). Treatment-emergent adverse events occurred in 273 (>99%) of 274 patients in the plinabulin group and 276 (99%) of 278 patients in the control group. Grade 3 or 4 gastrointestinal disorders occurred more frequently in the plinabulin group than in the placebo group, with the most frequent being diarrhoea (24 [9%] of 274 patients vs three [1%] of 278) and vomiting (six [2%] vs one [<1%]), as did transient grade 3 hypertension (50 [18%] vs eight [3%]). Treatment-emergent death was reported in 12 patients (4%) in the plinabulin group and ten patients (4%) in the placebo group. Plinabulin plus docetaxel significantly improved OS as second-line and third-line treatment in patients with advanced or metastatic EGFR wild-type NSCLC and could be considered as a new treatment option in this population. BeyondSpring Pharmaceuticals.

Paclitaxel/Ramucirumab versus Paclitaxel in 2nd-Line Therapy of Advanced Esophageal Squamous Cell Carcinoma: Randomized Phase II IKF-AIO-RAMOS Trial

Plain Language SummaryMetastatic and unresectable ESCCs still show poor prognosis. After failure or intolerance to first-line therapy, treatment options are limited and checkpoint inhibitors are the only approved therapeutic option. Our study adds further evidence to the use of antiangiogenic drugs in second-line treatment of advanced ESCC. Ramucirumab in combination with paclitaxel showed numerically improved OS and PFS compared to paclitaxel alone. However, due to the small sample size, the results have to be considered exploratory and more data are needed in this indication. We do not recommend the use of ramucirumab/paclitaxel in second-line treatment of advanced ESCC outside of clinical trials.

Comparative Effectiveness of Acupuncture Versus Non-surgical Modalities for Treating Plantar Fasciitis: A Network Meta-Analysis.

Plantar fasciitis, or plantar heel pain, causes inflammation of the plantar fascia due to various causes, with no clear consensus on the treatment protocol. Standard first-line treatment includes non-steroidal anti-inflammatory drugs and physiotherapy. Second-line treatment prior to surgery includes extracorporeal shockwave therapy (ESWT), ultrasound-guided (USG) therapy, corticosteroid injection (CSI), and platelet-rich plasma (PRP) injection. Recently, the use of acupuncture treatment has been gaining popularity, with increasing published evidence showing its effectiveness in treating plantar fasciitis. The objective of this study was to determine whether acupuncture intervention was a viable alternative treatment method for managing plantar fasciitis when compared to ESWT, USG therapy, CSI, and PRP injection. Data sources from PubMed, Google Scholar, Scopus, Science Direct, and China National Knowledge Infrastructure were reviewed. Clinical trials were searched from their inception over the period of January 2000 to October 2020. A total of 32 relevant papers were included for analysis, totaling 2390 samples. Visual Analog Scale (VAS) scores measuring pain were analyzed in terms of outcome after one and three months of treatment. Each time point was analyzed separately through a network meta-analysis using the frequentist approach. VAS scores for each intervention at baseline and the two-time points (i.e., one and three months) were included in the comprehensive meta-analysis. Then, differences in VAS scores were calculated in R studio (V4.1.2; RStudio: Integrated Development for R,RStudio, Inc., Boston, USA) using the netmeta package. The netmeta package was also used to perform the network meta-analysis and generate corresponding figures. Direct and indirect effects were assessed and visualized through a direct evidence plot and a node-splitting forest plot. Randomized controlled trials (RCTs) and non-RCTs involving treatments of acupuncture, ESWT, USG therapy, CSI, or PRP injection, either in comparison with each other or with a placebo, were included in our review. Our meta-analysis showed that at one month, VAS scores for acupuncture treatment had the highest mean difference (MD) of -1.33 (95% confidence interval (95% CI) = -2.19 to -0.46) compared to placebo, indicating thatacupuncture treatment was more effective than other treatment arms when compared to placebo. Analysis at threemonths showed that the highest-ranked treatment was PRP injection, with an MD of -2.67 (95% CI = -6.23 to 0.89). However, the CI for the net effect of all treatments crossed the null effect on the forest plot, indicating no statistically significant difference between the treatment and placebo. Acupuncture treatment should be considered as a second-line treatment for treatment of plantar fasciitis together with other common treatment options such as ESWT, PRP injection, CSI, and USG therapy. Further long-term studies measuring acupuncture treatment outcomes would be beneficial in the future.

Synchronous Oligometastasis and Oligoprogression as a Prognostic Marker in Patients With Extensive-Stage SCLC Treated With a Combination of Immune-Checkpoint Inhibitor and Chemotherapy (HOT2301)

IntroductionOligometastasis and oligoprogression (OP) has not been adequately defined in extensive-stage SCLC (ES-SCLC) and may be a good indication for adding local treatment. Therefore, this multicenter study aimed to investigate the prognostic impact of oligometastasis and OP in ES-SCLC. MethodsWe enrolled patients who received chemoimmunotherapy between September 2019 and June 2022. Patients were classified into oligometastasis and non-oligometastasis groups by determining the number of original tumor lesions and distant metastases (worsening or newly appearing lesions) at the time of initial diagnosis and disease progression after first-line treatment. ResultsWe retrospectively analyzed 265 consecutive patients with ES-SCLC. Synchronous oligometastasis (SOM) and OP was defined as less than or equal to five lesions in less than or equal to two organs, including lungs; 21.0% and 53.2% of patients had SOM and OP, respectively. Median progression-free survival was 5.8 months and 4.9 months in patients with and without SOM, respectively (hazard ratio [HR] = 0.72, 95% confidence interval [CI]: 0.51–1.02, p = 0.065). Median overall survival was 20.5 months and 15.0 months in patients with and without SOM (HR = 0.58, 95% CI: 0.37–0.95, p = 0.027) from the initiation of first-line treatment. The OP group revealed a better progression-free survival of 5.2 months (versus 3.2 mo, HR = 0.69, 95% CI: 0.50–0.96, p = 0.026) and overall survival of 15.1 months (versus 7.5 mo, HR = 0.44, 95% CI: 0.29–0.66, p = 0.027) from the initiation of second-line treatment compared with the non-OP group. The Lung Immune Prognostic Index score was significantly lower in the SOM and OP group. ConclusionsES-SCLC in patients with SOM and OP may be more indolent than that of the nonoligometastasis group, therefore, new treatment strategies, including the addition of local treatment, should be explored. Clinical trial registrationThis study was registered at UMIN-CTR (UMIN000053402).

L3MBTL1, a polycomb protein, promotes Osimertinib acquired resistance through epigenetic regulation of DNA damage response in lung adenocarcinoma

Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR-TKI) approved for patients with EGFR T790M resistance mutations as first- or second-line treatment of EGFR-positive patients. Resistance to Osimertinib will inevitably develop, and the underlying mechanisms are largely unknown. In this study, we discovered that acquired resistance to Osimertinib is associated with abnormal DNA damage response (DDR) in lung adenocarcinoma cells. We discovered that the polycomb protein Lethal(3) Malignant Brain Tumor-Like Protein 1 (L3MBTL1) regulates chromatin structure, thereby contributing to DDR and Osimertinib resistance. EGFR oncogene inhibition reduced L3MBTL1 ubiquitination while stabilizing its expression in Osimertinib-resistant cells. L3MBTL1 reduction and treatment with Osimertinib significantly inhibited DDR and proliferation of Osimertinib-resistant lung cancer cells in vitro and in vivo. L3MBTL1 binds throughout the genome and plays an important role in EGFR-TKI resistance. It also competes with 53BP1 for H4K20Me2 and inhibits the development of drug resistance in Osimertinib-resistant lung cancer cells in vitro and in vivo. Our findings suggest that L3MBTL1 inhibition is a novel approach to overcoming EGFR-TKI-acquired resistance.

Brief Communication on MAGE-A4 and Coexpression of Cancer Testis Antigens in Metastatic Synovial Sarcomas: Considerations for Development of Immunotherapeutics.

Therapeutic options for synovial sarcoma (SyS) have not evolved for several decades and the efficacy of second-line treatments is very limited. The expression of a large family of proteins known as cancer testis antigens (CTAs) in SyS has spurred the development of targeted T-cell therapies currently in clinical trials, such as those aimed at melanoma-associated antigen (MAGE)-A4 and New York esophageal squamous cell carcinoma 1 (NY-ESO-1), which have shown promising clinical efficacy. Extensive knowledge of the prevalence of expression and coexpression of CTAs is critical to design T-cell therapies with optimal coverage of the patient population. We analyzed the expression of CTAs of the MAGE-A family as well as NY-ESO-1 and preferentially expressed antigen in melanoma (PRAME) by RNA sequencing in a large cohort of 133 SyS samples from patients registered in the French sarcoma database (NETSARC+). Among MAGE-As, MAGE-A4 had the highest prevalence (65%), followed by MAGE-A10 (15%) and MAGE-A9 (13%). Almost all samples (92%) expressing any of the MAGE-As also expressed MAGE-A4. NY-ESO-1 was expressed in 65% of samples, with a large but incomplete overlap with MAGE-A4, whereas PRAME was present in 121 (91%) samples. Complementary immunohistochemical analyses were used to establish the positive correlation between RNA and protein expression for MAGE-A4 and NY-ESO-1. These data inform the strategy for optimal coverage of the SyS patient population with T-cell therapies, offering patients with SyS new options for single or combined second lines of treatment.

Efficacy and Safety of Durvalumab/Tremelimumab in Unresectable Hepatocellular Carcinoma as Immune Checkpoint Inhibitor Rechallenge Following Atezolizumab/Bevacizumab Treatment.

While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.

Irinotecan plus raltitrexed as second-line treatment in locally advanced or metastatic colorectal cancer patients: a prospective open-label, single-arm, multi-center, phase II study

BackgroundColorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size.MethodsThis is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety.ResultsA total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1–61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1–5.7) and median overall survival was 13.1 months (95% CI 12.2–15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths.ConclusionsThe combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients).Trial registrationClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.

Evaluation of ChatGPT-4's Performance in Therapeutic Decision-Making During Multidisciplinary Oncology Meetings for Head and Neck Squamous Cell Carcinoma.

Objectives First reports suggest that artificial intelligence (AI) such as ChatGPT-4 (Open AI, ChatGPT-4, San Francisco, USA) might represent reliable tools for therapeutic decisions in some medical conditions. This study aims to assess the decisional capacity of ChatGPT-4 in patients with head and neck carcinomas, using the multidisciplinary oncology meeting (MOM) and the National Comprehensive Cancer Network (NCCN) decision as references. Methods This retrospective study included 263 patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, and larynx who were followed at our institution between January 1, 2016, and December 31, 2021. The recommendation of GPT4 for the first- and second-line treatments was compared to the MOM decision and NCCN guidelines. The degrees of agreement were calculated using the Kappa method, which measures the degree of agreement between two evaluators. Results ChatGPT-4 demonstrated a moderate agreement in first-line treatment recommendations (Kappa = 0.48) and a substantial agreement (Kappa = 0.78) in second-line treatment recommendations compared to the decisions from MOM. A substantial agreement with the NCCN guidelines for both first- and second-line treatments was observed (Kappa = 0.72 and 0.66, respectively). The degree of agreement decreased when the decision included gastrostomy, patients over 70, and those with comorbidities. Conclusions The study illustrates that while ChatGPT-4 can significantly support clinical decision-making in oncology by aligning closely with expert recommendations and established guidelines, ongoing enhancements and training are crucial. The findings advocate for the continued evolution of AI tools to better handle the nuanced aspects of patient health profiles, thus broadening their applicability and reliability in clinical practice.

Metronomic chemotherapy using capecitabine and cyclophosphamide in metastatic breast cancer – efficacy, tolerability and quality of life results from the phase II METRO trial

BackgroundChemotherapy is commonly used in metastatic breast cancer (MBC) to prolong life and improve quality of life (QoL). The optimal dosing and sequencing beyond the second line of treatment are unknown and pose a risk of overtreatment. Continuous low oral doses of metronomic chemotherapy using capecitabine 500 mg three times daily and cyclophosphamide 50 mg once daily (MCT-CX) may be an effective and tolerable treatment option for patients with MBC. MethodsIn this open-label, single-arm single-centre phase II trial patients with MBC received MCT-CX until disease progression or unacceptable toxicity. The primary endpoint was the clinical benefit rate (CBR), defined as the proportion of participants with a best overall response of complete (CR) or partial response (PR) at any time, or stable disease (SD) for ≥ 24 weeks according to radiological evaluation. Toxicity was assessed according to the Common Toxicity Criteria v 4.0. QoL was assessed with the EORTC-30 questionnaire. ResultsIn total, 40 patients were included. Most participants (72%) presented with visceral disease and received MCT-CX beyond the second line (58%). The CBR was 45% (8 PR and 10 SD ≥ 24 weeks). Toxicities were low grade with hand-foot syndrome being the most common. There was no significant change in QoL over the first 24 weeks. ConclusionMCT-CX is a plausible treatment option in far advanced breast cancer, with almost half of trial participants responding to treatment without QoL impairments.

Determining Clinicopathologic Factors That Influence Treatment in Advanced Breast Cancer in Argentina After CDK4/6 Inhibitors.

The optimal treatment sequence for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) after progression on first-line cyclin-dependent kinase 4/6 inhibitor (CDKi) and endocrine therapy is unclear. Clinical and biological factors influencing treatment choices and outcomes in the second-line setting need to be elucidated. This is a retrospective analysis of a real-world cohort including patients with HR+/HER2- ABC who received CDKi and endocrine therapy in the first-line setting and progressed, requiring second-line treatment. Clinical and biological factors were analyzed to evaluate their association with daily treatment decisions and the prognostic role of progression-free survival (PFS) in the second-line setting. Two hundred thirty-five patients were included. Second-line treatments were hormone therapy (HT) based in 60% and chemotherapy based in 40% of patients. The second-line median PFS was 6.6 months, with no difference between treatment types. In multivariable analysis, postmenopausal status, lower Ki-67 expression, and non-de novo stage IV disease were associated with improved second-line (2L) PFS. Menopausal status significantly interacted with treatment type, with reduced PFS in premenopausal patients receiving HT-based treatments (4.7 v 8.7 months, P = .00045). In our study, treatment decisions reflected the current algorithm incorporated in our clinical guidelines, and prior treatment response was the most relevant factor to determine 2L treatment decision. Menopausal status interacted with the subsequent therapy efficacy in this setting. Hence, we consider that menopausal status should be routinely evaluated in the subgroup analysis of clinical trials.