Second-line Systemic Therapies Research Articles

S2k guideline: Diagnosis and therapy of localized scleroderma.

The updated S2k guideline deals with the diagnosis and therapy of localized scleroderma (LoS). LoSrepresents a spectrum of sclerotic skin diseases in which, depending on the subtype and localisation, structures such as adipose tissue, muscles, joints, and bones may also be affected. Involvement of internal organs or progression to systemic sclerosis does not occur. LoScan be classified into four main forms: limited, generalized, linear, and mixed forms, with some additional subtypes. For cases of limited skin involvement, the guideline primarily recommends therapy with topical corticosteroids. UV therapy can also be recommended. In subtypes with severe skin or musculoskeletal involvement, systemic therapy with methotrexate is recommended. During the active phase of the disease, systemic glucocorticosteroids can be used additionally. In cases of methotrexate and steroid refractory courses, contraindications, or intolerance, mycophenolate mofetil, mycophenolic acid, or abatacept can be considered as second-line systemic therapies. In the case of linear LoS, autologous adipose-derived stem cell transplantation can also be performed for correcting soft tissue defects.

An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab plus bevacizumab in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.

TPS576 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved frontline therapy for advanced HCC, but a minority of patients (pts) respond and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME), mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP3 with Bev. This study will evaluate the safety and efficacy of RP3 combined with Atezo plus Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC (NCT05733598). Methods: The 1L and 2L cohorts will each enroll up to 30 pts. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following 1 prior line of systemic therapy, which must have included a PD-1/PD-L1–directed agent. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, and an Eastern Cooperative Oncology Group performance status of 0 to 1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in the 1L cohort will receive Atezo 1200 mg and Bev 15 mg/kg every 3 weeks (Q3W) together with RP3 intratumorally Q3W for a total of up to 8 doses. Pts in the 2L cohort will receive RP3 every 2 weeks for 4 doses with Bev Q3W starting on cycle (C)1 day (D)1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint is the overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

Advanced cholangiocarcinomas: second-line systemic therapies in the erea of personalized medicine

Advanced cholangiocarcinomas: second-line systemic therapies in the erea of personalized medicine

Abrocitinib, tralokinumab and upadacitinib for treating moderate-to-severe atopic dermatitis.

Atopic dermatitis is a chronic relapsing inflammatory skin condition. One of the most common skin disorders in children, atopic dermatitis typically manifests before the age of 5 years, but it can develop at any age. Atopic dermatitis is characterised by dry, inflamed skin accompanied by intense itchiness (pruritus). To appraise the clinical and cost effectiveness of abrocitinib, tralokinumab and upadacitinib within their marketing authorisations as alternative therapies for treating moderate-to-severe atopic dermatitis compared to systemic immunosuppressants (first-line ciclosporin A or second-line dupilumab and baricitinib). Studies were identified from an existing systematic review (search date 2019) and update searches of electronic databases (MEDLINE, EMBASE, CENTRAL) to November 2021, from bibliographies of retrieved studies, clinical trial registers and evidence provided by the sponsoring companies of the treatments under review. A systematic review of the clinical effectiveness literature was carried out and a network meta-analysis undertaken for adults and adolescents at different steps of the treatment pathway. The primary outcome of interest was a combined response of Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4; where this was consistently unavailable for a step in the pathway, an analysis of Eczema Area and Severity Index 75 was conducted. A de novo economic model was developed to assess cost effectiveness from the perspective of the National Health Service in England. The model structure was informed through systematic review of the economic literature and by consulting clinical experts. Effectiveness data were obtained from the network meta-analysis. Costs and utilities were obtained from the evidence provided by sponsoring companies and standard UK sources. Network meta-analyses indicate that abrocitinib 200 mg and upadacitinib 30 mg may be more effective, and tralokinumab may be less effective than dupilumab and baricitinib as second-line systemic therapies. Abrocitinib 100 mg and upadacitinib 15 mg have a more similar effectiveness to dupilumab. Upadacitinib 30 and 15 mg are likely to be more effective than ciclosporin A as a first-line therapy. Upadacitinib 15 mg, abrocitinib 200 and 100 mg may be more effective than dupilumab in adolescents. The cost effectiveness of abrocitinib and upadacitinib for both doses is dependent on the subgroup of interest. Tralokinumab can be considered cost-effective as a second-line systemic therapy owing to greater cost savings per quality-adjusted life-year lost. The primary strength of the analysis of the three new drugs compared with current practice for each of the subpopulations is the consistent approach to the assessment of clinical and cost effectiveness. However, the conclusions are limited by the high uncertainty around the clinical effectiveness and lack of data for the primary outcome for comparisons with baricitinib and for the adolescent and adult first-line populations. The most significant limitation that Eczema Area and Severity Index 50 + Dermatology Life Quality Index ≥ 4 could not be obtained for the adolescent and adult first-line systemic treatment populations is due to a paucity of data for dupilumab and ciclosporin A. A comparison of the new drugs against one another in addition to current practice would be beneficial to provide a robust view on which treatments are the most cost-effective. This study is registered as PROSPERO CRD42021266219. This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: 135138) and is published in full in Health Technology Assessment; Vol. 28, No. 4. See the NIHR Funding and Awards website for further award information.

An open-label, multicenter study investigating RP3 oncolytic immunotherapy in combination with first- or second-line systemic atezolizumab and bevacizumab therapy in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.

TPS4178 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of bevacizumab (Bev) and atezolizumab (Atezo) is the preferred frontline therapy for advanced HCC, but a minority of patients (pts) respond, and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment, mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP3 is a genetically modified herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), an anti–CTLA-4 antibody-like molecule, CD40 ligand, and 4-1BB ligand. The direct oncolytic effect coupled with immune stimulation by RP3 in the tumor microenvironment is intended to provide systemic antitumor activity and enhance therapeutic response to anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP3 with Bev. This study will evaluate the safety and efficacy of RP3 combined with Atezo and Bev as first- (1L) and second-line (2L) systemic therapies for unresectable and advanced HCC. Methods: The 1L and 2L cohorts will each enroll up to 30 pts. Pts in the 1L cohort may not have received prior systemic treatment; pts in the 2L cohort must have progressed on or following one prior line of systemic therapy, which must have included a PD-1/PD-L1−directed agent. Key inclusion criteria include advanced, unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh Class A, and Eastern Cooperative Oncology Group performance status of 0−1. Key exclusion criteria include untreated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of tumor into any major blood vessel(s) and/or main bile ducts. Pts with a history of medically refractory hepatic encephalopathy and/or hepato-renal syndrome are also excluded. Pts in the 1L cohort will receive 1200 mg Atezo and 15 mg/kg Bev every 3 weeks (Q3W) together with RP3 intratumorally Q3W for a total of up to 8 doses. Pts in the 2L cohort will receive RP3 every 2 weeks for 4 doses with Bev Q3W starting on cycle (C) 1 day (D) 1, then RP3 and Bev Q3W for up to 4 more doses with Atezo Q3W being added on C4D1. The primary endpoint is overall response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Secondary endpoints are safety, ORR using HCC modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

A review of 2022 Chinese clinical guidelines on the management of hepatocellular carcinoma: updates and insights.

Significant improvements in the management of hepatocellular carcinoma (HCC) during the past three years have urged the timely update of clinical guidelines in China. In brief, aMAP score is newly recommended as an effective risk stratification tool to predict HCC occurrence especially for non-cirrhotic patients. Biomarker-based surveillance including 7 micro-RNA panel and GALAD score are advocated to assist early diagnosis. China liver cancer (CNLC) staging system proposed in the 2017 guideline continues to be the standard model for staging with modifications in the treatment allocations. Conversion therapies using multi-modal, high intensity strategies are advocated to facilitate subsequent resection for patients with technically unresectable CNLC stage Ia, Ib, IIa HCC, or technically resectable IIb, IIIa HCC. Super-selective transcatheter arterial chemoembolization (TACE) with the assistance of Cone-Beam CT if necessary is recommended to guarantee the efficacy of TACE. Hepatic arterial infusion chemotherapy (HAIC) using oxaliplatin, fluorouracil, and leucovorin (FOLFOX) regimen alone or in combination with systemic therapy is recommended for TACE-refractory patients or for patients with locally advanced HCC. The systemic treatments for HCC have evolved considerably since atezolizumab plus bevacizumab, and suntilimab plus bevacizumab analogue showing superior survival benefit to sorafenib, and donafenib with comparable efficacy with sorafenib are added to the first-line treatments. In addition to regorafenib, apatinib, camrelizumab and tislelizumab are added as the second-line systemic therapies for patients who progressed on sorafenib. Updates in the 2022 Barcelona Clinic Liver Cancer (BCLC) guidelines and Japanese Society of Hepatology (JSH) consensus statement are also introduced and compared with the 2022 Chinese guidelines.

Clinical practice guidelines and real-life practice in hepatocellular carcinoma: A Chinese perspective.

Liver cancer is the fourth most prevalent and the second most lethal cancer in China. Hepatitis B virus (HBV) infection represents a major risk factor for hepatocellular carcinoma (HCC). Liver ultrasonography plus alpha-fetoprotein every 6 months continues to be the predominant surveillance modality. The age-Male-ALBI-Platelets score was recommended in the recent 2022 Chinese guidelines to predict HCC occurrence. The Chinese liver cancer (CNLC) staging system proposed in the 2017 guidelines continues to be the standard model for staging with modifications in the treatment allocations. Considering the aggressive nature of HBV-associated HCC, multimodal and high-intensity strategies like the addition of immunotherapy-based systemic treatment to local therapies, including resection, ablation, and intra-arterial therapies, have been adopted in real-life practices in China. The latest Chinese guidelines recommend atezolizumab plus bevacizumab, suntilimab plus a bevacizumab analog, lenvatinib, sorafenib, donafenib, and FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy as first-line treatment without priority. Regorafenib, apatinib, camrelizumab, and tislelizumab have been added as second-line systemic therapies for patients who progressed on sorafenib. Systemic therapies adopted in real-life practice are sophisticated with various combination modalities and different sequences.

Correlation between efficacy endpoints in patients with advanced biliary tract cancer treated by systemic second-line therapies: Analysis of aggregated data from a systematic literature review

BackgroundOverall response rate (ORR) and progression-free survival (PFS) are commonly used as endpoints for phase II trials. However, the ultimate goal is to bring survival benefit for the patients. We aimed to assess the correlation between ORR, median PFS and overall survival (OS) using aggregated data from a systematic review of second-line systemic therapies in advanced biliary tract cancer (BTC) patients. MethodsClinical trials were identified using Medline database. Studies only enrolling patients with gallbladder cancer were not included. Searches were last updated on April 2020. Eligible studies reported OS, PFS and/or ORR data for BTC patients receiving second-line systemic chemotherapy. Pearson weighted correlation was estimated between OS and ORR and between median OS and PFS. ResultsSeventeen studies (N = 912 patients) were selected. There was a strong correlation between median OS/ORR in the overall analysis (r = 0.85; P < 0.0001), both for trials with chemotherapy (r = 0.90; P=0.0152) and targeted therapy (r = 0.84; P = 0.0006). In contrast, the correlation between median OS/PFS, albeit significant in the overall analysis (r = 0.80; P < 0.0001), remained significant only for targeted therapies in the sensitivity analysis (r = 0.83; P = 0.0009). ConclusionsORR seems to be a more interesting intermediate endpoint in BTC in second line for both chemotherapy and targeted therapies, while PFS may be relevant only for targeted therapy trials. Further well-designed studies for surrogacy evaluation should be performed to confirm this observation.

The suitability of treating atopic dermatitis with Janus kinase inhibitors

Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant morbidity and reduced quality of life, especially in patients with moderate-severe AD. Recently, topical and oral Janus kinase (JAK)-inhibitors were investigated as potential treatments for mild-moderate and moderate-severe AD. However, rare serious adverse-events observed with JAK-inhibitor therapy in AD, rheumatoid arthritis, and other immune-mediated disorders warrant careful consideration. Areas covered This review examines the efficacy and safety of topical and oral JAK-inhibitors for treatments in AD, and reviews potential treatment applications in patients with moderate-severe AD. Expert opinion JAK-inhibitors have rapid-onset and robust and durable efficacy, which give them considerable versatility for treating the gamut of AD patients. While the U.S. Food and Drug Administration has only approved upadacitinib and abrocitinib to treat moderate-severe AD refractory to treatment with other systemic medications including biologics, or when use of those therapies is not recommended, oral JAK-inhibitors have the potential to be used both as first-line or second-line systemic therapies in moderate-severe AD. However, oral JAK-inhibitors can lead to laboratory anomalies and rare serious adverse events. All of these important characteristics should be addressed in shared-decision making conversations, patient counseling, choosing appropriate therapies for patients, and monitoring patients in clinical practice.

Rosai\u2013Dorfman\u2013Destombes disease of the nervous system: a systematic literature review

BackgroundRosai–Dorfman–Destombes disease (RDD) is a rare histiocytic disorder with heterogeneous clinical manifestations and rare neurologic involvement. The existing clinical literature about neurologic RDD has yet to be critically examined.MethodsWe performed a four-database English-language systematic literature search for cases of RDD neurohistiocytosis, excluding secondary literature. Individual patient data for neurologic symptoms, disease sites, treatments, and responses were captured. Responses to first-line and second-line surgical interventions, post-surgical radiotherapy, and systemic therapies were analyzed.ResultsAmong 4769 articles yielded by literature search, 154 articles were fully reviewed, containing data on 224 patients with neurologic RDD. 128 (83.1%) articles were single case reports. 149 (66.5%) patients were male, 74 (33.5%) female, with a median age of 37.6 years (range 2–79). Presenting neurologic symptoms included headache (45.1%), focal neurological deficits (32.6%), visual symptoms (32.1%), and seizures (24.6%). RDD involvement was multifocal in 32 (14.3%) cases. First-line treatment involved resection in 200 (89.6%) patients, with subsequent progression in 52 (26%), including 41 (78.8%) with unifocal disease. No difference was observed in progression-free survival comparing post-operative radiotherapy to no radiotherapy following partial resection. Chemotherapy given alone as first-line treatment led to complete or partial response in 3/7(43%) patients. Second-line treatments led to complete or partial response in 18/37(37.5%) patients. Mutational data were reported on 10 patients (4.46%).ConclusionsThis review highlights the limited published data about neurologic RDD, which presents with varied symptomatology and outcome. Further study is needed about its mutational landscape, and more effective therapies are needed for recurrent and refractory disease.

Surrogate Indicators of Overall Survival in Advanced Hepatocellular Carcinoma

To the Editor, For more than a decade, the targeted drug sorafenib[1, 2] has been the dominant first-line treatment for patients with advanced hepatocellular carcinoma (HCC). However, due to the low overall response rate and high drug resistance rate, many new targeted drugs have been developed, including sunitinib, brivanib, linifanib, nintedanib, dovitinib, sorafenib plus erlotinib, lenvatinib, and donafenib. On the other hand, with the increasing use of immune checkpoint inhibitors in solid tumors, several trials investigated the efficacy and safety of immune checkpoint inhibitors in advanced HCC. Among these trials, only lenvatinib and donafenib as monotherapy were non-inferior to sorafenib in overall survival in untreated advanced HCC. Most of other trials did not meet their primary end point of overall survival. However, the efficacy of the combination therapy with PD-1 or PD-L1 inhibitor plus bevacizumab (VEGF inhibitor) is amazing.[3, 4] An expert panel convened by the American Association for the Study of Liver Diseases recommended time to progression as the primary endpoint in randomized phase 2 trials and overall survival as the main endpoint to measure effectiveness in phase 3 trials.[5, 6] In real world clinical practice, subsequent antitumor therapies after tumor progression and/or therapies for concurrent liver disease can confound the assessment of clinical benefit. In the recent issue of Journal of Hepatology, on behalf of EASL, Bruix and coworkers updated the recommendations of systemic treatment of HCC.7 This review proposed that “overall survival is the sole robust endpoint to assess the benefit from any intervention in advanced HCC” and “all proposed surrogates lack adequate validation”. Here, we tried to reveal the relationship among objective response rate (ORR), median overall survival (OS) time and median progression-free survival (PFS) time by presenting them in a same curve graph. The potential relationship between PFS and OS is revealed by representing the hazard ratio (with 95% confidence interval) of PFS and OS with a forest plot. We systematically searched PubMed and EMBASE databases and analyzed phase 3 clinical trials with large sample size. A total of 11 trials about first-line systemic therapies for advanced HCC published from 2008 to 2021 were included into analysis. All these 11 trials included a group of patients treated with sorafenib. In addition, 7 trials about second-line systemic therapies published from 2015 to 2021 were also included into analysis. The control group received placebo treatment in all these 7 trials. All these 18 trials reported ORR, median PFS and OS time. The ORR according to RECIST 1.1 in the sorafenib group ranged from 0.7% to 11.9% (median 6.1%). Among patients with sorafenib therapy, the median PFS and OS time was 3.75 (range 2.8 to 5.5) and 10.4 (range 6.5 to 14.7) months, re-spectively. The mean ORR of sorafenib was also calculated. The denominator equals the sum of the sample sizes for each sorafenib group. Percentage was obtained by the sum number of cases with complete or partial response in each trial divided by the denominator. The mean ORR of sorafenib was 6.0%. Actually, atezolizumab plus bevacizumab was associated with the highest ORR (27.3%) while donafenib with the lowest (4.6%). In addition, the median OS time of each trial tended to increase gradually with the increase of ORR and median PFS time (Fig. 1a). However, this trend was not significant in second-line treatment (Fig. 1b). And then, we describe the association between PFS and OS with forest plot (Fig. 1c). We found (1) PD-1 (sintilimab) or PD-L1 (atezolizumab) inhibitor plus bevacizumab was associated with the best survival benefit for patients with advanced HCC;[3, 4] (2) the significant benefit of PFS may not translate into significant benefit of OS (linifanib, lenvatinib, ramucirumab in REACH trial, S-1); (3) similar PFS generally does not translate into OS benefits (sunitinib, brivanib, sorafenib plus erlotinib), except in the ZGDH3 trial (donafenib); (4) a benefit in PFS could predict a benefit in OS when the hazard ratio for PFS is lower than 0.6 in most trials, except ZGDH3[8] (hazard ratio 0.91) and KEYNOTE 240 trial (hazard ratio 0.72).[9] Tumor progression is the leading cause of death in patients with HCC. Increased ORR and PFS may increase OS in firstline setting, but not in second-line therapy. In addition, the optimum cut-off value of hazard ratio for PFS in predicting benefit in OS is still pending.

Multicenter External Validation of a Nomogram for Predicting Positive Prostate-specific Membrane Antigen/Positron Emission Tomography Scan in Patients with Prostate Cancer Recurrence

BackgroundA nomogram has recently been developed to predict 68Ga-labeled prostate-specific membrane antigen (PSMA)-11 positron emission tomography (PET)/computed tomography (PSMA-PET) results in recurrent prostate cancer (PCa) patients. ObjectiveTo perform external validation of the original nomogram in a multicentric setting. Design, setting, and participantsA total of 1639 patients who underwent PSMA-PET for prostate-specific antigen (PSA) relapse after radical therapy were retrospectively included from six high-volume PET centers. The external cohort was stratified according to clinical setting categories: group 1: first-time biochemical recurrence (n = 774); group 2: PSA relapse after salvage therapy (n = 499); group-3: biochemical persistence after radical prostatectomy (n = 210); and group-4: advanced-stage PCa before second-line systemic therapies (n = 124). InterventionPSMA-PET in recurrent PCa. Outcome measurements and statistical analysisPSMA-PET detection rate was assessed in the overall population and in each subgroup. A multivariable logistic regression model was produced to evaluate the predictors of a positive scan. The performance characteristics of the model were assessed by quantifying the predictive accuracy (PA) according to model calibration. The Youden’s index was used to find the best nomogram’s cutoff. Decision curve analysis (DCA) was implemented to quantify the nomogram’s clinical net benefit. Results and limitationsIn the external cohort, the overall detection rate was 53.8% versus 51.2% in the original population. At multivariate analysis, International Society of Urological Pathology grade group, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p ≤ 0.02). The PA of the nomogram was identical to the original model (82.0%); the model showed an optimal calibration curve. The best nomogram’s cutoff was 55%. In the DCA, the nomogram revealed clinical net benefit when the threshold nomogram probabilities were ≥20%. The retrospective design is a major limitation. ConclusionsThe original nomogram exhibited excellent characteristics on external validation. The incidence of a false negative scan can be reduced if PSMA-PET is performed when the predicted probability is ≥20%. Patient summaryA nomogram has been developed to predict prostate-specific membrane antigen/positron emission tomography (PSMA-PET) results for recurrent prostate cancer (PCa). The nomogram represents an easy tool in the decision-making process of recurrent PCa.

Clinical Features and Treatment Approaches in Patients with Rosai-Dorfman Disease: The Mayo Clinic Experience

IntroductionRosai-Dorfman disease (RDD) is a rare subtype of non-Langerhans cell histiocytosis that is classically characterized by lymphadenopathy and accumulation of CD68-positive, S100-positive, and CD1a-negative histiocytes with frequent emperipolesis in sinuses of lymph nodes and lymphatics of internal organs. In this series, we report on the clinical features, treatment strategies utilized and outcomes of a large cohort of RDD patients seen at one institution.MethodsWe retrospectively reviewed the medical records of patients with biopsy-proven RDD evaluated at the Mayo Clinic from January 1, 1994 to September 2, 2016. Data abstracted from the medical records included: demographic characteristics, symptoms at disease presentation, treatment, and outcomes. In addition, radiologic and molecular findings were collected when available.ResultsA total of 55 patients with confirmed RDD were included in our study. The median age at diagnosis was 50 years (range, 2-79), including 4 pediatric subjects. The median duration from symptom onset to diagnosis was 6.4 months (range, 0-128; mean 18 months). There was a female preponderance (male 1: female 1.5). The most common presenting signs and symptoms were painful or painless subcutaneous masses (40%), lymphadenopathy (13%), bone pain (11%), constitutional symptoms (fevers, chills, myalgia, or weight loss: 11%), and abdominal pain (11%). The organ systems involved with RDD based on either histopathological or radiological findings are shown in the Table. In our series, extranodal presentation in the soft tissue (55%) was more common than a nodal presentation (38%). Other rare extranodal sites included one case each involving the parotid gland, thyroid gland, testicles, and rectum. The median number of biopsies required to establish diagnosis was 2 (range, 1-6). Next generation sequencing was performed on 2 patient samples, and showed a CDC73 truncation in exon 5 in the first case and a KRAS K117N mutation in the second case. BRAF V600E mutation testing was negative in 2 patients: one by immunohistochemistry and one by urine cell-free DNA PCR.Treatment data were available for 46 patients. Of these, 13% patients were observed. The most common first line therapeutic modalities used were surgical excision (39%) and corticosteroids (35%). Other first-line systemic therapies included rituximab in 2 patients and vinblastine in 1 patient. Approximately 13 (28%) patients developed recurrent disease and were treated with other modalities: surgery (n=4), radiation therapy (n=3), and systemic therapies like cladribine (n=4), CVP (cyclophosphamide, vincristine, and prednisone; n=1), and 6-mercaptopurine with prednisone (n=1).The median duration of follow-up after diagnosis was 20 months (range, 0-188). At the time of last follow-up, 4 patients were deceased. Of the deceased, 3 patients died from other malignancies (acute myeloid leukemia, peripheral T-cell lymphoma, and metastatic gall bladder carcinoma) and the cause of death for 1 patient was unknown.ConclusionsRDD is a rare histiocytic disorder presenting with diverse clinical manifestations. The diagnosis is often delayed due to inconclusive biopsies, and in some instances, multiple biopsy attempts are necessary to secure a definitive diagnosis. Approximately one-third of patients may require second-line systemic therapies. Next generation sequencing might yield targetable mutations in RDD patients that relapse or have progressive multi-organ disease. [Display omitted] DisclosuresNowakowski:Morphosys: Consultancy, Research Funding; celgene: Consultancy, Research Funding; Genetech: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; pharmacyclics: Consultancy; Abbvie: Consultancy; Nanostring: Research Funding. Sher:LAM Therapeutics, Inc: Research Funding. Parikh:Pharmacyclics: Honoraria; Pharmacyclics: Research Funding; AstraZeneca: Honoraria.

Real-world efficacy and safety of lenvatinib-base therapy for patients with unresectable hepatocellular carcinoma in China: A multicenter retrospective analysis.

e16192 Background: Lenvatinib has been approved as a first-line systemic for advanced hepatocellular carcinoma (HCC) after the randomized phase III REFLECT trial. The aim of this study was to assess the lenvatinib-base treatment patterns and safety in real-world clinical settings in China. Methods: In this multicenter retrospective study, A total of 278 patients with unresectable HCC were treated with lenvatinib-base treatment between October 2018 and November 2020 were analyzed. Therapeutic effect was determined using the RECIST 1.1 and mRECIST criteria. Progression free survival (PFS), overall survival (OS) and treatment-related adverse events (TRAE) were also evaluated. Results: Of 278 unresectable HCC patients (median age: 56.1±11.9 years), 220 (79.1%) had cirrhosis caused by HBV infection. 215 (77.3%) and 63 (22.7%) patients were classified as Child-pugh A and B class, respectively. 233 (83.8%) and 45 (16.2%) patients received lenvatinib in first-line and second-line systemic therapies, respectively. 223 (80.2%) patients were treated with lenvatinib plus arterially directed therapy (TACE or HAIC of FOLFOX) and 55 (19.8%) were treated with lenvatinib alone. The objective response rate were 34.9% (RECIST) and 47.5% (mRECIST), while the disease control rate were 75.5%. With a median follow-up period of 12.8 months, the median PFS and OS were 7.8 months (95% CI 7.1–8.4) and 17.2 months (95% CI 14.9–19.6), respectively. Results from the multivariate analysis showed that the significant independent favorable prognosis factors were tumor burden&lt; 50% (P=0.033), Child–Pugh A class (P&lt;0.01), AFP level &lt;200ng/mL (P=0.045), the combination with lenvatinib and arterially directed therapy (P&lt;0.01). TRAE occurred in 219 of 278 patients (78.8%), most common TRAE were hypertension (n=118; 42.4%) and hand-foot skin reaction (n=91; 32.7%). The most common grade 3–4 TARE were hypertension (n=23; 8.3%), decreased appetite (n=18; 6.5%), AST elevation (n=14; 5%), and diarrhea (n=14; 5%) across all study patients. Conclusions: In this multicenter real-world study, lenvatinib-base treatment could be accomplished with well tolerated and response for unresectable HCC patients. Combination with arterially directed therapy could likely improve the overall survival.

Erdafitinib treatment in Brazilian patients with metastatic urothelial carcinoma (mUC): real-world evidence from an Expanded Access Program.

Background:Erdafitinib is the first targeted therapy approved for the treatment of patients with metastatic urothelial carcinoma (mUC). Approval was based on a phase II single-arm trial that demonstrated significant activity of erdafitinib in patients with tumors harboring FGFR2/3 alterations. In Brazil, an Expanded Access Program (EAP) provided patients with early access to erdafitinib prior to market authorization. The current report describes characteristics and outcomes of patients with mUC on erdafitinib therapy.Methods:Patients with mUC that failed first- and second-line systemic therapies were screened for FGFR2/3 alterations in primary or metastatic tumor tissues. Patients with FGFR2/3 alterations were selected to receive erdafitinib at the standard dosing schedule and were followed prospectively to evaluate the efficacy and safety outcomes.Results:From 19 April 2019, through 13 March 2020, 47 patients with mUC from 10 Brazilian centers were tested for FGFR2/3 alterations. Alterations in FGFR2/3 were found in 12 patients (25.5%) and all of them were eligible for the EAP. Four patients (33%) had partial response, while two patients (17%) had stable disease. Progressive disease, the best response, was observed in five patients (42%). At a median follow-up of 16.2 months, the median time to treatment failure (TTF) was 2.8 months. When considering only patients with objective response, the median TTF was 5.3 months. Adverse events (AEs) were reported for any grade and grade 3 or higher in 10 patients (83%) and 5 patients (42%), respectively. The most common AE was hyperphosphatemia.Conclusion:This first real-world evidence report of heavily treated patients with mUC confirms the efficacy and safety of erdafitinib in a disease setting with a lack of treatment options.

Management of Non–Small-Cell Lung Cancer Patients Initially Diagnosed With 1 to 3 Synchronous Brain-Only Metastases: A Retrospective Study

BackgroundThe treatment options for newly diagnosed non–small-cell lung cancer (NSCLC) patients with 1 to 3 synchronous brain metastases (BM) remain controversial. The current study aimed to comprehensively analyze the characteristics, local treatment paradigms, and survival outcomes in these populations. Patients and MethodsA total of 252 NSCLC patients initially diagnosed with 1 to 3 synchronous brain-only metastases were enrolled onto this study. Local therapy (LT) to primary lung tumors (PLT) and BM included surgery, radiotherapy, or both. Median overall survival (mOS) was measured among patients who received LT to both PLT and BM (all-LT group), patients who were treated with LT to either PLT or BM (part-LT group), and patients who did not receive any LT (non-LT group). ResultsThe mOS for all-LT (n = 70), part-LT (n = 113), and non-LT (n = 69) groups was 33.2, 18.5, and 16.8 months, respectively (P = .002). The OS rates at 5 years for the all-LT, part-LT, and non-LT groups were 25.5%, 16.2%, and 0, respectively. Multivariable analysis revealed that all-LT versus non-LT, pretreatment Karnofsky performance status > 70, histology of adenocarcinoma, thoracic stage I-II, EGFR mutation, ALK positive, and second-line systemic therapies were independent prognostic factors for improved mOS. ConclusionsThe current study showed that LT for both PLT and BM is associated with superior OS in appropriately selected NSCLC patients initially diagnosed with 1 to 3 synchronous BM. Prospective trials are urgently needed to confirm this finding.

Pancreatic Insufficiency in Patients Under Sorafenib Treatment for Hepatocellular Carcinoma.

To describe the occurrence of malabsorption (MA) in hepatocellular carcinoma (HCC) patients under sorafenib, the potential relationship with pancreatic insufficiency (PI), and the role of pancreatic enzymes supplementation. With the increasing options of second-line systemic therapies for HCC, the recognition of drug intolerance using practical tools is crucial. It has been proposed that a MA syndrome could be due to sorafenib-induced pancreatic dysfunction. All sorafenib-treated patients with suspicion of MA (defined as decreased stool consistency lasting >4 wk or presenting ≥10% body weight loss without HCC progression) were prospectively evaluated by serum markers, endoscopy, and imaging techniques. We evaluated 81 sorafenib-treated patients and 21 developed MA suspicion (85.7% male, 81.5% Child-Pugh A, 52.4% BCLC-B, and 47.6% BCLC-C) within a median 5.9 months after starting sorafenib. The median treatment duration, follow-up, and overall survival after MA suspicion were 5.9, 20.3, and 20.3 months, respectively. Nine of them (42.9%) presented hyperparathyroidism secondary to vitamin D deficiency and 8 with PI. A gradual decrease in pancreatic volume of up to 19% was observed among patients with PI. Six of the 8 patients with PI received pancreatic enzymes, with complete recovery from MA symptoms and stabilization of pancreatic volume. We validated the association between MA and PI in 10% of sorafenib-treated patients. Pancreatic enzymes supplementation successfully led to symptomatic recovery. Awareness of this adverse event can help in the management of sorafenib irrespective of cancer type and likely, of other tyrosine kinase inhibitors for HCC patients.

The role of salvage lymph node dissection in nonmetastatic castration-resistant prostate cancer: A single center experience

ObjectiveTo evaluate oncologic outcomes of patients with nonmetastatic, castration-resistant prostate cancer treated with salvage lymph node dissection (sLND) or androgen-deprivation therapy (ADT) for lymph nodes (LN)-only recurrence. Materials and MethodsRetrospective analysis of 23 (51.1%) patients who underwent sLND and 22 (48.9%) men who received ADT for LN-only recurrence. Biochemical recurrence (BCR) was defined as prostate-specific antigen (PSA) >0.2 ng/ml with an increased trend and radiological recurrence (RAR) was defined as a positive imaging study after sLND or ADT. Second line systemic therapies (SST) were defined as any systemic therapy administered for progression. Predictors of BCR, RAR, and SST were assessed with Cox regression analyses. ResultsMean PSA reduction was significantly higher after sLND than ADT (62.8% vs. 17.7%; P = 0.04). Clinical outcomes were not statistically different between the 2 groups. However, there was a trend toward a longer time to BCR (13.3 vs. 6 months; P = 0.2) and RAR (21.1 vs. 14.2 months, P = 0.09) in sLND patients than ADT. Median time to SST was longer in the sLND group than ADT (P = 0.04). Univariable Cox regression analyses showed that PSA doubling time and pT stage were associated with RAR and SST (all P < 0.05). ConclusionsIn patients with nonmetastatic, castration-resistant prostate cancer, sLND resulted in greater PSA decrease than ADT. We noted a nonstatistically significant trend toward longer time to BCR and longer time to RAR for patients treated with sLND than ADT. Additionally, sLND may increase time to SST as compared to ADT.

Prediction nomogram for 68Ga-PSMA-11 PET/CT in different clinical settings of PSA failure after radical treatment for prostate cancer.

The objective of this study was to develop a clinical nomogram to predict gallium-68 prostate-specific membrane antigen positron emission tomography/computed tomography (68Ga-PSMA-11-PET/CT) positivity in different clinical settings of PSA failure. Seven hundred three (n= 703) prostate cancer (PCa) patients with confirmed PSA failure after radical therapy were enrolled. Patients were stratified according to different clinical settings (first-time biochemical recurrence [BCR]: group 1; BCR after salvage therapy: group 2; biochemical persistence after radical prostatectomy [BCP]: group 3; advanced-stage PCa before second-line systemic therapies: group 4). First, we assessed 68Ga-PSMA-11-PET/CT positivity rate. Second, multivariable logistic regression analyses were used to determine predictors of positive scan. Third, regression-based coefficients were used to develop a nomogram predicting positive 68Ga-PSMA-11-PET/CT result and 200 bootstrap resamples were used for internal validation. Fourth, receiver operating characteristic (ROC) analysis was used to identify the most informative nomogram's derived cutoff. Decision curve analysis (DCA) was implemented to quantify nomogram's clinical benefit. 68Ga-PSMA-11-PET/CT overall positivity rate was 51.2%, while it was 40.3% in group 1, 54% in group 2, 60.5% in group 3, and 86.9% in group 4 (p< 0.001). At multivariable analyses, ISUP grade, PSA, PSA doubling time, and clinical setting were independent predictors of a positive scan (all p≤ 0.04). A nomogram based on covariates included in the multivariate model demonstrated a bootstrap-corrected accuracy of 82%. The nomogram-derived best cutoff value was 40%. In DCA, the nomogram revealed clinical net benefit of > 10%. This novel nomogram proved its good accuracy in predicting a positive scan, with values ≥ 40% providing the most informative cutoff in counselling patients to 68Ga-PSMA-11-PET/CT. This tool might be important as a guide to clinicians in the best use of PSMA-based PET imaging.

An imaging-based review of systemic therapies and associated toxicities in metastatic pancreatic cancer as per the 2018 ASCO guidelines: what every radiologist should know.

To provide an overview of what radiologists should know about systemic agents utilized in the modern treatment of metastatic pancreatic cancer and their associated toxicities. The clinical landscape of metastatic pancreatic cancer has significantly evolved in recent years, with the advent of new first- and second-line systemic therapies. As these systemic treatment options continue to expand, knowledge of their clinically relevant features is becoming critical for radiologists. While the issues of surgical resectability and tumor response evaluation of advanced stages of pancreatic cancer have been thoroughly discussed in the radiology literature, the diagnostic importance of systemic therapies has tended to be less well appreciated. In this review, we provide a primer for radiologists outlining the radiologically pertinent features of modern systemic therapies used in the treatment of metastatic pancreatic ductal adenocarcinoma. These systemic agents are discussed from the standpoint of the newly updated 2018 ( https://doi.org/10.1007/s00261-019-01954-z ) guidelines for the treatment of metastatic pancreatic cancer from the American Society of Clinical Oncology (ASCO). Understanding the radiology relevance of these modern therapeutic agents is critical, especially with regard to treatment response and toxicity assessment. Knowledge of the modern systemic therapies utilized in the treatment of metastatic pancreatic cancer and their associated toxicity profiles is critical in diagnostic imaging interpretation.