Additional Survival Benefit Research Articles

Management and Treatment of Hepatocellular Carcinoma with Immunotherapy: A Review of Current and Future Options.

With mortality rates of liver cancer doubling in the last 20 years, this disease is on the rise and has become the fifth most common cancer in men and the seventh most common cancer in women. Hepatocellular carcinoma (HCC) represents approximately 90% of all primary liver cancers and is a major global health concern. Patients with HCC can be managed curatively with surgical resection or with liver transplantation, if they are diagnosed at an early stage. Unfortunately, most patients with HCC present with advanced stages of the disease and have underlying liver dysfunction, which allows only 15% of patients to be eligible for curative treatment. Several different treatment modalities are available, including locoregional therapy radiofrequency ablation, microwave ablation, percutaneous ethanol injection, trans-arterial chemoembolization, transarterial radio-embolization, cryoablation, radiation therapy, stereotactic radiotherapy, systemic chemotherapy, molecularly targeted therapies, and immunotherapy. Immunotherapy has recently become a promising method for inhibiting HCC tumor progression, recurrence, and metastasis. The term “Immunotherapy” is a catch-all, encompassing a wide range of applications and targets, including HCC vaccines, adoptive cell therapy, immune checkpoint inhibitors, and use of oncolytic viruses to treat HCC. Immunotherapy in HCC is a relatively safe option for treating patients with advanced disease in the USA who are either unable to receive or failed sorafenib/lenvatinib therapy and thus may offer an additional survival benefit for these patients. The purpose of this review is to elaborate on some of the most recent advancements in immunotherapy.

Retrospective analysis of clinical characteristics and prognostic factors of neuroendocrine carcinoma of the gynecologic tract: A preliminary report of ten years follow-up.

e18001 Background: To investigate the clinical characteristics and prognostic factors of neuroendocrine carcinoma of the gynecologic tract (NECGT). Methods: Patients with NECGT diagnosed during 2010 to 2019 were enrolled in this retrospective study. Clinical parameters were calculated, including age, childbearing history, initial symptoms, blood indexs, International Federation of Gynaecology and Obstetrics (FIGO) stages, treatment modalities and survival data. The cut-off values of parameters were screened by receiver-operating characteristic (ROC) curves and their significance was assessed by multivariate logistic regression. Results: We indentified forty five NECGT patients available with the median follow-up time of 5.5 months (9.7±1.98 months). 42 cases (93.3%) originated from cervix uteri, 2 cases (4.4%) from vagina and 1 case (2.2%) from fallopian tube. Irregular vaginal bleeding was the most frequent symptom at the first visit accounting for 75.6%. FIGO stages I to IV distributions were 16 (35.6%), 15 (33.3%), 6 (13.3%), and 8 patients (17.8%). Squamous carcinoma (16.7%) and adenocarcinoma (11.9%) were the common mixed pathological types. 66.7% patients underwent radical surgery, almost all of which received 4-6 cycles adjuvant chemotherapy and half followed by radiation therapy. While data analysis showed that adjuvant radiotherapy could not bring additional survival benefits (p = 0.523). The median PFS of enrolled patients was 14 months (1-78months). Pelvic recurrence (66.7%) and lymphatic metastasis (52.6%) were the main failure patterns. In multivariate analysis, leukocyte count (HR = 0.068, 95%CI: 0.007-0.673, p = 0.021), neutrophil-to-leukocyte ratio (HR = 0.151, 95%CI: 0.024-0.95, p = 0.044), lactic dehydrogenase (LDH) (HR = 6.632, 95%CI: 1.31-33.569, p = 0.022) and carbohydrate antigen-ca 125 (CA-125) (HR = 7.173, 95%CI: 1.25-41.06, p = 0.027) were the independent prognostic factors of PFS. In addition, age at natural menopause (ANM) later than 51.5years (p = 0.009) and an optimal maximum diameter > 62.1mm (p = 0.002) were closely related with poor survival. Conclusions: NECGT is a rare malignant tumor of female genital system. Surgery combined with chemotherapy is the essential treatment, addition of adjuvant radiotherapy did not improve survival. More high-quality clinical trials are needed to provide powerful evidence.

Role of adjuvant imatinib dose in radically resected GIST harboring KIT exon 9 mutations.

11533 Background: Gastrointestinal stromal tumors (GIST) with a driver mutation in KIT exon 9 (Ex9) represent about 10% of all newly diagnosed cases. In the metastatic setting, Ex9-mutated GIST patients benefit from higher doses of imatinib (800 mg/day vs standard 400 mg/day). The additional therapeutic benefit from a higher dose of imatinib in the adjuvant setting in this molecular subgroup has not been confirmed. Methods: We retrospectively identified 105 patients (pts) with resected Ex9-mutated GIST treated with adjuvant imatinib (800 mg/day or 400 mg/day) in 15 different European centers. Disease-Free Survival (DFS) and Imatinib Failure-Free Survival (IFFS) were calculated and analyzed according to the daily dose of imatinib and relevant clinical and pathological variables. Kaplan–Meier curves were used to estimate survival in univariate analyses, and the log-rank test was used to compare the groups. Hazard Ratios (HR) with 95% confidence intervals (CI) were calculated using a univariable Cox model. A multivariate Cox regression model was also performed. Results: Of the 105 pts who met the inclusion criteria, 69 (65.7%) were treated with 400 mg/day and 36 (34.3%) with 800 mg/day. The risk score (AFIP-Miettinen criteria) between the two dose groups was not statistically different (P = 0.29). Median DFS was 73.0 months (mo) in the 400 mg/day group and 61.9 mo in the 800 mg/day group (HR = 0.82, 95% CI: 0.47-1.47; P = 0.50). Median IFFS was 156.8 mo in the 400/day mg group and 117.4 mo in the 800 mg/day group (HR = 0.66, 95% CI: 0.34-1.29; P = 0.19). In a multivariable analysis, the variables statistically associated with DFS were mitotic count, the longest tumor diameter and the duration of adjuvant therapy. Mitotic count and the duration of adjuvant therapy were also associated with IFFS. Importantly, the daily imatinib dose was not associated with survival in either analysis (Table). Conclusions: This is the largest reported cohort of pts with Ex9-mutated GIST treated with either the 400 mg/day or the 800 mg/day dose of adjuvant imatinib. Although retrospective in nature, the data confirm the prognostic value of mitotic count and suggest that patients with Ex9-mutated GIST derive no additional survival benefit from the 800 mg/day dose. [Table: see text]

Potential use of homologous recombination deficiency score as an indicator of therapy selection in leiomyosarcoma patients.

e23539 Background: Leiomyosarcoma (LMS) is one of the most frequent sarcoma subtypes. While surgical resection is the standard treatment of LMS, chemotherapy and radiation have shown additional survival benefit. However, the treatment response is variable and selection of appropriate agents is difficult due to the great heterogeneity of LMS. Matching DNA damaging reagents or PARP inhibitors, to tumors with a general homologous recombination deficit (HRD), can help to deploy these reagents more precisely. We explored the correlation of HRD score with the activation of PARP signaling pathway and retrospectively tested the effect of platinum-based therapy on an LMS patient with high HRD score. Methods: Nineteen LMS samples were subjected to whole exome sequencing and their HRD scores were calculated using a published algorithm. Nine of the LMS samples were also subjected to RNA-seq analysis and undergone GSEA to profile PARP pathway expression. CIBERSORT was employed to profile infiltrating immune cells. Results: The 19 LMS samples are defined as HRD-high (11 samples) or HRD-low (8 samples) if their HRD score is above or equal to, or below the medium respectively. For the 9 samples undergone RNA-seq, 97 genes have differential expression between the two groups (p-value < 0.05, fold change≥ 2). GSEA revealed 23 enriched pathways. Interestingly, PPAR signaling pathway is the most highly enriched one (EnrichmentScore = 0.506, P.adj = 0.005). No other pathogenic germline or somatic mutation in HRD related genes, for example BRCA1/2, is enriched. Additionally, high HRD score is significantly correlated with infiltrating Tregs, monocyte, and M0 macrophages as found in CIBERSORT analysis. To retrospectively test whether HRD score can be used to predict the response to inhibitors of DNA repair pathway, we identified one patient who had received platinum-based combination therapy after failure of first-line chemotherapy. The patient is a 40-year-old female with stage IV LMS and has a high HRD score. She achieved PR with 6-month PFS and remains progression free up to the abstract date, supporting a good correlation between high HRD score and advanced chemotherapy in LMS patients. Conclusions: High HRD score is correlated with activated PPAR pathway and infiltrating Tregs, monocytes and M0 macrophages, and can potentially be used to identify LMS patients with good response to platinum-based chemotherapy even though they have no obvious germline and somatic mutation in genes involved in DNA repair.

Current trends in the management of lacrimal gland tumors: A National Cancer Database study.

e18573 Background: Lacrimal Gland (LG) tumors are rare with data limited to very few comparative trials. The original treatment is Orbital Exenteration followed by Radiotherapy (RT). Contemporary strategies like orbit sparing surgeries and Neoadjuvant Intra-arterial Chemotherapy (CT) are gaining popularity but remains controversial given the paucity of data. Our aim was to determine the pathological distribution and compare the treatment modalities used in LG tumors with the help of a large national database. Methods: From the 2004-2016 National Cancer Database (NCDB), we included Epithelial LG tumors. We excluded Lymphomas, Melanomas, Sarcomas and other metastatic lesions. Descriptive statistics, Hazard Ratio (HR) estimates and Kaplan Meier (KM) survival analysis were used. Results: A total of 669 LG tumors were identified. The distribution based on Pathology and treatment strategies used is represented in the table. The point survival estimate comparison between the surgical types and the various treatment groups showed no significance. Conclusions: SCC was the most common histological type. There was no difference in the overall outcome between radical and orbit sparing procedures. Adjuvant RT and adjuvant chemoradiation did not confer any additional survival benefit over surgery alone. Mallen-St Clair et. using the SEER database (321 LG patients) showed that RT improves Disease Specific Survival in SCC. Moving forward, larger population-based studies and prospective trials are needed to determine the most ideal management option. The NCDB is a joint project of the Commission on Cancer of the American College of Surgeons and the American Cancer Society. The data used in the study are derived from a de-identified NCDB file. The American College of Surgeons and the Commission on Cancer have not verified and are not responsible for the analytic or statistical methodology employed, or the conclusions drawn from these data by the investigator. [Table: see text]

Management of bronchopulmonary carcinoid: NCDB database analysis.

e21007 Background: There is a lack of data to guide the management of resectable bronchopulmonary carcinoid tumors (BCTs). Methods: The NCDB database was retrospectively reviewed to analyze the roles of surgery, chemotherapy and radiation. Patients with a diagnosis of clinically staged T1-2/N0-1 typical carcinoid (TC) and atypical carcinoid (AC) between 2004-2012 were included. Kaplan-Meier methods and multivariable analysis were performed. Results: A total of 2148 patients (TC 1874 & AC 274; T1/1648 & T2/500) were identified. The median age was 59 (range 18-89). There was a female (69.7%) and right lung (56.9%) predominance. Fifty-three patients received pneumonectomy, 68 chemotherapy, and 84 radiation therapy. The impact of age, histology (TC vs. AC), medical comorbidities (Charlson/Deyo score 0 vs. ≥1) and type of surgery [sublobar resection (SR) vs. lobectomy vs. lobectomy with mediastinal lymph node dissection (L/MLND)] were subsequently examined. AC, older age, and comorbidities were associated with shorter overall survival (OS) by both univariate and multivariable analysis. Patients who underwent lobectomy had longer OS (119 months) than those with SR (109 months) or L/MLND (115 months). However, this association was not significant by multivariable analysis with age incorporated as either a categorical ( < 60 vs. ≥60) or a continuous variable (Table). In the subgroup analysis of patients with T1, T2, TC and AC respectively, type of surgical resection was not significantly associated with OS by multivariable analysis. Conclusions: Patients with resectable BCTs have excellent OS. Atypical histology, older age, and comorbidities predicted inferior OS. There were insufficient data to support the use of perioperative chemotherapy or radiation therapy. Lobectomy was associated with prolonged OS by univariate analysis but this was not significant in the multivariable model, suggesting that SR is a reasonable approach for patients who cannot tolerate lobectomy. MLND did not seem to provide additional survival benefits. [Table: see text]

Initial experience of the adjuvant treatments to the local tumor for metastatic prostate cancer: Assessment of novel treatment algorithms, a multicenter, phase II randomized controlled trial (IP2-ATLANTA).

TPS5600 Background: Local cytoreductive and metastasis-directed interventions are hypothesised to confer additional survival benefit beyond standard systemic therapy in patients with de novo synchronous metastatic prostate cancer. There is accumulating prospective evidence for local cytoreductive therapy. In particular, the phase III study STAMPEDE which demonstrated improved overall survival in a low burden subgroup of men following cytoreductive radiotherapy. Cytoreductive prostatectomy and minimally invasive ablative therapies (MIAT) are now subject to similar trial evaluation. IP2-ATLANTA will evaluate progression-free and overall survival outcomes with the addition of sequential multi-modal local and metastasis-directed treatments in patients with newly diagnosed metastatic prostate cancer compared to standard care alone. Methods: Phase II, multicentre, three-arm randomised controlled trial using a positive comparator arm ( n=918 ). An internal pilot ( n=80) feasibility phase is incorporated. All men with new histologically diagnosed, hormone sensitive, metastatic prostate cancer, within three months of commencing ADT and of PS 0-2 are eligible. Patients are randomised (1:1:1) to: Control (Standard of Care) OR Intervention 1 (Minimally invasive ablative therapy to the prostate +/- pelvic lymph node dissection [PLND]) OR Intervention 2 (prostate radiotherapy +/- lymph nodes OR Radical prostatectomy +/- PLND). Metastatic burden pre-specified by CHAARTED definition. Men with low-burden disease in intervention arms are eligible for metastasis-directed therapy (stereotactic ablative radiotherapy [SABR] or surgery). Standard systemic therapy given in all arms (incl. docetaxel). Follow-up: min. 2-years; max. 4 years. Primary outcome: progression-free survival (PFS). Secondary outcomes: Overall survival; urinary, sexual & rectal side-effects; patient reported outcome measures. HRA ethical approval (Ref: 19/WA0005). To date, 28/80 (35%) patients have been recruited and randomised across 9 open sites in the internal pilot. Median recruitment rate is 85.7% (IQR 55–86). Internal pilot recruitment expected to be complete by April 2020. IP2-ATLANTA addresses an important research gap in the role of local and metastasis-directed therapy in men with newly diagnosed metastatic prostate cancer. Clinical trial information: NCT03763253 .

CA19-9 Change During Neoadjuvant Therapy May Guide the Need for Additional Adjuvant Therapy Following Resected Pancreatic Cancer.

Neoadjuvant therapy (NAT) is increasingly utilized for pancreatic cancer, however the added benefit of adjuvant therapy (AT) in this setting is unknown. We hypothesized that the magnitude of CA19-9 response to NAT can guide the need for further AT in resected pancreatic cancer. CA19-9 secretors who received NAT for pancreatic cancer during 2008-2016 at a single institution were analyzed and CA19-9 response (difference between pre- and post-NAT values) was measured. Kaplan-Meier estimators and Cox proportional hazard ratio models were used to determine the optimal CA19-9 response at which AT ceases to confer any additional survival benefit after NAT. A total of 241 patients (mean age 65.4years, 50% female) with complete CA19-9 data who underwent NAT followed by resection were analyzed. In a cohort of patients (n = 78) in whom CA19-9 normalized with a decrease > 50% after NAT (optimal responders), AT was not associated with additional survival benefit (40.6 vs. 39.0months, p = 0.815). Conversely, in the cohort of patients (n = 163) in whom NAT was not associated with normalization and a decrease of ≤ 50% in CA19-9 (suboptimal responders), receipt of AT was associated with a survival benefit (34.5 vs. 19.1months, p < 0.001) following NAT. A Cox proportional hazards model confirmed CA19-9 normalization and decrease > 50% during NAT to predict no additional survival benefit from AT. The magnitude of CA19-9 response to NAT may predict the need for further AT in resected pancreatic cancer. Prospective studies are needed to elucidate the optimal interplay of NAT and AT in pancreatic cancer.

Five Year Follow-Up of Staged Bilateral Lung Transplantation for High-Risk Patients with Interstitial Lung Disease: A Matched Case-Control Study

The choice of single (SOLT) or bilateral orthotopic lung transplant (BOLT) for interstitial lung disease (ILD) remains controversial. Our center adopted a staged BOLT approach for higher surgical risk ILD patients, in which they undergo a single lung transplant followed by a planned contralateral transplant at a later date. Long-term outcomes were compared to matched SOLT and BOLT recipients. Patients undergoing lung transplant for ILD at our institution 1/2009-8/2013 were eligible. Pediatric recipients, recipients of redo or multi-organ transplantation, and those with a diagnosis other than ILD were excluded. Staged BOLT recipients were matched to conventional SOLT and BOLT recipients in a 1:2:2 fashion based on criteria including age within 3 years and lung allocation score within 10 points. Patient and graft survival were estimated using the Kaplan Meier method. In staged BOLT recipients, the incidence of chronic lung allograft dysfunction (CLAD) was determined as persistent decline (≥20%) in FEV1 from baseline based on an average of two peak FEV1 values after second lung transplant, and compared to the incidence in control groups. A total of 192 patients with ILD met inclusion criteria. Of those, 12 (6.3%) received a staged BOLT, 106 (55.2%) received a conventional SOLT, and 74 (38.5%) received a conventional BOLT. Following matching, there were 24 control SOLTs and 24 control BOLTs. On unadjusted analysis, control SOLT, control BOLT, and staged BOLT recipients had comparable 5 year overall survival (p=0.29, Figure), graft survival (p=0.4), and incidences of CLAD (43.5%, 45.8%, 30.8%). At our institution, staged BOLT recipients exhibited long-term outcomes comparable to conventional SOLT and BOLT recipients with similar baseline characteristics. This novel approach may provide an additional long-term survival benefit for a small subset of patients who would have otherwise undergone an isolated SOLT.

Lessons learnt from scoring adjuvant colon cancer trials and meta-analyses using the ESMO-Magnitude of Clinical Benefit Scale V.1.1

Click here to listen to the PodcastBackgroundForm 1 of the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (ESMO-MCBS) serves to grade therapies with curative intent. Hitherto only few trials with curative intent have been field tested using form 1. We aimed to evaluate the applicability of the scale and to assess the reasonableness of the generated scores in early colon cancer, in order to identify shortcomings that may be rectified in future amendments.MethodsAdjuvant studies were identified in PubMed, Food and Drug Administration and European Medicines Agency registration sites, as well as ESMO and National Comprehensive Cancer Network guidelines. Studies meeting inclusion criteria were graded using form 1 of the ESMO-MCBS V.1.1 and field tested by ESMO Colorectal Cancer Faculty. Shortcomings of the scale were identified and evaluated.ResultsEighteen of 57 trials and 7 out of 14 meta-analyses identified met criteria for ESMO-MCBS V.1.1 grading. In stage III colon cancer, randomised clinical trials and meta-analyses of modulated 5-fluorouracil (5-FU) based chemotherapy versus surgery scored ESMO-MCBS grade A and randomised controlled trials (RCTs) and meta-analyses comprising oxaliplatin added to this 5-FU backbone showed a more modest additional overall survival benefit (grade A and B). For stage II colon cancer, the findings are less consistent. The fluoropyrimidine trials in stage II were graded ‘no evaluable benefit’ but the most recent meta-analysis demonstrated a 5.4% survival advantage after 8 years follow-up (grade A). RCTs and a meta-analysis adding oxaliplatin demonstrated no added benefit. Exploratory toxicity evaluation and annotation was problematic given inconsistent toxicity reporting and limited results of late toxicity. Field testers (n=37) reviewed the scores, 25 confirmed their reasonableness, 12 found them mostly reasonable. Moreover, they identified the inability of crediting improved convenience in non-inferiority trials as a shortcoming.ConclusionForm 1 of the ESMO-MCBS V.1.1 provided very reasonable grading for adjuvant colon cancer studies.

Radiotherapy in addition to surgical resection may not improve overall survival in WHO grade II spinal ependymomas

ObjectivesSpinal ependymomas are rare intramedullary neoplasms. The paucity of cases limits the ability to conduct large prospective studies. Current guidelines recommend maximal safe resection followed by adjuvant radiotherapy (RT) in cases of grade II spinal ependymomas with subtotal resections (STR) and all grade III spinal ependymomas. Herein we assess the impact of RT on survival in grades II and III spinal ependymomas. Patients and methodsThe National Cancer Database was queried for adult patients with WHO grades II or III spinal ependymomas diagnosed between 2004 and 2014 who underwent resection or biopsy. Kaplan-Meier and multivariable Cox regression models were used to determine the impact of radiotherapy on survival. ResultsA total of 1058 patients met inclusion criteria. Most patients (85.9 %) received a biopsy/STR versus gross total resection (GTR, 14.1 %). Radiotherapy was preferentially performed in those with residual tumor (p = 0.001). We found a 10-fold increased hazard of death in grade III versus grade II tumors (HR: 10.33; 95 % CI: 5.01–21.3; p < 0.001). Age positively correlated with worsened survival (HR: 1.04; 95 % CI: 1.02–1.10; p < 0.001). Adjuvant RT did not reduce the hazard of death for the cohort overall (HR: 1.08; 95 % CI: 0.55–2.10; p = 0.810) or among those with grade II tumors (HR: 0.90; 95 % CI: 0.38–2.10; p = 0.810). We found no additional survival benefit of GTR compared to biopsy/STR (HR: 0.52; 95 % CI: 0.19–1.50; p = 0.217). ConclusionWhile RT may improve progression-free survival, it may not impact overall survival in surgically resected grade II and III spinal ependymomas. Future studies should evaluate the impact of RT on local recurrence and symptomatic improvement.

Abstract C096: Modeling the clinical paradigm of lisavanbulin (BAL101553) deployment in patient-derived xenografts (PDX) of glioblastoma (GBM)

Abstract Lisavanbulin (LIS; BAL101553) is the prodrug of BAL27862, a microtubule-binding, tumor checkpoint controller and potential radiosensitizer. These studies evaluated optimal integration of LIS with standard of care radiation therapy (RT) and/or temozolomide (TMZ) using GBM PDX models. Distribution across the blood brain barrier was evaluated after a single 30 mg/kg oral LIS dose, and concentrations of the active metabolite BAL27862 were measured by liquid chromatography-tandem mass spectrometry. Similar BAL27862 concentrations were detected in the brain (B) and plasma (P) at both two (B:P ratio 1.29) and six hours (B:P ratio 1.64) post-dose. An in vivo screen of LIS monotherapy across 14 orthotopic GBM PDX models showed significant survival benefit (p&amp;lt;0.01) in seven models (median survival extension 24-87%). Extending from these results, LIS was evaluated in several of the sensitive models in combination with RT +/- TMZ. Two MGMT unmethylated PDXs, GBM6 and GBM150, were treated with vehicle or two weeks of RT +/- LIS. LIS dosing during the RT dosing period did not significantly improve median survival in either line (GBM6 survival with RT 54 days vs RT/LIS 58 days, p=0.16; GBM150 RT 86 days vs RT/LIS 101 days, p=0.21). However, prolonged LIS dosing from the start of RT until mice reached a moribund state demonstrated added benefit (GBM6 median 90 days vs RT 69 days, p=0.0001; GBM150 median 143 days vs RT 73 days, p=0.06). In GBM6, prolonged LIS dosing also significantly extended survival when combined with 2 weeks of RT/TMZ (median 101 days vs 66 days, p&amp;lt;0.0001), while LIS alone or RT/TMZ resulted in similar median survivals (63 days vs 66 days, respectively; p=0.68). This same RT/TMZ/LIS benefit was not seen in the MGMT methylated GBM12. Subsequent experiments were performed to evaluate integration of prolonged LIS dosing with concurrent RT/TMZ followed by 3 cycles of adjuvant TMZ (‘Stupp’ regimen). In MGMT methylated GBM39, LIS alone did not significantly extend survival, but LIS addition to the Stupp regimen doubled median survival (Stupp 249 days vs Stupp/LIS 502 days, p=0.0001). GBM150 demonstrated equal benefit from LIS alone or Stupp regimen (median 118 days vs 123 days, p=0.49). Stupp/LIS showed no additional survival benefit (median 98 days, p=0.97). In a second MGMT unmethylated, TMZ-resistant GBM26 PDX, LIS alone or combined with the Stupp regimen provided significant survival benefit: median survival 53 days for vehicle vs. 80 days for LIS (p=0.0001), 114 days for RT only (p&amp;lt;0.0001), 147 days for RT/LIS (p=0.30 relative to RT), 121 days for ‘Stupp’ regimen alone (p=0.57 relative to RT), and 172 days for Stupp/LIS (p=0.04 relative to Stupp). A follow-up GBM39 study revealed a significant increase in the mitotic marker phospho-histone H3 with LIS treatment relative to vehicle-treated controls (p=0.01) while Ki67 levels were similar (p=0.15). This suggests that LIS induces a mitotic arrest associated with microtubule deregulation. Collectively, these data provide a strong rationale to evaluate lisavanbulin (BAL101553) with RT +/- TMZ in GBM and provided the basis for an ongoing Phase I clinical trial. Citation Format: Danielle M Burgenske, Ann C Mladek, Jenny L Pokorny, Heidi A Lane, Felix Bachmann, Rachael A Vaubel, Mark A Schroeder, Katrina K Bakken, Lihong He, Zeng Hu, Brett L Carlson, Surabhi Talele, Gautham Gampa, Matthew L Kosel, Paul A Decker, Jeanette E Eckel-Passow, William F Elmquist, Jann Sarkaria. Modeling the clinical paradigm of lisavanbulin (BAL101553) deployment in patient-derived xenografts (PDX) of glioblastoma (GBM) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C096. doi:10.1158/1535-7163.TARG-19-C096

Functional Characterization of Gamma Delta T Cells and Allogeneic Activated NK Cells As Effector Cells for Tafasitamab (MOR208)

Introduction Tafasitamab (MOR208) is an Fc-enhanced, humanized, monoclonal antibody that binds to the human B cell surface antigen CD19. CD19 is broadly and homogeneously expressed across different B cell malignancies, including diffuse large B cell lymphoma (DLBCL), and amplifies B cell receptor signaling and induces tumor cell proliferation. Tafasitamab is currently in clinical development in patients with relapsed or refractory DLBCL in combination with the immunomodulatory drug lenalidomide (L-MIND study) and the chemotherapeutic agent bendamustine (B-MIND study). The modes of action of tafasitamab comprise antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and direct cytotoxicity (apoptosis). Tafasitamab carries two amino acid exchanges in the Fc region to increase its affinity to Fcγ receptors, including FcγRIIIa. FcγRIIIa plays a key role in mediating ADCC and is expressed on the surface of natural killer (NK) cells, as well as the majority of γδ T cells. MG4101 (a novel therapeutic agent consisting of cryopreserved, ex vivo-expanded, highly activated NK cells) has demonstrated potent anticancer activity in preclinical in vitro and in vivo studies. Currently, MG4101 is in clinical development in patients with malignant lymphoma and advanced solid tumors. Here, we have characterized two FcγRIIIa receptor-expressing cell types, γδ T cells and NK cells (MG4101), as effector cells for tafasitamab in vitro and explored the concept of supplementing MG4101 during tafasitamab therapy using disseminated in vivo models of non-Hodgkin's lymphoma. Methods γδ T cells (CD3+/γδ T cell receptor+) were derived from different donors by stimulation of peripheral blood mononuclear cells with zoledronate/IL-2 for 9-10 days. These were applied as effector cells in in vitro ADCC assays with tafasitamab in Mino and Jeko-1 mantle cell lymphoma (MCL) cell lines, as well as primary patient-derived chronic lymphocytic lymphoma (CLL) and MCL cells. Further, effector cell activity of MG4101 was assessed using tafasitamab-mediated ADCC assays in Raji and Ramos Burkitt's lymphoma cells. The concept of combining tafasitamab with allogeneic effector cell therapy in vivo was studied in two therapeutic survival models of disseminated lymphoma in SCID mice. In the Raji model, tafasitamab (0.05 µg/mouse) was given on Day 1 after intravenous (IV) tumor inoculation, while MG4101 (2x107 cells/mouse) was given on Days 1, 3, 6, 8 and 10. In the Ramos model, tafasitamab (10 mg/kg) and MG4101 (2x107 cells/mouse) were applied twice weekly for 3 weeks starting on Days 3 and 4, respectively, after IV tumor inoculation. Results Tafasitamab in combination with γδ T cells showed distinctly increased ADCC in Mino and Jeko-1 target cells in vitro, compared with a negative control IgG1 antibody. ADCC assays with patient-derived CLL and MCL target cells confirmed tafasitamab-mediated cytotoxic activity and demonstrated a clear enhancement in activity compared with the non-Fc-enhanced version of tafasitamab that was unable to induce substantial cytotoxicity. In vitro ADCC assays with tafasitamab and MG4101 on Raji and Ramos cell lines confirmed potent effector cell activity of the ex vivo-expanded, cryopreserved, allogeneic NK cells. In the disseminated Raji survival model, combination therapy with a single low dose of tafasitamab (0.05 µg) and MG4101 resulted in a distinct increase in survival of the mice with an increased life span (ILS) of 100% compared with monotherapy (ILS of 57% for tafasitamab and 50% for MG4101). Of note, the combination demonstrated a substantial and more than additive enhancement in survival in the more therapeutic Ramos survival model (Figure 1). Combination therapy with tafasitamab (10 mg/kg) and MG4101 NK cells resulted in superior antitumor activity (ILS of 103%) compared with either tafasitamab monotherapy (ILS of 49%) or MG4101 alone (ILS of 25%). Conclusions FcγRIIIa-expressing immune cell types, including NK cells and γδ T cells, are potent effector cells for tafasitamab-mediated ADCC. Combination therapy with tafasitamab and allogeneic MG4101 NK cells in vivo demonstrated a more than additive survival benefit compared with tafasitamab or MG4101 monotherapy in a disseminated therapeutic lymphoma model. Combination of tafasitamab supplemented with immune effector cells could represent a promising new approach for lymphoma therapy. Disclosures Her: GC LabCell: Employment, Patents &amp; Royalties. Cho:GC LabCell: Employment, Patents &amp; Royalties. Hwang:GC LabCell: Employment, Equity Ownership, Patents &amp; Royalties. Boxhammer:MorphoSys AG: Employment, Patents &amp; Royalties. Steidl:MorphoSys AG: Employment. Patra:MorphoSys AG: Employment. Schanzer:MorphoSys AG: Employment. Endell:MorphoSys AG: Employment, Patents &amp; Royalties.

Cytoreductive treatment strategies for de novo metastatic prostate cancer.

In the past decade, a revolution in the treatment of metastatic prostate cancer has occurred with the advent of novel hormonal agents and life-prolonging chemotherapy regimens in combination with standard androgen-deprivation therapy. Notwithstanding, the use of systemic therapy alone can result in a castrate-resistant state; therefore, increasing focus is being placed on the additional survival benefits that could potentially be achieved with local cytoreductive and/or metastasis-directed therapies. Local treatment of the primary tumour with the established modalities of radiotherapy and radical prostatectomy has been explored in this context, and the use of novel minimally invasive ablative therapies has been proposed. In addition, evidence of the potential clinical benefits of metastasis-directed therapy with ionizing radiation (primarily stereotactic ablative radiotherapy) is accumulating. Herein, we summarize the pathobiological rationale for local cytoreduction and the potentially systemic immunological responses to radiotherapy and ablative therapies in patients with metastatic prostate cancer. We also discuss the current evidence base for a cytoreductive strategy, including metastasis-directed therapy, in the current era of sequential multimodal therapy incorporating novel treatments. Finally, we outline further research questions relating to this complex and evolving treatment landscape.

Tumor Marker-Based Definition of the Transarterial Chemoembolization-Refractoriness in Intermediate-Stage Hepatocellular Carcinoma: A Multi-Cohort Study.

Background: For patients with hepatocellular carcinoma (HCC), the definition of refractoriness to transarterial chemoembolization (TACE), which might make them a candidate for systemic therapy, is still controversial. We aimed to derive and validate a tumor marker-based algorithm to define the refractoriness to TACE in patients with intermediate-stage HCC. Methods: This multi-cohort study was comprised of patients who underwent TACE for treatment-naïve intermediate-stage HCC. We derived a prediction model for overall survival (OS) using the pre- and post-TACE model to predict tumor recurrence after living donor liver transplantation (MoRAL) (i.e., MoRAL score = 11×√protein induced by vitamin K absence-II + 2×√alpha-fetoprotein), which was proven to reflect both tumor burden and biologic aggressiveness of HCC in the explant liver, from a training cohort (n = 193). These results were externally validated in both an independent hospital cohort (from two large-volume centers, n = 140) and a Korean National Cancer Registry sample cohort (n = 149). Results: The changes in MoRAL score (ΔMoRAL) after initial TACE was an independent predictor of OS (MoRAL-increase vs. MoRAL-non-increase: adjusted hazard ratio (HR) = 2.18, 95% confidence interval (CI) = 1.37–3.46, p = 0.001; median OS = 18.8 vs. 37.8 months). In a subgroup of patients with a high baseline MoRAL score (≥89.5, 25th percentile and higher), the prognostic impact of ΔMoRAL was more pronounced (MoRAL-increase vs. MoRAL-non-increase: HR = 3.68, 95% CI = 1.54–8.76, p < 0.001; median OS = 9.9 vs. 37.4 months). These results were reproduced in the external validation cohorts. Conclusion: The ΔMoRAL after the first TACE, a simple and objective index, provides refined prognostication for patients with intermediate-stage HCC. Proceeding to a second TACE may not provide additional survival benefits in cases of a MoRAL-increase after the first TACE in patients with a high baseline MoRAL score (≥89.5), who might be candidates for systemic therapy.

WHO SHOULD RECEIVE RADIOTHERAPY IN METASTATIC HORMONE-SENSITIVE PROSTATE CANCER?

SUMMARYThe standard of treatment of metastatic hormone-sensitive prostate cancer (mHSPC) is androgen deprivation therapy (ADT) with docetaxel or abiraterone. However, numerous retrospective studies suggested outcome benefit of prostate radiotherapy. Small randomized trial (HORRAD) showed no overall survival (OS) benefit of the addition of prostate radiotherapy to ADT but there was a trend toward survival benefit in a low volume disease. Although the results of large randomized study (STAMPEDE) have also not proved improvement of OS in unselected patients, robust improvement of failure-free survival was found. In addition, OS was significantly improved in patients with a low volume disease. In the absence of reliable molecular markers, the extent of metastatic disease has emerged as an important factor for treatment decision making. In this review, we summarize data from non-randomized as well as from randomized studies concerning prostate radiotherapy to contribute to the improvement of treatment tailoring for each individual patient with mHSPC in order to achieve the best possible treatment outcomes.

Development and validation of a novel MR imaging predictor of response to induction chemotherapy in locoregionally advanced nasopharyngeal cancer: a randomized controlled trial substudy (NCT01245959)

BackgroundIn locoregionally advanced nasopharyngeal carcinoma (LANPC) patients, variance of tumor response to induction chemotherapy (ICT) was observed. We developed and validated a novel imaging biomarker to predict which patients will benefit most from additional ICT compared with chemoradiotherapy (CCRT) alone.MethodsAll patients, including retrospective training (n = 254) and prospective randomized controlled validation cohorts (a substudy of NCT01245959, n = 248), received ICT+CCRT or CCRT alone. Primary endpoint was failure-free survival (FFS). From the multi-parameter magnetic resonance images of the primary tumor at baseline, 819 quantitative 2D imaging features were extracted. Selected key features (according to their interaction effect between the two treatments) were combined into an Induction Chemotherapy Outcome Score (ICTOS) with a multivariable Cox proportional hazards model using modified covariate method. Kaplan-Meier curves and significance test for treatment interaction were used to evaluate ICTOS, in both cohorts.ResultsThree imaging features were selected and combined into ICTOS to predict treatment outcome for additional ICT. In the matched training cohort, patients with a high ICTOS had higher 3-year and 5-year FFS in ICT+CCRT than CCRT subgroup (69.3% vs. 45.6% for 3-year FFS, and 64.0% vs. 36.5% for 5-year FFS; HR = 0.43, 95% CI = 0.25–0.74, p = 0.002), whereas patients with a low ICTOS had no significant difference in FFS between the subgroups (p = 0.063), with a significant treatment interaction (pinteraction < 0.001). This trend was also found in the validation cohort with high (n = 73, ICT+CCRT 89.7% and 89.7% vs. CCRT 61.8% and 52.8% at 3-year and 5-year; HR = 0.17, 95% CI = 0.06–0.51, p < 0.001) and low ICTOS (n = 175, p = 0.31), with a significant treatment interaction (pinteraction = 0.019). Compared with 12.5% and 16.6% absolute benefit in the validation cohort (3-year FFS from 69.9 to 82.4% and 5-year FFS from 63.4 to 80.0% from additional ICT), high ICTOS group in this cohort had 27.9% and 36.9% absolute benefit. Furthermore, no significant survival improvement was found from additional ICT in both groups after stratifying low ICTOS patients into low-risk and high-risks groups, by clinical risk factors.ConclusionAn imaging biomarker, ICTOS, as proposed, identified patients who were more likely to gain additional survival benefit from ICT+CCRT (high ICTOS), which could influence clinical decisions, such as the indication for ICT treatment.Trial registrationClinicalTrials.gov, NCT01245959. Registered 23 November 2010.

CA 19-9 Response: A Surrogate to Predict Survival in Patients With Metastatic Pancreatic Adenocarcinoma.

The objective of this study was to determine the features of carbohydrate antigen (CA) 19-9 decline that correlates best with survival benefit in patients with metastatic pancreatic cancer. This is a retrospective study of 225 patients with metastatic pancreatic cancer receiving first-line therapy. Analysis was performed by the Kaplan-Meier method and Cox-proportional hazards ratios. CA 19-9 decline was grouped into quartiles within different CA 19-9 baseline groups. Time to nadir and CA 19-9 decline at month-2 (M2) of therapy were evaluated for patients with a baseline level ≥1000 U/mL. No significant trend in survival was observed across baseline CA 19-9 levels. The greatest survival benefit was seen with a ≥75% decline to nadir. Among those with a ≥75% decline and baseline ≥1000 U/mL, 43 of 57 patients had a >50% decline at M2 of therapy and additional survival benefit was observed with a slower decline to nadir. Small sample sizes limited analysis of other baseline groups. CA 19-9 decline at M2 was not predictive. In patients with a CA 19-9 ≥1000 U/mL, serial CA 19-9 levels may be considered as a surrogate for serial imaging to evaluate treatment response, with a ≥75% decline indicating the greatest survival benefit. Survival was improved further in the setting of a slower decline to nadir with the highest benefit seen in patients with a nadir occurring at 4 months or longer.

Association between Adjuvant Chemotherapy and Outcome in Locally Advanced Rectal Cancer Patients with Pathologic Complete Response after Neoadjuvant Treatment and Surgery

Background: Neoadjuvant chemoradiotherapy induced pathologic complete response (pCR) is associated with an excellent outcome for locally advanced rectal cancer (LARC) patients. However, it is unclear if patients achieving a pCR could further benefit from adjuvant chemotherapy (ACT). Methods: This retrospective study recruited consecutive LARC patients who received neoadjuvant therapy and total mesorectal excision from 2010 to 2018. The pCR patients who received different ACT cycles were compared by propensity score matching. Overall survival (OS), disease free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by the Kaplan-Meier method and log-rank test. Findings: In total, 1041 consecutive pCR patients (median age, 55.0 years; 56.9% male) were included. Of whom, 303 (29.1%) patients received non-ACT treatment, and 738 patients (70.9%) received fluoropyrimidine-based ACT (range, 1-12 cycles; median, 4 cycles). Specifically, 57.6% of patients (425/738) received 1-4 cycles of ACT, and 42.4% of patients (313/738) received 5 or more cycles of ACT. After 1:3 propensity matching, 712 patients who received ACT were matched to 297 patients who did not receive ACT. The 3-year outcomes (OS, DFS, LRFS, and DMFS) of the ACT and non-ACT subgroups were similar (all P > 0.05). Moreover, the subsets of patients who received different ACT cycle(s) (0 vs. 1-4 cycles and 0 vs. ≥ 5 cycles) also had similar 3-year OS, DFS, LRFS, and DMFS (all P > 0.05). In a stratified analysis, ACT treatment did not improve the survival outcomes (OS, DFS, LRFS and DMFS) of the high-risk patients who with baseline cT3-4 and/or cN1-2 (all P > 0.05). Interpretation: ACT administration could not provide additional survival benefits for neoadjuvant treatment-induced pCR LARC patients, even if is given much more cycles. Particularly, for the baseline high-risk subset patients, a pCR status is a guarantee of excellent outcome and ACT would be unnecessary. Funding Statement: This study was supported by Natural Science Foundation of China (No. 81872188), International Centre for Genetic Engineering and Biotechnology Research Grant (No. CRP/CHN16-04_EC), Guangdong Natural Science Foundation for Distinguished Young Scholar (No. 2014A030306016), the Science and Technology Planning Project of Guangdong Province (No. 2017B090901065). Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: This study was approved by the Clinical Ethics Review Committee at the Sixth Affiliated Hospital of Sun Yat-sen University.

Morbidity, mortality and long-term outcome of lung cancer resections performed in palliative intent

Surgery is seldom used for palliation in advanced lung cancer and the published data on this issue are very limited. We aimed to assess the results of palliative lung resections and identify criteria to guide surgical therapy in this situation. This is a retrospective single-institution analysis of patients with palliative intended lung cancer resection. Survival analysis was performed by Kaplan-Meier method, log-rank test and Cox proportional hazards regression at a statistical significance level of P=0.05. Forty-eight patients received palliative intended lung resections (31 lobectomies, 4 bilobectomies, 13 pneumonectomies) with acceptable rates of severe complications (Clavien-Dindo >IIIa 29%) and 30-day mortality (4%). The most frequent indications were infection and hemoptysis. The median survival for the entire group was 12 months (95% CI: 6.9-17.1 months). Due to unexpectedly favorable histopathologic tumor stage, a switch to curative treatment in 17 completely resected patients resulted in a 2-year survival rate of 46%. In a subgroup of 20 patients with favorable prognostic factors as identified by uni- and multivariable analysis, a median survival of 26 months was observed. In well selected patients with lung cancer, resection in palliative intent can offer symptom relief and even a survival benefit with acceptable morbidity and low mortality. Prognostic factors were identified and can be used to guide operative treatment. Due to the low specificity of CT and FDG-PET/CT in the presence of inflammation or centrally located lung tumors, a large proportion of patients with lung resection in palliative intent experience a down-staging and frequently also a switch from palliative to curative treatment with additional survival benefit. Factors like expected complete resection, a squamous cell type and the ability to receive adjuvant therapy are useful to support the decision to perform palliative tumor resection.