Patients Achieved Disease Control Research Articles

Nab-paclitaxel plus gemcitabine in patients with locally advanced pancreatic cancer (LAPACT): a multicentre, open-label phase 2 study

Treatment options for patients with unresectable locally advanced pancreatic cancer are scarce. Results from a subanalysis of the phase 3 MPACT trial in metastatic pancreatic cancer suggested potential activity of nab-paclitaxel plus gemcitabine against locally advanced pancreatic cancer. The objective of this phase 2 trial was to evaluate safety and efficacy of nab-paclitaxel plus gemcitabine in previously untreated locally advanced pancreatic cancer. This international, open-label, multicentre, phase 2 trial (LAPACT) took place at 35 sites in five countries (USA, France, Spain, Canada, and Italy). Patients with Eastern Cooperative Oncology Group performance status of up to 1 underwent six cycles of induction with nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle). After induction, patients without progressive disease or unacceptable adverse events were eligible to receive continued therapy per investigator's choice: continued nab-paclitaxel plus gemcitabine, chemoradiation, or surgery. The primary endpoint was time to treatment failure; secondary endpoints were disease control rate, overall response rate, progression-free survival, overall survival, safety, and quality of life. The reported efficacy outcomes were analysed in the intention-to-treat population, and safety outcomes were analysed in the treated population. This trial is registered with ClinicalTrials.gov, NCT02301143, and EudraCT, 2014-001408-23 and is complete. Between April 21, 2015, and April 26, 2018, 107 patients were enrolled in the study. 106 received the study treatment; one patient enrolled but did not receive treatment. 44 (41%) of 107 enrolled patients discontinued induction; the most common reason for discontinuing induction was adverse events (22 [21%] patients). 62 (58%) of 107 enrolled patients completed induction treatment and 47 (44%) patients subsequently received continued treatment per investigator's choice: 12 (11%) continued nab-paclitaxel plus gemcitabine, 18 (17%) received chemoradiation, and 17 (16%) underwent surgery (seven had R0 resection status, nine had R1). 15 (14%) patients completed induction treatment but did not receive continued treatment. Median time to treatment failure was 9·0 months (90% CI 7·3-10·1); median progression-free survival was 10·9 months (90% CI 9·3-11·6), and median overall survival was 18·8 months (90% CI 15·0-24·0). During induction, 83 patients achieved disease control and the disease control rate was 77·6% (90% CI 70·3-83·5). 36 patients had a best response of partial response; the overall response rate during induction was 33·6% (90% CI 26·6-41·5). The most common treatment-emergent adverse events that were grade 3 or higher in the treated population during induction were neutropenia (35 [33%] of 106 patients), anaemia (12 [11%]), and fatigue (11 [10%]). The most common treatment-emergent serious adverse events during induction were pneumonia (five [5%] patients), pyrexia (five [5%]), and febrile neutropenia (three [3%]). No deaths were caused by treatment-related adverse events during the induction phase, and global quality of life was maintained in most patients. The data from this trial support the tolerability and activity of nab-paclitaxel plus gemcitabine for locally advanced pancreatic cancer, and a potential to convert unresectable, locally advanced disease to surgically resectable disease. The safety profile was generally consistent with previous findings. Celgene.

Abstract B14: CA 19-9 levels in patients with metastatic pancreatic adenocarcinoma receiving first-line therapy with liposomal irinotecan plus 5-fluorouracil/leucovorin and oxaliplatin (NAPOX)

Abstract Introduction: Liposomal irinotecan (nal-IRI) plus 5-fluorouracil/leucovorin (5-FU/LV) is approved for patients with metastatic pancreatic adenocarcinoma (mPAC) after disease progression following gemcitabine-based therapy. The combination of nal-IRI+5-FU/LV plus oxaliplatin (NAPOX) is being investigated as first-line treatment for patients with mPAC in a phase 1/2, open-label, dose exploration and dose expansion study (NCT02551991). This exploratory analysis investigated changes in carbohydrate antigen (CA) 19-9 levels, and their association with response rates, in patients with mPAC receiving NAPOX. Methods: After establishing a recommended dose in the exploration phase of study NCT02551991 (nal-IRI 50 mg/m2 [free-base equivalent], oxaliplatin 60 mg/m2, LV 400 mg/m2, 5-FU 2400 mg/m2 on days 1 and 15 of each 28-day cycle), 25 patients were enrolled into the dose expansion phase, resulting in a total of 32 patients treated at the selected dose level (pooled population; PP). The data cut-off for this interim analysis was when all treated patients had completed at least 16 weeks of follow-up. CA 19-9 levels were assessed at baseline and up to week 16. Results: Overall, 30 of the 32 treated patients in the PP had available CA 19-9 data at baseline. The median CA 19-9 level at baseline was 316 U/mL, with 23 (77%) patients having baseline CA 19-9 levels above the normal level (>37 U/mL). Among patients with baseline CA 19-9 levels >37 U/mL and measurements up to week 16 (n = 17), the median best reduction from baseline in CA 19-9 was 35.9%; a best CA 19-9 reduction of ≥20%, ≥50%, and ≥70% was achieved by 59% (10/17), 41% (7/17), and 24% (4/17) of patients, respectively. A total of 72% (23/32) treated patients achieved disease control by week 16 (DCR16), and the overall response rate (ORR; complete response or partial response over entire follow-up period) was 34% (11/32). In treated patients with any reduction in CA 19-9 by week 16, the DCR16 rate was 88% (14/16) and the ORR was 63% (10/16). Among patients with above-normal baseline CA 19-9 levels and any CA 19-9 reduction by week 16, the DCR16 rate was 83% (10/12) and the ORR was 67% (8/12). Rates of DCR16 and ORR increased with greater CA 19-9 reductions, reaching 100% and 75-83%, respectively, in patients with a CA 19-9 decrease of ≥70%. Conclusion: In patients with mPAC, first-line NAPOX therapy (with a dosing schedule of nal-IRI 50 mg/m2, oxaliplatin 60 mg/m2, LV 400 mg/m2, and 5-FU 2400 mg/m2 on days 1 and 15 of each 28-day cycle) resulted in substantial reductions in CA 19-9 levels from baseline, indicative of antitumor activity. Response rates were higher in patients with greater CA 19-9 reductions. Further assessment of CA19-9 levels and response rates over a longer follow-up period is ongoing. Citation Format: Farshid Dayyani, Patrick M. Boland, Andrew Dean, Christopher H. Lieu, Teresa Macarulla, Bin Zhang, Bruce Belanger, Yan Moore, Fiona Maxwell, Tiffany Wang, Zev A. Wainberg. CA 19-9 levels in patients with metastatic pancreatic adenocarcinoma receiving first-line therapy with liposomal irinotecan plus 5-fluorouracil/leucovorin and oxaliplatin (NAPOX) [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B14.

Single-nucleotide polymorphism variation (SNV): Possible candidates as predictive biomarkers to response and progression free survival (PFS) in cutaneous malignant melanoma (CMM) patients treated with immune checkpoint inhibitors (ICI)

Abstract Background Treating CMM patients with ICI have significantly increased PFS and overall survival (OS) for this patient population. In order to further improve ICI efficacy we need to identify predictive biomarkers to foresee which patient would benefit from treatment. Extensive research is being performed globally but with very little focus on host genotype variations. The aim of this study was to identify host genetic markers that can predict treatment outcome in patients with metastatic CMM. Methods We have genotyped 49 patients with metastatic CMM treated with ICI at Karolinska University Hospital in Sweden. Blood samples were collected before treatment start. As platform we have used the Axiom Precision Medicine Research Arrays (Affymetrix ®). We have conducted genome-wide and targeted analysis of approximately 488,000 and 4000 single nucleotide variants respectively, using Partek Genomic Suite Software®. Results 49 patients were included between July 2015 and August 2017, 22 females and 27 males. The median age was 68 years old (range 31 – 84). All patients had metastatic disease (33 M1C, 5 M1B, 11 M1A). ICI was first line treatment in most of the patients (n:40). Patients were treated with either nivolumab or pembrolizumab. Twenty-eight patients achieved disease control (with 8 complete responses) whereas 19 had progressive disease. Eleven patients were still responding at the cut-off date in 2018 November 30th, 1 missed follow-up and 2 were not included in the response analysis due to premature death. Median PFS was 6,9 months (range 0 – 40 months). The median OS was 19 months (range 0 – 40 months, 22 patients still alive at cut-off). We have in the targeted analysis identified one candidate significantly associated with both response and PFS. We are expanding the cohort and genotyping 40 additional patients. Conclusion Host genotype variations could identify novel predictive biomarkers candidates to ICI. Validation of our results with a bigger cohort is warranted. Legal entity responsible for the study Karolinska Institute. Funding Cancer Research Funds of Radiumhemmet, The Swedish Cancer Society and Knut and Alice Wallenberg Foundation. Disclosure All authors have declared no conflicts of interest.

Dual Epigenetic Agents Plus Rituximab-Gemcitabine-Oxaliplatin As a Salvage Treatment in Relapsed/Refractory Diffuse Large B Cell Lymphoma Patients

Background: Chemo-resistance is a core challenge in successful treatment of diffuse large B cell lymphoma (DLBCL). It has been previously reported that DNA hypermethylation and histone deacetylation are two major epigenetic modifications contributing to chemo-resistance in multiple tumors. Moreover, combination of histone deacetylase inhibitors (HDI) and DNA methyltransferase inhibitors (DNMTI) resulted in synergistic anti-lymphoma effect toward refractory and/or relapsed (R/R) DLBCL cells in vitro and in vivo xenografts. R-GemOx (rituximab, gemcitabine, and oxaliplatin), as a first-line chemotherapy regimen for elderly primary DLBCL patients or a salvage chemotherapy regimen for R/R DLBCL patients not candidates for high-dose therapy, has shown high activity with a relative low toxicity profile. Herein, we therefore aimed to assess the efficacy, safety, and feasibility of the dual epigenetic agents plus R-GemOx regimen (CD-R-GemOx) as a salvage treatment in R/R DLBCL patients. Methods: 13 R/R DLBCL patients including 8 males and 5 females, diagnosed with R/R DLBCL on the basis of the 2008 World Health Organization guidelines, who had failed from previous salvage treatment were exposed to dual epigenetic agents (Chidamide 30mg biw and Decitabine 10mg/m2 qd d1-d5) and sequential R-GemOx(rituximab 375 mg/m² qd d6; gemcitabine 1 g/m² d7,d14; and oxaliplatin 100 mg/m² d8) for salvage chemotherapy. Median age of these patients was 56 (35-67) years old. Most (10/13) patients have advanced Ann Arbor stages. The cycle was repeated every 4 weeks. Clinical efficacy were assessed after two cycles. Results: All thirteen (100%) patients achieved disease control response. Ten (76.9%) patients achieved an overall response at the end of the treatment, with three (23.1%) achieving a complete response. Common grade 3-4 adverse events were haematological toxicities (thrombocytopenia in ten [76.9%] patients, anaemia in six [46.2%], and neutropenia in twelve [92.3%]) and gastrointestinal complications (nausea in four [30.8%] patients, vomiting in one [7.7%], diarrhoea in six [46.2%] and mucositis in six [46.2%]). Besides, 6/13 (46.2%) cases manifested with pyrexia; 3/13(23.8%) cases manifested with increase of ALT and hyperbilirubinemia. All above toxicities were reversible and recovered within 1 month after chemotherapy. No neurological toxicities and treatment-related deaths were observed. Conclusions: Our study indicates that combination of dual epigenetic agents and R-GemOx is a safe and promising salvage approach to managing R/R DLBCL patients and may serve as an optimal salvage treatment for bridging autologous transplantation. Disclosures No relevant conflicts of interest to declare.

18F-FDG PET/CT in non-small-cell lung cancer patients: a potential predictive biomarker of response to immunotherapy.

The aim of this study was to assess the predictive role of fluorine-18-fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) in the evaluation of response to immunotherapy in patients affected by metastatic lung cancer. From a single-center database, data for 32 patients (median age: 69 years; range: 37-78) with metastatic lung cancer were retrospectively retrieved. All patients were treated with nivolumab. PD-L1 expression was available in 19/32 patients. All patients underwent F-FDG PET/CT before immunotherapy. Whole-body maximum standardized uptake value (SUVmaxwb), metabolic tumor volume (MTVwb), and total lesion glycolysis (TLGwb) were obtained as the sum of SUVmax, metabolic tumor volume, and total lesion glycolysis in all metabolic lesions. The best response to therapy was considered in terms of partial response (PR), stable disease (SD), and progressive disease (PD) on the basis of clinical and radiological follow-up. F-FDG PET/CT was positive in 30/32 (94%) patients. The majority of them had a pathological F-FDG uptake in the lung, lymph nodes, and bones. SUVmaxwb, MTVwb, and TLGwb were higher in patients with a positive PD-L1 expression than those with negative expression. Twenty-one patients achieved disease control (PR+SD), whereas 11 did not (PD). SUVmaxwb was significantly higher in patients without a response to therapy than those with a response to immunotherapy (median: 48.97 vs. 20.85; Student t-test: P = 0.002). Similarly, TLGwb and MTVwb were also higher in nonresponders than responders, although not statistically significant. However, the difference was more evident in women than men (median SUVmaxwb in responders and nonresponders for women and men: 17.86 vs. 85.89 and 21.38 vs. 44.38, respectively). The entire tumor burden evaluated by F-FDG PET/CT can be predictive of response to immunotherapy in patients with metastatic lung cancer. A large prospective multicenter trial is warranted to definitively assess the usefulness of F-FDG PET/CT as a predictive biomarker of response to immunotherapy.

Abstract 3216: CKD-516, a novel vascular disrupting agent, enhances anticancer activity of anti-PD-1 antibody in SMAD4-deficient colon cancer model

Abstract CKD-516 is a potent vascular disrupting agent (VDA), selectively acting on tumor vessels. A clinical study of CKD-516 combined with irinotecan is undergoing in colorectal cancer. There have been exponential gains in immune-oncology (I-O) in recent times through the development of immune checkpoint inhibitors (ICIs). ICIs demonstrated durable response and some patients achieved disease control for several years. However, there are still critical unmet medical needs for the combination therapies due to limited response rate of ICIs. The first step of the cancer-immunity cycle is dendritic cells (DCs) maturation which is necessary for the anticancer immunity. It is well known that mature DCs play critical roles in priming immune responses in cancer patients. We found that CKD-516 is able to induce DC maturation through Rho signaling pathway in DCs. A tumor suppressor gene, SMAD4 is associated with several cancers including stomach cancer, colorectal cancer, and pancreas cancer. The loss of SMAD4 is a poor prognostic biomarker in these cancer types and its mutation is related to poor clinical outcome on immunotherapies. A SMAD4-deficient mouse colorectal cancer cell line (3349LM) was primary cultured from a spontaneous intestinal adenocarcinoma formed in a Villin-Cre;Smad4(F/F);Trp53(F/F) mouse. CKD-516 showed a synergistic effect with anti-PD-1 antibody in 3349LM syngeneic model. In addition, 3349LM is also a MSS type cancer. Thus, CKD-516 displayed a therapeutic potential for several cancer patients who do not respond to immunotherapy. In summary, CKD-516 is a novel VDA with immune boosting effect. In SMAD4 deficient cancer model, CKD-516 has shown synergistic effects in combination with PD-1 antibody. Therefore, these data suggest that CKD-516 potentiates the anticancer activity of immunotherapy. Citation Format: Soo Jin Kim, Hark Kyun Kim, Keun Ho Ryu, Chung Il Hong. CKD-516, a novel vascular disrupting agent, enhances anticancer activity of anti-PD-1 antibody in SMAD4-deficient colon cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3216.

Efficacy and safety of trifluridine/tipiracil in third-line and beyond for the treatment of patients with metastatic colorectal cancer in routine clinical practice: patterns of use and prognostic nomogram.

Trifluridine/tipiracil combination has shown a benefit over placebo in the treatment of patients with chemorefractory metastatic colorectal cancer (mCRC). We evaluated the efficacy and safety of this combination in the real-life setting at eight Galician centers in Spain. This is a retrospective study of a cohort of patients with mCRC in treatment with trifluridine/tipiracil within usual clinical practice who have been previously treated or are not considered candidates for treatment with available therapies. A total of 160 mCRC patients were included. Our data showed that 11.9% of patients achieved disease control. Median progression-free survival was 2.75months; at 5.66months follow-up, median overall survival was 7.94months. Asthenia and neutropenia (48.1% both) were the most frequent adverse events. Overall survival was lower in patients with ECOG 2, multiple metastatic sites, platelets count 350,000/µl, alkaline phosphatase > 500IU/l, and carcinoembryonic antigen > 10ng/ml. The results of this study confirm the efficacy and safety of trifluridine/tipiracil in chemorefractory mCRC patients. However, patients in clinical practice differ from patients in clinical trials. Due to this, prognostic factors have special importance to offer the best therapeutic approach.

Metronomic Capecitabine With Cyclophosphamide Regimen in Unresectable or Relapsed Pseudomyxoma Peritonei

BackgroundNo standard treatment for advanced unresectable pseudomyxoma peritonei (PMP) has been defined so far. PMP is traditionally considered chemoresistant but nonrandomized series showed promising results with regimens for gastrointestinal tumors. Patients and MethodsWe conducted a single-center prospective single-arm trial. Inclusion criteria were histologically confirmed PMP, unresectable or progressive to surgery/previous treatments. Patients received a continuous metronomic regimen with capecitabine (625 mg/m2 twice per day) with cyclophosphamide (50 mg/d) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was progression-free survival (PFS); secondary end points were disease control rate (DCR), overall survival (OS), and safety. Exploratory analyses were the variation of circulating tumor biomarkers and neutrophil to lymphocyte ratio (NLR). ResultsTwenty-three consecutive patients were enrolled from April 2015 to October 2017. At a median follow up of 22.4 months, median PFS was 9.5 months and 1-year OS rate was 73.7%. Overall, DCR was 87% and 6 (27%) patients achieved disease control ≥12 months. The safety profile was manageable: 26% of patients reported Grade 3 drug-related adverse events and none Grade 4/5. NLR baseline < 3 versus ≥ 3 was associated with prolonged PFS (12.6 vs. 3.4 months; P = .0001). ConclusionMetronomic capecitabine with cyclophosphamide is a well tolerated regimen in unresectable/recurrent PMP, and its safety profile favorably compares with previously investigated regimens.

Presentation, Morbidity and Treatment Outcome of Acromegaly Patients at a Single Centre.

Introduction:The management of acromegaly, a rare and potentially curable disease, has undergone a paradigm shift in the past few decades. Many of the treatment modalities recommended for acromegaly are either too expensive or not available in many parts of India. There is a dearth of treatment and outcome data in Indian patients.Aim:Our aim was to study the clinical presentation, hormonal profile, radiology, management, and outcome of the disease at our center.Materials and Methods:Fifty one patients with acromegaly who attended the Department of Endocrinology, SKIMS, Srinagar, between October 2015 and April 2017, were included in the study. Clinical and hormonal profiles, comorbidities, treatment modalities, and outcome were evaluated.Results:The gender distribution was equal with the mean age of 42.3 ± 10.9 years at diagnosis. The majority (41) of the patients had macroadenoma. The most common presenting manifestations were acral enlargement and headache. Hypertension was present in 23, musculoskeletal manifestations in 19, and diabetes mellitus in 11 patients. Surgery was the most common method of treatment. Preoperatively only one patient with micro-adenoma had hypocortisolism, which was persistent in postoperative period, while no patient had preoperative or postoperative hypothyroidism or hypogonadism. As per the present consensus criteria, 23.7% patients achieved disease control (40% with microadenoma and only 19.5% with macroadenoma). The surgical complications occurred in 5 patients–CSF leak in 3 meningitis in 2 patients all except one having macroadenoma.Conclusions:The presentation of disease was generally comparable to that reported in literature. Cure rates were significantly lower than those reported from many large centers.

Abstract 213: Exome sequencing of paired primary and relapsed small cell lung cancers reveals increased copy number aberration complexity to be associated with disease relapse

Abstract Introduction: Although small-cell lung cancer (SCLC) is sensitive to first-line radiation and chemotherapy, nearly all patients recur often with treatment-resistant disease. Therefore, delineating subclonal architecture and molecular evolution of SCLC after treatment by comparing genomic profiles of recurrent and paired treatment-naïve tumors may provide new insights into mechanisms underlying recurrence and susceptibility to further treatment. Methods: Treatment-naïve and paired recurrent tumor samples from 9 patients with limited-stage SCLC treated with concurrent chemoradiation (CCRT) underwent whole exome sequencing (WES) and data is currently available for 6 pairs. All 6 patients had disease recurrence more than 3 months after finishing treatment. Genomic landscape including somatic mutations, somatic copy number aberrations (SCNA), subclonal architecture and transversion rate (percentage of base changes from pyrimidine to purine and vice-versa) were compared between treatment-naïve and paired recurrent tumor samples. Circulating cell-free DNA (cfDNA) collected at the time of recurrence was also subject to deep sequencing of 461 cancer genes. Results: SCNA analyses revealed significantly more complex chromosomal gains in relapsed SCLCs compared to pre-treatment primary tumors (7.7% vs 13.2% genes with copy number gain in primary and relapsed SCLC respectively, p=0.034). As expected, TP53 and RB1 were the most commonly mutated genes (83% and 67% respectively) and tobacco exposure related signatures were predominant in all samples. Primary and relapsed tumor pairs showed very similar genomic landscape including tumor mutational burden (11.8/MB in primary SCLC vs 9.7/MB in relapsed tumors), intra-tumor heterogeneity complexity (MATH score 38.2 in primary vs 39.2 in relapse) and transversion rates, that have been reported to be associated with alkylating-agent treatment (62% in primary vs 65% in relapse). An average of 72.25% (range: 53-86%) somatic mutations, including all canonical cancer gene mutations, were shared between primary SCLC and relapsed tumors. In addition, the subclonal architecture was also very similar between treatment-naïve primary SCLC and paired relapsed tumors. Of note, 5 out of 6 patients achieved disease control on retreatment with chemotherapy. Conclusion: Copy number gains may play a role in post-CCRT relapse of SCLC. Paired pre-treatment and relapse samples show genomic similarities which could account for benefit to subsequent treatment. Additional sample analysis and ctDNA assessment is ongoing to better address these findings, especially in patients with chemoresistant relapse. These findings also suggest that other molecular changes involving gene expression (eg. methylation) may play a role in SCLC relapse and resistance. Citation Format: Marcelo V. Negrao, Ming Tang, Ying Jin, Yamei Chen, Xiao Hu, Huarong Tang, Haimiao Xu, Kelly Quek, Jianhua Zhang, Xizeng Mao, Xingzhi Song, John V. Heymach, Ignacio Wistuba, Lauren A. Byers, Bonnie S. Glisson, Andrew Futreal, Ming Chen, Jianjun Zhang. Exome sequencing of paired primary and relapsed small cell lung cancers reveals increased copy number aberration complexity to be associated with disease relapse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 213.

A retrospective study of trifluridine/tipiracil in pretreated metastatic colorectal cancer patients in clinical practice

Aim: RECOURSE trial has shown a benefit for trifluridine/tipiracil (also known as TAS-102) over placebo in chemorefractory metastatic colorectal cancer (mCRC) patients. We evaluated efficacy and safety of patients treated with trifluridine/tipiracil in compassionate use. Patients &amp; methods: RETROTAS is a retrospective study designed to evaluate efficacy and safety of trifluridine/tipiracil in mCRC patients previously exposed or not a candidate to all available drugs. Results: A total of 85 mCRC patients were included. Our data showed that 37.6% of patients achieved disease control. Median progression-free survival was 2.3 months; at 16 months follow-up, median overall survival was 9.2 months. Conclusion: This real-life experience confirms the safety and efficacy of trifluridine/tipiracil, resulting as a valid option in chemorefractory mCRC treatment scenario.

Avelumab for patients with previously treated metastatic or recurrent non-small-cell lung cancer (JAVELIN Solid Tumor): dose-expansion cohort of a multicentre, open-label, phase 1b trial

Avelumab, a human Ig-G1 monoclonal antibody targeting PD-L1 and approved in the USA for the treatment of metastatic Merkel cell carcinoma, has shown antitumour activity and an acceptable safety profile in patients with advanced solid tumours in a dose-escalation phase 1a trial. In this dose-expansion cohort of that trial, we assess avelumab treatment in a cohort of patients with advanced, platinum-treated non-small-cell lung cancer (NSCLC). In this dose-expansion cohort of a multicentre, open-label, phase 1 study, patients with progressive or platinum-resistant metastatic or recurrent NSCLC were enrolled at 58 cancer treatment centres and academic hospitals in the USA. Eligible patients had confirmed stage IIIB or IV NSCLC with squamous or non-squamous histology, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), tumour biopsy or archival sample for biomarker assessment, and Eastern Cooperative Oncology Group performance status 0 or 1, among other criteria. Patient selection was not based on PD-L1 expression or expression of other biomarkers, including EGFR or KRAS mutation or ALK translocation status. Patients received infusional avelumab monotherapy 10 mg/kg every 2 weeks until disease progression or toxicity. The primary objective was to assess safety and tolerability. This trial is registered with ClinicalTrials.gov, number NCT01772004; enrolment in this cohort is closed and the trial is ongoing. Between Sept 10, 2013, and June 24, 2014, 184 patients were enrolled and initiated treatment with avelumab. Median follow-up duration was 8·8 months (IQR 7·2-11·9). The most common treatment-related adverse events of any grade were fatigue (46 [25%] of 184 patients), infusion-related reaction (38 [21%]), and nausea (23 [13%]). Grade 3 or worse treatment-related adverse events occurred in 23 (13%) of 184 patients; the most common (occurring in more than two patients) were infusion-related reaction (four [2%] patients) and increased lipase level (three [2%]). 16 (9%) of 184 patients had a serious adverse event related to treatment with avelumab, with infusion-related reaction (in four [2%] patients) and dyspnoea (in two [1%]) occurring in more than one patient. Serious adverse events irrespective of cause occurred in 80 (44%) of 184 patients. Those occurring in more than five patients (≥3%) were dyspnoea (ten patients [5%]), pneumonia (nine [5%]), and chronic obstructive pulmonary disease (six [3%]). Immune-related treatment-related events occurred in 22 patients (12%). Of 184 patients, 22 (12% [95% CI 8-18]) achieved a confirmed objective response, including one complete response and 21 partial responses. 70 (38%) had stable disease. Overall, 92 (50%) of 184 patients achieved disease control (they had a confirmed response or stable disease as their best overall response). One patient was initially thought to have died from grade 5 radiation pneumonitis during the study; however, this adverse event was subsequently regraded to grade 3 and the death was attributed to disease progression. Avelumab showed an acceptable safety profile and antitumour activity in patients with progressive or treatment-resistant NSCLC, providing a rationale for further studies of avelumab in this disease setting. Merck KGaA and Pfizer.

Stereotactic body radiation therapy for oligoprogression of metastatic disease from gastrointestinal cancers: A novel approach to extend chemotherapy efficacy.

Chemotherapy and targeted therapies are effective palliative options for numerous unresectable or metastatic cancers. However, treatment resistance inevitably develops leading to mortality. In a subset of patients, systemic therapy appears to control the majority of tumors leaving 5 or less to progress, a phenomenon described as oligoprogression. Reasoning that the majority of lesions remain responsive to ongoing systemic chemotherapy, we hypothesized that local treatment of the progressing lesions would confer a benefit. The present study describes the cases of 5 patients whose metastatic disease was largely controlled by chemotherapy. The oligoprogressive lesions (≤5) were treated with stereotactic body radiotherapy (SBRT), justifying continued use of an effective systemic regimen. A total of 5 patients with metastatic disease on chemotherapy, with ≤5 progressing lesions amenable to SBRT, were treated with ablative intent. Primary tumor site and histology were as follows: 2 with metastatic colon adenocarcinoma, 2 with metastatic rectal adenocarcinoma and 1 with metastatic pancreatic adenocarcinoma. Imaging was performed prior to SBRT and every 3 months after SBRT. In total, 4 out of the 5 patients achieved disease control for >7 months with SBRT, without changing chemotherapy regimen. The median time to chemotherapy change was 9 months, with a median follow-up time of 9 months. The patient who failed to respond developed progressive disease outside of the SBRT field at 3 months. In conclusion, the addition of SBRT to chemotherapy is an option for the overall systemic control of oligoprogressive disease.

A world of hurt: failure to achieve treatment goals in patients with gout requires a paradigm shift

Background: Gout continues to be underdiagnosed and poorly managed despite the potential for cure. US and European management guidelines recommend treating to target serum urate (sUA) levels of <6 mg/dL (or <5 mg/dL to durably improve severe symptoms), with use of regular sUA monitoring, but studies suggest relatively poor adherence to these recommendations. This study investigates the real-world state of gout management in the United States by describing the characteristics of a large patient population treated in primary care and rheumatology settings. Methods: A retrospective chart audit, conducted among 124 primary care physicians and 125 rheumatologists, included 1245 patients with gout. Physicians completed structured case report forms capturing 12 months of sUA laboratory values, flare counts, comorbidities, types and doses of treatment, treatment duration, diagnosis date, physician specialty and socio-demographic factors. Focusing on the xanthine oxidase inhibitors (n = 858), descriptive statistics and multivariate models characterized relationships between patient characteristics, disease control, and treatment. Results: Only 83 (11%) patients achieved disease control, defined as a 12-month average sUA ≤6 mg/dL, no flares, and no tophi. Patients with greatest disease severity (defined as sUA >6 mg/dL, ≥2 flares per year, and tophi) were more likely to have kidney disease and other comorbidities. In a multivariate model, predictors of more severe gout were rheumatologist (vs primary care) management, febuxostat (vs allopurinol) use and presence of comorbid conditions. Conclusion: Our findings confirm the inadequacy of gout management in the real-world setting. Regular monitoring, including sUA measurement as recommended in guidelines, is important to assess gout control. Our analyses also demonstrate that patients with more severe gout are more likely to have comorbid conditions, be treated by a specialist and use newer therapies.

Efficacy and safety of an intensified schedule of tremelimumab for chemotherapy-resistant malignant mesothelioma: an open-label, single-arm, phase 2 study

CTLA4 blockade by tremelimumab 15 mg/kg every 90 days provided preliminary evidence of activity in patients with pretreated malignant mesothelioma; however, retrospective exposure-response analysis of data from patients with melanoma suggested that this schedule could result in underexposure to tremelimumab. We therefore investigated the efficacy and safety of an intensified schedule of tremelimumab in patients with advanced malignant mesothelioma. In this open-label, single-arm, phase 2 study, participants aged 18 years or older with unresectable, advanced malignant mesothelioma (measurable in accordance with the Response Evaluation Criteria in Solid Tumors [RECIST]), a life expectancy of 3 months or more, an Eastern Cooperative Oncology Group performance status of 2 or less, and who had failed a first-line platinum-based regimen were enrolled at the University Hospital of Siena, Siena, Italy. Participants received tremelimumab 10 mg/kg once every 4 weeks for six doses, then every 12 weeks until disease progression, unacceptable toxic effects, or refusal to continue treatment. The primary endpoint was the proportion of patients achieving an immune-related objective response (complete or partial), assessed in all patients who received at least one dose of the study drug. This study is registered with the European Union Clinical Trials Register, number 2012-002762-12, and ClinicalTrials.gov, number NCT01655888. Between July 30, 2012, and July 15, 2013, we enrolled 29 patients with a median age of 65 years (range 42-78), stage III (n=11) or IV (n=18) disease, and an Eastern Cooperative Oncology Group performance status of 0-1 (n=23) or 2 (n=6). Malignant mesothelioma histology was epithelioid (n=21, including one peritoneal), biphasic (n=6), sarcomatoid (n=1), or undefined (n=1). Patients received a median of six doses of tremelimumab (range 1-13). After a median follow-up of 21·3 months (IQR 18·7-25·9), four immune-related-partial responses were recorded, one at the first tumour assessment (after about 12 weeks) and three at the second tumour assessment (about 24 weeks), with two responses occurring after initial progressive disease and one response after initial stable disease. 15 (52%) of patients achieved disease control, with a median duration of 10·9 months (95% CI 8·2-13·6). According to modified RECIST, one patient (3%) achieved a partial response and 11 (38%) patients achieved disease control rate. Grade 1-2 treatment-related adverse events occurred in 26 (90%) patients and grade 3-4 adverse events in two (7%) patients. The most common treatment-related adverse events were gastrointestinal, dermatological, and fever. Our results suggest that the intensified schedule of tremelimumab investigated seems to have clinical and immunological activity in patients with advanced malignant mesothelioma, and a good safety profile. The same intensified schedule is now being investigated in an ongoing randomised, double-blind, placebo-controlled, phase 2b study. Associazione Italiana per la Ricerca sul Cancro, Istituto Toscano Tumori, and MedImmune.

Trabectedin in combination with doxorubicin for first-line treatment of advanced uterine or soft-tissue leiomyosarcoma (LMS-02): a non-randomised, multicentre, phase 2 trial

Metastatic leiomyosarcomas of uterine or soft-tissue origin have poor prognosis and moderate chemosensitivity. Trabectedin has shown activity in pretreated leiomyosarcoma. We did a single-group, multicentre, phase 2 trial (LMS-02) to assess the effect of first-line doxorubicin and trabectedin combination on disease control and survival. Adults (18 years to physiological age ≤70 years) with measurable metastatic or unresectable uterine leiomyosarcoma or soft-tissue leiomyosarcoma who had not received any previous chemotherapy were enrolled at 19 centres in France. Treatment consisted of 60 mg/m(2) intravenous doxorubicin followed by 1·1 mg/m(2) trabectedin in a 3 h intravenous infusion on day 1, both by the central venous route, and 6 mg subcutaneous pegfilgrastim on day 2, repeated every 3 weeks for up to six cycles. Surgery for residual disease was permitted. The primary endpoint was the proportion of patients achieving disease control, defined as complete or partial response or stable disease. Stratification was done by anatomical site and analyses were per protocol. This study is registered with ClinicalTrials.gov, number NCT02131480. Between July 28, 2010, and May 10, 2013, 109 patients were enrolled and treated, of whom 108 were assessable for response: 47 in the uterine leiomyosarcoma group and 61 in the soft-tissue leiomyosarcoma group. 32 (68%) patients in the uterine leiomyosarcoma group and 45 (74%) in the soft-tissue leiomyosarcoma group received all six cycles of treatment. Of 47 patients with uterine leiomyosarcoma, 28 (59·6%, 95% CI 44·3-73·6) achieved a partial response and 13 (27·7%, 15·6-42·6) stable disease; 41 (87·2%, 74·3-95·2) patients achieved disease control. Of 61 patients with soft-tissue leiomyosarcoma, two (3·3%, 95% CI 0·4-11·7) achieved a complete response, 22 (36·1%, 25·0-50·8) had a partial response, and 32 (52·5%, 40·8-67·3) had stable disease; 56 (91·8%, 81·9-97·3) of patients achieved disease control. The most common grade 3-4 treatment-associated adverse events were neutropenia (84 [78%] of 108 patients), increased alanine aminotransferase concentration (42 [39%]), thrombocytopenia (40 [37%]), anaemia (29 [27%]), febrile neutropenia (26 [24%]), and fatigue (21 [19%]). Despite expected but manageable toxic effects, these results support the activity of doxorubicin plus trabectedin as first-line treatment for uterine leiomyosarcoma and soft-tissue leiomyosarcoma. This combination should be developed further in a phase 3 trial against the present standard of care. Pharmamar and Amgen.

Retention of Platinum Sensitivity till Late Stages of Tumour Progression May Imply Improved Prognosis of Oesophageal and Gastric Cancers

Background: We report on the outcomes of patients with metastatic oesophago-gastric (OG) cancer progressing after first-line platinum-based chemotherapy (PBCT) who received a re-challenge schedule of PBCT (r-PBCT) as second-line therapy. Patients and Methods: Patients with metastatic OG cancer treated with first-line PBCT (n = 138) between January 2009 and June 2013 were selected for the purpose of the study. Treatment-related outcomes were assessed including response rates, progression-free survival (PFS) and overall survival (OS). Results: 43 (32%) patients progressed (group A: platinum resistant (PR)) and 95 (68%) patients showed a response (group B: platinum sensitive (PS)) or had stable disease after first-line PBCT. Approximately 20% (9/43) of the patients in group A received second-line chemotherapy compared to 50% (38/80) in group B. Most patients (39/47) received r-PBCT, and the remaining patients (8/47) were treated with irinotecan-based chemotherapy. More than 50% (20/39) of the patients achieved disease control, with median PFS and OS of 3 months (95% confidence interval (CI) = 2.0-4.0 months) and 5.7 months (95% CI = 4.7-6.7 months) after commencement of r-PBCT. The actuarial median OS of patients responding to second-line or second and third lines of r-PBCT was 26.7 and 30.1 months, respectively. Conclusion: In platinum responders, r-PBCT appears to be an appropriate second-line option with survival outcomes comparable to those of other agents.

ET-30 * A PHASE I TRIAL OF AZD7451, A TROPOMYOSIN-RECEPTOR KINASE (TRK) INHIBITOR, FOR ADULTS WITH RECURRENT GLIOBLASTOMA MULTIFORME (GBM)

BACKGROUND: We have shown that inhibition of TrkA both genetically and pharmacologically results in profound inhibition of glioma stem cell migration in vitro and in vivo. AZD7451 is the first in class of highly potent and selective Trk inhibitors and therefore may have significant anti-glioma cell invasive properties. METHODS: We conducted an open label phase I study of AZD 7451 mesylate, with a standard 3 + 3 dose escalation scheme, to determine the MTD and describe pharmacokinetics. The drug was administered as an oral solution (10 mg/ml) at 12 mg, 24 mg, 40 mg, and 60 mg daily. DL3 and DL4 were administered with divided twice daily dosing. Plasma concentrations of AZD7451 were measured with ultra-performance liquid chromatography and tandem mass spectrometry using samples obtained at baseline and various points through the first 4 week cycle of therapy. RESULTS: 14 patients were enrolled. There were no radiographic responses to therapy, and no patients achieved disease control beyond cycle 2. There were no DLTs. Unexpected treatment related toxicities included grade 1-2 thrombocytopenia and anemia. No neurological adverse events related to therapy were observed. All patients were evaluable for C1D1 pharmacokinetics. The majority of samples were below the limit of quantitation (LLOQ) of 0.5 ng/mL by ∼ 4 h post-dose. AZD7451 T1/2 ranged from 20-50 min with once daily or BID dosing. No statistically significant increases in CMAX, AUCINF, T1/2, or volume of distribution were observed as dose increased. CONCLUSIONS: Based on the interim PK analysis for AZD7451 indicating poor oral bioavailability, short <60 min plasma T1/2 half-life, and rapid clearance kinetics, PK exposures are insufficient in humans to inhibit Trk at target plasma concentrations necessary for efficacy in preclinical models. The absence of DLT's or early efficacy signals in GBM patients is also consistent with poor AZD7451 exposures in humans.

Aset Study: Final Results of Patients with Locally Recurrent or Metastatic Renal Cell Carcinoma (Rcc) Treated with Mgn1601

ABSTRACT Aim: Allogeneic tumor cells gene-modified via MIDGE® vectors to express IL-7, GM-CSF, CD80, and CD154, immunomodulated with dSLIM® constitute the therapeutic cancer vaccine MGN1601, whose safety, immunological effects, and clinical efficacy were assessed in heavily pre-treated patients with RCC. Methods: The multicenter, single-arm phase 1/2 ASET study consisted of 8 vaccinations over 12 weeks during the treatment phase (TP). Following re-evaluation, patients with at least disease stabilization entered an extension phase (EP, 5 vaccinations until week 120). Overall, 19 patients were included and received at least one MGN1601 injection (ITT); 17 had ≥3 lines of previous therapy. Results: The TP was completed by 10 of 19 patients (53%) per-protocol (PP). Only 9.2% (10/109) of adverse events were drug-related and no drug-related serious adverse event was reported. Two patients achieved disease control after TP and continued in EP: One had PD after 48 weeks, the other remained in sustained partial response for over 120 weeks. Median OS was 24.8 weeks for ITT and 115.3 weeks for PP. Analysis of baseline characteristics revealed absolute lymphocyte counts, neutrophil to lymphocyte ratios, platelets, MSKCC score, and liver metastasis as putative predictive factors of longer overall survival. Immunological analyses revealed improved immune function during MGN1601 treatment: Patients' PBMC showed a significant increase in IL-2 secretion in 7 of 10 analyzed patients upon stimulation with recall antigens. Re-stimulation of patients' PBMC with MGN1601 cells or peptide mixes of tumor associated antigens resulted in >2-fold increase of IFN-gamma secreting cells in 4 of 9 patients. Four of 5 patients showed an increase of single activation marker and all 5 patients developed vaccine cell binding antibodies. Conclusions: Administration of MGN1601 was safe, improved patients' immune function and showed promising OS in a subgroup of heavily pretreated RCC patients who could receive therapy over 12 weeks (PP population). These results warrant further evaluation in a larger, controlled trial. Baseline biomarkers may allow identifying patients more likely to benefit from this vaccination. Disclosure: K. Kapp: is an employee of Mologen AG; M. Schroff: is CEO of Mologen AG; M. Schmidt: is an employee of Mologen AG; B. Wittig: has share ownership in Mologen AG and has received research funding from Mologen AG. All other authors have declared no conflicts of interest.

ASET study: Long-term follow-up data of patients with metastatic renal cell carcinoma treated with MGN1601.

LBA399 Background: The cell-based therapeutic cancer vaccine MGN1601 is a fixed combination of allogeneic tumor cells modified via MIDGE vectors to express IL-7, GM-CSF, CD80, and CD154 plus the immunomodulator dSLIM. In the ASET trial heavily pretreated patients with metastatic renal cell carcinoma (mRCC) were enrolled to assess safety, immunological effects, and clinical efficacy of MGN1601. Methods: The ASET study was a multicenter, single-arm phase 1/2 study. The treatment phase consisted of 8 intradermal vaccinations over 12 weeks. Following evaluation, patients with at least disease stabilization entered an extension phase (EP, 5 vaccinations over 120 weeks). Overall, 19 patients were included and received at least one MGN1601 injection (ITT); the majority (N=17) had ≥3 lines of previous therapy. Results: Of 19 patients, 10 (55%) completed the treatment phase per-protocol (PP); 9 patients discontinued the study due to disease progression (PD) or rapid deterioration. Overall, 110 adverse events were documented (grade 1-2: 80.9%) of which only 10 (9.1%) were drug-related. No drug-related serious adverse event was reported. PBMCs from patients increased cytokine secretion after re-stimulation with standard antigens, confirming an improved cellular immune function. Two patients achieved disease control (PR, SD) after 12 treatment weeks and continued in the extension phase: One patient had PD after 60 weeks, the other remains in sustained partial remission after completion of the EP. Median overall survival (OS) was 24.8 weeks in the ITT population and 115.3 weeks in the PP population. Univariate analysis of pre-treatment characteristics revealed absolute lymphocyte counts, neutrophil to lymphocyte ratios, platelets, MSKCC score, and liver metastasis as putative predictive factors of longer overall survival. Conclusions: MGN1601 administration was safe and showed promising OS in a population of heavily pretreated RCC patients who could receive therapy over 12 weeks (PP population). These results warrant further evaluation in a larger, controlled clinical trial. Baseline biomarkers and factors may allow identifying patients more likely to benefit from this innovative vaccination approach. Clinical trial information: NCT01265368.