Terms Of Disease Control Rate Research Articles

Safety and Efficacy of Lenvatinib in Very Old Patients with Unresectable Hepatocellular Carcinoma.

Data concerning the use of lenvatinib in very old patients (≥ 80years) are limited, although the incidence of hepatocellular carcinoma (HCC) in this patient population is constantly increasing. This analysis aimed to evaluate the efficacy and safety of lenvatinib in a large cohort of very old patients (≥ 80years) with unresectable HCC. The study was conducted on a cohort of 1325 patients from 46 centers in four Western and Eastern countries (Italy, Germany, Japan, and the Republic of Korea) who were undergoing first-line treatment with lenvatinib between July 2010 and February 2022. Patients were stratified according to age as very old (≥ 80years) and not very old (< 80years). The median overall survival (OS) was 15.7 months for patients < 80years old and 18.4months for patients ≥ 80years old [hazard ratio (HR) = 1.02, 95% confidence interval (CI) 0.84-1.25, p = 0.8281]. Median progression free survival (PFS) was 6.3months for patients < 80years old and 6.5months for patients ≥ 80years old (HR = 1.07, 95% CI 0.91-1.25, p = 0.3954). No differences between the two study groups were found in terms of disease control rate (DCR; 80.8% versus 78.8%; p = 0.44) and response rate (RR; 38.2% versus 37.9%; p = 0.88). Patients < 80years old experienced significantly more hand-foot skin reaction (HFSR) grade ≥ 2 and decreased appetite grade ≥ 2. Conversely, patients ≥ 80years old experienced significantly more fatigue grade ≥ 2. In the very old group, parameters associated with prognosis were AFP, albumin-bilirubin (ALBI) grade, Barcelona Clinic Liver Cancer (BCLC), and Child-Pugh score. BCLC stage was the only independent predictor of overall survival (OS; HR = 1.59, 95% CI 1.11-2.29, p = 0.01115). Our study highlights the same efficacy and safety of lenvatinib between very old and not very old patients.

Is oligoprogression a potentially curable disease in epidermal growth factor receptor mutant lung adenocarcinoma?

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown impressive results in EGFR mutant lung cancer (LC) patients in terms of disease control rate with a positive impact on overall survival. Nevertheless, after months of treatment with targeted therapy, progression inevitably occurs. Some patients develop oligoprogression and local treatment is required for optimal disease control while maintaining EGFR-TKIs. This work features a clinical case of a patient harboring an EGFR mutant LC undergoing oligoprogression to EGFR-TKIs, first into the brain and afterward to the primary tumor, requiring local ablative strategies, including primary tumor resection three years after the start of osimertinib. Currently, the patient is still alive and continues with a complete response upon EGFR-TKIs maintenance. Hence, oligoprogression, even in driven oncogenic tumors, represents a distinct biological entity and potential curative disease that deserves particular consideration in multidisciplinary tumor boards. In this case, tumor primary resection after three years of the initial diagnosis represents a paradigm shift in the treatment of EGFR mutant patients.

Efficacy and safety of regorafenib plus biweekly TAS-102 for refractory metastatic colorectal cancer (REGTAS): A multicenter single-arm phase II trial.

e15567 Background: Both regorafenib and TAS-102 have shown significant, but limited survival benefits for metastatic colorectal cancer (mCRC) patients who progressed after standard treatments. Due to their unique mechanisms of action and non-overlapping toxicities, a preliminary phase I study (REMETY) has demonstrated that regorafenib combined with TAS-102 in a four-week standard schedule was feasible and safe, but at the cost of recommended phase II dose of TAS-102 being 25 mg/m2 BD. This study aimed to evaluate the efficacy and safety of biweekly TAS-102 plus regorafenib in refractory mCRC. Methods: REGTAS is a multicenter phase II trial involving patients with chemo-refractory mCRC. Prior treatment with 5-FU, oxaliplatin, irinotecan, anti-VEGF antibody and anti-EGFR antibody for RAS wild type was required. Regorafenib was administered at 120 mg/day for 21 days in a four-week cycle, or a dose-escalation strategy (80 mg/day, followed by weekly increase of 40 mg to 120 mg/day). TAS-102 was given biweekly (30mg/m2 BD, on Day 1-5). The primary endpoint was progression-free survival (PFS). The secondary endpoint included safety, disease control rate (DCR) and overall survival (OS). Results: From March 1st 2022 to December 31st 2022, 16 patients were enrolled form five centers. All patients received at least one cycle of treatment, and 13 patients had at least one evaluation. The median age was 56.5 years old including 9 (52.9%) males. 11 (68.7%) patients were enrolled within 18 months from diagnosis of mCRC. RAS and BRAF mutation were detected in 8 (50.0%) and 1 (6.3%) patients. Among 13 evaluable patients, 11 achieved SD and 2 had PD, with the DCR of 84.6% (95% CI: 54.6%-98.1%). The median PFS was 4.9 months (95% CI: 2.8-7.0). Twelve patients were alive, and the median OS was not reached. All patients experienced treatment-related adverse events (TRAEs) and 4 (25.0%) had grade 3 or higher TRAEs. No grade 5 TRAE occurred. The most common TRAEs of any grade were hand-foot syndrome (62.5%), hypertension (68.8%), fatigue (50.0%), neutropenia (43.8%), thrombocytopenia (31.3%) and alanine aminotransferase increased (25.0%). Conclusions: Regorafenib plus biweekly TAS-102 exhibited promising benefits in terms of DCR and PFS, and could be a novel treatment option for patients with refractory mCRC. The adverse events were generally tolerable and manageable. Further studies are needed to confirm these preliminary findings. Clinical trial information: The registration number is still under approval .

A phase Ib/II study of sotorasib combined with chemotherapy for second-line treatment of KRAS p. G12C–mutated advanced pancreatic cancer.

TPS4194 Background: Kirsten rat sarcoma viral oncogene homolog( KRAS) p.G12C mutation is an oncogenic driver mutation in several solid tumors. Sotorasib is a specific, irreversible, small molecule inhibitor of KRASG12C that has demonstrated durable clinical benefit in NSCLC, with mild and manageable toxicities. Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related death in the world, although recent advances in chemotherapeutic regimens for metastatic PDAC provide better clinical outcomes. KRAS p.G12C mutations are found in 1-2% of PDAC. Modest single agent activity of Sotorasib was observed in chemo-refractory PDAC patients (pts). Combination of Sotorasib with approved PDAC chemotherapy regimens is expected to enhance antitumor efficacy. This study is designed to evaluate safety, tolerability and efficacy of Sotorasib in combination with second line chemotherapy in pts with KRASp.G12C mutated advanced PDAC who have progressed on first-line chemotherapy. Methods: This investigator initiated study run through Hoosier Cancer Research Network, is a phase Ib/II study evaluating Sotorasib in combination with either Liposomal Irinotecan/5-Fluorouracil/Leucovorin or Gemcitabine/nab-paclitaxel. Physician choice of chemotherapy based on first line chemotherapy regimen used. Histologically confirmed PDAC pts who have KRAS p.G12C mutation identified through tumor or blood based testing, progressed on first-line chemotherapy, adequate organ function and performance status are eligible. A safety lead-in will be conducted to evaluate the safety of Sotorasib at a dose of 960 mg in combination with each of the two chemotherapy regimens. A “3+3” dose de-escalation design will be used for each combination separately. All patients treated at the RP2D in the initial safety cohort will be evaluable for response and included in the first stage of Simon’s two stage design. The phase II trial conducted at the RP2D follows Simon’s two-stage “minimax” design. The trial is designed to test whether addition of Sotorasib to chemotherapy will improve the objective response rate (ORR), from 16% to 31%. In Stage 1, 22 evaluable patients will be enrolled, and the trial will be stopped if 3 or fewer of the 22 evaluable patients respond. If ≥ 4 responses are observed, an additional 28 patients will be enrolled in Stage 2, for a total of 50 evaluable patients. Up to 59 subjects will be enrolled across 15 academic cancer institutions in order to obtain the required number of 50 evaluable subjects, assuming 15% attrition rate. Primary endpoint is to determine the objective response rate (ORR) by RECIST 1.1. The secondary endpoint to evaluate safety, and further evaluate efficacy in terms of disease control rate, duration of response, progression-free survival and overall survival. Correlative endpoints will determine biomarkers based on analysis of blood and/or tumor on study. Clinical trial information: IND 159412.

Immunotherapy and chemo-immunotherapy for non–small cell lung cancer with novel actionable oncogenic driver alterations.

9057 Background: Immune checkpoint inhibitors (IO) single agent or in combination with platinum chemotherapy (CT-IO) are standard of care for Stage IV non-small cell lung cancer (NSCLC) according to PD-L1 expression. While the efficacy of IO among patients (pts) with common EGFR and ALK alterations appears to be limited, its activity in pts with novel oncogenic drivers alterations is not well characterized. Compared to non-oncogene-addicted NSCLC, the overall response rate (ORR) seems to be similar in BRAF and c-MET altered NSCLC, lower in RET altered NSCLC, while data are less consistent in HER2 and EGFR exon 20 (EGFRex20) altered NSCLCs. Methods: From January 2016 to January 2022, we retrospectively enrolled pts with Stage IV NSCLC that received IO or combination CT– IO in any line, ECOG PS 0 - 2 and detection of MET exon 14 skipping mutations (METex14), BRAF mutations (V600E or non-V600E), RET rearrangement, HER2 point mutations (HER2mut)/exon 20 insertions (HER2ex20) or uncommon EGFR mutations (uEGFRmut)/EGFRex20. A review of clinicopathologic and molecular features and an analysis of response to combination or single-agent IO were conducted. Results: Among sixty-four pts enrolled, 20 (31%) had METex14, 19 (30%) had EGFR alterations [12 (19%) EGFRex20, 7 (11%) uEGFRmut], 8 (12%) had BRAF mutation (3 V600E and 5 non-V600E), 13(20%) had HER2 alterations [7 (11%) HER2ex20, 6 (10%) HER2mut] and 4 (6%) were RET rearranged. 43 received IO single agent and 21 received CT-IO. With a median follow up of 22 months (m), median progression free survival (mPFS) was 5.40 m (0.95 CI 4.73-6.9) overall, 6.77m in CT-IO arm (0.95 CI 5.37-NA) and 5.10m in IO arm (0.95 CI 2.60-6.7), with a trend to better mPFS for CT-IO (p 0.054). Regarding specific mutations irrespectively from treatment arm, NSCLC harboring METex14 showed a mPFS of 5.33 m (0.95 CI, 2.30-13.9), BRAF 9.9 m (0.95 CI, 6.70-NA), EGFR 4.93 m (0.95 CI, 1.80-6.9), HER2 11.4 (0.95 CI, 4.2-NA), RET 5.28 (0.95 CI, 1.42-NA). Disease control rate (DCR) was better in the CT-IO arm vs IO one in the overall population (84.2% vs 50%, p 0.013). Conclusions: Novel driver alterations seem to show a benefit from IO treatments. CT-IO seems to have a better outcome in terms of DCR. Therefore, IO-based treatment should be evaluated also in tumors harboring novel driver alterations. [Table: see text]

Hepatic Arterial Infusion of Chemotherapy for Advanced Hepatobiliary Cancers: State of the Art.

Simple SummaryLiver functional failure is one of the leading causes of cancer-related death. Systemic chemotherapy usually offers a modest benefit in terms of disease control rate, progression-free survival, and overall survival at the cost of a significant percentage of adverse events. Liver malignancies are mostly perfused by the hepatic artery while the normal liver parenchyma by the portal vein network. On these bases, the therapeutic strategy consisting of hepatic arterial infusion of chemotherapy takes place. This review aims to summarize the current knowledge on this approach from different points of view, such as techniques, drugs pharmacology and pharmacokinetics, and clinical outcomes for advanced hepatobiliary cancers. Most of the collected studies have several limitations: non-randomized retrospective design, a relatively small number of patients, the hepatic arterial administration of different chemotherapeutic agents, as well as its combination with a great heterogeneity of systemic agents. However, despite these limitations, the presented data show favorable results in terms of safety and efficacy for hepatic arterial infusion of chemotherapy, with respect or in alternative to the gold standard treatment, even when they are combined with systemic treatments. Therefore, this therapeutic strategy may be an alternative or an integrative treatment option for advanced hepatobiliary cancers. Further and larger prospective, randomized, multi-center studies, with well-defined inclusion criteria and treatment strategies, are required to confirm the presented data.Liver functional failure is one of the leading causes of cancer-related death. Primary liver tumors grow up mainly in the liver, and thus happens for liver metastases deriving from other organs having a lower burden of disease at the primary site. Systemic chemotherapy usually offers a modest benefit in terms of disease control rate, progression-free survival, and overall survival at the cost of a significant percentage of adverse events. Liver malignancies are mostly perfused by the hepatic artery while the normal liver parenchyma by the portal vein network. On these bases, the therapeutic strategy consisting of hepatic arterial infusion (HAI) of chemotherapy takes place. In literature, HAI chemotherapy was applied for the treatment of advanced hepatobiliary cancers with encouraging results. Different chemotherapeutic agents were used such as Oxaliplatin, Cisplatin, Gemcitabine, Floxuridine, 5-Fluorouracil, Epirubicin, individually or in combination. However, the efficacy of this treatment strategy remains controversial. Therefore, this review aims to summarize the current knowledge on this approach from different points of view, such as techniques, drugs pharmacology and pharmacokinetics, and clinical outcomes for advanced hepatobiliary cancers.

Differential response rates in early-phase cancer clinical trials (EPCCT).

3133 Background: The primary objective of EPCCT (phase I and non-randomised phase II trials) is to determine the safety and tolerability of new therapeutic agents. Response rates (RR) in these trials have typically been reported at around 10-15%. Increasingly RR and survival outcomes are now investigated in EPCCT as primary or secondary objectives. Methods: Retrospective data analysis was performed on patients (pts) enrolled onto an EPCCT between January 2018 and December 2019 at The Christie NHS Foundation Trust, UK. Data on demographics, prior systemic treatment, sites of disease, performance status, comorbidities, types of therapy, RR, progression free survival (PFS), and overall survival (OS) were collected. Statistical analyses were performed with univariable and multivariable models. Objective response rate (ORR) was defined as the proportion of pts with complete response (CR) and partial response (PR). Duration of response (DOR) was from initial response to progressive disease (PD). Disease control rate (DCR) was defined as CR+PR+ stable disease (SD). Results: A total of 247 pts were treated across 46 EPCCTs. Median age 61 years; 57% female. Sixty-six percent of pts had ≥2 lines of treatment and the majority were ECOG PS 0/1 (98%). Eighty-one percent of pts had ≥2 sites of metastatic disease, and 13 major tumour types were included. Monotherapy trials (159 pts) were predominantly targeted therapies (TT; 60%), or immunotherapies (IO; 20%). Combination therapy trials (88 pts) were TT-based (68%) or IO-based (32%). Data for RR analyses was available for 231 pts. ORR across all trials was 15% (CR 2%) and DCR was 63%. The median DOR was 8.3 months (mos) (95% CI: 7.0 – 9.7) with 28% of pts responding for &gt;6 mos and 7% for &gt;12 mos. ORR in pooled IO treated pts was 27%, DCR was 65% with sustained response &gt;6 mos seen in 37% of these pts. ORR in pooled TT treated pts was 9.4%, DCR was 60% and sustained response &gt; 6 mos seen in 25% of pts. ORR for IO v TT treated pts was significantly different, p=0.007 (pearson chi square), but no significant difference was seen for DCR. Median PFS for all patients was 5.0 mos (95% CI: 4.1 – 6.0) and OS was 10.4 mos (95% CI: 8.4 – 13.0). OS for those with a PR is not reached (HR for PR v PD, 0.006 (95% CI: 0.002 – 0.18). Pts with SD appear to have significantly better OS compared to those with PD (14.6 v 4.2 mos, HR 0.2 (95% CI: 0.1 – 0.3). Multivariable Cox proportional hazards analysis for OS was significant for male gender (HR 1.9, p=0.002), presence of liver metastasis (HR 2.0, p=0.001), low Hb (HR 0.8, p=0.03) and log (LDH) (HR 1.9, p&lt;0.001). Conclusions: Two-thirds of pts enrolled on EPCCTs benefitted in terms of DCR with significant OS improvement in those with PR and SD. Higher ORR were seen in pts receiving IO-based treatments however DCR was similar in IO and TT pts. Gender, presence of liver metastases, Hb count and LDH level contributed significantly to survival differences.

Efficacy and safety of domestic and imported gefitinib in patients with advanced non-small cell lung cancer.

Gefitinib is a first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It was approved by the U.S. Food and Drug Administration (FDA) for clinical use in 2003. However, gefitinib has only come to China in recent years. Previous studies have not compared the efficacy and safety of domestic and imported gefitinib. Therefore, we conducted this study. This study included 227 patients with advanced non-small cell lung cancer (NSCLC) who received gefitinib treatment in four medical institutions: The First Affiliated Hospital of USTC, Division of life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Fudan University Shanghai Cancer Center, Shandong Provincial Institute of Cancer Prevention and Jiangsu Cancer Hospital, from January 2017 to July 2018. The patients were divided into a Yiruike group (55 patients treated with domestic gefitinib, Yiruike) and an Iressa group (172 patients treated with imported gefitinib, Iressa). Because gefitinib resistance usually occurs within 8-10 months of gefitinib administration, the patients were followed up for one year to observe their conditions and compare the occurrence of adverse reactions between the two groups. The two groups had no significant difference in baseline data. The median progression-free survival (PFS) of Yiruike group and that of Iressa group were 10.270±2.036 and 12.970±1.634 months, respectively. The mean PFS of Yiruike group and that of Iressa group were 12.598±1.083 and 15.958±0.987 months, respectively. The one-year disease control rate (DCR) of Yiruike group and that of Iressa group were 61.8% and 59.3%, respectively. The differences were all insignificant (P>0.05). The incidence of adverse reactions in these two groups were not significantly different. Yiruike was slightly superior to Iressa in terms of DCR. However, comparisons of bioequivalence and DCR were not sufficient for evaluating a drug. Other comparisons require long-term follow-up studies with a large sample size.

Immunotherapy in advanced Non-Small Cell Lung Cancer patients with poor performance status: The role of clinical-pathological variables and inflammatory biomarkers

BackgroundThe introduction of immunotherapy has improved the prognosis of patients with Non-Small Cell Lung Cancer (NSCLC). However, data in poor ECOG Performance Status (PS) patients remain scant due to their exclusion from randomized trials. Material and methodsWe analyzed data of patients with advanced NSCLC treated with immunotherapy in two Italian Centers, to evaluate the impact of PS (0-1 vs 2) on disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Chi-square test was used to compare clinical-pathological variables, their impact on survival was evaluated through Cox proportional hazard models. ResultsAmong 404 patients included, PS was 0 in 137 (33.9 %), 1 in 208 (51.5 %) and 2 in 59 (14.6 %) patients; 143 were female and 90 had squamous NSCLC. Clinical-pathological variables were uniformly distributed except for higher prevalence of liver metastases in patients with poor PS. We found that PS2 patients showed worse outcomes in terms of DCR (21.8 % vs 50.3 %, p = 0.001), PFS [2.0 (95 % CI 1.6–3.0) vs 3.0 (95 % CI 2.7–4.0) months, p < 0.0001] and OS [4.0 (95 % CI 2.8–5.7) vs 13.2 (95 % CI 11.0−15.8) months, p < 0.0001]. PS2 status, negative PDL1 expression and early corticosteroids exposure as well as higher Neutrophil to Lymphocyte Ratio and LDH at baseline were associated with worse outcomes at univariate and multivariable analysis. Subgroup analysis confirmed poor outcomes in PS2 patients with high LDH and concomitant corticosteroid therapies. The incidence of Grade 3/4 adverse events was 11.3 % in PS 0−1 and 10.2 % in PS 2 patients (p = 0.81). ConclusionOur data confirm reduced efficacy of immunotherapy in patients with poor PS even though a good safety. Despite PS remains the most powerful independent prognostic factor for NSCLC, LDH levels and steroids exposure could support the decision making in PS2 patients.

The Efficacy and Safety of Regorafenib in Combination With Anti-PD-1 Antibody in Refractory Microsatellite Stable Metastatic Colorectal Cancer: A Retrospective Study

BackgroundMicrosatellite stable (MSS) or mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is resistant to immune checkpoint inhibitors. However, a recent Japanese trial showed that regorafenib plus nivolumab had encouraging anti-cancer activity in MSS or pMMR mCRCs.Materials and MethodsWe retrospectively reviewed the efficacy and safety data of combination therapy with regorafenib plus anti-PD-1 antibody in patients with refractory MSS or pMMR mCRC in the medical centers of Shandong Province in China.ResultsTwenty-three patients with MSS or pMMR mCRC received regorafenib plus anti-PD-1 antibody. Eighteen (78.3%) patients experienced stable disease as best response, five (21.7%) patients had progressive disease, and no partial response was observed. The disease control rate (DCR) was 78.3% (18/23), and the median progression-free survival (PFS) was 3.1 months (95% CI, 2.32-3.89). Four of five (80.0%) patients with progressive disease had baseline liver metastasis, while nine of 18 (50.0%) patients with stable disease displayed no liver metastasis. One patient receiving radiofrequency ablation treatment for liver and abdominal wall metastases prior to combination treatment experienced a remarkably prolonged PFS of 9.2 months with SD. Neither liver metastasis status nor previous exposure to regorafenib was associated with treatment outcome. Treatment-related grade 3 toxicities were observed in 5/23 (21.7%) patients.ConclusionNo objective response was observed with the combination of regorafenib plus anti-PD-1 antibody, suggesting its little clinical activity in unselected Chinese patients with pMMR/MSS mCRC. Meanwhile, it exhibited some potential benefit in this cohort in terms of DCR and PFS. Adverse events were generally tolerable and manageable. Prospective studies with large sample sizes are needed to verify the findings. This combination strategy plus local ablative therapy might be worthy of further exploration.

Analysis of pemetrexed-based chemotherapy in the treatment of advanced colorectal cancer.

BackgroundIn this study, we evaluated the therapeutic efficacy and toxicity profile of chemotherapy combinations containing pemetrexed for patients with metastatic colorectal cancer. We investigated the optimal chemotherapy treatment regimen to provide a new option for third-line or after treatment of patients with advanced colorectal cancer.MethodsA total of 88 eligible patients with metastatic colorectal cancer were included in this study from April 2009 to March 2019 at the Department of Oncology, the First Affiliated Hospital of Nanjing Medical University. The baseline information and treatment outcomes of the patients were collected. Statistical analyses of different chemotherapy regimens focusing on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and toxicity were conducted. The superior treatment regimen was determined, and its clinical outcomes were compared with those of the other treatment combinations to explore the factors that potentially contributed to the curative effect.ResultsThe 88 patients in this study received 18 treatment regimens. In total, 53 patients had progressive disease (PD), 34 patients had stable disease (SD), 1 patient was assessed as complete response (CR), and no patients had a partial response (PR). The optimal regimen was pemetrexed + S-1 + bevacizumab. The 21 patients treated with this regimen exhibited a higher DCR [61.90% vs. 32.84%, odds ratio (OR) =3.324; 95% confidence interval (CI): 1.201–9.196, P=0.018] than patients treated with the other chemotherapy regimens. Moreover, the median PFS of this regimen was 4.57 (2.62–6.51) months, which was significantly longer [hazard ratio (HR) =0.566; 95% CI: 0.330–0.971, P=0.039] than the 2.57 (2.18–2.95) months of the other regimens. In terms of toxicity, leukopenia (34.1%) and neutropenia (34.1%) had the highest incidence of all-grade adverse events (AEs). Grade 3–4 AEs included neutropenia (15.9%), leukopenia (11.4%), thrombocytopenia (2.3%), and anemia (1.1%).ConclusionsThe combination of pemetrexed + S-1 + bevacizumab was found to be the optimal treatment regimen. This combination was superior to the other treatment regimens in terms of DCR and PFS with controllable toxicity. These results warrant further prospective exploratory clinical trials for pemetrexed-based chemotherapy in metastatic colorectal cancer.

Oligorecurrence Non-small Cell Lung Cancer After Failure of First-Line Chemotherapy: Computed Tomography-Guided 125I Seed Implantation vs. Second-Line Chemotherapy.

Purpose: To compare the efficacy and safety of computed tomography (CT)–guided 125I seed implantation with second-line chemotherapy in treatment of oligorecurrence non–small cell lung cancer after failure of first-line chemotherapy.Methods: Data of oligorecurrence non–small cell lung cancer patients after failure of first-line chemotherapy at two institutions were retrospectively reviewed from January 2013 to July 2018. A total of 53 patients who received the treatment of 125I seed implantation or second-line chemotherapy were eligible for this study. In group A, 25 patients, 84 lesions, received CT-guided permanent 125I seed implantation, whereas in group B, 28 patients, 96 lesions, received second-line chemotherapy. The outcomes were measured in terms of disease control rate, overall survival, quality of life, and complications.Results: The median follow-up period was 13 months (range, 5–42 months). Disease control rate in group A was higher than that in group B (70.8 vs. 42.3%, P = 0.042) at 6 months after treatment. The median overall survival was 12.8 months (95% confidence interval, 10.5–15.1 months) in group A and 15.2 months (95% confidence interval, 12.2–18.2 months) in group B, with no significant difference (P = 0.847). Since the fourth month, the number of patients in group A with a non-decreasing Karnofsky Performance Scale score was more than that in group B (P < 0.05). The incidence of grade 3 or higher complications especially hematologic toxicity in group A was significantly lower than that in group B (P < 0.05).Conclusion: Radioactive 125I seed implantation is safe and feasible in selected non–small cell lung cancer patients with oligorecurrence after failure of first-line chemotherapy and seems to provide a better long-term quality of life in these patients compared with second-line chemotherapy.

748P - Multicentric prospective study of validation of angiogenesis-related gene polymorphisms in HCC patients treated with sorafenib: Final results of INNOVATE study

BackgroundIn two retrospective studies we analyzed endothelial-derived nitric oxide synthase (eNOS) and angiopoietin-2 (ANGPT2) polymorphisms, and patients with eNOS-786CC+TC genotype and ANGPT2rs55633437 GG genotypes had significantly higher median PFS and OS compared to those with other genotypes. On the basis of these preliminary results, our aim was to validate in a prospective study these data in patients with HCC treated with sorafenib (S). MethodsThe primary outcomes were PFS. 160 total sample size was planned with the aim to confirm a HR of 0.58. Event-time distributions were estimated using the Kaplan-Meier method and survival curves were compared using the log-rank test Results165 patients were prospectively enrolled in the study between 03/2015 and 06/2018. Median OS was 13.1 months and median PFS was 4.2 months. We confirmed that eNOS-786CC+CT genotype was significantly associated with a higher median PFS (2.4 vs 5.9 months, HR 0.43, 95% CI 0.26-0.70 p=0.0007) and OS (15.7 vs 8.6 months, HR 0.38, 95% CI 0.24-0.60 p<0.0001) than the other genotypes. We did not confirm that ANGPT2rs55633437 GG genotypes were significantly associated with a lower median OS (p=0.55) and PFS (p=0.13). No differences were found between eNOS-786 TTand eNOS-786 CT/CCgenotypes in terms of disease control rate and best response. No correlations were found between eNOS polymorphisms and toxicity. Following adjustment for clinical covariates positive in univariate analzsis, multivariate analysis confirmed eNOS as the only independent prognostic factor predicting OS (p=0.0072). After progression to S in all population we highlight that patients with the eNOS-786CC+CT genotype was significantly associated with a lower median OS (HR 0.56, p=0.03) and a trend was found for patients treated with regorafenib (HR 0.13 p=0.057). ConclusionsOur Italian multicenter, prospective study met its primary and secondary end points, and we confirmed that eNOS-786CC+CT genotype may be capable of identifying a subset of HCC patients who have a higher median OS and PFS. For the first time in ten years of sorafenib research our study confirms the prognostic role of a biological marker in a prospective study. Clinical trial identificationNCT02786342. Legal entity responsible for the studyUniversity of Modena. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Therapeutic efficacy comparison of six major EGFR-TKIs in non-small-cell lung cancer patients with an activating EGFR mutation: A network meta-analysis.

e20671 Background: EGFR-TKIs are the standard in the first line treatment for patients with advanced NSCLC with EGFR activating mutations.This network meta-analysis was undertaken to compared all the EGFR-TKIs in terms of PFS, overall survival (OS), objective response rate (ORR) and disease control rate (DCR). Methods: The PubMed and Embase databases were screened for relevant studies. We extracted data of ORR, DCR, PFS, and OS from enrolled studies and performed multiple treatment comparisons based on bayesian network meta-analysis. Due to the differences in design of each clinical study, two rounds of analysies were performed. We first compared the therapeutic efficacy of the first-generation TKIs (erlotinib and gefitinib), second-generation TKIs (afatinib or dacomitinib) and third-generation TKIs based on A7471028, ARCHER 1009, LUX-Lung 7, ARCHER 1050 and FLAURA studies. The following comparison between first-generation TKIs (gefitinib, erlotinib and icotinib) and second-generation TKIs was performed based on ICOGEN, A7471028, ARCHER 1009, WJOG 5108L, CTONG 0901, LUX-Lung 7 and ARCHER 1050 studies. Results: Eight trials with 2154 patients and 6 TKIs (gefitinib, erlotinib, icotinib, afatinib, dacomitinib and osimertinib) were included. The first round analysis indicated that Osimertinib ranked best among all the TKIs in terms of DCR, 1y-PFS and 1y-OS. Afatinib ranked first among these similar agents with ORR. The second round analysis showed that second-generation TKIs had potentially better efficacy compared with first-generation TKIs. Icotinib seemed to work best in first-generation TKIs and ranked first among first- and second-generation TKIs in terms of 1y-OS. Conclusions: The third-generation TKIs had better therapeutic efficacy compared with the first-generation TKIs and the second-generation TKIs. However, the second-generation TKIs had better efficacy compared with first-generation TKIs. [Table: see text]

Phase II Brentuximab Vedotin Trial for Relapsed or Refractory High-CD30-Expressing Non-Hodgkin Lymphomas

Background: The treatment outcome of Brentuximab vedotin (BV) has not been related with CD30 expression in previous studies enrolling patients with a wide range of CD30 expression level. This study explored the efficacy of BV in high-CD30-expressing non-Hodgkin lymphoma (NHL) patients, excluding those with other than anaplastic large cell lymphoma (ALCL). As CD30 expression is associated with Epstein-Barr virus (EBV) infection and multiple myeloma oncogene-1 (MUM1) expression of tumor cells, we also performed a post-hoc analysis for their association with outcome of BV. Methods: This phase II study enrolled relapsed or refractory high-CD30-expressing NHL, other than ALCL, with BV administered intravenously at 1.8 mg/kg every 3 weeks. The primary endpoint was > 40% disease control rate, consisting of complete response (CR), partial response (PR), or stable disease, after a maximum of 16 cycles of BV. We defined high CD30 expression as ≥ 30% tumor cells positive for CD30 by immunohistochemistry. Findings: In total, 33 patients were enrolled, with diffuse large B-cell lymphoma (n=12), peripheral T-cell lymphoma (n=8), extranodal NK/T-cell lymphoma (n=7), primary mediastinal large B-cell lymphoma (n=3), transformed mycosis fungoides (n=2), and angioimmunoblastic T-cell lymphoma (n=1). The disease control rate was 48.5% (16/33) including six CR and six PR; six patients (4CR, 2PR) maintained their response over 16 completed cycles. Response to BV was not significantly associated with the extent of patients' CD30 expression. Over a median of 29.2 months of follow-up, the median progression-free and overall survival rates were 1.9 months and 6.1 months, respectively. Survival did not differ based on the extent of CD30 expression or subtype. The most common adverse events were fever (39%), neutropenia (30%), fatigue (24%), and peripheral sensory neuropathy (27%). Post hoc analyses of the associations between MUM1 and outcomes showed a higher response among MUM1-negative patients (55.6%, 5/9) compared with MUM1-positive patients (13.3%, 2/15). Interpretation: BV performance as a single agent was acceptable in terms of disease control rates and toxicity profiles in relapsed or refractory high-CD30-expressing NHL patients, especially MUM1-negative patients. MUM1 negativity may be a biomarker predicting response to BV. Clinical Trial Registration Number: (Clinicaltrials.gov identifier: NCT02280785) Funding Statement: Takeda Pharmaceutical Company Limited Declaration of Interests: The authors declare that they have no conflicts of interest. Ethics Approval Statement: The Institutional Review Board of each participating institute approved this study.

Outcome Analysis of First-line Somatostatin Analog Treatment in Metastatic Pulmonary Neuroendocrine Tumors and Prognostic Significance of 18FDG-PET/CT

IntroductionPulmonary carcinoids (PCs) are classed according to the World Health Organization 2004 classification as typical or atypical carcinoids. Owing to their rarity, no dedicated clinical trials with somatostatin analogs (SSAs) have been carried out on primary PCs. Patients and MethodsFrom January 2007 to December 2015, 30 patients with metastatic PCs underwent first-line SSA treatment (20 with octreotide long-acting repeatable 30 mg and 10 with lanreotide 120 mg every 28 days). Eight (23.3%) patients had typical carcinoids and 23 (76.7%) had atypical carcinoids. ResultsThe median age was 65.5 years (range, 47-82 years). All patients (23 males and 7 females) were Gallium-68-DOTA-TOC-positron emission tomography/computed tomography (PET/CT)-positive (29 patients) or octreoscan-positive (1 patient). Of the 20 patients who performed fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT), 14 (70.0%) were positive and 6 negative (30.0%). The median treatment duration was 10 months (range, 2-59 months). One patient achieved a partial response (3.3%), and 26 (86.6%) showed stable disease. One patient interrupted SSA treatment owing to symptomatic cholelithiasis. Five-year survival was 53.0% (95% confidence interval [CI], 15.0%-80.0%). The median progression-free survival (mPFS) was 11.1 months (95% CI, 7.0-15.0 months). Negative 18FDG-PET/CT patients had an mPFS of 15.2 months (95% CI, 7.6 months to not reached) compared with 7.0 months (95% CI, 4.0-10.1 months) for 18FDG-PET/CT-positive patients. No differences in mPFS were found in relation to TTF1-value, histologic subtype, and presence of extrahepatic metastases. ConclusionSSAs showed antitumor activity in terms of disease control rate and PFS and proved safe, even in patients with poor Eastern Cooperative Oncology Group status. 18FDG-PET/CT would appear to be a prognostic factor.

Phase II study evaluating the association of gemcitabine, trastuzumab, and erlotinib as first-line treatment in patients with metastatic pancreatic adenocarcinoma (GATE 1).

379 Background: This study aimed to assess the efficacy and tolerance of the combinationof chemotherapy and two targeted therapies as a first-line treatment in metastatic pancreatic cancer patients. Methods: We designed a phase 2 open-label, non-comparative, multicenter study (NCT01204372). Patients received weekly 1000 mg/m² gemcitabine (3 weeks out of 4), weekly trastuzumab (4 mg/kg the first week, 2 mg/kg afterwards) and erlotinib 100 mg/day per os. The primary endpoint was the disease control rate (DCR) according to RECIST. Using a Fleming’s single-stage procedure, the trial was considered positive if 29 patients had a controlled disease (out of 57 evaluable patients). Secondary endpoints included the safety, the progression-free survival (PFS) and the overall survival (OS). An ancillary study addressed the EGFR, HER2 and KRAS status of the patients. Results: Between June 2010 and July 2013, 62 patients were recruited (37 men). The median age was 62 years (range 35-77). Performance status was 0 (n=27) and 1 (n=35). 10 patients had had a surgery of the primary tumor (PT), of whom 6 had been treated with a gemcitabine-based adjuvant chemotherapy (&gt; 6-month delay). PT were localized in the head (n=25), corpus (n=22) and tail (n=15) of pancreas. The number of metastatic sites varied from 1 (n=25) to ≥ 3 (n=15). The baseline median left ventricular ejection fraction was 65% (range 51-86%). All patients were evaluable for safety and 59 patients for efficacy. Main first cycle treatment-related toxicities included: grade 3 anorexia (27%), asthenia (13%), diarrhea (10%), anemia (6%), and thrombocytopenia (3%); grade 3-4 neutropenia (24%), and mucositis (6%); grade 2-3 cutaneous events (35%). No complete responses were observed. 11 patients had a partial response, 33 a stable disease and 15 a disease progression. Therefore, the DCR was 74.6% (95%CI: 61.6-85.0%). Definitive results for the secondary endpoints will be presented at the meeting. Conclusions: Our results showed that combining gemcitabine, trastuzumab and erlotinib is efficient in terms of DCR. A further study is necessary to investigate this promising association. Funding (Roche SAS). Clinical trial information: NCT01204372.

723P - Gemcitabine Plus Cisplatin Versus Capcitbine Plus Cisplatin for Locally Advanced or Metastatic Biliary Tract Cancer

ABSTRACT Aim: Combination chemotherapy with gemcitabine and cisplatin is regarded as a standard chemotherapy for patients with advanced biliary tract cancer (BTC). Results of phase 2 trials of 5-FU or its derivatives combined with cisplatin in BTCs have shown modest benefits. It remains unclear whether capecitabine combined with cisplatin would show similar effects compared with standard therapy using gemcitabine with cisplatin. Methods: A clinical database was used to identify all patients with locally advanced or metastatic BTC (cholangiocarcnoma, gallbladder cancer) who treated with first-linechemotherapy in the Asan Medical Center. All patients received either cisplatin (25mg/m2) followed by gemcitabine (1000mg/m2), each administered on days 1 and 8 every 3 weeks (GP-W group), or capecitabine (1000 mg/m2 twice daily) on days 1-14, and cisplatin (60 mg/m2) on day 1 every 3 weeks (XP group). Patients' medical characteristics, radiological responses, and survival status were analyzed. Results: Of the 134 patients who met the inclusion criteria, 78 received XP and the other 56 were treated with GP-W. There were gallbladder cancer (25 [32%]) and cholangiocarcinoma (53 [68%]) in XP group, 15[27%] and 41[73%] in GP-W group (P = 0.57). The two groups were balanced including site of tumor except for a higher proportion of patients with relapsed setting in XP group (29 [37%] vs 6 [11%]). After a median follow-up duration of 26.2 months (95% CI 24.2-28.2), progression-free survival (PFS) was 5.7 month (95% C.I. 4.3 – 7.1) for XP and 4.1 month (95% C.I. 3.0 – 5.2) for GP-W. (hazard ratio [HR, GP-W vs XP] 0.81, 95% CI, 0.55-1.21, P = 0.31). The overall survival (OS) was 11.0 months (95% CI 7.1 - 14.9) for XP and 9.8 months (95% C.I. 7.5 - 12.2) for GP-W. (HR = 0.84, 95% CI 0.57–1.23, P = 0.36). The two groups showed same response rates (XP vs GP-W, 7 [9%] vs 5 [9%]) and were not stastically different in terms of disease control rate (75% vs 74%, P = 1.00). Conclusions: The XP regimen seems to be as effective as GP-W in patients with advanced BTC. The XP regimen might be a viable option due to efficacy and conveniance, such as one visit schedule per one cycle. Disclosure: All authors have declared no conflicts of interest.

Activity, efficacy, and safety of nab-paclitaxel (Nab-P) and gemcitabine (G) in heaviliy pretreated advanced pancreatic cancer (APDAC) patients (pts): A multicenter retrospective analysis.

e15255 Background: There is no standard of care for APDAC pts who have progressed to a first line chemotherapy (CT) and all investigated drugs have showed only moderate activity and limited efficacy. Nab-P has shown efficacy in combination with G as first line therapy in APDAC in a randomised phase III trial and it seems to be active in G resistant pts. Methods: APDAC pts who received off-label combination of nab-P 125 mg/m2 and G 1000 mg/m2 on days 1, 8, and 15 of a 28 day cycle as 2ndor further line of treatment in five Italian centers were retrospectively analyzed. We evaluated activity in terms of Disease Control Rate (DCR: Stable Disease + Partial Response + Complete Response, SD+PR+CR), efficacy (Progression Free Survival, PFS and Overall Survival, OS) and safety. Results: 34 pts (M/F: 20/14) median age of 60 (range 41-83) and ECOG Performance Status of 0/1/2: 8/17/9 respectively, were evaluated in our analysis. Median CA19.9 baseline level was 892 U/I, 17.6% pts had biliary stent, 21 pts (61.8%) ha...

Vinorelbine in pemetrexed-pretreated patients with malignant pleural mesothelioma

BackgroundPemetrexed-platinum chemotherapy is the standard first-line treatment of unresectable malignant pleural mesothelioma (MPM). At progression, patients are generally selected to experimental trials, when available, or, in every-day clinical practice, they are offered second-line chemotherapy. The optimal treatment has not yet been defined. The aim of this retrospective, single-center study was to evaluate the activity and toxicity of vinorelbine administered to a consecutive series of pemetrexed-pretreated MPM patients. MethodsVinorelbine 25mg/m2 was administered intravenously as a single agent on days 1, 8 every three weeks, either as second-line (2L) or further-line (>2L) therapy. Treatment was repeated for a maximum of 6 cycles, until progression, or unacceptable toxicity. ResultsFifty-nine patients were included in this analysis. Vinorelbine was given to 34 patients as 2L, and to 25 as >2L treatment. The median age was 69 years (range 45–80). Forty-two patients (71.2%) had a good EORTC prognostic score. Partial response was observed in 9 (15.2%) cases, stable disease in 20 (33.9%). The overall disease control rate (DCR) was 49.1%. Median progression-free survival (PFS) and overall survival (OS) were 2.3 and 6.2 months, respectively. ECOG performance status (PS) (HR0 vs. 1–2 0.50; 95%CI: 0.3–0.8; p=0.014) and PFS≥6 months following first-line (FL) chemotherapy (HRFL-PFS>6ms vs. <6ms 0.50; 95%CI: 0.3–0.9; p=0.031) were significantly associated to OS in multivariate analysis. No difference was observed in terms of DCR, PFS, and OS in relation to age, histology, sex, line of vinorelbine therapy, or response to FL treatment. Hematological toxicity was acceptable, with grade 3/4 neutropenia occurring in 5 (8.4%) patients, and there were no cases of febrile neutropenia. The main non-hematological toxicities were grade 2 fatigue in 17 (28.8%) and constipation in 7 (11.8%) patients. ConclusionsVinorelbine was moderately active in pemetrexed-pretreated MPM patients, with an acceptable toxicity profile, particularly in patients with ECOG-PS0 and FL-PFS ≥6 months.