Efficacy Of Cytotoxic Chemotherapy Research Articles

Efficacy of cytotoxic chemotherapy in recurrent/metastatic adenoid cystic carcinoma (ACC).

6111 Background: Despite aggressive local therapy, many ACC patients (~50%) develop recurrent and/or metastatic (R/M) disease. However, there is no standard of care or FDA-approved systemic therapy for this population. Based on small phase II trials, mostly including multiple salivary gland histologies, cytotoxic chemotherapy is recommended for symptomatic patients with high tumor burden, but its efficacy and impact on survival in R/M ACC remain unsubstantiated. Methods: A retrospective cohort study was conducted at MD Anderson Cancer Center with an institutional ACC database (N=769). Patients diagnosed with R/M ACC and treated with single-agent or combination palliative-intent chemotherapy were included. The primary endpoints were overall response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Secondary endpoints were median overall survival (mOS) and progression-free survival (mPFS) on chemotherapy for the entire cohort and stratified by growth pattern (solid v non-solid), line of therapy (1 v >2), chemotherapy regimen, and stage at diagnosis (M0 v M1). Results: 48 out of 115 patients who received chemotherapy were evaluated for response per RECIST.Median age at diagnosis was 43.6 years. 56% were male, 79% had M0 stage at diagnosis, 67% had minor salivary gland primary tumors, 52% had solid growth pattern, 31% had non-solid growth pattern, and 54% received first-line chemotherapy. The most common regimens were Platinum/Vinorelbine (38%), Platinum/Taxane (27%) and CAP (15%).The ORR and DCR rates were 12.5% and 56.3% respectively; 6 had partial response, 21 had stable disease, and 21 had progressive disease. The ORR and DCR rates were 20% and 52% for solid and 6.7% and 73.3% for non-solid growth pattern, respectively. The mOS from diagnosis was 7 years (95% CI, 3.5-10.7). The mOS on chemotherapy was 16 months (95% CI, 10.8-24.5). There was a significant difference in mOS between solid and non-solid growth pattern (10.8 v 24.1 months, p=0.015), but not by line of therapy, regimen, or stage at diagnosis. The mPFS on chemotherapy was 4.3 months (95% CI, 2.8-6.3 months). There was a significant difference in mPFS between solid and non-solid growth pattern (4.0 v 7.3 months, p=0.018), but not by line of therapy, regimen, or stage at diagnosis. Conclusions: In this largest to date real-world data on chemotherapy in ACC, response and survival outcomes were lower than historical data. The efficacy of chemotherapy may vary by growth pattern and other patient and tumor factors, which requires further investigation. Given the low ORR and overall slow-growing disease pattern, tumor volumetrics may be better than RECIST to assess treatment benefit.

Sacituzumab govitecan: A narrative drug review

Breast cancer is the most common cancer worldwide. Advanced triple-negative breast cancer (TNBC) has a poorer outcome as compared to human epidermal growth factor receptor 2 (HER2) or hormone receptor-driven cancers. Although checkpoint inhibitors, poly (ADP-ribose) polymerase inhibitors (PARPi), and trastuzumab deruxtecan have improved outcomes in a subset of patients, the efficacy of cytotoxic chemotherapy beyond the frontline setting remains abysmal. Sacituzumab, an antibody-drug conjugate against Trop2, has shown efficacy in metastatic TNBC, among other cancers, and is a promising agent in this setting. To prepare this review, we searched various websites, including the European Medicines Agency, Drug Manual, United States Food and Drug Administration, PubMed, and Science Direct, using the search term, “Sacituzumab govitecan.” We shortlisted 337 articles that had been published between January 1, 2017 and August 15, 2023, of which 60 were included. This review discusses the clinical indications, adverse effects, safety, pharmacodynamics, pharmacokinetics, and the key research trials that investigated the use of sacituzumab govitecan.

Phase I trial of CA-4948, an IRAK4 inhibitor, in combination with FOLFOX/PD-1 inhibitor +/- trastuzumab for untreated unresectable gastric and esophageal cancer.

TPS4168 Background: Activated NFκB has been linked to aggressive phenotype, poor survival outcomes and resistance to chemotherapy in multiple gastrointestinal cancers including gastroesophageal cancer (GEC). Preclinical studies established that: 1) Genotoxic stress incurred by chemotherapy induces TLR9, which signals through IRAK4 to drive pro-survival NFκB signaling; 2) The survival mechanism through IRAK4 is independent of cancer types and mutational profiles based on colorectal and pancreatic cancer models; and 3) IRAK4 inhibition reduces tumor desmoplasia and revitalizes intratumoral T cells, setting the stage for successful combination with immune checkpoint inhibitors in a highly aggressive autochthonous pancreatic cancer mouse model. These data combined provide a strong rationale to add CA-4948 to systemic therapy for multiple advanced gastrointestinal malignancies, where resistance to chemotherapy is inevitable and benefit of PD-1 inhibitors is limited to small population. CA-4948 is a novel, first-in-class reversible inhibitor of IRAK4. In a phase I trial, patients with relapsed/refractory hematologic malignancies tolerated CA-4948 monotherapy well with mild fatigue, neutropenia, and nausea as most common adverse events. Recommended phase 2 dose (RP2D) was determined as 300 mg orally twice daily. CA-4948 has not been tested in combination with cytotoxic chemotherapy or immune checkpoint inhibitors for solid tumors in clinic. We hypothesize that inhibition of IRAK4 with CA-4948 will potentiate the effect of immune checkpoint inhibitor while deepening the efficacy of cytotoxic chemotherapy in GEC. Methods: This is a phase I trial of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab for unresectable GEC. During Dose Escalation, we will investigate CA-4948 in combination with FOLFOX/nivolumab by BOIN algorithm evaluating 4 different dose levels. Starting dose of CA-4948 for Part A will be 200 mg twice daily. Once RP2D is determined, the study will proceed to Dose Expansion, including Cohorts A and B. Cohort A will enroll up to 12 patients with HER2 negative disease at the RP2D of CA-4948 determined at the Dose Escalation phase. Cohort B will investigate CA-4948 in combination with FOLFOX/pembrolizumab and trastuzumab. The initial 6 patients in Cohort B will be considered safety lead-in to confirm the safety and tolerability at the RP2D, followed by additional patients, up to 12 patients treated at the RP2D. The primary objective is to determine the safety and RP2D of CA-4948 in combination with FOLFOX/PD-1 inhibitor with or without trastuzumab. Secondary objectives are to determine the preliminary efficacy of the combination. Correlative studies to evaluate pharmacodynamic effects and to identify biomarkers associated with disease response are planned. Clinical trial information: NCT05187182.

Second-line therapy improves overall survival in primary refractory non-small cell lung cancer (NSCLC) patients

BackgroundThe effect of palliative chemotherapy for non-small cell lung cancer (NSCLC) is well established. Recently, immune checkpoint inhibitors have shown promising efficacy in NSCLC patients. However, little is known about the efficacy of cytotoxic chemotherapy in patients whose tumors are refractory to first-line chemotherapy. We investigated the outcome of all consecutive and unselected patients receiving palliative chemotherapy in a single institution to assess the efficacy of second-line chemotherapy in primary refractory NSCLC.Patients and methodsPatients with metastatic NSCLC diagnosed between 1990 and 2016 were assessed. Outcome parameters were collected and patients were characterized as either having primary progressive disease or clinical benefit [CB; defined as complete/partial remission (CR, PR) or stable disease (SD)]. Probabilities of survival were calculated using the Kaplan–Meier estimator. The log-rank test was used for comparing groups. Cox models were used to explore the prognostic value of covariables.ResultsThe analysis included 576 patients. Median overall survival (OS) was 9.5 months [95% confidence interval (CI) 8.47-10.47]; 62.7% of patients were treated with a platinum-based first-line therapy. Two hundred twenty-two patients (38.5%) were primary refractory to first-line therapy. Median OS was significantly shorter for those patients [7.4 versus 11.5 months, hazard ratio (HR) 1.61 (95% CI 1.34-1.93), P < 0.0001]. Poorer initial performance status was significantly associated with primary refractory disease (P = 0.015). Eighty-one (36.5%) primary refractory patients received a second-line therapy. Median OS was significantly longer for refractory patients receiving second-line therapy versus best supportive care [10.1 versus 5.0 months, HR 0.53 (95% CI 0.40-0.72), P < 0.0001].ConclusionsNearly 40% of patients are primary refractory to palliative first-line therapy and have a poor prognosis. Active second-line therapy can significantly improve the outcome. Therefore, patients with primary refractory NSCLC should be offered further active therapy. These real-life data for primary refractory patients form the basis for further research in sequencing of current palliative treatment options.

Abstract 817: Pancreatic acinar carcinoma - a rare entity with a targetable BRAF V600E mutation

Abstract Background: Pancreatic acinar carcinomas account for less than 1% of all pancreatic cancers and are considered genetically distinct entities form other pancreatic carcinomas. The pathogenesis of this malignancy is incompletely understood, and the efficacy of cytotoxic chemotherapy is not well defined especially in unresectable or metastatic disease. Methods: We identified one patient with pancreatic acinar carcinoma who was treated at our institution and was found to have a unique targetable pathogenic mutation on tumor sequencing. Results: A 64-year-old male patient was diagnosed with localized pancreatic acinar carcinoma during workup for epigastric pain. He underwent distal pancreatectomy with final pathology consistent with stage T3N0 acinar cell carcinoma without any adenocarcinoma component. He subsequently received six months of adjuvant chemotherapy with gemcitabine plus capecitabine, derived from evidence on pancreatic adenocarcinoma due to the size of his original tumor. Seven months after completion of adjuvant therapy, he was found to have local recurrence within the surgical bed and was treated with three cycles of systemic chemotherapy with FOLFIRINOX. During a following planned surgical resection, multiple liver lesions were seen intraoperatively, and surgery was aborted. Liver lesions were biopsied and hybrid capture next-generation sequencing was performed which revealed: a BRAF V600E gain of function mutation, CDKN2A loss as well as MYCN amplification. The patient declined further chemotherapy and his treatment was switched to Encorafenib (BRAF inhibitor) plus Binimetinib (MEK inhibitor). He attained a partial response to therapy at his first restaging CT scan after 2 months of therapy (-39% per RECIST 1.1). Both mass at the surgical bed as well as liver metastases were decreased in size. He tolerated treatment very well without significant adverse events (including no clinically significant rash). Conclusions: While BRAF rearrangements as described in the literature may occur in 15-23% of patients with acinar cell carcinoma of the pancreas, BRAF activating mutations and in particular the BRAF V600E substitution has not been reported. This particular substitution is commonly present in melanoma, hairy cell leukemia, Langerhans cell histiocytosis and less frequently in lung and colon cancer. A combination of BRAF and MEK inhibition may be used in patients with tumors harboring this activating mutation with variable efficacy across different histologies. In light of the rarity of acinar cell carcinomas of the pancreas and the lack of established systemic treatment guidelines, tumor sequencing should be considered if no other therapies are available. This is the first case reported in the literature of a patient with acinar cancer of the pancreas and BRAF V600E mutation where targeted therapy has shown an early response. Citation Format: Vaia Florou, Chris Nevala-Plagemann, Sean Mulvihill, Ignacio Garrido-Laguna. Pancreatic acinar carcinoma - a rare entity with a targetable BRAF V600E mutation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 817.

Efficacy and risk of cytotoxic chemotherapy in extensive disease-small cell lung cancer patients with interstitial pneumonia

BackgroundSmall cell lung cancer (SCLC) is characterized by a high propensity for metastases and a poor prognosis irrespective of high sensitivity for initial chemotherapy. Although interstitial pneumonia (IP) is one of risk factors for lung cancer, efficacy of cytotoxic chemotherapy for patients with SCLC with IP remains unclear. Our study aims to evaluate the efficacy of systemic chemotherapy and assess risk of acute exacerbation (AE)-IP with cytotoxic drugs for extensive disease (ED)-SCLC patients with IP.MethodsWe performed a retrospective study of 192 consecutive ED-SCLC patients with IP (n = 40) and without IP (n = 152) between 2008 and 2016.Result31 of 40 ED-SCLC patients with IP and 130 of 152 patients without IP received systemic chemotherapy. The efficacy of chemotherapy in patients with IP was not inferior to that in patients without IP (overall survival [OS], 7.1 [95% confidence interval (CI): 0.2–14.0] vs. 10.0 [95% CI: 8.2–11.8] months, P = 0.57). Pretreatment serum levels of lactate dehydrogenase (LDH; 651.7 ± 481.0 vs. 301.4 ± 110.7 U/mL, P = 0.01) and C-reactive protein (CRP; 8.9 ± 9.6 vs. 1.8 ± 1.8 U/mL, P = 0.008) were correlated with developed AE-IP in the ED-SCLC patients with IP.ConclusionSystemic chemotherapy was effective even in ED-SCLC patients with IP. However, the risk of developed AE-IP that was high in patients with IP and should be evaluated using serum LDH and CRP levels before initial chemotherapy.

Safety and efficacy of cytotoxic chemotherapy in hepatocellular carcinoma after first-line treatment with sorafenib

BackgroundBefore the targeted therapies era, cytotoxic chemotherapy (CCT) was an option for advanced hepatocellular carcinoma (HCC), even with the lack of supporting evidence. Since the last decade, sorafenib has been established as the first-line therapy. Although new agents are being incorporated, CCT is still considered in regions where new drugs are not available or for patients who progressed through the approved therapies and remain in good clinical condition. We aimed to describe our experience regarding the use of CCT as second-line treatment after sorafenib.MethodsA database of 273 patients was evaluated. Patients that received CCT after sorafenib progression were selected for the analysis. Descriptive statistics was used for categorical and continue variables. Median survival was estimated with Kaplan-Meier curves. Variables were found to be significant if the two-sided p value was ≤ 0.05 on multivariate testing using the Cox regression model.ResultsForty-five patients received CCT; 33 (73.3%) had Child-Pugh classification A, and 34 (75.6%) had stage C according to the Barcelona Clinic Liver Cancer (BCLC) staging system. The most used regimen was doxorubicin in 25 patients (55.6%). Median overall survival (OS) was 8.05 months (95% confidence interval [CI] 2.73 – 9.88 months). The 6-month and 1-year survival probability was 52.4% and 27.36%, respectively. Eastern Cooperative Oncology Group performance status (ECOG PS) 0–1 and disease control with sorafenib was independently associated with better OS in patients treated with CCT. Any-grade toxicities were observed in 82.2% and grade 3–4 in 44.4% of the patients.ConclusionIn accordance with previous studies, CCT had a notable rate of adverse events. The poor prognosis of this cohort suggests that CCT may not alter the natural history of HCC after sorafenib progression.

Pre-clinical activity of targeting the PI3K/Akt/mTOR pathway in Burkitt lymphoma.

Though outcomes for pediatric Burkitt lymphoma (BL) have improved significantly in recent decades with intensive multi-agent chemotherapy and the addition of rituximab, chemotherapy resistance remains a significant impediment to cure following relapse. Activation of the PI3K/AKT pathway has been implicated in Burkitt lymphomagenesis and increased PI3K/AKT activation has been associated with worse outcomes in adults with aggressive B-cell non-Hodgkin lymphoma (B-NHL). Inhibitors of the PI3K/AKT pathway have been approved for the treatment of refractory indolent B-NHL and continue to be investigated for treatment of aggressive B-NHLs. We investigated the activation of the PI3K/AKT pathway in a cell line model of resistant BL and the ability to target this pathway with small molecule inhibitors in BL cell lines. We found that cell lines resistant to rituximab and chemotherapy exhibited increased activation of PI3K/AKT and that inhibition of AKT or PI3K results in in vitro anti-lymphoma activity. To investigate the role of PI3K/AKT activation on the efficacy of cytotoxic chemotherapy, we exposed cells to inhibitors in combination with chemotherapy and noted a synergistic increase in response to chemotherapy. Overall these findings highlight the role of PI3K/AKT in chemotherapy resistance in BL cells and may represent a tractable therapeutic target.

Nonconventional responses and survival benefit of immunotherapy in advanced lung cancer.

e14572 Background: Objective response rates (ORR) utilizing RECIST or WHO criteria have been traditionally used as clinical endpoints to assess efficacy of cytotoxic chemotherapy. However in the era of immunotherapeutic agents, response rate assessment can be misleading due to nonconventional responses resulting in premature discontinuation of treatment. Wolchok et al proposed immune-related response criteria (irRC) to assess immune responses in melanoma. He also noted that stable disease which is not indicative of antitumor activity could be a potential surrogate marker of better clinical outcome. Brahmer et al reported nonconventional pattern of responses with Nivolumab in lung cancer. Methods: A retrospective chart review was done to assess differences in responses utilizing both RECIST v1.1 and irRC criteria in lung cancer patients treated with Nivolumab. Patients who received minimum of 4 cycles of Nivolumab were included in the study. The CT scans were reviewed by a senior radiologist. We reviewed 64 patients treated with Nivolumab between 4/30/2015 to 6/21/2016 and 30 patients were found eligible. Results: Patient characteristics. Male 53%; median age 61 years; squamous 47%; adeno 40%; small cell 13%; Median cycles of Nivolumab 6. Response rates utilizing both criteria was essentially similar with only 2 patients showing dis-concordant responses (6.6%). We utilized RECIST responses criteria for further analysis. Partial response (PR) 2/30; stable disease (SD) 12/30; progressive disease (PD) 15/30 and not evaluable (NE) 1/30. ORR 6.6%. Kaplan–Meier curve was used to analyze difference in survival between patients with PR+SD and PD. The median survival for PD was 9 months and PR+SD was not reached at median follow up of 1 year. Overall survival at 1 year for PD 33% and PR+SD 60% (p = 0.048). Hazard ratio for PD was 3.060 (p = 0.60). Conclusions: Patients with stable disease had a better survival and should be considered as responders though traditionally not included in the ORR. However irRC did not help in differentiating nonconventional immune responses in lung cancer patients. [Table: see text]

Distinct implications of different BRCA mutations: efficacy of cytotoxic chemotherapy, PARP inhibition and clinical outcome in ovarian cancer.

Approximately a fifth of ovarian carcinoma (OC) is associated with inherited germline mutations, most commonly in the DNA repair genes BRCA1 or BRCA2 (BRCA). BRCA1- and BRCA2-associated OCs have historically been described as a single subgroup of OC that displays a distinct set of characteristics termed the “BRCAness” phenotype. The hallmarks of this phenotype are superior clinical outcome and hypersensitivity to platinum-based chemotherapy and poly-(ADP-ribose) polymerase (PARP) inhibitors. However, growing evidence suggests that BRCA1- and BRCA2-associated OCs display distinct characteristics, most notably in long-term patient survival. Furthermore, recent data indicate that the site of BRCA1 mutation is important with regard to platinum and PARP inhibitor sensitivity. Here, we summarize the body of research describing the BRCAness phenotype and highlight the differential implications of different BRCA mutations with regard to clinicopathologic features, therapy sensitivity and clinical outcome in OC.

P2.03a-004 Second-line Therapy Improves Overall Survival in Primary Refractory Non Small-Cell Lung Cancer (NSCLC) Patients

The effect of palliative chemotherapy for non-small cell lung cancer (NSCLC) is well established. However, little is known on the efficacy of cytotoxic chemotherapy in patients whose tumors are refractory to first-line chemotherapy. We analyzed the outcome of all consecutive and unselected patients receiving palliative chemotherapy in a single institution to assess the efficacy of second-line chemotherapy in primary refractory NSCLC. 462 consecutive patients with palliative treatment for NSCLC at the University Hospital Basel between 1990 and 2009 were analyzed. Measured outcomes were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Patients with progressive disease (PD) as best response to first-line treatment were compared to patients with stable disease (SD), partial (PR) or complete remission (CR). Chi-square test was used for discrete, and Mann Whitney U tests for continuous variables, respectively. Probabilities of survival were calculated using the Kaplan-Meier estimator. The log-rank test was used for comparing groups. Median age was 63 years, 71% were male, 81% were smokers and 53% had adenocarcinoma. Median OS of the whole cohort was 11.3 months. 62.3% of patients were treated with a platinum-based (48.3% cisplatin-based) first-line therapy. Median PFS for first-line therapy was 3.0 months. 192 patients (41.6%) were primary refractory on first-line therapy. Median OS was significantly shorter for refractory patients compared to patients with CR, PR or SD (9.2 vs. 14.5 months, p<0.0001). Poorer initial performance status was significantly associated with primary refractory disease (p=0.015). All other baseline characteristics did not differ between refractory and responding patients. 67 (35%) primary refractory patients received a second-line therapy. The clinical benefit rate (CR+PR+SD) from second-line therapy was lower in primary refractory patients (33.9% vs. 43.5%, p=0.023). Median PFS for second-line therapy was shorter for primary refractory patients (2.2 vs. 4.6 months, p=0.26). Median OS was significantly longer for refractory patients receiving second-line chemotherapy vs. best supportive care (13.6 vs. 5.5 months, p<0.0001). More than 40% of patients are primary refractory to palliative first-line therapy. These patients have a poor prognosis. However, active second-line chemotherapy can significantly improve the outcome compared to best supportive care. Median OS for patients receiving second-line chemotherapy was close to patients with initial response or stable disease. Patients with primary refractory NSCLC should be offered further active therapy. These real life data for primary refractory patients form the basis against which immunotherapies, the current standard second line treatment, can be compared.

P-262 The impact of variations in KRAS codon 12 and 13 point mutation on the efficacy of cytotoxic chemotherapy for metastatic colorectal cancer (CRC)

P-262 The impact of variations in KRAS codon 12 and 13 point mutation on the efficacy of cytotoxic chemotherapy for metastatic colorectal cancer (CRC)

The efficacy of first-line chemotherapy is associated with KRAS mutation status in patients with advanced non-small cell lung cancer: a meta-analysis.

Non-small cell lung cancer (NSCLC) patients harboring KRAS mutation were associated with worse prognosis and lower response to epidermal growth factor receptor (EGFR) target therapy than those with wild-type tumors. However, whether the underlying biological differences are associated with the efficacy of cytotoxic chemotherapy in advanced NSCLC patients remained controversial. We searched electronic databases for eligible literatures. The primary outcomes were objective response rate (ORR), 6-month and 1-year progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effect model. Subgroup analyses stratified by literature type, mutation analysis method, therapeutic regimen, patient origin, and EGFR mutation status in KRAS wild-type patients were proposed. Heterogeneity and publication bias were quantitatively evaluated. A total of ten studies involving 1,677 advanced NSCLC patients with known KRAS mutation status who had received first-line chemotherapy were included. KRAS mutants had lower ORR than wild-type patients (25.1 vs. 34.4%) significantly (OR 0.67, 95% CI 0.50-0.88, P = 0.004). Additionally, patients with KRAS mutation had numerically lower 6-month (51.0 vs. 56.8%) and 1-year (10.3 vs. 13.3%) PFS rate than wild-type patients, but there was no significant difference between the two groups (OR 0.75, 95% CI 0.54-1.04, P = 0.08; OR 0.75, 95% CI 0.47-1.21, P = 0.25). Results of the subgroup analyses were almost concordant with the overall ones. This comprehensive analysis revealed that advanced NSCLC patients with KRAS mutations had significantly lower ORR and potentially lower 6-month/1-year PFS rate compared with wild-type patients after first-line chemotherapy.

The Efficacy of First-Line Chemotherapy is Associated with Kras Mutation Status in Patients with Advanced Non-Small Cell Lung Cancer: a Meta-Analysis

ABSTRACT Aim: Non-small-cell lung cancer (NSCLC) patients harboring KRAS mutations were associated with worse prognosis and lower response to epidermal growth factor receptor (EGFR) targeted therapy including EGFR tyrosine kinase inhibitors (EGFR-TKIs) and anti-EGFR monoclonal antibodies than those with wild-type tumors. However, whether the underlying biological differences are associated with the efficacy of cytotoxic chemotherapy in advanced NSCLC patients remains controversial. Thus, we sought to perform a meta-analysis incorporating all available evidences to evaluate the clinical outcome according to the KRAS mutation status in patients with advanced NSCLC treated with front-line conventional chemotherapy. Methods: We searched electronic databases for eligible literature. The primary outcomes were objective response rate (ORR), six-month and one-year progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effects model. Subgroup analyses stratified by literature type, mutation analysis method, therapeutic regimen, patient origin, EGFR mutation status in KRAS wild-type patients were proposed. All calculations were performed using REVIEW MANAGER version 5.0. Heterogeneity and publication bias were quantitatively evaluated. Results: A total of 10 studies involving 1677 advanced NSCLC patients with known KRAS mutation status who had received first-line chemotherapy were included. KRAS mutants had lower ORR than wild-type patients (25.1% vs. 34.4%) significantly (OR 0.67, 95% CI 0.50-0.88, P = 0.004). Additionally, patients with KRAS mutation had numerically lower six-month (51.0% vs. 56.8%) and one-year (10.3% vs. 13.3%) PFS rate than wild-type patients, but there was no significant difference between the two groups (Six-month PFS: OR 0.75, 95% CI 0.54-1.04, P = 0.08; One-year PFS: OR 0.75, 95% CI 0.47-1.21, P = 0.25). Results of the subgroup analyses were almost concordant with the overall ones. Conclusions: This comprehensive analysis revealed that advanced NSCLC patients with KRAS mutations had significantly lower ORR and potentially lower six-month/one-year PFS rates compared with wild-type patients after first-line chemotherapy. KRAS mutation status should be considered as an essential factor in studies regarding chemotherapy regimens or other non-targeted agents. Disclosure: All authors have declared no conflicts of interest.

Impact of EGFR mutation status on tumor response and progression free survival after first-line chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis.

Non-small-cell lung cancer (NSCLC) patients harboring sensitive epidermal growth factor receptor (EGFR) mutations derive greater benefits from EGFR-tyrosine kinase inhibitors (EGFR-TKIs) than those with wild type tumors. However, whether EGFR mutation status is associated with the efficacy of cytotoxic chemotherapy or prognosis in advanced NSCLC patients remained controversial. Thus, we sought to conduct a meta-analysis to answer this question. Electronic databases were searched for eligible literatures. The primary outcomes were objective response rate (ORR) and 6-month progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effects model. Subgroup analyses stratified by study types, EGFR mutation detection methods, chemotherapy regimens, and patient origins were proposed. A total of 14 studies involving 1,772 advanced NSCLC patients with known EGFR mutation status who had received first-line chemotherapy were included. Patients with positive EGFR mutation had numerically higher ORR than wild type patients (36.2% vs. 30.1%) without significant differences (OR 1.24, 95% CI, 0.90 to 1.70; P=0.19). However, patients with EGFR mutants had significantly superior 6-month PFS rate than wild-type patients (58.6% vs. 47.2%; OR 1.88, 95% CI, 1.33 to 2.65; P=0.0003). Results of the subgroup analyses were concordant with the overall ones. This comprehensive analysis revealed that advanced NSCLC patients with sensitivity EGFR mutation had higher 6-month PFS rate and potentially greater ORR compared with wild-type patients after first-line chemotherapy. It suggested that EGFR mutation status should be considered a significant factor for patient stratification in evaluating the efficacy of antitumor agents in addition to EGFR-TKIs.

ENDOCRINE TUMOURS: Approach to the patient with advanced differentiated thyroid cancer

Patients with advanced thyroid cancer may benefit froml-thyroxine treatment at doses that suppress serum TSH level, local treatment interventions, and radioiodine therapy. In those patients who are refractory to radioiodine therapy and in whom progressive disease has been documented, the efficacy of cytotoxic chemotherapy is poor. Encouraging results have been obtained with the use of kinase inhibitors that should be offered as first-line treatment, preferably in the context of a prospective trial.

Prognostic and predictive value of CA-125 in the primary treatment of epithelial ovarian cancer: potentials and pitfalls

The serum cancer antigen 125 (CA-125) remains a reliable biomarker in the therapeutic management of epithelial ovarian cancer (EOC). Monitoring the efficacy of cytotoxic chemotherapy (CT) and the early detection of relapse during the follow up of patients in remission represent the two most common clinical situations where the CA-125 has been successfully applied. There are however other scenarios along the course of the disease where the CA-125 can potentially aid in the decision-making process. Preoperative levels of CA-125 can help in selecting a subset of patients where an optimal cytoreduction may not be easily achieved. Perioperative variations in the CA- 125 levels after primary surgery and, more importantly, the nadir value of the CA-125 after primary chemotherapy, are associated with patient outcome. This review focuses on the clinical relevance of dynamic changes in CA-125 levels during the primary treatment of EOC and its potential influence both in the patient management and in the design of clinical trials in the adjuvant setting.

Abstract C231: Colony-stimulating factor-1 receptor blockade reprograms malignant mesothelioma tumor microenvironments and decreases tumor growth.

Abstract Malignant mesothelioma (MM) is a debilitating, frequently incurable cancer that exhibits a high degree of resistance to standard cytotoxic chemotherapy (CTX). Novel therapeutic approaches to treat this disease are desperately needed. In the vast majority of cases, MM is associated with prior exposure to asbestos fibers, resulting in a chronic pro-inflammatory state in pleura. As such, we hypothesized that infiltration of MM by leukocytes fosters tumorigenesis. To investigate this, we evaluated MMs resected from patients (n=16) and compared the complexity of immune cells infiltrating MM to those found in normal pleura (n=4). Using polychromatic fluorescent-activated cell sorting (FACS) on freshly resected whole tissues, we found a significant increased presence of CD11b+CD14+HLA-DR+ monocytes/macrophages in MM (37.3 ± 4.4% of total CD45+ cells) as compared to normal pleural tissue (13.8 ± 6.5% of total CD45+ cells), and a further increase in MM resected from patients treated with neoadjuvant CTX (48.8 ± 5.5% of CD45+ cells). To determine if increased presence of CD11b+CD14+HLA-DR+ leukocytes was associated with varied expression of cytokines regulating leukocyte maturation/recruitment, we examined mRNA expression of tissues/tumors. We found increased expression of Colony Stimulating Factor 1 (CSF1), and Colony-Stimulating Factor-1 Receptor (CSF-1R) mRNA, a critical cytokine-signaling axis regulating monocyte/macrophage differentiation and recruitment into tumors, in MM tumors compared to normal pleura, and even higher levels in tumors resected from patients treated with CTX. Since recent experimental data has revealed that tumor-associated macrophages (TAMs) secrete proangiogenic, prosurvival, and pro-invasive factors that foster tumor progression, we evaluated macrophage depletion in MM as a novel therapeutic strategy. We conducted studies evaluating PLX3397 (Plexxikon Inc., Berkeley, CA), a novel, orally bioavailable, small-molecule tyrosine kinase inhibitor of CSF-1R. Using a syngeneic orthotopic murine model of MM, we found that treatment of mice with PLX3397 alters the tumor immune microenvironment by decreasing TAM infiltration and increasing the proportion of CD8+ cytotoxic T lymphocytes within tumors. This reprogramming of the tumor immune microenvironment was associated with alterations in the tumor microvasculature as evidenced by a decrease in CD31+ structures, as well as a decrease in VEGFA mRNA expression. Ultimately, these changes resulted in an increase in tumor cell apoptosis (p=0.04) and a decrease in tumor burden (p=0.0008). These studies indicate that: 1) macrophages potentiate mesothelioma development, and 2) depletion of mesothelioma-associated macrophages may improve the efficacy of cytotoxic chemotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C231.

Abstract 454: Targeting macrophages in a preclinical model of malignant mesothelioma

Abstract Malignant pleural mesothelioma (MPM) is a debilitating, incurable cancer that exhibits a high degree of resistance to standard chemotherapy; thus, we sought to identify novel therapeutic targets for treatment. In the vast majority of cases, MPM is associated with exposure to asbestos fibers, which result in a chronic pro-inflammatory state. As such, we hypothesized that MPMs were infiltrated by leukocytes possessing tumor-potentiating activities. To address this, we evaluated MPMs, resected from 26 patients, by flow cytometry and found that tumors were highly infiltrated with macrophages (31 ± 4.6% of total CD45+), a percentage that is significantly higher that that observed in other thoracic malignancies (NSCLC cancer, 9%; esophageal, 4%). Since recent experimental data has revealed that tumor-associated macrophages (TAMs) secrete proangiogenic, prosurvival, and proinvasive factors that foster tumor progression, we evaluated macrophage-depletion in MPM as a novel therapeutic strategy. Using a syngeneic murine transplantation model and liposomal-encapsulated clodronate that efficiently deplete phagocytic macrophages, as monotherapy, and in combination with chemotherapy, we revealed a significant decrease in tumor growth and a decrease in tumor-burden in tumor-bearing mice depleted of macrophages. Furthermore, when macrophage-depletion was combined with the cytotoxic agents gemcitabine and TRAIL, an even greater reduction in tumor burden was observed as compared to mice treated with either agent alone. These studies indicate that: 1) mesothelioma-associated macrophages provide a protumor function, and 2) depletion of mesothelioma-associated macrophages may improve efficacy of cytotoxic chemotherapy. Ongoing studies to reveal the effect of macrophage-depletion plus chemotherapy in limiting MPM development in NF2ko/+ mice exposed to asbestos are underway. This work was supported by an NIH T32 training grant to Dr. Blakely, and by a DoD Mesothelioma Program grant (PR080717) to Drs. Broaddus and Coussens. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 454. doi:10.1158/1538-7445.AM2011-454

Abstract 5030: Necitumumab (IMC-11F8), a recombinant human anti EGFR antibody, increases the antitumor effects of cisplatin/paclitaxel in human NSCLC xenograft models

Abstract Epidermal growth factor receptor (EGFR) targeted antibodies may have a role in the treatment of non-small cell lung cancer (NSCLC), based on preclinical and clinical data. Here we have demonstrated a significant benefit of adding necitumumab, a recombinant human IgG1 antibody targeting EGFR, to cisplatin+paclitaxel administered at its maximum tolerated dose, in subcutaneous xenograft tumor models established in nu/nu athymic mice with A549 or NCI-H1650 NSCLC cell lines. Necitumumab monotherapy or cisplatin+paclitaxel therapy inhibited xenograft tumor growth with a T/C% of 47 and 63, respectively in A549 tumor model. A similar anti tumor effect was seen in NCI-H1650 xenograft tumors treated with necitumumab monotherapy or cisplatin+paclitaxel therapy with a T/C% of 37 and 50, respectively. Furthermore, the combination of necitumumab with cisplatin+paclitaxel significantly inhibited tumor growth with a magnitude greater than any of the therapies alone in A549 xenograft tumors with a T/C% of 33 and in NCI-H1650 xenograft tumors with a T/C% of 18. Combination treatment resulted in partial regressions (3 out of 9 mice) in A549 and maximum tumor regressions (10 out of 12) in NCI-H1650. Chi-Squared test for all animals in the treatment groups showed p=0.02 in A549 and p=3.0E-08 in NCI-H1650 xenograft tumors. In vitro analysis on A549 and NCI-H1650 cell lines treated with cisplatin+paclitaxel, with/without necitumumab (5 μg/ml) demonstrated that this combination benefit was associated with the increased apoptotic index in both models. Cell cycle arrest during combination therapy was also observed as an increase in the percentage of cells in G2/M phase in A549 and S or G2/M phase in NCI-H1650 cell lines. We are further utilizing SABiosciences PCR arrays to demonstrate combination benefit related gene function in apoptosis, cell cycle signaling pathways and drug specific biomarkers in both A549 and NCI-H1650 cell lines. Thus our results demonstrate the potential utility of necitumumab for enhancing the efficacy of cytotoxic chemotherapy in both in A549 and NCI-H1650 cell lines and xenograft tumors models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5030. doi:10.1158/1538-7445.AM2011-5030