Docetaxel In Non-small Cell Lung Cancer Research Articles

Abstract 4341: Indoleamine 2,3-dioxygenase 1 is highly expressed in tertiary lymphoid structures and associated with improved outcome in patients with advanced non-small cell lung cancer treated with anti-PD1/PDL1 inhibitors

Abstract Background: Immune checkpoint inhibitors (ICI) has revolutionized the management of patients with non-small cell lung cancer (NSCLC). However, most patients with advanced NSCLC patients displayed primary resistance to ICI. Indoleamine 2,3-dioxygenase 1 (IDO1) may play a role in primary resistance by catabolizing tryptophan to several immunosuppressive metabolites such as kynurenine. The aim of our study was to investigate the role of IDO1 expression in the outcome of NSCLC patients treated with immunotherapy. Methods: We analyzed the largest NSCLC gene expression (GE) dataset worldwide including 891 pre-treatment tumors from POPLAR and OAK studies, two RCT assessing the efficacy of atezolizumab vs docetaxel in NSCLC. We then confirm our findings with multiplex immunofluorescence (mIF) and digital pathology analysis to investigate the correlation between expression of IDO1 by tumor cells and spatial distribution of CD8+ T cells. Results: The PFS of IDO1high patients was significantly higher than IDO1low (3.81 vs 1.89months, p=7.13e-09). Strikingly, high IDO1 expression was also associated with better ORR (19.9% vs 5.2%, p=9.93e-05) and improved OS (15.9 vs 9.65 months, p=6.35e-06). When adjusting for covariates (histological subtype, TLS signature, PD-L1 expression), IDO1 remained independently associated with PFS (HR 1.54, p=4.1e-4) and OS (HR 1.43, p=8.2e-3). None of these correlations were observed in the docetaxel arm, suggesting a predictive value of IDO1 GE specifically for response to atezolizumab. Using a deconvolution approach, the tumor microenvironment composition differed significantly between IDO1high and IDO1low tumors. Indeed, IDO1high tumors were characterized by the highest expression of genes specific to immune populations such as interferon-gamma-producing T helper 1 (Th1) cells, CD8+ T cells, natural killer cells, cytotoxic lymphocytes, and B cells. To further validate our findings, we performed mIF on 53 NSCLC tumors. Overall, elevated IDO1 expression by tumor cells was correlated with increased CD8+/PD1+ T cells infiltration (p=0.001). Spatial cell distribution analysis also revealed that the relative distance between tumor cells and CD8+ T cells was significantly lower in IDO1high compared to IDO1low patients. Interestingly, 52% of tumors were characterized by the presence of TLS and IDO1 was observed in most TLS analyzed. Conclusions: IDO1 expression by tumor cells in NSCLC is associated with improved outcome in patients with NSCLC, independently of PDL1 expression score. IDO1 overexpression in NSCLC is associated with increased immune activity and may represent a negative feedback mechanism to CD8+ T cell infiltration. Citation Format: Jean-Philippe Guegan, Florent Peyraud, Christophe Rey, Oren Ngouala, Ophélie Odin, Imane Nafia, Isabelle Soubeyran, Sylvestre Le Moulec, Alban Bessede, Antoine Italiano. Indoleamine 2,3-dioxygenase 1 is highly expressed in tertiary lymphoid structures and associated with improved outcome in patients with advanced non-small cell lung cancer treated with anti-PD1/PDL1 inhibitors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4341.

Overall Survival With Second-Line Pembrolizumab in Patients With Non–Small-Cell Lung Cancer: Randomized Phase III Clinical Trial Versus Propensity-Adjusted Real-World Data

To compare and characterize overall survival (OS) differences between clinical trial data from the KEYNOTE-010 trial and real-world data (RWD) from the Flatiron Health database in patients with programmed death ligand 1 (PD-L1)-expressing advanced non-small-cell lung cancer (NSCLC) who received second-line pembrolizumab monotherapy. Clinical trial data were from the randomized phase II/III KEYNOTE-010 trial that enrolled patients from August 28, 2013, to February 27, 2015. At data cutoff for KEYNOTE-010, the median survival follow-up time for pembrolizumab patients was 11.2 months. RWD were from Flatiron Health advanced NSCLC database and included patients who initiated second-line pembrolizumab from January 26, 2015, to February 28, 2019. At data cutoff for Flatiron, the median survival follow-up time for pembrolizumab-treated patients was 6.1 months. Clinical trial data from KEYNOTE-010 and RWD from Flatiron were analyzed without adjustment, with propensity adjustment, and filtered per the main KEYNOTE-010 eligibility criteria (EC) of histologically/cytologically confirmed PD-L1-positive NSCLC, Eastern Cooperative Oncology Group performance status of 0/1, no prior therapy with docetaxel for NSCLC, and laboratory values indicative of adequate organ function in addition to prior line of therapy requirements. Among 243 patients from KEYNOTE-010 and 782 from Flatiron, median age was 63 v 68 years, and 64% v 54% were male, respectively. OS data from KEYNOTE-010 and Flatiron were similar without any adjustment (n = 782; hazard ratio [HR], 0.96; 95% CI, 0.80 to 1.15) and after both filtering and propensity adjustment (n = 221; HR, 0.99; 95% CI, 0.73 to 1.34). Without any adjustment, as well as after applying similar EC and appropriate statistical methods, RWD demonstrated similar effectiveness for pembrolizumab in second-line NSCLC as observed in randomized clinical trials.

Correlation of EGFR G873R mutation with prognosis of docetaxel in non-small cell lung cancer.

BackgroundClinical features of epidermal growth factor receptor (EGFR) mutations have been commonly recognized in variant cancers. The role of EGFR mutations in non-small cell lung cancer (NSCLC) has spurred research and drug development efforts. However, there are still mutations that have not been widely reported, and their influences on NSCLC have not been fully elucidated; EGFR G873R mutation is just one of them. The aim of this study was to investigate the correlation between EGFR G873R mutation and the prognosis of chemotherapy in NSCLC.MethodsA total of 54 patients with NSCLC were enrolled in this study. Immunohistochemical staining was used to detect the expression of EGFR. A DNA extraction kit (GeneRead DNA FFPE Kit) was used to extract total DNA from resected cancer tissues. Genomic DNA targets were amplified by polymerase chain reaction (PCR), and then the amplicons were purified and sequenced. Statistical methods were performed to detect the relationship between EGFR G873R mutation and various clinicopathological features and the effect of EGFR G873R mutation on the prognosis of chemotherapy.ResultsEGFR G873R mutation did not show statistical significance, with EGFR high expression identified in 30 cases (P>0.05). Patients with EGFR G873R mutation had a significantly favorable prognosis of docetaxel (P=0.032), and for patients treated with docetaxel, EGFR G873R mutation was significantly correlated with better 5-year disease-free survival (DFS; P=0.026) and overall survival (OS; P=0.026). However, there was no statistical significance found between EGFR G873R mutation and the prognosis of vinorelbine (P>0.05), and for patients treated with vinorelbine, EGFR G873R mutation had no statistical significance with 5-year DFS (P>0.05) and OS (P>0.05).ConclusionsEGFR G873R mutation was remarkably correlated with the prognosis of docetaxel in NSCLC, which indicates that EGFR G873R may be employed as a promising biomarker to identify individuals with better prognosis of docetaxel and as an antitumor target for NSCLC treatment.

Incidence and Risk of Colitis With Programmed Death 1 Versus Programmed Death Ligand 1 Inhibitors for the Treatment of Cancer

Colitis is a major immune-related adverse event associated with programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, but the risk of colitis with PD-1 versus PD-L1 inhibitors is not well characterized. We performed a meta-analysis for the incidence of all grade and grade 3-4 colitis with PD-1 inhibitor (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 inhibitor (atezolizumab, avelumab, and durvalumab) monotherapy using a fixed effects model. We also conducted subgroup meta-analyses of non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) trials, and a network meta-analysis of randomized trials comparing PD-1 or PD-L1 inhibitors with docetaxel for NSCLC. We also analyzed the Food and Drug Administration Adverse Event Reporting System database to estimate the reporting odds ratio of each medication. PD-1 inhibitors were associated with a higher incidence of all grade and grade 3-4 colitis compared with PD-L1 inhibitors in the analysis of all cancer types [1.49% vs. 0.83%, relative risk; 1.80, 95% confidence interval (CI); 1.22-2.67 for all grade colitis, and 0.85% vs. 0.34%, relative risk; 2.52, 95% CI; 1.46-4.37 for grade 3-4 colitis]. The meta-analyses of NSCLC and UC trials, and the network meta-analysis of NSCLC trials were also suggestive of a higher risk of colitis with PD-1 versus PD-L1 inhibitors. The reporting odds ratio of colitis with PD-1 versus PD-L1 inhibitors was 1.80 (95% CI; 1.53-2.14). In this meta-analysis of clinical trials exploring PD-1 and PD-L1 inhibitors in solid tumors, PD-1 inhibitors were associated with a higher risk of colitis.

Incidence and risk of colitis with programmed death-1 versus programmed death-ligand 1 inhibitors for the treatment of cancer.

e15087 Background: Programmed death 1 (PD-1) inhibitors and Programmed Death-Ligand 1 (PD-L1) inhibitors are immune checkpoint inhibitors (ICIs) approved for treatment of several different cancers. Colitis is a major immune-related adverse event associated with ICIs, but the risk of colitis with PD-1 versus PD-L1 inhibitors is not well characterized. Methods: We performed a meta-analysis for the incidence of all grade and grade 3-4 colitis with PD-1 inhibitor (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 inhibitor (atezolizumab, avelumab, and durvalumab) monotherapy using a fixed effects model. We also conducted subgroup meta-analyses of non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) trials, and a network meta-analysis of randomized trials comparing PD-1 or PD-L1 inhibitors with docetaxel for NSCLC. We analyzed Food and Drug Administration Adverse Event Reporting System (FAERS) database to estimate the reporting odds ratio (ROR) of each medication, which provides the estimated relative risk most valid in spontaneous report database. Results: We identified 88 studies that met inclusion for the analysis. PD-1 inhibitors were associated with higher incidence of all grade and grade 3-4 colitis compared to PD-L1 inhibitors in the analysis of all cancer types (1.49% vs 0.83%, relative risk (RR); 1.80, 95% confidence interval (CI); 1.22-2.67 for all grade colitis, and 0.85% vs 0.34%, RR; 2.52, 95% CI; 1.46-4.37 for grade 3-4 colitis). The meta-analyses on NSCLC and UC, and the network meta-analysis on NSCLC also showed the tendency that PD-1 inhibitors are associated with higher risk of all grade and grade 3-4 colitis, though only the analysis on UC for all grade colitis showed a significant difference. (1.95% vs 0.64%, RR; 3.05, 95% CI; 1.18 - 7.88) Retrospective analysis showed ROR of 16.78 (95% CI; 15.8-17.8) for PD-1 inhibitors, and 12.93 (95% CI; 10.74-15.42) for PD-L1 inhibitors. We found that ROR of PD-1inhibitors was 1.17 (95% CI; 0.97-1.43) compared to PD-L1 inhibitors. Conclusions: Our study showed that PD-1 inhibitors have higher risk of colitis than PD-L1 inhibitors.

Efficacy and safety of apatinib plus docetaxel for non-squamous non-small cell lung cancer with bone metastases.

e21741 Background: The skeletal system is one of the most common distant sites of metastatic non-small cell lung cancer (NSCLC) which may lead to skeletal-related events (SREs). Bone metastasis can reduced quality of life. Vascular endothelial growth factor receptor (VEGFR)-targeted therapy is effective against bone metastasis in animal models. Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2 (VEGFR2), which is inhibits tumor angiogenesis. Therefore, we aimed to investigate the efficacy and safety of apatinib plus docetaxel for NSCLC with bone metastases. Methods: Eligible patients of NSCLC with bone metastases who received first-line platinum-based chemotherapy. Treated with apatinib (500 mg, qd, orally) plus docetaxel (60mg/m2, q3w, iv) and zoledronic acid (4mg, q3w, iv). Treatment was continued until disease progression or unacceptable toxic effects. Results: Between July 2017 and June 2019, 10 patients were enrolled. All patients available for efficacy and safety evaluation. the objective response rate (ORR) was 50% and the disease control rate (DCR) was 80%. The median progression-free survival (PFS) was 6.5 months, The proportions of patients with SREs were 20%. The most common Grade 1 or 2 adverse events included hypertension (30%, 3/10), fatigue (30%, 3/10), digestive tract reaction (30%, 3/10), leukopenia (20%, 2/10). Conclusions: Apatinib plus docetaxel prolonged PFS and reduced the incidence of SREs, with acceptable toxic effects. The therapeutic regime may be an option for NSCLC with bone metastases. Clinical trial information: NCT03127319.

Retrospective cohort study on the safety and efficacy of docetaxel in Japanese non-small cell lung cancer patients with nondialysis chronic kidney disease stage 3b or higher.

BackgroundIt has been reported that 20% of lung cancer patients have renal impairment caused by chronic kidney disease (CKD). Since docetaxel is predominantly excreted by the hepatobiliary system, it is administered to non‐small cell lung cancer (NSCLC) patients with renal impairment. However, few clinical data are available on the toxicity and efficacy of docetaxel for patients with nondialysis renal impairment. Furthermore, some cases of tubular nephrotoxicity caused by docetaxel in NSCLC patients have been reported. Therefore, a retrospective cohort study was conducted to assess the influence of nondialysis CKD on the toxicity and efficacy of docetaxel in NSCLC patients.MethodsNSCLC patients who received docetaxel were assessed for renal function, occurrence of adverse events and treatment efficacy.ResultsA total of 34 NSCLC patients who received docetaxel were studied. Eight (23.5%) patients had nondialysis CKD stage 3b or higher, with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2. Although the differences were not statistically significant, the starting dose of docetaxel (mg/m2) was lower (60 mg/m2; 37.5% vs. 69.2%) in patients with an eGFR <45 than that in patients with an eGFR ≥45. No significant association was observed between pretreatment eGFR and hematological and nonhematological toxicities. No significant difference was observed in the disease control rate (62.5% vs. 65.4%, P = 1.000) or in the median overall survival (10.7 vs. 11.7, P = 0.735) between patients with an eGFR <45 and those with an eGFR ≥45.ConclusionDocetaxel is a reasonable option for NSCLC patients with nondialysis CKD stage 3b or higher. Dose reduction of docetaxel is also a possibility for NSCLC patients with CKD stage 3b or higher.

Efficacy and Safety of Addition of Anti-PD1 to Chemotherapy in Treatment of Non-Small Cell Lung Cancer.

Patients with previously treated non-small-cell lung cancer (NSCLC) have limited treatment options. A novel treatment based on programmed death 1 (PD-1)/programed death ligand 1 (PD-L1) inhibitors has emerged as promising therapeutic options for advanced NSCLC. We assessed oncological outcomes of PD-L1 antibody versus docetaxel in previously treated NSCLC. The purpose of this meta-analysis was to analyse the oncological outcomes of anti-PD1 to chemotherapy in the treatment of non-small-cell lung cancer. Overall survival (OR=0.68,95%CI=0.61-0.75, P<0.00001) and progression-free survival (OR=0.84,95%CI=0.77-0.92, P=0.0002) were longer with anti-PD1 than with docetaxel in NSCLC. Anti-PD1 was associated with even greater objective response rate than docetaxel (OR=1.61,95%CI=1.16-2.24, P=0.004). Treatment-related adverse events of grade 3-5 did favor anti-PD1 over docetaxel (OR=0.21,95%CI=0.10-0.42, P<0.00001). Among patients with advanced NSCLC, we found that there was a superior survival benefit and with a favorable safety profile with anti-PD1 than with docetaxel. More large-scale randomized controlled trials are needed to identify relevant biomarkers that have an effect on predicting the population that would most likely benefit from PD-1/PD-L1 for pretreated advanced NSCLC patients.

Application of liquid chromatography–tandem mass spectrometry to study the effect of docetaxel on pharmacokinetics and tissue distribution of apatinib in mice

Apatinib, a highly selective small-molecule inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2), has attracted many attentions due to its anticancer activity in various malignancies containing non-small-cell lung cancer (NSCLC). Our previous preclinical study confirmed the enhanced anti-tumor efficacy of combined treatment between apatinib and docetaxel for NSCLC. However, the effects of docetaxel on pharmacokinetics and tissue distribution of apatinib are not clear. In present study, a reliable HPLC-MS/MS method was established for determination of apatinib. This method had a good linearity in the range of 1–5000 ng/mL, and the recovery and matrix effect were 100.1–103.5%, 77.6–83.5%, respectively. Plasma exposure level of apatinib and the values of Cmax, AUC0–12h, T1/2, and MRT were not affected by multi-dose of docetaxel. The tissue distributions (kidney, heart, lung, spleen) of apatinib in combined treatment group were lower at 0.25 h but higher at 2 h, and that in intestine and liver were not significantly changed compared with control group. However, pre-treatment with docetaxel had no significant effect on AUC0–4h of apatinib in tissues in mice. In conclusion, plasma and tissues exposure levels of apatinib were not affected by long-termed treatment with docetaxel, indicating that docetaxel is less likely to increase the side effect of apatinib such as hypertension, hand-foot syndrome and so on.

39P - Efficacy of Tumor Treating Fields (TTFields) and anti-PD-1 in non-small cell lung cancer (NSCLC) preclinical models

Background: Tumor Treating Fields (TTFields) are an effective anti-neoplastic treatment modality delivered via non-invasive application of low intensity, intermediate frequency, alternating electric fields. TTFields is approved for the treatment of both newly diagnosed and recurrent glioblastoma. TTFields interrupt mitosis in cancer cells by disrupting microtubules and septin filaments, which play key roles in mitosis. The mitotic effects of TTFields include abnormal chromosome segregation that trigger different forms of cell death. We evaluated TTFields’ effect on immunogenic cell death and its efficacy when combined with an immune checkpoint inhibitor (αPD1) in NSCLC. Methods: Murine Lewis lung carcinoma (LLC) cells were treated with TTFields using the inovitroTM system. Levels of cell surface calreticulin (CRT) and intracellular ATP levels were evaluated using flow cytometry. High mobility group box 1 (HMGB1) secretion was measured using an ELISA assay. Mice inoculated with LLC cells were treated with isotype control, TTFields, αPD-1, or TTFields + αPD-1. Tumor volume monitoring and intra-tumor immune cell profiling were performed. Results: TTFields induced elevated cell surface expression of CRT, decreased ATP levels, and promoted HMGB1 secretion. In vivo, the combined treatment of TTFields + α-PD-1 led to a significant decrease in lung tumor volume compared to all three other groups (P < 0.001). Significant increase in CD45+ tumor infiltrating cells was observed in the TTFields + αPD-1-treated mice. Infiltrating cells demonstrated a significant upregulation of surface PD-L1 expression. Both F4/80+CD11b+ cells and CD11c+ cells exhibited higher tumor infiltration and elevated PD-L1 expression, as compared to the control group. These findings indicate enhanced inflammatory antitumor environment conferred by the combination of TTFields + αPD-1. Conclusions: Our results demonstrate that TTFields treatment potentiates immunogenic cell death in NSCLC cancer cells. Combining TTFields with specific immunotherapies such as anti-PD-1 may enhance antitumor immunity and result in increased tumor control. A phase III clinical study on TTFields in combination with either PD-1 inhibitors or docetaxel in NSCLC is underway. Legal entity responsible for the study: Novocure Ltd Funding: Novocure Ltd Disclosure: U. Weinberg: Full time employee of Novocure. T. Voloshin, O.T. Yitzaki, N. Kaynan, M. Giladi, A. Shteingauz, M. Munster, S. Cahal, E.D. Kirson: Full time employee of Novocure Ltd. Y. Palti: Shareholder at Novocure Ltd, NY.

HSP90 inhibition enhances antimitotic drug-induced mitotic arrest and cell death in preclinical models of non-small cell lung cancer.

HSP90 inhibitors are currently undergoing clinical evaluation in combination with antimitotic drugs in non-small cell lung cancer (NSCLC), but little is known about the cellular effects of this novel drug combination. Therefore, we investigated the molecular mechanism of action of IPI-504 (retaspimycin HCl), a potent and selective inhibitor of HSP90, in combination with the microtubule targeting agent (MTA) docetaxel, in preclinical models of NSCLC. We identified a subset of NSCLC cell lines in which these drugs act in synergy to enhance cell death. Xenograft models of NSCLC demonstrated tumor growth inhibition, and in some cases, regression in response to combination treatment. Treatment with IPI-504 enhanced the antimitotic effects of docetaxel leading to the hypothesis that the mitotic checkpoint is required for the response to drug combination. Supporting this hypothesis, overriding the checkpoint with an Aurora kinase inhibitor diminished the cell death synergy of IPI-504 and docetaxel. To investigate the molecular basis of synergy, an unbiased stable isotope labeling by amino acids in cell culture (SILAC) proteomic approach was employed. Several mitotic regulators, including components of the ubiquitin ligase, anaphase promoting complex (APC/C), were specifically down-regulated in response to combination treatment. Loss of APC/C by RNAi sensitized cells to docetaxel and enhanced its antimitotic effects. Treatment with a PLK1 inhibitor (BI2536) also sensitized cells to IPI-504, indicating that combination effects may be broadly applicable to other classes of mitotic inhibitors. Our data provide a preclinical rationale for testing the combination of IPI-504 and docetaxel in NSCLC.

Long progression-free survival with first-line paclitaxel plus platinum is associated with improved response and progression-free survival with second-line docetaxel in advanced non-small-cell lung cancer.

Paclitaxel and docetaxel are two taxanes approved for the treatment of non-small-cell lung cancer (NSCLC). However, there is limited evidence regarding the efficacy of docetaxel in NSCLC previously treated with a paclitaxel-platinum doublet (PP). The aim of our study was to evaluate the response to docetaxel in NSCLC patients with prior PP treatment. Patients with stage IV NSCLC treated with PP that presented disease progression and received docetaxel as second-line treatment were included. Demographics, clinical characteristics, EGFR mutation status, objective response (OR), overall survival (OS), progression-free survival (PFS), and PFS without chemotherapy after first line with PP were analyzed. Sixty-three patients were evaluated. Median age was 58 years, 54% of patients were women, 53% were never-smokers, and 39% had EGFR mutations. OR and median PFS for PP were 36.5% and 6.7 months, respectively. OR and median PFS for docetaxel were 19% and 3.8 months, respectively. Patients with EGFR mutations had better response to docetaxel compared with wild-type patients (26 vs. 17%, p = 0.028). However, only long PFS (>6 months) to first-line PP was independently associated with a higher OR [RR 6.3, 95% CI (1.03-38.4), p = 0.046], and longer PFS [0.49 (0.25-0.9)] and OS [0.2 (0.06-0.7), p = 0.008] to second-line docetaxel compared with patients with short PFS (≤6 months) to PP. Previous use of PP does not preclude a favorable response to docetaxel in NSCLC. Long PFS with PP may help select NSCLC patients who benefit from second-line docetaxel.

The role of βIII-tubulin in non-small cell lung cancer patients treated by taxane-based chemotherapy

The aim of this study is to evaluate whether class III β-tubulin (TUBB3) expression could predict progression-free survival or overall survival in relapsed non-small cell lung cancer (NSCLC) patients treated with taxene-based chemotherapy. Immunohistochemistal staining was used to examine the expression of TUBB3 in resected lung tumor specimens obtained from 56 patients treated with platinum-based chemotherapy against recurrent tumors after curative resections. Excision repair cross-complementation group 1, breast cancer susceptibility gene 1, vascular endothelial growth factor, Ki-67, CD34, and p53 were also correlated with clinical features and outcome after treatment. Of the 56 patients enrolled in the study, 29 were treated by carboplatin plus paclitaxel as first-line treatment, and 24 patients received docetaxel monotherapy as second- or third-line treatment. A positive TUBB3 expression is closely associated with a poor response to taxane-based chemotherapy. TUBB3 expression was an independent prognostic factor for predicting poor progression-free survival after docetaxel administration. However, TUBB3 expression could not predict outcome after carboplatin plus paclitaxel treatment. The other biomarkers tested were not independent prognostic factors for predicting outcome after taxane-based chemotherapy. TUBB3 expression is associated with resistance to taxane-based chemotherapy and is an independent prognostic factor for predicting poor progression-free survival after docetaxel treatment alone. TUBB3 expression may be a predictive marker for chemoresistance to docetaxel in NSCLC with postoperative recurrent disease.

Efficacy and safety profile of oxaliplatin and docetaxel in patients with advanced non-small cell lung cancer (NSCLC)

17061 Background: Platinum-based doublets are used as treatment for advanced or metastatic non-small cell lung cancer (NSCLC), but chemotherapy must be tailored to decrease side effects. Oxaliplatin is more potent than cisplatin, requiring fewer DNA adducts to provide equivalent cytotoxicity in vitro studies. Oxaliplatin was active as a single agent and in combination with vinorelbine, paclitaxel, and gemcitabinein phase II studies of patients with NSCLC. A phase II study was conducted to evaluate the efficacy and safety of oxaliplatin combined with docetaxel for NSCLC. Methods: Patients with stage-IIIB or -IV, chemotherapy-naive NSCLC received docetaxel 70 mg/m2, oxaliplatin 130 mg/m2, and pegfilgrastim 6 mg every 21 days for up to 6 cycles. The primary endpoint was overall response rate (ORR); secondary endpoints were progression-free and overall survival (PFS and OS), and safety. Results: Twenty-nine patients were treated; 15 (51.7%) were women, 25 (76%) were white, 17 (58.6%) were hispanic, 21 (72.4%) had adenocarcinomas, 24 (83%) had a PS ECOG 1, 93% had stage-IV disease and 28% had brain metastases. There were 10 partial responses in 27 evaluable patients for an ORR of 37% (90% confidence interval [CI], 21.7%–54.7%). Median PFS for 29 treated patients was 4.6 months (95% CI, 2.6–6.5 months); 12-month PFS was 14.8% (95% CI, 3.4%– 34.0%). Median OS was 10.9 months (95% CI, 8.9–16.8 months); 12-month OS was 40% (95% CI, 18.5%–60.8%) and 18-month OS was 16% (95% CI, 1.4%–45.7%). There were no unusual or unexpected adverse events. The most common grade-3 and -4 toxicities were anemia (14% of patients) and hyperglycemia (10%). There were only 2 reports of neutropenia; both were grade 1 or 2. Conclusions: These phase II findings suggest that the combination of oxaliplatin and docetaxel is active and well tolerated, and offers a feasible treatment alternative for patients with advanced or metastatic NSCLC. [Table: see text]

Compliance with oral topotecan in patients with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)

7092 Background: Compliance with chemotherapy can affect treatment efficacy and patient safety. Selecting an oral chemotherapy regimen with good tolerability in appropriate patients is important. To determine general level of compliance of oral topotecan, a retrospective analysis was conducted on 3 international open-label, multicenter, 2-arm randomized, phase III studies of patients with NSCLC and SCLC. Methods: Patients were randomized to receive oral topotecan d1–5 q21d as follows: Study 387 (Ramlau et al, Proc ASCO, 2005) 2.3 mg/m2/d second-line vs IV docetaxel for NSCLC; Study 389 (Eckardt et al, Proc ASCO, 2005) 1.7 mg/m2/d first-line with cisplatin vs etoposide/cisplatin for extensive-disease SCLC; and Study 478 (O’Brien et al, Lung Cancer 2005) 2.3 mg/m2/d second-line vs best supportive care for SCLC. Oral topotecan was administered to the patient in the clinic on day 1 of each course and the patient was responsible for self-administering the oral capsules the remaining 4 days of dosing. Patient compliance was defined as 100x(sum of number of caps taken across courses)/(sum of number of caps dispensed across courses), where number of caps taken = number of caps dispensed-number of caps returned. Results: Accrual per arm was (387), 414 patients; (389) 389; (478) 71. In the treated population for all three groups, adherence to oral topotecan was high, with &gt;90% of patients recording at least 90% overall compliance (Table). Mean age (% ≥65 years/%PS 2) was (387) 58.8 years (29.2%/14%), (389) 59.7 (32.6%/13%), and (478) 59.8 (33.8%/27%). Median oral topotecan dose intensity (% target) for each course was (387) 87%, (389) 95%, and (478) 98%. The most common reason for dose reductions or delays was hematological toxicity. Conclusions: Oral topotecan can be administered on an outpatient basis with a high degree of patient compliance in the treated population, which included those ≥65 years and those with poor PS. [Table: see text] [Table: see text]