Second-line Treatment Of NSCLC Research Articles

P2.26 Budget Impact Analysis of Immunotherapy as Second-line Treatment of NSCLC at MX's National Institute of Cancer

P2.26 Budget Impact Analysis of Immunotherapy as Second-line Treatment of NSCLC at MX's National Institute of Cancer

Nivolumab cost effective for second-line treatment of NSCLC

Nivolumab cost effective for second-line treatment of NSCLC

Nab-paclitaxel as First Line Treatment for NSCLC in Elderly Patients More Than 75 Years Old.

Introduction: Lung cancer is still the leading cause of cancer among cancer patients. Although there are novel therapies as second line treatment for NSCLC, there is an issue for elderly patients. Patients and Methods: We collected retrospectively data from 60 patients >75 years of age. Thirty of these patients received nab-paclitaxel and first line treatment and were compared to thirty patients that received only best supportive care. Results: The median life of patients at the date of disease progression, although increased by the administration of the drug (92 days versus 70) was not confirmed statistically significantly (Mann-Whitney test: W = 280, p = 0.138). The administration of drug seems to keep stable the biological condition of patients (McNemar's test: χ2 = 0.033, p = 0.99). Patients with chemotherapy the death rate was increased by 50% as compared to those with best supportive care (12 vs 8), the median life until the unfortunate event surpassed statistically significantly the latter (150 days of life as compared to 108, Mann-Whitney test: W = 57.5, p = 0.045). Discussion: Nab-paclitaxel as a monotherapy could be considered as a first line treatment option for patients > 75 years of age without any previous cardiological medical history when compared to best supportive care.

The Role of Epithelial–Mesenchymal Transition and IGF-1R Expression in Prediction of Gefitinib Activity as the Second-Line Treatment for Advanced Nonsmall-Cell Lung Cancer

Objective: Except for EGFR gene mutation, there is still lack of predictive factors for gefitinib activity as the second-line treatments for advanced NSCLC with wild-type (WT) EGFR or patients with mutant EGFR but showed poor response. Our purpose was to assess the predictive value of epithelial-mesenchymal transition (EMT) and IGF-1R for gefitinib efficacy as the second-line treatment for NSCLC. Methods: 53 advanced NSCLC patients who accepted gefitinib as the second-line treatment were enrolled in this study. Expression of E-cadherin, vimentin, and IGF-1R was determined by immunohistochemistry. EGFR gene mutation was determined by liquidchip technique. Results: The positive rate of EMT, IGF-1R, and EGFR gene mutation was 54.7%, 58.5%, and 39.6%, respectively. EMT (−) was positively correlated with EGFR gene mutation (p = .034) and EMT (+) was associated with IGF-1R (+) (p = .000). EMT (−) was associated with a significantly higher objective response rate (ORR) for all the 53 patients (41.7% vs. 6.9%, p = .024) and showed a higher ORR tendency than EMT (+) in EGFR mutation patients (50.0% vs. 28.6%) and WT EGFR patients (20.0% vs. 4.5%) (p > .05). EMT (−) showed a significant longer median survival time (MST) than EMT (+) for all 53 patients (8 months vs. 4 months) and WT EGFR patients (6 months vs. 3 months) (p < .05). IGF-1R (−) showed a higher ORR tendency than IGF-1R (+) in EGFR mutation patients (54% vs. 30%) and WT EGFR patients (18.2% vs. 4.8%) (p > .05). Conclusion: EMT is correlated with efficacy of gefitinib as the second-line treatment for NSCLC, and combined detection of EMT and IGF-1R may be used as new predictors besides EGFR mutation, especially for patients with WT EGFR.

A meta-analysis of comparing EGFR-TKI with chemotherapy as the second-line treatment of NSCLC patients with wild-type EGFR.

e19166 Background: The efficacy of comparing the EGFR-TKI with standard chemotherapy in the second-line treatment of advanced NSCLC with wide-type EGFR were still controversial. To derive a more precise estimation of the two regimens, a meta-analysis was performed. Methods: Medical databases and conference proceedings were searched for randomized controlled trials which compared EGFR-TKI (gefitinib or erlotinib) with standard second-line chemotherapy (docetaxel or pemetrexed) in patients with NSCLC. Endpoints were overall survival, progression-free survival and overall response. Results: Three eligible trials (INTEREST, TITAN and TAILOR) were identified. Lacking for data of overall survival of TAILOR trial, So we only make a preliminary meta-analysis for overall survival. The intention to treatment (ITT) analysis demonstrated that the patients receiving EGFR-TKI had a significantly shorter progression-free survival (PFS) than patients treated with chemotherapy (hazard ratio (HR) = 1.31; 95% confidence intervals (CI) = 1.10-1.56; P = 0.002). The overall survival (OS) and overall response rate (ORR) were coparable between this two groups (HR = 0.96; 95%CI = 0.77-1.19; P = 0.69; relative risk (RR) = 0.37; 95%CI = 0.09-1.54; P = 0.17). Conclusions: Although chemotherapy had a clear superiority in PFS as second-line treatment for patients without EGFR mutations compared with EGFR-TKI, OS and ORR were equal in this two regimens. The toxicity profiles might play an important role in the decision to choose EGFR-TKI or chemotherapy. These findings still need to be verified in larger confirmatory studies in future.

A phase I study of Debio 0932, an oral HSP90 inhibitor, in patients with solid tumors.

3026 Background: Debio 0932 is an oral second-generation heat shock protein 90 (HSP90) inhibitor that has shown extended tumor retention, blood-brain-barrier penetration, and promising anti-tumor activity both as monotherapy and combination against a broad range of tumors in pre-clinical models. Here we report the results of the dose escalation part of a phase I study in patients with advanced solid tumors or lymphoma (NCT01168752). Methods: This was an open-label, non-randomized, 3 + 3 dose-escalation study to determine the maximum tolerated dose (MTD) of Debio 0932 when given QD or Q2D during the first 30 days of treatment in patients with advanced solid tumours or lymphoma resistant to standard therapy. The starting dose in both treatment groups was 50mg. Doses were increased according to an algorithm based on observed toxicity and dose limiting toxicities (DLT). Tumor assessments were performed every 8 weeks. Results: Patient characteristics and results are summarized below. DLTs occurred at 1600mg in both dose groups. Adverse events (AE) were mostly CTCAE grade 1 or 2, with no apparent dose relationship. No ocular or cardiac toxicity was observed. The main reason for treatment withdrawal was progressive disease. Investigator-reported cases of SD and PR were observed. Conclusions: Debio 0932 mono-therapy was generally well tolerated and showed promising signs of efficacy in patients with advanced solid tumors. The recommended phase II dose, established at 1000mg QD, will be tested in an additional 30 patients in an ongoing expansion study. A phase I-II study of Debio 0932 in combination with standard of care in the first- and second-line treatment of NSCLC is planned. [Table: see text]

Erlotinib = docetaxel for second-line treatment of NSCLC

Erlotinib = docetaxel for second-line treatment of NSCLC

9074 Pattern of use of second-line treatment for NSCLC in the Nordic countries

9074 Pattern of use of second-line treatment for NSCLC in the Nordic countries

I Am No One. No One Is Perfect…Therefore I Am Perfect

At present, the INTEREST trial 2 is the only trial that shows the noninferiority of gefitinib in comparison with docetaxel in terms of 1-year survival rate. Such a result was not reached by Maruyama et al in the V-16-32 trial, 1 and it is unlikely that it can be hypothesized on the basis of the trial of Thatcher et al (ISEL trial), 3 which did not demonstrate any superiority of gefitinib in comparison with placebo. In our opinion, the assumption of every-3-weeks docetaxel as the gold standard of second-line treatments in NSCLC is fairly questionable. The TAX 317 trial demonstrated an improvement in overall survival with docetaxel 75 mg/m 2 when compared with best supportive care, 4 but only 55 patients were treated with this dose because of the relevant adverse effects observed with the original dose of docetaxel. After the TAX 317 trial, the clinical research has gone three different ways: first, to identify different schedules of docetaxel administration (weekly v every 3 weeks), using the design of the superiority trial; second, to compare novel molecules to every-3-weeks docetaxel, using the design of the noninferiority trial; and third, to use epidermal growth factor receptor inhibitors (gefitinib and erlotinib) as an alternative to chemotherapy. In this context, the clinical development of gefitinib was quite controversial. It was registered for clinical use on the basis of two strongly questioned phase II trials (the IDEAL I and IDEAL II trials) 5-6 ; afterwards, it dramatically fell down after the negative results of the ISEL trial, 3 and now it is trying to take a new lease on life mainly on the basis of the data of the INTEREST trial. 2 Apart from the interesting suggestions of the INTEREST trial, the key question that remains without any answer is who gets benefit from these data, as well as from those of all the other noninferiority trials designed and conducted in second-line treatment of NSCLC. Figure 1 reports the hazard ratios of all the randomized clinical trials published as full text that compared pemetrexed, 7 oral topotecan, 8 or gefitinib 1-2 with docetaxel using a noninferiority statistical design. All but the V-16-32 trial showed a noninferiority of the novel drug (pemetrexed, oral topotecan, and gefitinib) versus docetaxel 75 mg/m 2 , which is known to have found its role uniquely on the outcome of the 55 patients of the TAX 317 trial. 4 A few years ago, Garattini and Bertele ` 9 warned clinicians against

NSCLC: Update der 2nd line Therapie nach ASCO 2007

Since the year 2000 second line therapy for pre-treated non-small cell lung cancer patients has been established. There are currently two chemotherapeutic agents - docetaxel (Taxotere) and pemetrexed (Alimta) - which have been approved for second line treatment in Austria in addition to the tyrosinkinase-inhibitor erlotinib (Tarceva). In randomised trials these agents have shown a clear advantage over best supportive care in pre-treated patients in terms of overall survival and quality of life. However, these compounds also cause considerable drug-specific toxicities. Therefore there is an urgent need for new treatment options with higher efficacy and a lower burden of toxicity. At ASCO 2007, results of randomised trials were presented concerning new chemotherapeutic agents, such as vinflunine as well as targeting agents such as gefitinib, without affecting outcome. Another trial comparing a standard dose of pemetrexed with a higher dose also showed no improvement in outcome. A comparison of immediate application with delayed application of docetaxel after primary treatment demonstrated improved progression-free survival in selected patients in the immediate study arm but this did not translate to a survival benefit. The results of these trials may add further treatment options to the present portfolio of agents and concepts in this setting and give some optimism for the near future. At present, no changes need to be made in the options for standard second-line treatment of NSCLC in view of the results presented at ASCO 2007.

Gemcitabine in combination with oxaliplatin as second-line therapy of advanced and metastatic NSCLC

18157 Background: Single agent gemcitabine is active as second line therapy in NSCLC. Oxaliplatin may be non-cross resistant with the other platinum-containing agents used as first-line therapy in NSCLC. The combination of gemcitabine and oxaliplatin (GEMOX) is synergistic in pre-clinical models. Methods: A phase II, non-randomized trial was designed to assess the efficacy and tolerability of gemcitabine 1,000 mg/m2 over 100 min in combination with oxaliplatin 100 mg/m2 over 2 hours both given on days 1 and 15 of each 28-day cycle. Patients with NSCLC were eligible if they had progressed after first line treatment. Primary endpoint was tumor response rate. Planned sample size is 30 patients over a period of 2 years. Functional Assessment of Cancer Therapy- Lung (FACT-L) v.4 questionaire was used to assess quality of life of patients on therapy. Results: Twenty-two patients have been enrolled. 13 males (59%) and 9 females (41%). 15 Hispanic (68%), 4 Caucasian (18%), and 3 African-American (13%). Median age is 55 yrs. Histologic subtypes are as follows: adenocarcinoma, 12; NSCLC not otherwise specified 7; squamous cell carcinoma, 3. Nine patients had an ECOG performance status (PS) of 0 (41%) and 13 had a PS of 1 (59%). Two patients were never smokers. A total of 56 cycles have been administered (median 2, range 1 to 6). GEMOX as second-line therapy was given to 18 patients (81%), third-line to 4 patients (18%). Two patients died on study from disease progression leading to respiratory and multi-organ failure. The following Grade 3 and 4 adverse events were seen in 2 patients each: fatigue, dyspnea, anemia, and multi-organ failure. Cancer pain was seen in 1 patient. Twenty patients are available for assessment of response. Two patients had a confirmed partial response (10%) and another eight had stable disease (40%). Preliminary results of FACT-L analysis in 19 pts shows improvement in Lung Cancer Subscale (LCS) score in 25% of the patients after 2 cycles of therapy. Conclusions: Combination gemcitabine and oxaliplatin is active and well tolerated as second line treatment for NSCLC. Improvement of LCS score after 2 cycles suggests a clinical benefit that is beyond the observed response rate of 10%. No significant financial relationships to disclose.

Phase I-II trial of daily thalidomide in combination with docetaxel in patients with relapsed non-small cell lung cancer: A final analysis

17060 Background: Recent studies have shown that inhibition of vascular endothelium growth factor (VEGF) in combination with chemotherapy can improve the antitumor efficacy of chemotherapy in NSCLC. This study tested the effectivness and toxicity of thalidomide (an inhibitor of VEGF) combined with docetaxel as second-line therapy for progressive NSCLC. Methods: Patients(pts) with recurrent/progressive NSCLC, prior chemotherapy, measurable/evaluable disease, ECOG performance status (PS) 0–2 and adequate hematologic, renal and hepatic function were enrolled. Pts with uncontrolled CNS disease or hypercoagulable state were excluded. Doxetaxel 75 mg/M2 was administered every 3 weeks (maximum of 8 cycles). Thalidomide was administered orally at a starting dose of 50 mg daily escalated by 50 mg every 3 weeks to a maximum dose of 200mg day and continued until disease progression, dose limiting toxicity, or completion of chemotherapy. Primary end-point was overall survival (OS), secondary end points were time to disease progression(TTP) by Kaplan Meyer method and response rate (RECIST criteria). Results: Of 28 enrolled patients, 26 were eligible for treatment and 25 were evaluable for disease progression and survival. For evaluable pts: mean PS = 1, median age 64.5 years, median number of prior chemotherapy regimens + 1.2. Response rate was 19.1% (1 complete response, 4 partial responses). Stable disease was observed in 9 patients (34.6%). TTP was 2.7 months (95% confidence interval [CI] 2.1–5.0+): median OS was 5.4 months (95% CI 3.1–9.3+). One episode each of febrile neutropenia requiring hospitalization and pulmonary embolism was observed. No grade 3–4 neuropathy was shown. Nonhematologic adverse events included constipation, alopecia, nausea and anorexia. Conclusions: These data suggest thalidomide in doses of 200mg/ day may be combined with docetaxel 75 mg/m2 every 3 weeks in the second line treatment of NSCLC. The response rate, TTP and OS compare favorably with previously reported studies with docetaxel in this population. No significant financial relationships to disclose.

Predictors for toxicity profiles of weekly docetaxel in non-small cell lung cancers

17153 Background: Weekly docetaxel has been proved recently to be safer and equivalently effective compared with traditional tri-weekly docetaxel as second-line treatment for NSCLC. However, the risk factors for toxicity of weekly docetaxel in this group of patients are still unknown. Methods: We reviewed advanced NSCLC patients receiving 2nd line or 3rd line weekly docetaxel from 1999 to 2003 from cancer registry and pharmacy records in our hospital. Clinical characteristics, previous chemotherapy regimens, laboratory data, docetaxel administration schedules/dosage, and treatment efficacy were retrospectively collected. Logistic regression was performed to identify risk factors for adverse outcomes. Cox’s proportional hazards model was used to analyze cumulative-dose related adverse events. Results: A total 155 patients were analyzed for treatment effect and toxicity. The overall response rate of weekly docetaxel (36–40 mg/m2) was 5.16% and median survival of all patients was 8.1 months. The incidence of treatment withdrawal due to adverse events was 43.23 % and significantly related to previous anthracycline use (odds ratio 4.582; P = 0.0144) and chronic hepatitis B or C virus (HBV/HCV) infection(odds ratio 3.928; P=0.0058). The incidence of grade 3 or 4 neutropenia was 23.2% and was significantly associated with old age (odds ratio 7.232; P &lt; 0.001), lower baseline white count(odds ratio 5.57; P &lt; 0.05), and chronic HBV/HCV infection(odds ratio 3.25; P &lt; 0.05). The incidence of fluid retention was 41.29% and the median cumulative dose of docetaxel at onset was 327 mg/m2. Abnormal liver function significantly increased the risk for fluid retention(odds ratio 2.368; P &lt; 0.05); steroid premedication (odds ratio 0.184; P &lt; 0.01), higher albumin(odds ratio 0.237; P &lt; 0.01), and previous surgical resection(odds ratio 0.341; P &lt; 0.05) decreased the risk. Conclusions: Salvage weekly docetaxel for NSCLC patients in Taiwan remains toxic. Part of the reasons for the significant toxicities is that chronic HBV/HCV infection, which occurs in around 20% of general populations in Taiwan, represents a significant risk factor for neutropenia, fluid retention, and treatment withdrawal. The role of prophylactic anti-viral agents in these patients should be explored in the future. [Table: see text]

Update on the Role of Topotecan in the Treatment of Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) is an aggressive disease that is generally resistant to chemotherapy. As a result, the prognosis for patients with NSCLC is poor. Currently, platinum-based regimens are the standard of care for patients with advanced NSCLC. However, these regimens are associated with severe and often cumulative hematologic and nonhematologic toxicities, limiting dose intensity. Therefore, novel chemotherapeutic agents and combination regimens may improve the outcome for these patients. A variety of new agents and combinations have been investigated in the treatment of NSCLC. However, to date, no clearly superior single-agent or combination regimen has emerged. Topotecan (Hycamtin; GlaxoSmithKline; Philadelphia, PA), a topoisomerase I inhibitor, is currently approved for the treatment of patients with relapsed small cell lung cancer (SCLC) and is associated with manageable, noncumulative, hematologic toxicities. In addition, topotecan demonstrates a favorable nonhematologic tolerability profile compared with agents currently used in the treatment of patients with NSCLC. The success of topotecan in patients with SCLC has made it an attractive option in the NSCLC setting. Topotecan-based combination regimens in the first-line treatment of NSCLC have demonstrated promising antitumor activities with favorable toxicity profiles. Many topotecan combination regimens have induced stable disease, a response that may offer meaningful clinical benefit in the palliative treatment of patients with advanced disease. Topotecan plus gemcitabine (Gemzar; Eli Lilly and Company; Indianapolis, IN) and single-agent topotecan may be particularly appropriate for patients in the second-line setting, in which palliation of symptoms is an important outcome of chemotherapy. Herein, the future role of topotecan in the first- and second-line treatment of NSCLC and the potential role of resistance mechanisms obtained from in vivo dose-response studies in designing future combination regimens are discussed.

Randomized phase III trial of Taxol®/Carboplatin versus Taxol®Cisplatin in patients with advanced non-small cell lung cancer

platinum or non-platinum chemotherapy von Pawel J1, Manegold C2, Mattson K3, Postmus PE4, Smit EF4, Clarke S5, Saarinen A.1 Asklepios FachkIinik MŸnchen-Gauting, Germany; 2Thoraxklinik, Heidelberg, Germany; 3Division of Pulmonary Medicine, Helsinki University Central Hospital, Finland; 4Department of Pulmonary Diseases, Vrije Universiteit Amsterdam, 5Sydney Cancer Center, Sydney, Australia Purpose: Although new chemotherapeutic agents for NSCLC have been introduced, a critical need for active second-line agents still exists. This study evaluates the activity of MTA (multitargeted antifolate), in the treatment of NSCLC pts who relapsed following front-line therapy. MTA inhibits multiple folate-dependent enzymes and has activity in multiple tumors, i.e. NSCLC, breast, mesothelioma, head and neck, pancreas, and colon cancers. Methods: Pts with Stage IIIb or IV NSCLC who had relapsed during or within 3 months of prior therapy entered into 2 cohorts, depending on whether their prior therapy did (PT) or did not contain platinum (NP) (i.e. mitomycin, docetaxel, paclitaxel, vinorelbine, and/or gemcitabine). All pts received MTA 500 mg/m2 every 21 days with prophylactic dexamethasone. Results: 43 of 67 pts enrolled are evaluable for response. In the PT arm, 3 partial responses (PRs) were reported, for an overall response rate (RR) of 13%. In the NP arm, 1 complete and 5 PRs in 20 evaluable pts was reported, for a RR of 30%. Grade 3/4 toxicity (as % of cycles) includes Hgb: 6/1, WBC: 19/3, ANC: 14/9, platelets: 3/4, bilirubin: 2/0, elevated transaminases: 3/0, and infection: 1/2, respectively. One pt discontinued due to drug-related pneumonia. Four on-study deaths are not thought to be drug-related. Conclusion: MTA is active in the second-line treatment of NSCLC and appears noncross resistant with a variety of front-line agents.

Docetaxel useful in second-line treatment of NSCLC?

Docetaxel useful in second-line treatment of NSCLC?