TATTON: a multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancer.

BACKGROUND: Osimertinib is a potent, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). The multi-arm phase Ib TATTON study (NCT02143466) was designed to assess the safety and tolerability of osimertinib in combination with other targeted therapies: selumetinib (MEK1/2 inhibitor), savolitinib (MET-TKI), or durvalumab [anti-programmed cell death ligand 1 (anti-PD-L1) monoclonal antibody]. PATIENTS AND METHODS: Patients with advanced EGFR-mutant non-small-cell lung cancer and disease progression on a prior EGFR-TKI were enrolled and allocated to dose-escalating cohorts combining osimertinib 80 mg orally (p.o.) once a day with selumetinib (25-75 mg p.o. twice a day; continuous or intermittent), savolitinib (600-800 mg p.o. once a day), or durvalumab (3-10 mg/kg intravenous every 2 weeks). RESULTS: At data cut-off (28 February 2018), 77 patients were enrolled and received osimertinib plus selumetinib (n = 36), savolitinib (n = 18), or durvalumab (n = 23). Most common adverse events (any grade), occurring in ≥20% of patients across dose groups, were: selumetinib arm-diarrhea (75%), rash (58%), nausea (47%); savolitinib arm-nausea (67%), rash (56%), vomiting (50%); durvalumab arm-rash (48%), vomiting (43%), diarrhea (39%). Dose-limiting toxicities were reported in the selumetinib 25 mg (n = 1), 50 mg (n = 1), and 75 mg (n = 4) continuous-dose groups, savolitinib 600 mg (n = 1) and 800 mg dose groups (n = 2), and durvalumab 10 mg/kg (n = 1) dose group. The objective response rate was 42% (95% confidence interval 26% to 59%), 44% (22% to 69%), and 43% (23% to 66%) in the selumetinib, savolitinib, and durvalumab arms, respectively. CONCLUSION: Our results demonstrate the feasibility of combining osimertinib 80 mg with selumetinib or savolitinib at identified tolerable, active doses. A combination of osimertinib with durvalumab was not feasible due to increased reporting of interstitial lung disease. Osimertinib-based combination therapies represent a compelling approach now being further investigated. CLINICAL TRIALS NUMBER: NCT02143466.

A randomized, open-label, phase III trial comparing amrubicin versus docetaxel in patients with previously treated non-small-cell lung cancer.

Background: Amrubicin is approved for treating non-small-cell lung cancer (NSCLC) and small-cell lung cancer. However, no direct comparisons between amrubicin and docetaxel, a standard treatment for NSCLC, have been reported. Patients and methods: We conducted a randomized phase III trial of Japanese NSCLC patients after one or two chemotherapy regimens. Patients were randomized to amrubicin (35 mg/m2 on days 1-3 every 3 weeks) or docetaxel (60 mg/m2 on day 1 every 3 weeks). Outcomes included progression-free survival, overall survival, tumor responses, and safety. Results: Between October 2010 and June 2012, 202 patients were enrolled across 32 institutions. Median progression-free survival (3.6 versus 3.0 months; P = 0.54) and overall survival (14.6 versus 13.5 months; P = 0.86) were comparable in the amrubicin and docetaxel groups, respectively. The overall response rate was 14.4% (14/97) and 19.6% (19/97) in the amrubicin and docetaxel groups, respectively (P = 0.45). The disease control rate was 55.7% in both groups. Adverse events occurred in all patients, and included grade ≥3 neutropenia occurred in 82.7% and 78.8% of patients in the amrubicin and docetaxel groups, respectively, grade ≥3 leukopenia occurred in 63.3% and 70.7%, and grade ≥3 febrile neutropenia occurred in 13.3% and 18.2% of patients in the amrubicin and docetaxel groups, respectively. Of eight cardiac-related events in the amrubicin group, three were considered related to amrubicin and resolved without treatment discontinuation. Conclusions: This was the first phase III study to compare amrubicin and docetaxel in patients with pretreated NSCLC. Amrubicin did not significantly improve the primary endpoint of PFS compared with docetaxel. Clinical trial registration: NCT01207011 (ClinicalTrials.gov).

Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study.

BACKGROUND: A phase III study (Lung Cancer Evaluation of TS-1) previously demonstrated noninferiority in terms of overall survival (OS) at interim analysis for carboplatin-S-1 compared with carboplatin-paclitaxel for first-line treatment of advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 564 patients were randomly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1-14 or carboplatin-paclitaxel on day 1 every 21 days. Updated results and post hoc subgroup analysis according to tumor histology are presented. RESULTS: The updated analysis revealed a median OS of 15.2 months in the carboplatin-S-1 arm and 13.1 months in the carboplatin-paclitaxel arm, with a hazard ratio (HR) of 0.956 [95% confidence interval (CI) 0.793-1.151], consistent with the previous primary analysis. Median OS was 14.0 months in the carboplatin-S-1 arm and 10.6 months in the carboplatin-paclitaxel arm (HR 0.713; 95% CI 0.476-1.068) for patients with squamous cell carcinoma (SCC), with corresponding values of 15.5 and 13.9 months (HR 1.060; 95% CI 0.859-1.308) for those with non-SCC. CONCLUSIONS: These results establish the efficacy and safety of carboplatin-S-1 in patients with advanced NSCLC regardless of tumor histology.

Volume measurement of crowns in mandibular primary central incisors by micro-computed tomography.

OBJECTIVE: To determine sex differences in the tissue proportions of crowns of mandibular primary central incisors in Chinese children and to quantify the volume of crown components in three dimensions using micro-computed tomography (micro-CT). MATERIALS AND METHODS: The specimens used in this study were 41 mandibular first deciduous incisor teeth with intact crowns (21 males and 20 females) obtained from patients between 5-6 years of age. Each specimen was scanned using micro-CT at a resolution of 0.05 mm and 3D-rendered images were created. The volume of each component of the crown was measured and examined for differences in different sex and ages. RESULTS: The pulp chamber volume decreased with age and the volume ratio of the pulp chamber to the whole crown was significantly smaller in 6-year-olds than in 5-year-olds (p < 0.05). CONCLUSIONS: Males had significantly larger tooth crown volumes and dentin volumes than females did (p < 0.001), while the volume of enamel showed no sexual dimorphism.

Fractional model for Middle East respiratory syndrome coronavirus on a complex heterogeneous network.

In this paper, we present a new fractional epidemiological model on a heterogeneous network to investigate Middle East respiratory syndrome (MERS-CoV), which is caused by a virus in the coronavirus family. We also consider the development of equations for the camel population, given that it is the primary animal source of the virus, as well as direct human interaction with this population. The model is configured in an SIS form for both the human population and the camel population. We study the equilibrium positions of the system and the conditions for the existence of each of them, as well as the local stability of each equilibrium position. Then, we provide some numerical examples that compare real data and numerical results.

A fractional complex network model for novel corona virus in China.

As is well known the novel coronavirus (COVID-19) is a zoonotic virus and our model is concerned with the effect of the zoonotic source of the coronavirus during the outbreak in China. We present a SEIS complex network epidemic model for the novel coronavirus. Our model is presented in fractional form and with varying population. The steady states and the basic reproductive number are calculated. We also present some numerical examples and the sensitivity analysis of the basic reproductive number for the parameters.

A multicenter cohort study of osimertinib compared with afatinib as first-line treatment for EGFR-mutated non-small-cell lung cancer from practical dataset: CJLSG1903.

BACKGROUND: FLAURA, the prospective trial of osimertinib as a first-line therapy compared with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), did not show superior survival benefit for osimertinib in either the subgroup of Asians or the subgroup with the L858R mutation. In addition, the superiority of osimertinib compared with second-generation EGFR-TKI is thus far unclear. PATIENTS AND METHODS: We reviewed the clinical data of all consecutive patients who were treated with osimertinib or afatinib as first-line therapy between May 2016 and October 2019 from 15 institutions in Japan. We defined the groups based on first-line EGFR-TKI as the afatinib group and the osimertinib group. Outcomes included time to discontinuation of any EGFR-TKI (TD-TKI), overall survival (OS), and time to treatment failure, with propensity score analysis carried out as an exploratory analysis in the survival and subgroup analyses. RESULTS: A total of 554 patients were enrolled. Data on 326 patients in the osimertinib group, and 224 patients in the afatinib group were analyzed. TD-TKI adjusted by propensity score in the afatinib and osimertinib groups was 18.6 months (95% confidence interval 15.8 to 22.0) and 20.5 months (95% confidence interval 13.8 to not reached), respectively, without significant difference (P = 0.204). OS adjusted by propensity score favored the afatinib group with a significant difference (P = 0.018). Subgroup analysis with propensity score showed that patients with L858R and without brain metastasis had superior survival benefit with afatinib compared with osimertinib (P < 0.001). CONCLUSIONS: TD-TKI in the afatinib group was not significantly prolonged compared with the osimertinib group in the practical data. In the exploratory analysis of patients with L858R-mutated non-small-cell lung cancer without brain metastasis, afatinib showed more benefit in OS over osimertinib.

Novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions.

In the present study, the authors evaluated the diagnostic utility of a novel thin bronchoscope with a 1.7-mm working channel for peripheral pulmonary lesions. A total of 118 patients were included in this prospective study. Bronchoscopic examination was performed using a 5.9-mm standard bronchoscope. If no visible endobronchial lesion was found, transbronchial biopsies were performed with 1.5-mm biopsy forceps under fluoroscopic guidance and the bronchus were washed with 10-20 mL of saline solution, using a prototype 3.5-mm thin bronchoscope with a 1.7-mm working channel. Endobronchial lesion was visualised with the standard bronchoscope in 16 patients, and the other 102 patients underwent biopsies with the thin bronchoscope. The mean bronchus levels reached with the standard bronchoscope and the thin bronchoscope were 2.3 and 4.3 generations, respectively. Endobronchial abnormality was revealed with the thin bronchoscope in a further 14 patients. Diagnostic material was obtained in 50 of 68 (74%) patients with malignant disease and 18 of 30 (60%) patients with benign disease. Four patients did not return to follow-up. The diagnostic yield was 57%, even in lesions <20 mm. There were no major complications. In conclusion, bronchoscopy using a 3.5-mm thin bronchoscope with a 1.7-mm working channel is useful and safe for the diagnosis of peripheral pulmonary lesions.

Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: a pharmacogenetic analysis.

Irinotecan unexpectedly causes severe toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38, which is further conjugated and detoxified by UDP-glucuronosyltransferase (UGT) 1A1 enzyme. Genetic polymorphisms of the UGT1A1 would affect an interindividual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. In this case-control study, retrospective review of clinical records and determination of UGT1A1 polymorphisms were performed to investigate whether a patient with the variant UGT1A1 genotypes would be at higher risk for severe toxicity by irinotecan. All patients previously received irinotecan against cancer in university hospitals, cancer centers, or large urban hospitals in Japan. We identified 26 patients who experienced severe toxicity and 92 patients who did not. The relationship was studied between the multiple variant genotypes (UGT1A1*28 in the promoter and UGT1A1*6, UGT1A1*27, UGT1A1*29, and UGT1A1*7 in the coding region) and the severe toxicity of grade 4 leukopenia (< or =0.9 x 10(9)/liter) and/or grade 3 (watery for 5 days or more) or grade 4 (hemorrhagic or dehydration) diarrhea. Of the 26 patients with the severe toxicity, the genotypes of UGT1A1*28 were homozygous in 4 (15%) and heterozygous in 8 (31%), whereas 3 (3%) homozygous and 10 (11%) heterozygous were found among the 92 patients without the severe toxicity. Multivariate analysis suggested that the genotype either heterozygous or homozygous for UGT1A1*28 would be a significant risk factor for severe toxicity by irinotecan (P < 0.001; odds ratio, 7.23; 95% confidence interval, 2.52-22.3). All 3 patients heterozygous for UGT1A1*27 encountered severe toxicity. No statistical association of UGT1A1*6 with the occurrence of severe toxicity was observed. None had UGT1A1*29 or UGT1A1*7. We suggest that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients. This research warrants a prospective trial to corroborate the usefulness of gene diagnosis of UGT1A1 polymorphisms prior tb irinotecan chemotherapy.

Phase I clinical and pharmacokinetic study of a 14-day infusion of etoposide in patients with lung cancer.

PURPOSE: A phase I study was conducted to determine the maximum-tolerated dose (MTD) of a 14-day continuous infusion of etoposide, and to evaluate the pharmacokinetics in patients with lung cancer. PATIENTS AND METHODS: Etoposide was administered continuously through a central venous catheter using a pump. The starting dose level was 300 mg/m2 over 14 days, with dose escalations of 100 mg/m2 over 14 days until unacceptable toxicities occurred. Pharmacokinetic studies were performed in all patients. RESULTS: Twenty-one patients, 20 with non-small-cell lung cancer and one with refractory small-cell lung cancer, received 37 courses. No World Health Organization (WHO) grade III or greater toxicity occurred at doses up to 400 mg/m2 over 14 days. At 700 mg/m2 over 14 days, all four patients experienced grade III or IV leukocytopenia, and two developed grade III stomatitis. No cumulative toxicity was observed. A steady concentration of etoposide was achieved 24 hours after the start of chemotherapy, and it was significantly correlated with surviving fractions of leukocytes (r = -.64, P = .001) and platelets (r = -.68, P < .001). The leukocyte count at the termination of chemotherapy predicted the nadir count (r = .93, P < .001). CONCLUSION: Steady blood levels of etoposide were maintained for prolonged periods, during 14-day continuous infusions. Leukocytopenia and stomatitis were dose-limiting. Nadir counts and surviving fractions of leukocytes were predicted by the leukocyte count at the end of chemotherapy and the concentration of etoposide, respectively. The recommended dose for phase II trials is 600 mg/m2 over 14 days.

Phase I and pharmacologic study of docetaxel and irinotecan in advanced non-small-cell lung cancer.

PURPOSE: We conducted a phase I trial of docetaxel, a new antimicrotubule agent, combined with irinotecan (CPT-11), a topoisomerase I inhibitor. The aim was to determine the maximum-tolerated dose (MTD) of docetaxel combined with CPT-11, as well as the dose-limiting toxicities (DLTs) of this combination in advanced non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Thirty-two patients with stage IIIB or IV NSCLC were treated at 4-week intervals with docetaxel (60 minutes, day 2) plus CPT-11 (90 minutes, days 1, 8, and 15). The starting doses of docetaxel/CPT-11 were 30/40 mg/m(2), and doses were escalated in 10-mg/m(2) increments until the MTD was reached. RESULTS: The MTD of docetaxel/CPT-11 was 50/60 mg/m(2) (level 5A), or 60/50 mg/m(2) (level 5B). Neutropenia and diarrhea were the DLTs. CPT-11 did not affect the pharmacokinetics of docetaxel. There were 11 (37%) partial responses among 30 patients. The median survival time was 48 weeks, and the 1-year survival rate was 44.9%. CONCLUSION: The combination of docetaxel and CPT-11 seems to be active against NSCLC, with acceptable toxicity. The recommended dose for phase II studies is 50 mg/m(2) of CPT-11 (days 1, 8, and 15) and 50 mg/m(2) of docetaxel (day 2) administered every 28 days.

Multi-institutional validation study of carboplatin dosing formula using adjusted serum creatinine level.

Creatinine clearance (Ccr) is widely used as a practical substitute for glomerular filtration rate (GFR) in the Calvert formula: carboplatin dose (mg) = target area under the concentration versus time curve (AUC, mg ml(-1) min) x [GFR (ml min(-1)) + 25]. However, it causes systematic overdosing when the creatinine levels are measured by an enzymatic peroxidase-antiperoxidase method (PAP-Cr). We previously suggested an amended dosing formula to adjust this overdosing: carboplatin dose (mg) = AUC (mg ml(-1) min) x [adjusted Ccr (ml min(-1)) + 25], where the Ccr was adjusted by adding 0.2 (mg dl(-1)) to serum PAP-Cr. In this study, we prospectively validated this formula in 55 patients from six institutions. Target AUC ranged from 3 to 7 mg ml(-1) min, and Ccr was measured by 24-h urine collection. Estimation of carboplatin clearance with the amended formula was unbiased [mean prediction error (MPE) +/- SE = 2.9 +/- 3.4%] and acceptably precise [root mean squared error, (RMSE) = 24.7%], whereas the Calvert formula using non-adjusted Ccr overpredicted carboplatin clearance systematically (MPE +/- SE = 24.9 +/- 4.9% and RMSE = 36.1%). The improvement in the bias and precision of the estimation was seen in all of the participating institutions as shown by decrease in the absolute value of MPE and RMSE for each institution. The Chatelut formula also highly overestimated carboplatin clearance when PAP-Cr was used, but the adjustment of PAP-Cr yielded a decrease in MPE by 30.4% and in RMSE by 21.3%. These results confirmed the necessity of adjusting the serum PAP-Cr in carboplatin dosing formulas.

Pharmacological analysis of etoposide in elderly patients with lung cancer.

To analyze the pharmacological characteristics of etoposide in elderly patients, we conducted a Phase I trial of a 14-day administration of oral etoposide on 12 chemotherapy-naive patients, ages 75 years or older, with lung cancer. The pharmacological profiles of etoposide in elderly patients were compared with those of younger patients in our previous studies (H. Minami et al., J. Clin. Oncol., 11: 1602-1608, 1993; H. Minami et al., J. Clin. Oncol., 13: 191-199, 1995; Y. Ando et al., Jpn. J. Cancer Res., 87: 200-205, 1996). The sigmoid Emax model and logistic regression model were used for pharmacodynamic analysis. The maximum tolerated dose for elderly patients was 75 mg/body/day. The apparent oral clearance in elderly patients was 37+/-10 (mean +/- SD) ml/min, which was not different from that in younger patients (44+/-12 ml/min). The area under the concentration-versus-time curve of etoposide over the treatment period (total AUC) that produced a 50% decrease in absolute neutrophil counts was significantly different between elderly and younger patients, 14.3+/-2.5 and 21.6+/-2.7 mg x min/ml, respectively (P = 0.048). The incidence of grade 3 or 4 neutropenia at total AUC of 30 mg x min/ml (corresponding to a plasma concentration of 1.5 microg/ml for 14 days) was 81% in elderly patients but only 48% in younger patients. Although there was no pharmacokinetic difference between elderly and younger patients, equivalent exposure to etoposide resulted in severer myelosuppression in elderly patients. These findings suggest that prolonged etoposide administration with plasma concentration maintained at 1-2 microg/ml may cause severe myelotoxicity in elderly patients.

Removal of broken fragment of biopsy forceps with magnetic extractor.

Transbronchial lung biopsy performed on a 51-year-old woman for the evaluation of nodular densities with cavities in the bilateral apical areas was complicated by the breakage of the biopsy forceps. The broken fragment of the forceps was successfully retrieved by use of the magnetic extractor through a fiberoptic bronchoscope under fluoroscopic guidance.

Cytokine content in pleural effusion. Comparison between tuberculous and carcinomatous pleurisy.

Tuberculous pleurisy is a good model for resolution of local cellular immunity. It would be expected that tuberculous pleural fluid contains a variety of immunologically important cytokines because of the accumulation of immunocompetent cells in the pleural cavity. We studied interleukin 1 (IL-1), interleukin 2 (IL-2), and interferon gamma (IFN-gamma) levels in pleural fluid of 20 patients with tuberculous pleurisy and compared them with those in pleural fluid of 20 patients with malignant pleurisy. We also evaluated adenosine deaminase (ADA) levels in both effusions. Tuberculous pleural fluid had higher levels of IL-1, IL-2, IFN-gamma, and ADA than malignant pleural fluid. Although the difference of IL-1 level between tuberculous and malignant pleural fluid was modest, that of IL-2, IFN-gamma, and ADA was dominant. These findings suggest that activated T lymphocytes in tuberculous pleural fluid concern the production of lymphokines at the morbid site and they effectively exert local cellular immunity through the action of such lymphokines.

Successful resection of alpha-fetoprotein-producing lung cancer.

We present a case of successfully resected alpha-fetoprotein (AFP)-producing primary lung cancer. AFP in the serum decreased from 289 ng/ml to an undetectable level after a curative operation. The resected tumor was stained positively by the immunohistochemical study for AFP. The histologic appearance of the tumor was well-differentiated adenocarcinoma similar to that of fetal gut epithelium and apparently different from extragonadal germ cell tumor. This case provides evidence that lung cancer cells possess the potential to produce AFP.

Chemotherapy for small-cell lung cancer: more is not better.

As have many other chemosensitive tumors, small-cell lung cancer (SCLC) has a well-documented chemotherapy dose-response relationship. However, a relationship between dose and survival has not yet been established. The effect of dose on survival should be examined in terms of both the dose used over a certain period (dose intensity) and the total dose of drugs employed, and neither the total dose of drugs used nor the duration of maintenance chemotherapy has been proven to provide an overall survival benefit. In the case of the dose-intensive approach there is no evidence for a significant survival benefit of either high-dose or dose-intensive weekly chemotherapy. Stem-cell support may be a promising means of increasing dose intensity, but the indications are limited and it should be considered highly experimental. Given the relatively good condition of patients in most comparative clinical trials, more is not better in chemotherapy for SCLC, at least in clinical practice.

Mitomycin C, vinblastine and cisplatin combination chemotherapy in the treatment of advanced non-small cell lung cancer.

Thirty-one patients with previously untreated advanced non-small cell lung cancer were treated with mitomycin C (10 mg/m2, day 1), vinblastine (5 mg/m2, days 1 and 15), and cisplatin (80 mg/m2, day 1). Combination chemotherapy was repeated at 4-week intervals until disease progression or unacceptable toxicity. The overall response rate was 52.0%, with a median survival time of 8 months. The median duration of response was 16 weeks (range, 7-49 weeks), and 23% of the patients survived for more than 1 year. Toxicity included moderate myelosuppression, mild nephropathy, and severe nausea and vomiting. This combination therapy of anticancer agents appears to have antitumor activity, but not to have satisfactory therapeutic activity for advanced non-small cell lung cancer.

Phase II study of a 72-h concurrent continuous infusion of cisplatin and etoposide in advanced non-small-cell lung cancer.

We conducted a phase II study to evaluate the antitumor activity and safety of concurrent continuous infusion of cisplatin and etoposide in advanced non-small-cell lung cancer (NSCLC). Cisplatin (30 mg/m2 daily) and etoposide (80 mg/m2 daily) were given as a 24-h continuous infusion for 72 h to 48 patients with previously untreated advanced NSCLC. Of the 46 evaluable patients, 9 achieved a partial response, for an overall response rate of 20% (95% confidence interval, 9.4%-33.9%). The median duration of response was 23 weeks. The median duration of survival for all patients was 34.4 weeks. The major toxicity was hematologic. Leukopenia (WHO grade > or = 3) was observed in 22 patients (48%) and thrombocytopenia (WHO grade > or = 3), in 13 patients (28%). In all, 20 patients (43%) experienced severe anemia (WHO grade > or = 3). Nonhematologic toxicity mainly consisted of moderate to severe alopecia in 33 patients (72%) and moderate to severe nausea and vomiting in 25 patients (54%). No significant nephrotoxicity was seen. We conclude that a 72-h concurrent continuous infusion of cisplatin and etoposide does not appear to be active against advanced NSCLC.

Combination effects of cisplatin, vinorelbine and irinotecan in non-small-cell lung cancer cell lines in vitro.

PURPOSE: Isobologram analysis has been widely used for evaluating the combined effect of two antitumor drugs in vitro as a pre-clinical screening test. In this study, we tried to extend two-dimensional isobologram analysis to three dimensions for evaluating the effects of a three-drug combination. METHODS: We selected three anticancer agents, cisplatin, vinorelbine and irinotecan. Each of them has been classified as having good single-agent activity against non-small-cell lung cancer (NSCLC). Human NSCLC cell lines (EBC-1, PC-3, RERF-LC-MS) were incubated for 4 days in the presence of the three drugs and cytotoxic activities were determined by a tetrazolium-based colorimetric assay (MTT assay). The data were analyzed by three dimensional isobologram analysis. RESULTS: The effects of the three drugs were additive against EBC-1 (a squamous cell carcinoma cell line), subadditive against PC-3 (an adenocarcinoma cell line) and from subadditive to supraadditive against RERF-LC-MS (an adenocarcinoma cell line). CONCLUSIONS: Our findings suggest that the effects of cisplatin, vinorelbine and irinotecan in combination are additive against NSCLC in vitro. These results encourage clinical trials of the three agents in combination chemotherapy for the treatment of NSCLC.