Efficacy and safety of rociletinib versus chemotherapy in patients with EGFR-mutated NSCLC: the results of TIGER-3, a phase 3 randomized study

Introduction: The TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs. Methods: Patients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). Results: Enrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6-5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8-8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4-2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28-1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively). Conclusions: Rociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point

Effects of gemcitabine on renal function in patients with non-small cell lung cancer

Gemcitabine is a novel fluorine-substituted cytarabine (Ara-C) analogue with activity against a range of solid tumours. Besides dose-limiting haematological toxicity, renal side-effects were observed from phase I and II studies concerning elevations of serum creatinine, proteinuria and erythrocyturia. The aim of this study was to investigate the effect of gemcitabine on renal function in 11 untreated patients with non-small cell lung cancer (NSCLC). Gemcitabine was given as weekly infusions of 1250 mg/m(2) for 3 weeks, followed by 1 week rest. This comprised one cycle (maximum of six cycles). The glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were measured simultaneously with a constant infusion of I-125-iothalamate and I-131-hippuran, respectively. Tubular damage was monitored by excretion of tubular enzymes (lactic dehydrogenase (LDH), alkaline phosphatase (ALP), gamma-glutamyltransferase (GT) and beta(2)-microglobulin); glomerular damage was monitored by excretion of albumin in the urine. In 9 patients, the effect of the first infusion was evaluated. After the first infusion of gemcitabine, no change was observed in renal function. After two, three, and six cycles of treatment, no significant changes in GFR and ERPF were noticed in 9 evaluable patients. However, in 3 patients, a decrease in GFR of > 10% was observed after multiple cycles. In one of them this was accompanied with albuminuria (360 mg/24 h) and erythrocyturia. There were no significant changes in urinary excretion of tubular enzymes or albumin. In conclusion, we did not observe acute renal toxicity with gemcitabine. No significant cumulative effects of gemcitabine on renal function could be detected, although 3 patients, treated with multiple cycles of gemcitabine, showed a moderate decrease in renal function. Glomerular damage might play a role in the development of renal function loss. (C) 1998 Elsevier Science Ltd

SURGICAL RESECTION FOR SMALL-CELL CARCINOMA OF THE LUNG - A RETROSPECTIVE STUDY

Background - A retrospective review was undertaken of the survival of 21 patients with histologically proven small cell carcinoma of the lung resected between 1977 and 1991.Methods - Twenty one patients (20 men) of median age 60 (range 44-73) years underwent surgical resection. Patients were subjected to standard clinical staging procedures. Preoperative diagnosis was small cell carcinoma of the lung in 13, non-small cell lung cancer in one, and uncertain in seven patients. Clinical staging was stage I disease in 11 and stage II in 10 patients.Results - Resection included pneumonectomy in 12 cases, lobectomy in eight, and one wedge resection. Resection was complete in 16 patients. Postoperative histopathological examination confirmed small cell carcinoma of the lung in 19 specimens and mixed small cell and nonsmall cell carcinoma of the lung in two. Pathological staging was stage I in 11, stage II in three, and stage III in seven patients. The final pathological diagnosis of the resected specimens (n=18) was atypical carcinoid in one, pure small cell carcinoma of the lung in 15, and mixed small cell and non-small cell carcinoma of the lung in two patients. Fourteen patients also received chemotherapy and 10 received prophylactic cranial irradiation postoperatively. Excluding the patient with a final diagnosis of atypical carcinoid, the median survival (n=20) was 29 months (range two to 133+). Median survival for patients with pathological stage I and II disease (n=13) was 40 months (range nine to 133+) and for patients with pathological stage III disease (n=7) 20 months (range two to 116+). The median disease free survival was 23 months. Eleven patients relapsed between two and 101 months. There was no advantage for those patients who received postoperative chemotherapy.Conclusion - Curative resection offers the best chance for long term survival in patients with small cell carcinoma of the lung with very limited stage disease.</p

SURGICAL RESECTION FOR SMALL-CELL CARCINOMA OF THE LUNG - A RETROSPECTIVE STUDY

Background - A retrospective review was undertaken of the survival of 21 patients with histologically proven small cell carcinoma of the lung resected between 1977 and 1991. Methods - Twenty one patients (20 men) of median age 60 (range 44-73) years underwent surgical resection. Patients were subjected to standard clinical staging procedures. Preoperative diagnosis was small cell carcinoma of the lung in 13, non-small cell lung cancer in one, and uncertain in seven patients. Clinical staging was stage I disease in 11 and stage II in 10 patients. Results - Resection included pneumonectomy in 12 cases, lobectomy in eight, and one wedge resection. Resection was complete in 16 patients. Postoperative histopathological examination confirmed small cell carcinoma of the lung in 19 specimens and mixed small cell and nonsmall cell carcinoma of the lung in two. Pathological staging was stage I in 11, stage II in three, and stage III in seven patients. The final pathological diagnosis of the resected specimens (n=18) was atypical carcinoid in one, pure small cell carcinoma of the lung in 15, and mixed small cell and non-small cell carcinoma of the lung in two patients. Fourteen patients also received chemotherapy and 10 received prophylactic cranial irradiation postoperatively. Excluding the patient with a final diagnosis of atypical carcinoid, the median survival (n=20) was 29 months (range two to 133+). Median survival for patients with pathological stage I and II disease (n=13) was 40 months (range nine to 133+) and for patients with pathological stage III disease (n=7) 20 months (range two to 116+). The median disease free survival was 23 months. Eleven patients relapsed between two and 101 months. There was no advantage for those patients who received postoperative chemotherapy. Conclusion - Curative resection offers the best chance for long term survival in patients with small cell carcinoma of the lung with very limited stage disease