SATURN: A DOUBLE-BLIND, RANDOMIZED, PHASE III STUDY OF MAINTENANCE ERLOTINIB VS PLACEBO FOLLOWING NONPROGRESSION WITH FIRST-LINE PLATINUM-BASED CHEMOTHERAPY IN PATIENTS WITH ADVANCED NSCLC

Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczesna A, Juhasz E, Esteban Gonzalez E, Molinier O, Klingelschmitt G, Giaccone G, on behalf of the SATURN Investigators; Istituto Clinico Humanitas IRCCS, Rozzano, Italy; Institute of Oncology Ion Chiricuta, Cluj-Napoca, Romania; Pavlov State Medical University, St. Petersburg, Russian Federation; Institute of Oncology, Vilnius University, Vilnius, Lithuania; Mazowieckie Centrum Leczenia Chorob Pluc I Gruzlic, Otwock, Poland; Koranyi National Institute for Pulmonology, Budapest, Hungary; Hospital Universitario Central de Asturias, Oviedo, Spain; Centre Hospitalier Le Mans, Le Mans, France; F. Hoffmann-La Roche, Basel, Switzerland; CCR, National Cancer Institute, NIH, Bethesda, MD.

Non–small-cell lung cancer (NSCLC) is routinely managed with platinum-based doublet chemotherapy¹; however, responses to traditional chemotherapy are often brief, with a median time-to-progression of 3 to 5 months. Although second-line chemotherapy with docetaxel or pemetrexed can prolong survival after platinum-based therapy, few options are available for the treatment of patients with disease progression following these agents, or for those who are not eligible for these medications.^1,2 Thus, many patients with advanced disease continue to experience disease progression, and satisfactory treatment remains to be found.³

The epidermal growth factor receptor (EGFR), which helps to regulate signaling involved in cell proliferation, apoptosis, angiogenesis, invasion, and metastasis, plays a large role in cancer development and progression.⁴ Erlotinib, an EGFR tyrosine kinase inhibitor, has shown promising anti-tumor activity in patients with NSCLC, including those in whom first- or second-line chemotherapy has proven unsuccessful. Specifically, the use of erlotinib following failure of first- or second-line chemotherapy for NSCLC has been shown to increase survival time by approximately 2 months (ie, 6.7 months with erlotinib vs 4.7 months with placebo).²

The SATURN (Phase III Sequential Tarceva in Unresectable NSCLC) study, a phase III, double-blind, randomized-clinical trial, was conducted to evaluate the efficacy and safety of erlotinib as maintenance therapy following standard first-line chemotherapy in patients with advanced NSCLC. Patients with no evidence of disease progression after 4 cycles of platinum-based chemotherapy were randomized to receive either 150 mg per day of erlotinib (n = 438) or placebo (n = 451) until disease progression or intolerable toxicity. Baseline demographics were similar for both treatment groups (Table).⁵

Table. Baseline Demographics

Data from Cappuzzo et al.⁵

Progression-free survival (PFS; the primary end point) was significantly extended in patients treated with erlotinib, as compared with those given placebo (hazard ratio [HR] = 0.71; 95% confidence interval [CI], 0.62–0.82; P <.0001),⁵ and physicians at the International Association for the Study of Lung Cancer world conference reported that erlotinib reduced the risk of disease progression by 19%.⁶ Similar PFS findings were seen in EGFR immunohistochemistry-positive (IHC+) patients (ie, those whose tumors overexpress EGFR; HR = 0.69; 95% CI, 0.58–0.82; P <.0001). The response rate with erlotinib was more than twice that of placebo (12% vs 5%), and the disease control rate was significantly improved in patients who received erlotinib compared to those who received placebo (40.8% vs 27.4%; P <.0001). Overall, erlotinib was well-tolerated, and the majority of treatment-related adverse events were mild to moderate in nature; the most commonly reported events included rash (60% with erlotinib vs 9% with placebo) and diarrhea (20% with erlotinib vs 5% with placebo). Approximately 2.3% of those treated with erlotinib experienced a serious treatment-related adverse event. Investigators concluded that erlotinib is safe and effective as first-line maintenance treatment of advanced NSCLC.⁵

This study was well-designed to demonstrate the impact of erlotinib on disease progression in patients with NSCLC. Baseline similarities between groups helped to eliminate any discrepancies that may have been caused by confounding variables. Furthermore, the subanalysis of patients who were EGFR IHC+ played an important role in validating the mechanism via which erlotinib may be effective. The findings of this study demonstrate that erlotinib significantly improves disease control, and although investigators did not sufficiently elaborate on serious treatment-related adverse events, it is evident that it is generally well-tolerated in this treatment population. These findings pave the way for a new treatment approach in advanced NSCLC because erlotinib may eventually be indicated for maintenance treatment of advanced NSCLC.³

References
1. National Comprehensive Cancer Network (NCCN). Non–small-cell lung cancer V.2.2009. NCCN Clinical Practice Guidelines in Oncology. Available at: http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed August 31, 2009.
2. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated non–small-cell lung cancer. N Engl J Med. 2005;353:123-132.
3. OSI: tarceva approved as maintenance treatment for lung cancer. Seeking Alpha Web site. July 14, 2009. Available at: http://seekingalpha.com/article/148649-osi-tarceva-approved-as-maintenance-treatment-for-lung-cancer?source=from_friend. Accessed August 31, 2009.
4. Ciardiello F, De Vita F, Orditura M, Tortora G. The role of EGFR inhibitors in nonsmall cell lung cancer. Curr Opin Oncol. 2004;16:130-135.
5. Cappuzzo F, Ciuleanu T, Stelmakh L, et al. SATURN: A double-blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol. 27:15s, 2009 (suppl;abstr 8001).
6. Cappuzzo F, et al. Efficacy and safety of erlotinib as first-line maintenance in NSCLC following non-progression with chemotherapy: results from the phase III SATURN study International Association for the Study of Lung Cancer. Presented at: 13th World Conference on Lung Cancer; San Francisco, CA; July 31, 2009-August 4, 2009.