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Treatment Paradigms in Advanced Non–Small-Cell Lung Cancer Caroline E

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Treatment Paradigms in Advanced Non–Small-Cell Lung Cancer Caroline E Treatment Paradigms in Advanced Non–Small-Cell Lung Cancer Caroline E. McCoach, MD, PhD, and Karen Kelly, MD Dr McCoach is a clinical research fellow Abstract: Lung cancer is the most common cause of cancer-relat- and Dr Kelly is a professor of medicine, ed death worldwide, owing to its metastatic spread at the time of an associate director for clinical research, diagnosis. As a result, chemotherapy is the standard of care for the and the Jennifer Rene Harmon Tegley majority of patients. In recent years, the role of chemotherapy has and Elizabeth Erica Harmon Endowed Chair in Cancer Clinical Research in the expanded to include maintenance therapy and approved second- department of internal medicine at the and third-line treatments. Nonetheless, traditional chemotherapy University of California, Davis Medical has modestly improved outcomes in patients with advanced Center in Sacramento, California. non–small-cell lung cancer (NSCLC). Research efforts have been redirected toward the integration of molecularly-targeted agents Address correspondence to: into a treatment algorithm with unprecedented survival rates Karen Kelly, MD UC Davis Comprehensive Cancer Center in selected patients. This article will provide an update on the 4501 X Street, Suite 3016 multiple systemic regimens available to treat NSCLC, and discuss Sacramento, CA 95817 emerging molecular-based therapies. Phone: 916-734-3735 Fax: 916-734-7946 E-mail: [email protected] Introduction Lung cancer is the leading cause of cancer-related death worldwide, contributing to an estimated 1.4 million deaths every year.1 This high mortality rate results from the inability to detect lung cancer in its early stage. As a consequence, the majority of patients are diag- nosed with advanced disease, for which no curative therapy exists. Platinum-based chemotherapy has been the mainstay of treatment for several decades, and has been shown to prolong survival, palliate symptoms, and enhance quality of life. However, the benefits of this treatment are short-lived. Over the past 2 decades, unprecedented advances in the treatment of metastatic non–small-cell lung cancer (NSCLC) have occurred. The successful alignment of our increased knowledge of the molecular biology of lung cancer with drug devel- opment has launched a new era of “precision medicine.” Moreover, maintenance therapy and treatment beyond the first line are now common practice. This review summarizes recent advances in the Keywords Non–small-cell lung cancer, molecularly targeted treatment of NSCLC, provides a treatment algorithm, and discusses therapy, chemotherapy, maintenance therapy promising new therapies currently in development. Clinical Advances in Hematology & Oncology Volume 11, Issue 10 October 2013 629 MCCOACH AND KELLY First-Line Therapies A second molecular target in NSCLC is the gene rearrangement of the anaplastic lymphoma kinase (ALK) Molecularly-Targeted Regimens gene with the echinoderm microtubule-associated pro- The first druggable molecular target in NSCLC was the epi- tein-like 4 (EML4-ALK) gene. The ALK fusion protein dermal growth factor receptor (EGFR). When ligands bind product leads to constitutive activation of multiple path- to this receptor, the intracellular pathway is activated, lead- ways responsible for growth, proliferation, and survival.17 ing to cell growth, proliferation, and activation of additional ALK fusion proteins are found in approximately 4% of all signaling pathways.2 Mutations in EGFR lead to constitutive NSCLCs.18-20 Clinically, the ALK rearrangement is associ- activation of the receptor, resulting in uncontrolled cellular ated with adenocarcinoma, a younger age at diagnosis, proliferation, tumor growth, and metastases.3,4 The inci- and a lack of smoking history.17 dence of EGFR mutations varies by smoking status, ethnic A phase 1 study of crizotinib (Xalkori, Pfizer), a small background, and tumor histology.5 By tumor histology, molecular ALK inhibitor, demonstrated an ORR of 61% EGFR mutations occur in 30% of adenocarcinomas and and a median PFS of 9.7 months in 143 heavily pretreated in 7% of non-adenocarcinomas. Two mutations—deletions patients with ALK-positive tumors.21,22 Because of its in exon 19 and L858R—are responsible for the majority therapeutic benefit, crizotinib was approved for the treat- of EGFR mutations in NSCLC, and confer sensitivity to ment of patients with ALK-positive tumors. Recently, the EGFR-tyrosine kinase inhibitors (TKIs).6 PROFILE 1007 (A Phase III Trial of Crizotinib Versus The first trial to demonstrate a benefit for an EGFR- Standard of Care in Patients With Advanced Non–Small- TKI in the frontline setting was IPASS (Iressa Pan-Asia Cell Lung Cancer With a Specific Alteration of the Study). This landmark study compared carboplatin plus Anaplastic Lymphoma Kinase Gene) trial confirmed the paclitaxel with gefitinib (Iressa, AstraZeneca) in patients therapeutic benefit of crizotinib over standard second-line with advanced NSCLC.7 As shown in Table 1, a significantly chemotherapy with docetaxel or pemetrexed (Alimta, Eli longer progression-free survival (PFS) was observed in the Lilly; Table 1).23 This study demonstrated a median PFS subset of patients with EGFR-mutated tumors who received of 7.7 months in the crizotinib group compared with 3 gefitinib (hazard ratio [HR], 0.48;P <.001) compared with months in the chemotherapy group (HR, 0.49; P<.001). patients who received chemotherapy. However, in patients Patients who received crizotinib had a 65% ORR, com- with a wild-type EGFR tumor, PFS was longer in the che- pared with 20% for patients who received chemotherapy motherapy arm (HR, 2.85; P<.001). These findings, along (P<.0001). A preliminary survival analysis did not detect with the results of 4 other randomized clinical trials (Table a difference in OS between the 2 groups. 1), convincingly demonstrate the benefit of an EGFR-TKI Given the proven benefit of EGFR and ALK inhibitors, as the treatment of choice for patients with EGFR-mutated the National Comprehensive Cancer Network (NCCN) and tumors, with all studies showing significantly increased the American Society of Clinical Oncology (ASCO) recom- objective response rates (ORR) and prolonged PFS.8-14 mend testing all patients with adenocarcinoma for EGFR Overall survival (OS) was not improved, owing to crossover. mutations and ALK gene fusion.24,25 To assist clinicians and In May 2013, erlotinib (Tarceva, Astellas Pharma Inc) and a pathologists in selecting patients for this therapy, a compre- companion EGFR diagnostic test were approved by the US hensive molecular testing guideline was published.26 Food and Drug Administration (FDA) for the first-line treat- ment of patients whose tumors harbor an EGFR mutation. Chemotherapy Regimens Afatinib (Gilotrif, Boehringer Ingelheim), a second- Despite recent advances in targeted therapies for subsets generation irreversible EGFR-TKI, has also shown ben- of patients with oncogene-driven lung adenocarcinomas, efit in the first-line setting. Two phase 3 trials comparing chemotherapy remains the standard of care for patients afatinib with a platinum doublet in patients with EGFR- with advanced-stage NSCLC. Over the last 2 decades, mutated tumors produced results similar to those with combination chemotherapy options for lung cancer first-generation EGFR-TKIs (Table 1).15,16 The median patients have increased. Paclitaxel, docetaxel, gemcitabine, PFS for the afatinib arms were 11.1 months (HR, 0.58; and vinorelbine are all acceptable platinum partners in the P<.001) and 11 months (HR, 0.28; P<.0001). Response first-line setting. In fact, no significant differences in PFS rates significantly favored afatinib. Based on these data, and OS were demonstrated among 4 commonly used afatinib was approved on July 12, 2013 for the first-line regimens, with a median PFS of 3.6 months, an OS of treatment of patients with advanced-stage lung cancer 7.9 months, and a 1-year survival rate of 33% (Table 1).27 whose tumors harbor an EGFR exon 19 deletion or Importantly, doublet regimens have demonstrated activ- L858R mutation. To evaluate whether there is an optimal ity and tolerability in elderly patients and in patients with EGFR-TKI, a randomized trial comparing afatinib with a poor performance.28,29 Thus, more and more patients erlotinib (LUX-LUNG 8) is ongoing. now have the opportunity to benefit from chemotherapy. 630 Clinical Advances in Hematology & Oncology Volume 11, Issue 10 October 2013 TREATMENT PARADIGMS IN ADVANCED NON–SMALL-CELL LUNG CANCER Since there are several options, choosing a regimen is The primary endpoint of superiority regarding OS was predominantly based on toxicity profile and schedule of not met. The arm containing pemetrexed had a slightly administration, in association with other patient factors. better median PFS at 6.0 months compared with 5.6 One additional cytotoxic chemotherapeutic agent— months in the carboplatin/paclitaxel/bevacizumab arm. pemetrexed—has shown a benefit in advanced lung cancer. Whether this level of improvement is clinically meaning- Pemetrexed was originally approved as monotherapy in the ful is questionable. Currently, paclitaxel/carboplatin plus second-line setting. Upon its evaluation with cisplatin in bevacizumab followed by bevacizumab maintenance is untreated patients, it was shown to improve OS and offer the standard of care for bevacizumab-eligible patients less toxicity.30 In a preplanned analysis, a statistically signifi- (non-squamous histology, no history of hemoptysis, and
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