Review Recent advances in the management of advanced non–small-cell lung cancer Charu Aggarwal, MD, MPH, and Corey J. Langer, MD Department of Medicine, Hematology-Oncology Division, University of Pennsylvania, Philadelphia Lung cancer is the leading cause of cancer-related mortality among men and women in the United States. Non–small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Most patients with NSCLC present with advanced disease and median overall survival in this incurable setting remain dismal. Accumulating evidence suggests that both histology and molecular signature have prognostic and predictive value for NSCLC. Recent advances in the molecular characterization of NSCLC tumors have made individualized treatment approaches feasible. Personalized chemotherapy and targeted biological therapy based on a tumor’s individual biologic and molecular profile can optimize efficacy while minimizing toxicity. Molecular testing for activating mutations in the epidermal growth factor receptor (EGFR) domain and EML4-ALK translocation are routinely used to guide therapeutic decisions. Several new treatments that irreversibly target EGFR family members are in development for patients with NSCLC. Novel EML4-ALK inhibitors such as LDK378 are promising agents with encouraging early efficacy data. KRAS mutations are the most common mutation in adenocarcinomas. Although no agents for this subset of NSCLC have been approved, there are several agents in clinical development, including selumetinib, an MEK inhibitor, that seem promising. A growing body of evidence suggests that NSCLC is subject to immune surveillance. Immunotherapeutic interventions, including vaccine therapy and antigen-independent immunomodulatory strategies, may improve outcomes in NSCLC. In this review, we summarize recent advances in non–small-cell lung cancer, with an emphasis on investigational strategies for individualized treatment. ung cancer is the most common cause of For patients with advanced NSCLC, 4-6 cycles of cancer-related death worldwide.1 Between platinum-based chemotherapy is the usual ap- L85% and 90% of lung cancers are non– proach.2 Histology plays an important role in out- small-cell lung cancer (NSCLC), and 40% of pa- comes. For patients with adenocarcinoma, front- tients with newly diagnosed NSCLC present with line pemetrexed and platinum have been shown to advanced disease. Adenocarcinoma is the most yield superior efficacy and an improved side effects common subtype of NSCLC, accounting for profile compared with the gemcitabine–platinum 40%-50% of cases, with squamous cell carcinoma combination.3,4 Maintenance therapy for patients (25%-30% of cases) and large cell carcinomas without disease progression after first-line chemo- (10%-15% of cases) being the second and third therapy has recently emerged as a new treatment most common subtypes. paradigm for some patients.5 Erlotinib and pem- Early stage NSCLC represents a minority of etrexed has been shown to improve survival both cases and is often curable with surgery with or as “continuation” and “switch” maintenance6,7 in without adjuvant chemotherapy, which has been patients with nonsquamous carcinoma histology. shown to improve outcome in resected patients Bevacizumab added to first-line chemotherapy with nodal involvement. In the locally advanced produces modest improvement in outcomes com- setting, radiation therapy (XRT), surgery, and pared with chemotherapy alone; however, it is chemotherapy are used alone or in combination to generally reserved for nonsquamous tumors and maximize therapeutic benefit. In this regard, che- patients without ongoing hemoptysis and other motherapy that is given concurrently with XRT is contraindications for bevacizumab use.8 Patients superior to XRT alone. However, most patients with activating mutations in the epidermal growth with NSCLC present with distant metastases factor receptor (EGFR) domain or EML4-ALK where chemotherapy is the mainstay of treatment. translocation benefit from first-line treatment with erlotinib or crizotinib, respectively.9-12 These muta- Manuscript received January 3, 2013; accepted January 31, 2013. tions are seen in a relatively small subset of Correspondence Charu Aggarwal, MD, MPH, Department of Medicine, Hematology-Oncology Division, University of NSCLC patients. They are common in patients Pennsylvania, 16 Penn Tower, 3400 Spruce Street, Philadel- phia, PA 19104 ([email protected]). Commun Oncol 2013;10:109-114 © 2013 Frontline Medical Communications Disclosures The authors have no disclosures. DOI: 10.12788/j.cmonc.0005 Volume 10/Number 4 April 2013 Ⅲ COMMUNITY ONCOLOGY 109 Review with adenocarcinoma, never smokers, and patients of East patients (P Ͻ .0001). No complete responses to treatment Asian origin. Even though KRAS is the most common were noted; 29 patients (7%) had a partial response in the mutation found in NSCLC, we currently do not have an afatinib group, as did 1 patient in the placebo group. effective targeted therapy for this subset of NSCLC. Objective RRs (ORRs) confirmed by independent analy- More recently, immunotherapy has been demonstrated to sis were 7.4% and 0.5%, in the afatinib and placebo be an attractive option for the treatment of NSCLC.13-15 groups, respectively (P Ͻ .01). Median PFS was longer in Despite the addition of new therapies, the median overall the afatinib group (3.3 months) than it was in the placebo survival of patients in advanced stages of disease remains group (1.1 months; hazard ratio [HR], 0.38; P Ͻ .0001). dismal. One-year survival rates are 40%-50% at best, and However, this benefit failed to translate into a survival 2-year survival rates are consistently below 15%-20%. advantage. Median overall survival (OS) was 10.8 months Although these percentages are starting to improve, only in the afatinib group and 12 months in the placebo group 3%-5% of advanced NSCLC patients survive 5 years after (HR, 1.08; P ϭ .74). The 2 most common adverse events diagnosis. Personalized chemotherapy based on a patient’s associated with afatinib were diarrhea (87%; grade 3, individual biologic and molecular profile is a promising 17%) and rash/acne (78%; grade 3, 14%). approach to optimize efficacy with the available agents. LUX-Lung 2 was a subsequent multicenter phase 2 This review focuses on recent advances in treatment ap- open-label single-arm study that evaluated the efficacy of proaches for advanced non–small-cell lung cancer, with a afatinib in patients with advanced NSCLC with an special emphasis on novel molecularly targeted agents and EGFR-activating mutation.19 Afatininb at a dose of the emerging role of immunotherapy. 40 mg or 50 mg once daily was administered to 129 patients. The investigators reported an ORR of 67% New agents for NSCLC with EGFR mutation (confirmed ORR of 60%), a disease control rate (DCR) of Erlotinib, a reversible oral tyrosine kinase inhibitor that 86%, median PFS of 14 months, and median OS of 24 targets the EGFR domain, was originally approved in months. Comparable efficacy was observed in the first- unselected patients in the second- and third-line setting and second-line settings. In patients with an exon 19 after progression on platinum-based therapy. The results deletion or a L858R mutation, the ORRs were 69% and of several large phase 3 randomized trials have established 59%, respectively; DCRs were 93% and 83%; and PFS the place of the EGFR TKIs in the treatment algo- was 13.7 months and 16.1 months. Again, the most rithm,10,16 and erlotinib is currently considered the stan- common drug-related adverse events were diarrhea (95%; dard of care for front-line treatment of patients whose grade 3, 19%) and rash/acne (91%; grade 3, 21%). tumors harbor an activating mutation in the EGFR do- The LUX-Lung 3 trial was reported at the 2012 an- main. Despite this advance with response rates (RRs) in nual meeting of the American Society of Clinical Oncol- the 50%-70% range, the median progression-free survival ogy. In this phase 3 trial, the investigators compared (PFS) is about 9-10 months in most studies, with most 40 mg afatinib and intravenous pemetrexed plus cisplatin patients with EGFR-mutant tumors sustaining disease (pemetrexed–cisplatin; 500 mg/m2 ϩ 75 mg/m2 q21 days progression by 1 year, mostly because of the development up to 6 cycles) as first-line therapy in 345 NSCLC pa- of resistance by multiple disparate pathways. Several new tients who harbored an EGFR-activating mutation. The treatments that irreversibly target EGFR family members ORR was significantly higher in patients who received are under development for patients with NSCLC. One afatinib than in those who received the pemetrexed– such agent is afatinib, an oral irreversible ErbB family cisplatin combination (56% vs 23%, respectively; P Ͻ inhibitor that targets EGFR and HER2, that has shown .0001). Median PFS was significantly better for afatinib activity in an erlotinib- and gefitinib-resistant lung cancer than for pemetrexed–cisplatin (11.1 vs. 6.9 months; HR, model.17 A randomized, double-blind, phase 2b/3 study 0.58; P ϭ .0004). In 308 patients with common muta- (LUX-Lung 1) evaluated afatinib plus best supportive tions (exon 19 deletion or L858R), the median PFS was care (afatinib–BSC) compared with placebo–BSC in pa- 13.6 months. This is the largest trial to date to demon- tients who had received 1 or 2 previous chemotherapy strate the superiority of an EGFR TKI to a state-of-the- regimens and had disease progression after at least 12 art platinum-based doublet and the first trial to use peme- weeks of treatment with erlotinib or gefitinib.18 Most of trexed–cisplatin as a comparator. It was also the first trial the patients (81%) had received 24 weeks or more of prior to examine an irreversible HER1/HER2 TKI in this EGFR TKI, so that they represented a population that setting. It will likely lead to approval of this drug by the had previously derived benefit from this class of agents.