TS TS, another potential predictive marker, is a key enzyme in folate metabolism and a major target of several chemotherapy drugs, including pemetrexed. This marker is currently being evaluated as a predictive biomarker for improved outcomes with pemetrexed in patients with non-squamous cell NSCLC.49,52 To date, low expression of TS has been associated with improved outcomes with pemetrexed. The predictive power of TS expression will be tested prospectively in the EPIC (Elderly and Poor Performance Status Individualized Chemotherapy) trial, in which patients with previously untreated advanced NSCLC will be randomized to standard therapy or individualized therapy based on TS, ERCC1, and RRM1 mRNA levels.

Although initial studies suggest a role for molecular markers in the prediction of response to chemotherapy, their incorporation into the clinical practice will depend on the results from prospective randomized trials.

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The development of novel treatment options for NSCLC is increasingly based on the ability to detect driver mutations in tumor specimens from patients with lung cancer and then selectively target those molecular lesions. To this end, the National Cancer Institute’s Lung Cancer Mutation Consortium (LCMC) has identified driver mutations in tumors from 1,000 patients and provided the results to clinicians so that patients can receive optimized treatment or be entered into targeted therapeutic trials.53 Currently, the LCMC has 14 member institutions that enroll patients with stage IIIB/IV lung cancer for tumor testing for mutations or alterations in the following 10 genes: KRAS, EGFR, HER2, BRAF, PIK3CA, AKT1, MEK1, NRAS, ALK (rearrangements), and MET (amplifications). In 2011, 830 patients had been enrolled, with an average of 50 additional patients enrolling monthly. Driver mutations were reported in 60% of patients. The prevalence of mutations detected were as follows: KRAS, 25%; EGFR, 23%; ALK rearrangements, 6%; BRAF, 3%; PIK3CA, 3%; MET amplifications, 2%; HER2, 1%; MEK1, 0.4%; NRAS, 0.2%; and AKT1, 0%.53 These findings are important to facilitate selective treatment for patients with available agents and provide a rationale for the development of therapies for multiple other targets. As a result of these recent discoveries, several investigational agents are in clinical development for the treatment of patients with NSCLC. Those in later stages of development are described below.

Dual, irreversible EGFR/HER2 tyrosine kinase inhibitors As previously noted, an important consideration with currently available EGFR inhibitors is the development of resistance. This issue may be overcome with the use of second-generation irreversible EGFR inhibitors. One example of a novel irreversible EGFR inhibitor is afatinib (BIBW 2992), which inhibits EGFR/HER1, HER2, and HER4 and is currently in phase 3 trials for patients with lung cancer. Results of a phase 2b/3 study (LUX-Lung 1) of afatinib plus usual care versus placebo plus usual care in patients who progressed after one to two lines of chemotherapy and at least 12 weeks of erlotinib or gefitinib were recently reported.54 The study randomized 585 patients to receive treatment with afatinib (n = 390) or placebo (n = 195). While no significant OS benefit was observed with afatinib, median PFS was longer in the afatinib group (3.3 months; 95% CI, 2.79-4.40) compared with the placebo group (1.1 months; 0.95-1.68; HR = 0.38; 95% CI, 0.31-0.48; P < 0.0001). In addition, 7% of patients had a partial response versus one patient in the placebo group. As with other agents in this class, common side effects were diarrhea (87%) and rash or acne (78%). In the first-line setting for patients with activating EGFR mutations, the LUX-Lung 3 trial, showed a significant improvement in response rate (56% versus 23%; P < 0.0001) and prolongation of PFS (11.1 versus 6.9 months; HR 0.58, 95% CI 0.43-0.78; P = 0.0004) for afatinib compared to pemetrexed plus cisplatin.55 Preliminary results of an ongoing trial evaluating the combination of afatinib and cetuximab for patients with EGFR mutant NSCLC progressing through first-line erlotinib in 45 patients showed a response rate (RR) of 51% and a disease control rate (DCR) of 93%, generating great interest in the use of irreversible EGFR inhibitors.56

Dacomitinib, an irreversible inhibitor of EGFR/HER1, HER2, and HER4, is also under evaluation in lung cancer. A phase 3 trial of dacomitinib as monotherapy after progression during standard chemotherapy is underway (BR26; NCT01000025), and a randomized, double-blinded phase 3 clinical trial (ARCHER; NCT01360554) is comparing the efficacy of dacomitinib versus erlotinib in patients with advanced NSCLC with or without mutated KRAS.

Immunotherapy Although immunotherapy in lung cancer has been associated with disappointing results, recent studies targeting programmed death 1 (PD-1) have been encouraging. The PD-1 protein is a T-cell co-inhibitory receptor, and one of its ligands, PD-L1, plays a central role in tumor evasion of the host immune system. A blockade of interactions between PD-1 and PD-L1 enhances immune function in vitro and mediates antitumor activity in preclinical models. In a phase 1 study of the anti-PD1 antibody BMS 936558, 76 patients with NSCLC were accrued, with a RR of 18% and PFS of 26% at 24 weeks.57 Response rates were observed in all dose levels and were higher in squamous histology compared to non-squamous (33% versus 12%). Of note, responses were not observed among patients with PD-L1-negative tumors. In a second simultaneously presented phase 1 study, 75 patients with NSCLC were treated with the anti-PD-L1 antibody.58 At 24 weeks, the RR was 10% and the PFS was 31%, showing that both PD1 and PD-L1 are valid and promising targets.


In the last few years, important advances have contributed to the understanding of the molecular pathogenesis of lung cancer and facilitated the discovery of new therapeutic targets and drugs. Recent studies have shown significant benefit from the use of personalized therapy, where the appropriate drug is administered in patients who have a specific predictor for response. Furthermore, preliminary studies indicate an expanding role of immunotherapy in patients with NSCLC, with durable responses observed after the use of antibodies targeting the PD1-PDL1 pathway. Because only a small percentage of patients achieve benefit from each specific therapy, it remains important to continue the search for predictors for response in an attempt to maximize the therapeutic benefits and decrease the unnecessary risk of toxicity in those with a low probability of response. ■

Dr. Morgensztern is Assistant Professor, Division of Oncology, Yale University School of Medicine, New Haven, Connecticut

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