Effects of erlotinib in EGFR mutated non-small cell lung cancers with resistance to gefitinib.

PURPOSE: Most lung cancers with activating epidermal growth factor receptor (EGFR) mutations respond to gefitinib; however, resistance to this tyrosine kinase inhibitor (TKI) invariably ensues. The T790M mutation occurs in 50% and MET amplification in 20% of TKI-resistant tumors. Other secondary mutations (D761Y and L747S) are rare. Our goal was to determine the effects of erlotinib 150 mg/d in EGFR mutated patients resistant to gefitinib 250 mg/d, because the EGFR TKI erlotinib is given at a higher biologically active dose than gefitinib. EXPERIMENTAL DESIGN: Retrospective review of 18 EGFR mutated (exon 19 deletions, L858R, and L861Q) patients that were given gefitinib and subsequently erlotinib. Seven patients had tumor resampling after TKI therapy and were analyzed for secondary EGFR mutations and MET amplification. RESULTS: Most patients (14 of 18) responded to gefitinib with median progression-free survival of 11 months (95% confidence interval, 4-16). After gefitinib resistance (de novo or acquired), 78% (14 of 18) of these patients displayed progressive disease while on erlotinib with progression-free survival of 2 months (95% confidence interval, 2-3). Six of 7 resampled patients acquired the T790M mutation, and 0 of 3 had MET amplification. Only 1 gefitinib-resistant patient with the acquired L858R-L747S EGFR, which in vitro is sensitive to achievable serum concentrations of erlotinib 150 mg/d, achieved a partial response to erlotinib. CONCLUSIONS: In EGFR mutated tumors resistant to gefitinib 250 mg/d, a switch to erlotinib 150 mg/d does not lead to responses in most patients. These findings are consistent with preclinical models, because the common mechanisms of TKI resistance (T790M and MET amplification) in vitro are not inhibited by clinically achievable doses of gefitinib or erlotinib. Alternative strategies to overcome TKI resistance must be evaluated.

Comparison of Genomic Driver Oncogenes in Vietnamese Patients With Non-Small-Cell Lung Cancer in the United States and Vietnam.

PURPOSE: Discoveries of oncogenic driver alterations in non-small-cell lung cancer (NSCLC) have been accompanied by the development of effective targeted therapies. The frequencies of these mutations vary between populations but are less well characterized in the Vietnamese population. In this study, we analyzed the frequencies of lung cancer driver oncogenic alterations in Vietnamese patients compared with Vietnamese patients treated in the United States. METHODS: We collected data on tumor and disease characteristics of Vietnamese patients with NSCLC treated at Stanford. In addition, we collected NSCLC tumor specimens from patients with NSCLC diagnosed in Hue, Vietnam, and performed next-generation-based genotyping on these samples. The molecular and clinical characteristics of these groups were compared. RESULTS: Fifty-nine Vietnamese patients were identified at Stanford. Of the 44 patients with molecular testing results, there were 21 (47.7%) with EGFR alterations, six (13.6%) with ALK alterations, two (4.5%) with KRAS alterations, one (2.3%) with BRAF alterations, and no ROS1 or RET alterations. Across all stages, the median overall survival for patients with a tumor having a targetable genomic alteration driver mutation was 42.4 months, compared with 27.1 months for patients without such alterations. In the 45 genotyped samples from Vietnam, there were 26 (57.8%) with EGFR, 11 (24.4%) with KRAS, and one each (2.2%) with ALK, ROS1, and RET. CONCLUSION: The majority of tumors from both Stanford and Vietnam had targetable oncogenic alterations. This suggests that routine implementation of molecular testing may have a significant, positive impact on the treatment of Vietnamese patients with NSCLC, but affordability of testing and treatments remains a barrier to adoption.

Review of the current targeted therapies for non-small-cell lung cancer.

The last decade has witnessed the development of oncogene-directed targeted therapies that have significantly changed the treatment of non-small-cell lung cancer (NSCLC). In this paper we review the data demonstrating efficacy of gefitinib, erlotinib, and afatinib, which target the epidermal growth factor receptor (EGFR), and crizotinib which targets anaplastic lymphoma kinase (ALK). We discuss the challenge of acquired resistance to these small-molecular tyrosine kinase inhibitors and review promising agents which may overcome resistance, including the EGFR T790M-targeted agents CO-1686 and AZD9291, and the ALK-targeted agents ceritinib (LDK378), AP26113, alectinib (CH/RO5424802), and others. Emerging therapies directed against other driver oncogenes in NSCLC including ROS1, HER2, and BRAF are covered as well. The identification of specific molecular targets in a significant fraction of NSCLC has led to the personalized deployment of many effective targeted therapies, with more to come.

First-line treatment of EGFR-mutant non-small-cell lung cancer: the role of erlotinib and other tyrosine kinase inhibitors.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) were initially established as second- or third-line treatment of advanced non-small-cell lung cancer (NSCLC). Subsequent studies, including IPASS, OPTIMAL, and EURTAC, have demonstrated that these TKIs are effective first-line therapeutic options in patients with tumors harboring activating mutations in the EGFR gene. The TKIs are better tolerated than conventional chemotherapy, with frequent yet mild side effects such as rash and diarrhea, and rarely interstitial lung disease. Because most patients on TKIs develop resistance due to a variety of mechanisms, the use of TKIs in the acquired-resistance setting and in the setting of earlier-staged cancers is being extensively studied. Here we review the major trials leading to the established use of EGFR TKIs in NSCLC, followed by discussion of recently completed and ongoing trials using the next-generation EGFR inhibitor afatinib.

Patterns of care for non-small-cell lung cancer at an academic institution affiliated with a national cancer institute-designated cancer center.

PURPOSE: Evidence-based treatment guidelines for non-small-cell lung cancer (NSCLC) exist to improve the quality of care for patients with this disease. However, how often evidence-based decisions are used for care of NSCLC is poorly understood. PATIENTS AND METHODS: We examined patterns of care and rate of adherence to evidence-based guidelines for 185 new NSCLC patients seen between 2007 and 2009. Evidence-based care status was determined for 150 patients. RESULTS: Eighty-one percent of the patients were white, the mean age was 66 years, 49% were women, 11% were never smokers, 83% had Eastern Cooperative Oncology Group performance status 0 to 1, 49.7% of tumors were adenocarcinomas, 57.1% of never smokers had tumors genotyped (EGFR, ALK, KRAS), and 13.3% participated in clinical trials. The rate of evidence-based treatment adherence was 94.1% (16 of 17), 100% (21 of 21) and 100% (36 of 36) in patients with stages I, II, and III NSCLC, respectively. Stage IV disease, with adherence of 76.3% (58 of 76), was correlated with a higher rate of nonadherence when compared with stages I-III (odds ratio 16.33; 95% CI, 1.94 to 137.73). In patients with stage IV disease, the rate of evidence-based adherence was 95% (72 of 76) for first-line therapy, 95.2% (40 of 42) for second-line therapy, and only 33.3% (6 of 18) for third-line therapy (P < .001). There was no significant correlation between evidence-based adherence status and the patient's age, sex, performance status, smoking history, ethnicity, or the treating physician. CONCLUSION: These data point toward the need for improved evidence-based use of resources in the third-line setting of stage IV NSCLC.

Case series of treatment approaches in fit nonagenarians with stage IV non-small-cell lung cancer.

An increasing number of nonagenarians are treated for non-small-cell lung cancer (NSCLC); however guidelines and case series describing the care of very elderly patients with advanced NSCLC are not available. Medical records of patients treated at Beth Israel Deaconess Medical Center between 2007 and 2009 who had NSCLC were reviewed, and those with stage IV NSCLC and age 90 or older were included in this case series. Three successive fit nonagenarians were identified out of the one hundred and one cases with stage IV NSCLC, and their clinical course was summarized. The first case depicts a conservative approach (best supportive care), while the later cases describe the use of platinum-based (carboplatin-pemetrexed) and anti-epidermal growth factor targeted therapies. This series illustrates the diversity of approaches now available and the evolving treatment paradigm as it applies to fit elderly with NSCLC, including nonagenarians. It also emphasizes the importance of considering performance status rather than biologic age when making treatment decisions.

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancers dependent on the epidermal growth factor receptor pathway.

Most advanced non-small-cell lung cancers (NSCLCs) with activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions or L858R) initially respond to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. However, over time (median of 6-12 months), most tumors develop acquired resistance to EGFR TKIs. Intense research in these NSCLCs has identified two major mechanisms of resistance to gefitinib/erlotinib: secondary resistance mutations and "oncogene kinase switch" systems. The secondary T790M mutation occurs in 50% of EGFR-mutated patients with TKI resistance, and in vitro, this mutation negates the hypersensitivity of activating EGFR mutations. Sensitive detection methods have identified a proportion of TKI-naive tumors that carry T790M, and these resistant clones may be selected after exposure to gefitinib or erlotinib. Other secondary resistance mutations (D761Y, L747S, T854A) seem to be rare. The amplification of the MET oncogene is present in 20% of TKI-resistant tumors; however, in half of the cases with this "oncogene kinase switch" mechanism the T790M is coexistent. It is possible that other kinases (such as insulin-like growth factor-1 receptor [IGF-1R]) might also be selected to bypass EGFR pathways in resistant tumors. The growing preclinical data in EGFR-mutated NSCLCs with acquired resistance to gefitinib or erlotinib has spawned the initiation or conception of clinical trials testing novel EGFR inhibitors that in vitro inhibit T790M (neratinib, XL647, BIBW 2992, and PF-00299804), MET, or IGF-1R inhibitors in combination with EGFR TKIs, and heat shock protein 90 inhibitors. Ongoing preclinical and clinical research in EGFR-mutated NSCLC has the potential to significantly improve the outcomes of patients with these somatic mutations.