Abstract
Background: Lung cancer is the second most common cancer in the United States among men and women, and it is the most common cause of cancer-related death. Non–small cell lung cancer (NSCLC) represents approximately 85% of all lung cancer cases. Historically, patients with metastatic NSCLC received similar cytotoxic chemotherapy regimens. Genotyping studies have revealed genetic/molecular abnormalities in lung cancer. These driver mutations render a cancer dependent on that specific mutation's biochemical pathway for its growth and survival. With the development of tyrosine kinase inhibitors and antibodies against specific driver mutations, the landscape of lung cancer treatment has changed from treatment based on histologic subtype to treatment based on molecularly defined subtypes.
Methods: In this article, we review the current molecular-targeted therapies in lung cancer.
Results: We review landmark trials that have led to approval of molecular-targeted therapies against epidermal growth factor receptor, anaplastic lymphoma kinase, and ROS1. We also explore less common mutations/molecular abnormalities and review data on the use of targeted therapies against them. Finally, we offer a treatment algorithm for patients with metastatic NSCLC that harbors actionable mutations.
Conclusion: Patients with advanced NSCLC should undergo mutational testing to evaluate for actionable mutations. If such a mutation is discovered, targeted therapy should be considered for first-line treatment.
- Anaplastic lymphoma kinase
- carcinoma–non-small cell lung
- molecular targeted therapy
- receptor–epidermal growth factor
- ROS1
INTRODUCTION
Lung cancer is the second most common cancer in the United States among men and women, and it is the most common cause of cancer-related death. In 2017, an estimated 222,500 new cases of lung cancer will be diagnosed and an estimated 155,870 deaths related to lung cancer will occur.1
The 2 classes of lung cancer are small cell lung cancer and non–small cell lung cancer (NSCLC). NSCLC represents approximately 85% of all lung cancer cases.2 Histologically, NSCLC has several subtypes, including adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and mixed histology. Genotyping studies have revealed genetic/molecular abnormalities in the various subtypes of lung cancer. In adenocarcinoma, several driver mutations have been identified, including mutations/alterations of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS1.3 These driver mutations cause the signaling protein to be constitutively activated, leading to increased cell proliferation, angiogenesis, metastasis, and decreased apoptosis. Similarly, genotyping in squamous cell lung cancer has resulted in the discovery of several genetic abnormalities.4
For metastatic NSCLC, historically, all patients received similar first-line and second-line chemotherapy regimens. With the development of tyrosine kinase inhibitors (TKIs) and antibodies against specific driver mutations, the landscape of lung cancer treatment has changed from treatment based on histologic subtype to treatment based on molecularly defined subtypes. In this article, we review the current molecular-targeted therapies in lung cancer.
EPIDERMAL GROWTH FACTOR RECEPTOR
The EGFR is a cell-surface protein that when activated by the binding of the ligand to its extracellular component leads to a series of events that result in increased cell proliferation, angiogenesis, metastasis, and decreased apoptosis. EGFR is overexpressed in a majority of NSCLC cases. Activating mutations in EGFR most commonly occur as either in-frame amino acid deletions in exon 19 or L858R substitutions in exon 21.5 An EGFR mutation makes the cancer cell reliant on EGFR for survival, a process termed oncogene addiction.6 The phenomenon of oncogene addiction allows for response of these tumors to EGFR-specific TKIs.7 Several EGFR TKIs are available in the United States, including erlotinib, gefitinib, afatinib, and osimertinib.
The Iressa Pan-ASia Study (IPASS) randomized previously untreated patients with advanced lung adenocarcinoma (stages IIIB and IV) to receive gefitinib or carboplatin-paclitaxel, a standard first-line chemotherapy regimen.8 Patients were nonsmokers or light smokers and Asian, characteristics that had previously been associated with a higher frequency of EGFR mutations. The primary endpoint was progression-free survival (PFS). A total of 1,217 patients underwent randomization. The PFS for the subgroup of patients who were positive for an EGFR mutation was 9.6 months vs 6.3 months favoring gefitinib (hazard ratio [HR] 0.48; 95% confidence interval [CI] 0.36-0.64; P<0.001). However, among patients who were negative for the EGFR gene mutation, PFS was significantly longer for the patients randomized to carboplatin-paclitaxel. Median overall survival was 18.6 months for gefitinib vs 17.3 months for carboplatin-paclitaxel. This study confirmed that patients with an EGFR mutation responded better to gefitinib than to cytotoxic chemotherapy.
The EURopean TArceva vs Chemotherapy (EURTAC) trial randomized patients with advanced NSCLC (stages IIIB and IV) with EGFR mutations (exon 19 deletion or L858R mutation in exon 21) to receive erlotinib or standard platinum-based chemotherapy doublet.9 The primary endpoint was PFS, and 173 patients underwent randomization. Median PFS was 9.7 months vs 5.2 months favoring erlotinib (HR 0.37; 95% CI 0.25-0.54; P<0.0001).
The LUX-Lung 3 trial randomized patients with EGFR mutation–positive lung adenocarcinoma to receive afatinib or cisplatin-pemetrexed.10 The primary endpoint was PFS, and 345 patients underwent randomization. Median PFS was 11.1 months vs 6.9 months favoring afatinib (HR 0.58; 95% CI 0.43-0.78; P=0.0004).
The Table presents information on these and other trials evaluating EGFR TKIs in the treatment of advanced NSCLC.
Studies of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (TKIs) in the Treatment of Advanced Non–Small Cell Lung Cancer
In general, resistance to EGFR TKIs develops at 9-12 months.8-14 In approximately 50% of cases, the mechanism of resistance is a second-site mutation, T790M within exon 20. In approximately 3% of cases, the mechanism of resistance is histologic transformation to small cell lung cancer.15 Other less common mechanisms of resistance include amplifications of MET, HER2, and MAPK and mutations in BRAF and PIK3CA.15 It is important to perform a repeat biopsy at the time of progression for patients on an EGFR TKI to evaluate for the specific mechanism of resistance.
Osimertinib is an oral, irreversible EGFR TKI that has efficacy against EGFR-mutated NSCLC with the T790M resistance mutation. The AURA3 trial randomized 419 patients with T790M-positive advanced NSCLC who had disease progression on first-line EGFR TKI therapy to osimertinib or platinum-based chemotherapy (cisplatin or carboplatin with pemetrexed).16 PFS, the primary endpoint, was 10.1 months in the osimertinib cohort vs 4.4 months in the platinum-doublet chemotherapy cohort (HR 0.30; 95% CI 0.23-0.41; P<0.001). Osimertinib is approved for patients who harbor the T790M mutation and who have progressed on a first-line EGFR TKI.
Overall, patients tolerate EGFR TKIs much better than standard cytotoxic chemotherapy. The most common side effects include gastrointestinal upset (nausea, diarrhea) and dermatologic manifestations (a maculopapular, acneiform rash). There is an association between development of a rash while on an EGFR TKI and response and/or survival.17 The positive correlation between rash and response/survival is stronger with erlotinib than with gefitinib.
ANAPLASTIC LYMPHOMA KINASE
A fusion gene of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the ALK gene occurs in approximately 3.8% of all NSCLC cases.18,19 This fusion gene encodes a cytoplasmic protein with constitutive tyrosine kinase activity. The 3 US Food and Drug Administration–approved ALK inhibitors are crizotinib, ceritinib, and alectinib; several more are in development.
In a phase 1 dose-escalation trial, crizotinib had an overall response rate of 57% with an estimated probability of 6-month PFS of 72%.20 The PROFILE 1014 study was a phase 3 trial that randomized treatment-naïve patients with locally advanced/recurrent/metastatic NSCLC with a positive ALK gene rearrangement to receive crizotinib or standard pemetrexed plus platinum chemotherapy.21 The primary endpoint was PFS. Median PFS was 10.9 months in the crizotinib cohort vs 7.0 months in the pemetrexed plus platinum chemotherapy cohort (HR 0.45; 95% CI 0.35-0.60; P<0.001).
Ceritinib is approved for patients with ALK-positive, metastatic NSCLC who have progressed on crizotinib. In a single-arm phase 1/2 trial, 80 patients with metastatic ALK-positive NSCLC who had progressed on crizotinib received ceritinib.22 The objective response rate was 56% (95% CI 45%-67%); the median PFS was 7.0 months.
Ceritinib has also been shown to have efficacy in the first-line setting. The ASCEND-4 study was a phase 3 trial in which 376 previously untreated patients with stage IIIB/IV ALK-rearranged nonsquamous NSCLC were randomized to receive ceritinib or standard pemetrexed plus platinum chemotherapy.23 The primary endpoint was PFS. Median PFS was 16.6 months in the ceritinib cohort vs 8.1 months in the pemetrexed plus platinum chemotherapy cohort (HR 0.55; 95% CI 0.42-0.73; P<0.00001). Importantly, ceritinib showed efficacy for patients with brain metastases; the overall intracranial response rate was 73.7% vs 27.3% with pemetrexed plus platinum chemotherapy.
Alectinib is another ALK inhibitor approved for patients with ALK-positive, metastatic NSCLC who have progressed on crizotinib. The approval was based on 2 single-arm trials.24,25 The first trial was a phase 2 study that enrolled patients with ALK-positive NSCLC who had progressed on crizotinib to receive alectinib. The primary endpoint, overall response rate, was 48% (95% CI 36%-60%).24 The second trial was also a phase 2 study that enrolled patients with crizotinib-refractory ALK-positive NSCLC to receive alectinib. The primary endpoint, overall response rate, was 50% (95% CI 41%-59%).25
Mechanisms of resistance to ALK TKIs include biologic factors (increased EGFR signaling, ALK mutations, etc) and pharmacologic factors (failure of the drug to adequately reach the central nervous system).26 In approximately 30%-35% of cases, the mechanism of resistance is increased EGFR signaling; in approximately 28%-49% of cases, the mechanism of resistance is an ALK target alteration (ALK mutation or ALK amplification).27,28 For patients with progressive disease, the National Comprehensive Cancer Network (NCCN) guidelines for NSCLC suggest that if a patient is asymptomatic, continuing the initial ALK inhibitor is reasonable.29 If the patient is symptomatic, local therapy and continuation of the ALK inhibitor or switching to another ALK inhibitor should be considered.
Side effects of crizotinib include visual disturbance (blurry vision, diplopia, photophobia), gastrointestinal upset, and elevated liver function tests. Side effects of ceritinib and alectinib include gastrointestinal upset, elevated liver function tests, and myelosuppression.
ROS1
ROS1 is a receptor tyrosine kinase of the insulin receptor family; it is located on chromosome 6. A ROS1 gene rearrangement results in constitutive activation of the tyrosine kinase. ROS1 gene rearrangements occur in approximately 2% of all NSCLC cases.30 Crizotinib has shown activity in patients with advanced NSCLC with a ROS1 gene rearrangement.
In a phase 1 study that included an expansion cohort of patients with advanced ROS1-rearranged NSCLC, patients were treated with crizotinib and assessed for safety, pharmacokinetics, and response to therapy.31 The objective response rate was 72%, and the median PFS was 19.2 months.
OTHER MUTATIONS
Several less common mutations in lung cancer have been identified. For example, in lung adenocarcinoma, mutations in HER2, BRAF, MET, and RET occur, each at incidences of 1%-3%.5 The NCCN guidelines for NSCLC contain a section on “Emerging Targeted Agents for Patients with Genetic Alterations,” including HER2 mutations, BRAF V600E mutations, high-level MET amplification or MET exon 14 skipping mutations, and RET rearrangements.29
In a retrospective review of 65 patients with advanced NSCLC that harbored a HER2 in-frame insertion in exon 20, in which 16 patients received anti-HER2 treatments after conventional therapy, the overall response rate was 50%, and the median PFS was 5.1 months.32
In a phase 2 basket study of vemurafenib (a selective oral inhibitor of the BRAF V600 kinase) in BRAF V600 mutation–positive non-melanoma cancers, a cohort of 20 patients with NSCLC had an overall response rate of 42%.33 In a phase 2 trial of pretreated patients with metastatic BRAF V600E–mutant NSCLC, the combination of dabrafenib (an oral BRAF inhibitor) and oral trametinib (an oral inhibitor of mitogen-activated extracellular kinase 1 and 2) resulted in an overall response rate of 63.2%.34
The use of crizotinib in patients with MET exon-14-altered NSCLC has been studied. In an expansion cohort of the phase 1 PROFILE 1001 study, 21 patients with MET exon 14–altered NSCLC received crizotinib. The objective response rate was 44% (95% CI 22%-69%).35 Data are also available on antitumor activity with the use of cabozantinib36 and vandetanib37 in patients with NSCLC who harbor a RET gene fusion. In an open-label phase 2 trial, 25 patients with metastatic RET-arranged NSCLC received cabozantinib, a multi-TKI with activity against RET.36 The overall response rate was 28% (95% CI 12%-49%). In an open-label phase 2 trial, 18 patients with advanced RET-rearranged NSCLC who had failed platinum-based chemotherapy received vandetanib.37 Three patients had a partial response, and 8 patients had stable disease.
TREATMENT ALGORITHM FOR PATIENTS WITH ADVANCED/METASTATIC NON–SMALL CELL LUNG CANCER
All patients with metastatic NSCLC should undergo molecular profiling to evaluate for actionable mutations. The NCCN guidelines for NSCLC recommend broad molecular profiling, including testing for less frequent driver mutations for which drugs are readily available.27 While most of these mutations are less common in the squamous-cell subtype of NSCLC, we recommend a standardized approach for both squamous cell and nonsquamous cell subtypes of NSCLC. If a driver mutation is discovered, a targeted treatment should be started. We provide a diagnostic and treatment algorithm in the Figure.
Treatment algorithm for patients with advanced/metastatic non–small cell lung cancer. ALK, anaplastic lymphoma kinase; BRAF, B-Raf proto-oncogene; CNS, central nervous system; EGFR, epidermal growth factor receptor; PD-L1, programmed death-ligand 1; ROS1, ROS1 proto-oncogene; RET, RET proto-oncogene.
CONCLUSION
Patients with advanced NSCLC should undergo mutational testing to evaluate for actionable mutations. If such a mutation is discovered, targeted therapy should be considered for first-line treatment.
This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care, Medical Knowledge, and Practice-Based Learning and Improvement.
ACKNOWLEDGMENTS
Robert A. Ramirez, DO, FACP serves as a consultant for Ipsen Biopharmaceuticals Inc. and BioTheranostics Inc., as well as a speaker for Merck & Co. Inc., Genentech, Astra Zeneca, and Ipsen Biopharmaceuticals. Ryan Griffin, MD has no conflicts of interest to disclose.
- © Academic Division of Ochsner Clinic Foundation 2017