Alectinib in Combination With Bevacizumab in ALK Positive NSCLC
Study Details
Study Description
Brief Summary
Lung cancer remains the most lethal malignancy in both sexes around the world. It is estimated that lung cancer caused 234,030 deaths in the United States in 2016, accounting for 28% of all cancer-related deaths. In 2012 alone, a total of 6,697 deaths from lung cancer were registered in Mexico; this number exceeds the death toll from other common solid neoplasms (i.e., stomach, prostate, breast, and liver). In addition to its high incidence, lung cancer patients face a dismal prognosis, with an overall 5-year survival ranging from 5-16%.
In the last two decades, the outlook for a subset of Non-small cell lung cancer (NSCLC) patients has shifted. Novel approaches have been able to identify that a significant number of patients present tumors with actionable mutations, opening the possibility of treatment with targeted therapies, which have increased survival outcomes in these patients. A number of specific therapies have been developed over the past decade, such as epidermal growth factor receptor (EGFR) inhibitors or anaplastic lymphoma kinase (ALK) inhibitors.
Additionally, treatment options for patients with NSCLC with actionable mutations has increased in the last two decades, with several third generation inhibitors available, which have different efficacy and tolerability profiles, nonetheless, global 5-year survival rates remain below 20%, which highlights the need to explore therapeutic combinations which might derive in greater long-term survival for this patient subgroup. Although encouraging data has been reported in terms of adding Bevacizumab to EGFR-TKIs, this scheme has not been explored for patients who have ALK-rearranged NSCLC and who are candidates for ALK-inhibitors.
Currently, Alectinib has been shown to offer several advantages compared to first-generation ALK-TKIs, including a stronger ALK-inhibition, better outcomes in patients with Central Nervous System (CNS) involvement and longer duration of response. However, the addition of Bevacizumab to therapy with Alectinib in treatment naïve or previously treated NSCLC patients remains unexplored.
Based on this data and the need to continue searching for safe and effective therapeutic options, a phase II, single arm trial assessing Alectinib in combination with Bevacizumab in untreated and previously treated patients with Advanced or Metastatic Non-Squamous ALK-rearranged NSCLC has been designed.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
Detailed Description
BACKGROUND The burden of Lung Cancer Lung cancer remains the most lethal malignancy worldwide, claiming more lives compared to any other malignant disease in both developed and developing countries, as well as globally. Although some countries have accomplished a decrease in incidence rates, most regions, particularly those in the developing world, face the challenge of an epidemic of paramount importance, which is likely to take hundreds of thousands of lives in the coming years. In Latin America, regional trends show that lung cancer incidence and mortality are on the rise, in México, for example, trends from the Global Cancer Statistics group (GLOBOCAN) show that it is likely that incident lung cancer cases will double by 2030, compared to those reported in 2010.
The management of lung cancer, therefore, requires a surge in our efforts. For many decades, lung cancer treatment was based on the use, alone or in combination, of radiotherapy, surgery and chemotherapy. The scarce therapeutic options were further limited by their lack of long-term efficacy, with a 5-year survival rate for lung cancer patients which ranged from 5-16%, and which remained unchanged from the 1970´s to the dawn of this new century. Nowadays, the therapeutic outlook for lung cancer patients is changing dramatically. Novel data regarding the molecular mechanisms of the disease led to the development of targeted treatments, including Tyrosine Kinase Inhibitors (TKIs) which can dramatically improve outcomes in specific subgroups of lung cancer patients.
Anaplastic Lymphoma Kinase Translocation (ALK) Between 6-8% of Non-Small Cell Lung Cancer cases have been shown to harbor the fusion gene of echinoderm microtubule based protein-like4 (EML4) and the anaplastic lymphoma Kinase (ALK) because of a chromosomal inversion in 2p21 and 2p23.
The formation of ALK fusion proteins results in the activation and deregulation of gene expression and signaling, which contributes to increased cell proliferation and survival in tumors expressing these genes. This is supported by reports which state that the TRK-fused gene (TFG) and kinesin family member 5B (KIF5B) genes may also serve as ALK fusion partners in some patients with NSCLC. Expression of these ALK fusion genes causes their transformation and enhanced proliferation. Tumors that contain the EML4-ALK fusion oncogene or its variants are associated with specific clinical features, including never or light smoking history, younger age, and adenocarcinoma with signet ring or acinar histology. Alterations of the ALK gene are generally found in a mutually exclusive relationship with mutations in epidermal growth factor receptor (EGFR) or Kirsten rat sarcoma (KRAS). Nonetheless, EGFR mutations may develop as a resistance mechanism after treatment with ALK inhibitors.
Wild-type ALK is hardly expressed in most normal human tissues, but is expressed at higher levels in a few limited types of tissues such as developing and mature tissue of the nervous system (glial cells, neurons, endothelial cells and pericytes. In contrast, an aberrant ALK with constitutively active kinase results from the formation of the EML4-ALK fusion gene by chromosomal translocation and will likely be expressed in cells with this genotype.
Patients with advanced NSCLC who have this genetic abnormality are preferably treated with an ALK inhibitor. This observation is based on a previous phase III study which compared treatment with standard chemotherapy vs. crizotinib (ALK-TKI) in treatment-naïve patients with ALK-rearrangement. Results from this trial demonstrated a prolonged progression-free survival (PFS) along with an improved response rate and quality of life in patients treated with crizotinib. Due to a potentially confounding crossover effect, differences in overall survival (OS) did not reach statistical significance. In spite of these encouraging results, patients treated with crizotinib have short-lived responses, with an average of 10 months of therapy before discontinuation. Other shortcomings of first-generation ALK-inhibitors include their ineffectiveness in the context of the central nervous system as well as the development of resistance mechanisms.
- Alectinib Alectinib is a second-generation ALK inhibitor that has activity in crizotinib-resistant disease. Additionally, Alectinib has been shown to provide adequate CNS activity and has a more complete blockade of ALK. It received FDA approval for first-line treatment of ALK-positive metastatic NSCLC, as well as for patients who have progressed on or are intolerant to crizotinib.
Initial approval of Alectinib for ALK-rearranged NSCLC previously treated with crizotinib came in 2015. Bases for approval were derived from an initial study, in which 122 patients with evaluable, ALK-rearranged, crizotinib-resistant disease were included. Eighty percent had progressed after prior platinum-based chemotherapy. With a median follow-up of 47 weeks, Alectinib was associated with an overall objective response rate (ORR) of 50%, a disease control rate (DCR: objective response plus stable disease) of 79%, and a median duration of response of 11 months. The median progression-free survival (PFS) was 8.9 months.
A second phase II study including 69 patients with measurable advanced ALK-rearranged NSCLC who had progressed on crizotinib found that Alectinib was associated with an ORR of 48% at a follow-up of 4.8 months.
Further, Alectinib received approval in 2017 and is now recommended as a first-line therapeutic option in ALK-rearranged NSCLC. Approval was based on results from the trial comparing alectinib (Alecensa) with crizotinib (Xalkori) as first-line treatment against ALK-positive non-small cell lung cancer (ALEX) trial, a global study including 303 patients which compared treatment with Alectinib vs. crizotinib for ALK-rearranged metastatic NSCLC patients who had not received previous systemic therapy. Study results reported an improved PFS, with a hazard ratio (HR) of 0.53. Additionally, patients receiving Alectinib had a significantly lower incidence of CNS progression (12% vs. 45%) and a higher proportion of patients with response duration of ≥12 months (64% vs. 36%). Further, grade 3 to 5 toxicities were less frequent with Alectinib (41% vs. 50%).
In another study published in 2017, the J-ALEX trial, 207 Japanese ALK-rearranged, crizotinib-naïve NSCLC patients were randomly assigned to Alectinib vs. crizotinib. At a planned interim analysis, results demonstrated improved PFS with Alectinib; median PFS was not reached in the Alectinib arm compared to 10.2 months in the crizotinib arm (hazard ratio [HR] 0.34, 99.7% Confidence Interval [CI] 0.17-0.70). Alectinib was also better tolerated, with the most frequent adverse event being constipation (36%). Patients receiving crizotinib experienced nausea (74%), diarrhea (73%), visual disturbances (55%), and alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) elevations (>30%), among other toxicities.
Data to support the FDA approval for those who have progressed on or are intolerant to crizotinib comes from two phase II studies, both demonstrating response rates to Alectinib of approximately 50 percent in patients with ALK-rearranged locally advanced or metastatic NSCLC who had progressed on crizotinib.
- Brain Metastases Alectinib appears to have important clinical activity in patients with brain metastases, including patients with symptomatic brain metastases, patients with leptomeningeal disease, and patients who have CNS relapse on ceritinib.
Alectinib has also demonstrated improved outcomes relative to crizotinib among patients with brain metastases in 2 phase III trials. In the J-ALEX study, among 43 patients with ALK-positive NSCLC with brain metastases, Alectinib demonstrated improved PFS relative to crizotinib (HR 0.08, CI 0.01-0.61). Similarly, in ALEX, among those with CNS metastases, Alectinib improved PFS relative to crizotinib (HR 0.40, 95% CI 0.25-0.64) and intracranial response rate (81% versus 50%).
Evidence of the activity of Alectinib among patients with brain metastases who have crizotinib-resistant disease comes from phase II studies. In a pooled analysis of two phase II studies, among 136 patients with baseline CNS metastases (70% of whom had prior CNS radiotherapy) the CNS ORR, DCR, and duration of response for Alectinib were 43%, 85%, and 11.1 months, respectively.
- Vascular endothelial growth factor (VEGF) Vascular endothelial growth factor (VEGF) is a potent endothelial-specific angiogenic factor that is expressed in a wide array of tumors. In NSCLC, high levels of VEGF expression are associated with a poor prognosis, suggesting that treatment targeted toward this pathway might be useful.
One approach to blocking the VEGF pathway is the administration of bevacizumab, a recombinant humanized monoclonal antibody (MoAb) that binds VEGF, thereby preventing its interaction with the VEGF receptor.
For good performance status patients with non-squamous NSCLC, the addition of bevacizumab to a platinum based doublet offers a higher response rate, a longer PFS, and improved OS compared with chemotherapy alone.
The effect of adding bevacizumab to platinum-based doublets is illustrated by the two largest trials, in which bevacizumab was continued as maintenance after completion of the planned chemotherapy In the Eastern Cooperative Oncology Group trial E4599, 878 previously untreated patients with advanced, non-squamous NSCLC were randomly assigned to paclitaxel plus carboplatin or the same chemotherapy plus bevacizumab (15 mg/kg) on day 1 of each cycle. Bevacizumab was continued as monotherapy on the same schedule after completion of six cycles of chemotherapy until there was evidence of progressive disease.
Patients receiving chemotherapy plus bevacizumab had statistically significant increases in the ORR (35% vs. 15% with paclitaxel plus carboplatin alone), OS (median 12.3 vs. 10.3 months), one-year and two-year survival rates (51% vs. 44% and 23% vs. 15%, respectively), and PFS (6.2 vs. 4.5 months).
In the AVAiL trial, 1043 patients were randomly assigned to cisplatin plus gemcitabine every three weeks with either low-dose bevacizumab (7.5 mg/kg), high-dose bevacizumab (15 mg/kg), or placebo on day 1 every three weeks. The cisplatin plus gemcitabine was continued for a maximum of six cycles, while the bevacizumab or placebo was continued as maintenance until there was evidence of progressive disease. PFS was significantly improved with both low-dose and high-dose bevacizumab (median 6.7, 6.5, and 6.1 months, for the 7.5 mg/kg, 15 mg/kg, and placebo groups, respectively). With a median follow-up of 13 months, the benefit in terms of PFS was maintained, as was the improvement in response rate (38%, 35%, and 22%, respectively). However, there were no significant differences in OS when comparing the three treatment arms (median survival 13.6, 13.4, and 13.1 months respectively; HR for death 0.93 and 1.03 vs. placebo).
In a meta-analysis based upon four trials (2194 patients), the addition of bevacizumab significantly increased both OS and PFS compared to chemotherapy alone (hazard ratios for death or progression 0.90, 95% CI 0.81-0.99 and 0.72, 95% CI 0.66-0.79, respectively). The effect on OS was significantly greater in patients with adenocarcinoma compared to other histology subtypes. The addition of bevacizumab increased the risk of grade ≥3 toxicity.
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Bevacizumab and TKI (Anti EGFR) The combination therapy of bevacizumab plus a TKI has been previously explored in a phase II trial. The study included 154 previously untreated patients who were randomly assigned to erlotinib plus bevacizumab or erlotinib alone. All patients´ tumors contained either an exon 19 deletion or the amino acid substitution at position 858 in EGFR, from a leucine (L) to an arginine (R) (L858R) mutation. PFS, the primary endpoint of the trial, was significantly increased with the combination regimen (median 16 versus 9.7 months, HR 0.54, 95% CI 0.36-0.79). A similar magnitude of benefit was seen with both types of mutation. OS data are pending.
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Alectinib and Bevacizumab To this date there is no published data of interaction and clinical efficacy of a combination therapy with Alectinib plus bevacizumab in patients with advanced NSCLC.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Intervention Patients in this intervention arm will receive the therapeutic combination of Alectinib dosed PO 600 mg bis in die (BID) with meals and Bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or other reasons specified in the protocol |
Drug: Alectinib
Alectinib dosed 600 mg twice a day (BID) with meals until disease progression, unacceptable toxicity, or other reasons specified in the protocol
Other Names:
Drug: Bevacizumab
Bevacizumab 15 mg/kg intravenously every 3 weeks until disease progression, unacceptable toxicity, or other reasons specified in the protocol
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Progression-free survival [Through study completion, an average of 18 months]
PFS based on response criteria according to RECIST 1.1 in untreated and previously treated patients with Advanced or metastatic ALK-rearranged Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab
Secondary Outcome Measures
- Objective response rate [8 weeks]
To assess the ORR, based on response criteria according to RECIST 1.1, in untreated and previously treated patients with Advanced or Metastatic ALK-rearranged Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab.
- Brain- ORR [8 weeks]
To assess the brain ORR, based on response criteria according RECIST 1.1, in untreated and previously treated patients with Advanced or metastatic Non-Squamous NSCLC who receive treatment with Alectinib plus Bevacizumab.
- Overall survival [Through study completion, an average of 18 months]
To assess the OS in untreated and previously treated patients with Advanced or metastatic Non-Squamous ALK-rearranged NSCLC who receive treatment with Alectinib plus Bevacizumab.
- Time to developing brain metastases [Through study completion, an average of 18 months]
To assess the time since inclusion until developing brain metastases in untreated and previously treated patients with Advanced or metastatic Non-Squamous ALK-rearranged NSCLC who receive treatment with Alectinib plus Bevacizumab.
- Disease-related symptom improvement [12 weeks since treatment start]
To measure disease-related symptoms we will apply the Lung Cancer Symptom Scale (LCSS). The LCSS is designed as a disease-specific measure of quality of life particularly for use in clinical trials. It evaluates six major symptoms associated with lung mallignancies and their effect on overal symptomatic distress, functional activities, and global quality of life. The scale consists of two segments, one completed by the patient (9 items) and one completed by the health care professional (6 items). Scoring is assigned as follows: The patient scale consists of 9 visual analogue scales (100 mm horizontal line). Patient puts a mark on line to indicate intensity of response to the items in question (0 = lowest rating). The observer scale consists of a 5-point categorical scale (100=none; 75=mild; 50=moderate; 25=marked; 0=severe). The score is equal to the length of line marked by patient. An average of the aggregate score of all 9 items is the total score (0-100, 0= least symptom burden).
Eligibility Criteria
Criteria
Inclusion Criteria:
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Men and women, ≥18 years of age.
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Subjects with NSCLC with known ALK-rearrangement tested with FDA-approved test (IHQ or FISH).
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Subjects with sufficient tissue to test for ALK-rearranged using IHQ or FISH.
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Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2
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Karnofsky Performance Status of ≥70
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Subjects with histologically confirmed Stage 3B (IIIB), 4 (IV) or recurrent NSCLC (per the 8th International Association for the Study of Lung Cancer classification, non-squamous histology, with prior systemic chemotherapy (platinum-based) given as primary therapy for advanced disease. Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last administration of the prior regimen occurred at least 3 weeks prior to enrollment. Prior treatment with ALK inhibitors is permitted as long as the last administration occurred 3 weeks prior to enrollment.
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Subjects with CNS metastases are only eligible if the CNS metastases are adequately treated with radiotherapy and/or surgery and subjects are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 1 week prior to randomization.
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Patients receiving radiotherapy or radiosurgery with a dose exceeding 30 Gy will have 3 weeks for neurological stabilization before randomization.
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This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
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Measurable disease by CT as per RECIST 1.1 criteria.
- The target lesions may be located on a previously irradiated field exists if documented progression of disease (radiographic) in that site.
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At least 12 weeks of life expectancy.
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Signed written informed consent
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Patients should have a signed and dated form of written informed consent approved by the institutional committee in accordance with regulatory and institutional guidelines. This must be obtained before performing any procedure related to the protocol that are not part of the normal care of the patient.
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Patients must be willing and able to comply with scheduled visits, treatment program, laboratory testing including filling of questionnaires the results reported by the patient and other study requirements.
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Reproductive Status
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Women with reproductive potential (WOCBP) should use contraceptive methods based on tables found in Appendix 2. When a teratogenic drug test is used, and / or a drug for which there is not enough information to assess teratogenicity (have not been conducted preclinical studies) are required to use a highly effective method of contraception (failure rate less than 1 % per year). Individual methods of contraception should be determined in consultation with the researcher.
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The WOCBP must have a negative pregnancy test in serum or urine (minimum sensitivity 25 IU / L or equivalent units of HCG) 24 hours before starting the investigational product.
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Women should not be breastfeeding.
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Sexually active men WOCBP should use any method of contraception with a failure rate of less than 1% per year. The investigator should review contraceptive methods and the time period during which contraception to use. Men who are sexually active with WOCBP, follow the instructions of birth control for a period of 90 days, plus the time required for the investigational drug is subject to five half-lives
Exclusion Criteria:
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Subjects with known EGFR mutations which are sensitive to available targeted inhibitor therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] substitution mutations) are excluded. All subjects with non-squamous histology must have been tested locally for EGFR mutation status; use of an FDA-approved test is strongly encouraged (EGFR mutation testing may be performed during the Screening Period, Non-squamous subjects with unknown or indeterminate EGFR status may not be included).
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Subjects with untreated CNS metastases are excluded.
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Subjects with previous malignancies (except non-melanoma skin cancers, and the following in situ cancers: bladder, gastric, colon, cervical/dysplasia, melanoma, or breast) are excluded unless a complete remission was achieved at least 2 years prior to study entry and no additional therapy is required or anticipated to be required during the study period.
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Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as Vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
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Treatment with other investigational drugs or other anti-cancer therapy, or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with this trial
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Radiographical evidence of cavitated or necrotic tumors
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Centrally located tumors with radiographical evidence (CT or MRI) of local invasion of major blood vessels
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History of clinically significant hemoptysis within the past 3 months
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History of major thrombotic or clinically relevant major bleeding event in the past 6 months.
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Known inherited predisposition to bleeding or thrombosis
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Medical History and Concurrent Diseases
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Any medical condition or serious uncontrolled or active infection with hepatitis or HIV that could be reactivated.
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Other concurrent malignancies requiring intervention.
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All toxicities attributed to a previous treatment for cancer other than alopecia or fatigue, must have resolved to Grade 1 (NCI CTCAE version 4) or baseline, prior to administration of study drug.
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Prior treatment with tumor vaccines or other anti-tumor immune stimulating agents.
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Prior treatment with Alectinib.
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Prior treatment with Bevacizumab
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Subjects with a history of interstitial lung disease.
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Subjects must be recovered from the effects of major surgery, traumatic injury or substantially at least 7 days before the first dose of study treatment.
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Physical Findings and Laboratory Tests
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Positive for the surface antigen of hepatitis B virus (HBV HBsAg) or hepatitis C ribonucleic acid (HCV RNA) Evidence indicating acute or chronic infection
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Known history of positive test for Human Immunodeficiency Virus (HIV) or Acquired Immune Deficiency Syndrome (AIDS).
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Allergies and Adverse Drug Reactions to
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History of severe hypersensitivity to other monoclonal antibodies.
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Previous history of severe hypersensitivity reaction to paclitaxel.
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History of allergy or intolerance (unacceptable adverse event) to components of the study drug, or herbal teas that contain Polysorbate 80.
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Sexual and Reproductive Status
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WOCBP pregnant or who are nursing
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Women with a positive pregnancy test in recruitment or prior to administration of the study drug.
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Other Exclusion Criteria
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Any other serious medical condition or uncontrolled active infection, findings on physical examination, laboratory findings, altered mental status, or psychiatric condition that, in the investigator's opinion, would limit the ability of an individual to meet the requirements of study, significantly increase the risk to the subject, or which affects the interpretability of the study results.
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Prisoners or subjects who are involuntarily incarcerated.
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Subjects who are compulsorily admitted for treatment of a mental or physical illness (eg, infectious disease). Eligibility criteria for this study were carefully considered to ensure the safety of study subjects, and to ensure that the results of the study can be used
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Instituto Nacional de Cancerologia | Mexico City | Mexico | 14080 |
Sponsors and Collaborators
- Instituto Nacional de Cancerologia de Mexico
- Roche Pharma AG
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
- Arrieta O, Guzmán-de Alba E, Alba-López LF, Acosta-Espinoza A, Alatorre-Alexander J, Alexander-Meza JF, Allende-Pérez SR, Alvarado-Aguilar S, Araujo-Navarrete ME, Argote-Greene LM, Aquino-Mendoza CA, Astorga-Ramos AM, Austudillo-de la Vega H, Avilés-Salas A, Barajas-Figueroa LJ, Barroso-Quiroga N, Blake-Cerda M, Cabrera-Galeana PA, Calderillo-Ruíz G, Campos-Parra AD, Cano-Valdez AM, Capdeville-García D, Castillo-Ortega G, Casillas-Suárez C, Castillo-González P, Corona-Cruz JF, Correa-Acevedo ME, Cortez-Ramírez SS, de la Cruz-Vargas JA, de la Garza-Salazar JG, de la Mata-Moya MD, Domínguez-Flores ME, Domínguez-Malagón HR, Domínguez-Parra LM, Domínguez-Peregrina A, Durán-Alcocer J, Enríquez-Aceves MI, Elizondo-Ríos A, Escobedo-Sánchez MD, de Villafranca PE, Flores-Cantisani A, Flores-Gutiérrez JP, Franco-Marina F, Franco-González EE, Franco-Topete RA, Fuentes-de la Peña H, Galicia-Amor S, Gallardo-Rincón D, Gamboa-Domínguez A, García-Andreu J, García-Cuéllar CM, García-Sancho-Figueroa MC, García-Torrentera R, Gerson-Cwilich R, Gómez-González A, Green-Schneeweiss L, Guillén-Núñez Mdel R, Gutiérrez-Velázquez H, Ibarra-Pérez C, Jiménez-Fuentes E, Juárez-Sánchez P, Juárez-Ramiro A, Kelly-García J, Kuri-Exsome R, Lázaro-León JM, León-Rodríguez E, Llanos-Osuna S, Llanos-Osuna S, Loyola-García U, López-González JS, López y de Antuñano FJ, Loustaunau-Andrade MA, Macedo-Pérez EO, Machado-Villarroel L, Magallanes-Maciel M, Martínez-Barrera L, Martínez-Cedillo J, Martínez-Martínez G, Medina-Esparza A, Meneses-García A, Mohar-Betancourt A, Morales Blanhir J, Morales-Gómez J, Motola-Kuba D, Nájera-Cruz MP, Núñez-Valencia Cdel C, Ocampo-Ocampo MA, Ochoa-Vázquez MD, Olivares-Torres CA, Palomar-Lever A, Patiño-Zarco M, Pérez-Padilla R, Peña-Alonso YR, Pérez-Romo AR, Aquilino Pérez M, Pinaya-Ruíz PM, Pointevin-Chacón MA, Poot-Braga JJ, Posadas-Valay R, Ramirez-Márquez M, Reyes-Martínez I, Robledo-Pascual J, Rodríguez-Cid J, Rojas-Marín CE, Romero-Bielma E, Rubio-Gutiérrez JE, Sáenz-Frías JA, Salazar-Lezama MA, Sánchez-Lara K, Sansores Martínez R, Santillán-Doherty P, Alejandro-Silva J, Téllez-Becerra JL, Toledo-Buenrostro V, Torre-Bouscoulet L, Torecillas-Torres L, Torres M, Tovar-Guzmán V, Turcott-Chaparro JG, Vázquez-Cortés JJ, Vázquez-Manríquez ME, Vilches-Cisneros N, Villegas-Elizondo JF, Zamboni MM, Zamora-Moreno J, Zinser-Sierra JW. [National consensus of diagnosis and treatment of non-small cell lung cancer]. Rev Invest Clin. 2013 Mar;65 Suppl 1:S5-84. Spanish.
- Choi YL, Soda M, Yamashita Y, Ueno T, Takashima J, Nakajima T, Yatabe Y, Takeuchi K, Hamada T, Haruta H, Ishikawa Y, Kimura H, Mitsudomi T, Tanio Y, Mano H; ALK Lung Cancer Study Group. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med. 2010 Oct 28;363(18):1734-9. doi: 10.1056/NEJMoa1007478.
- Doebele RC, Pilling AB, Aisner DL, Kutateladze TG, Le AT, Weickhardt AJ, Kondo KL, Linderman DJ, Heasley LE, Franklin WA, Varella-Garcia M, Camidge DR. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res. 2012 Mar 1;18(5):1472-82. doi: 10.1158/1078-0432.CCR-11-2906. Epub 2012 Jan 10.
- Inamura K, Takeuchi K, Togashi Y, Nomura K, Ninomiya H, Okui M, Satoh Y, Okumura S, Nakagawa K, Soda M, Choi YL, Niki T, Mano H, Ishikawa Y. EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers. J Thorac Oncol. 2008 Jan;3(1):13-7. doi: 10.1097/JTO.0b013e31815e8b60.
- Ou SH, Bartlett CH, Mino-Kenudson M, Cui J, Iafrate AJ. Crizotinib for the treatment of ALK-rearranged non-small cell lung cancer: a success story to usher in the second decade of molecular targeted therapy in oncology. Oncologist. 2012;17(11):1351-75. doi: 10.1634/theoncologist.2012-0311. Epub 2012 Sep 18. Review.
- Pulford K, Lamant L, Morris SW, Butler LH, Wood KM, Stroud D, Delsol G, Mason DY. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1. Blood. 1997 Feb 15;89(4):1394-404.
- Soda M, Choi YL, Enomoto M, Takada S, Yamashita Y, Ishikawa S, Fujiwara S, Watanabe H, Kurashina K, Hatanaka H, Bando M, Ohno S, Ishikawa Y, Aburatani H, Niki T, Sohara Y, Sugiyama Y, Mano H. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007 Aug 2;448(7153):561-6. Epub 2007 Jul 11.
- Spiro SG, Silvestri GA. One hundred years of lung cancer. Am J Respir Crit Care Med. 2005 Sep 1;172(5):523-9. Epub 2005 Jun 16. Review.
- Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015 Mar;65(2):87-108. doi: 10.3322/caac.21262. Epub 2015 Feb 4.
- Alectinib plus Bevacizumab