The FDA on December 12, 2014 approved CYRAMZA® for use in combination with TAXOTERE® (Docetaxel) for the treatment of patients with metastatic Non Small Cell Lung Cancer (NSCLC) with disease progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving CYRAMZA®. CYRAMZA® injection for intravenous infusion is a product of Eli Lilly and Company.
Tag: Lung Cancer: Non-Small Cell
Molecular Testing for Selection of Patients with Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline
SUMMARY: There is now growing body of evidence suggesting superior outcomes when advanced NSCLC patients with specific genomic alterations receive targeted therapies. Following review of 127 studies by experts and input from a scientific advisory panel, The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) offered evidence-based recommendations for the molecular analysis of lung cancers for Epidermal Growth Factor Receptor (EGFR ) mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements, thereby selecting patients with lung cancer, for treatment with EGFR and ALK tyrosine kinase inhibitors. The ASCO review panel has endorsed these guidelines which specifically address the following questions:
1) Which patients should be tested for EGFR mutations and ALK rearrangements?
EGFR or ALK testing is recommended for all patients with advanced lung adenocarcinoma or tumors with an adenocarcinoma component, irrespective of clinical characteristics such as smoking history, sex, race, or other clinical factors. Tumor samples of other histologies for which an adenocarcinoma component cannot be excluded because of sampling, can be considered for testing, particularly if clinical criteria are suggestive (eg, younger age, lack of smoking history). Both primary tumors and metastatic lesions are suitable for testing. When fully excised lung cancer specimens are available, EGFR and ALK testing is not recommended in lung cancers that lack any adenocarcinoma component, such as pure squamous cell carcinomas, pure small-cell carcinomas, or large-cell carcinomas lacking IHC (ImmunoHistoChemistry) evidence of adenocarcinoma differentiation.
2) When should a patient specimen be tested for EGFR mutation or ALK rearrangement?
Testing should be ordered at the time of diagnosis of advanced disease or recurrence. For patients with earlier stage disease who undergo surgical resection, testing at the time of diagnosis is encouraged so that molecular information is available to an oncologist at the time of recurrence, for a subset of patients who subsequently experience recurrence. Tissue should be prioritized for EGFR and ALK testing.
3) How rapidly should test results be available?
Laboratory turnaround times of 5 to 10 working days (2 weeks) for EGFR and ALK results are recommended.
4) How should specimens be processed for EGFR mutation testing?
Pathologists should use Formalin-Fixed, Paraffin-Embedded (FFPE) specimens or fresh frozen or alcohol-fixed specimens for PCR based EGFR mutation tests. EGFR and ALK testing can be performed with cytology samples, with cell blocks being preferred over smear preparations.
5) How should EGFR testing be performed?
EGFR testing should detect mutations in samples composed of as few as 50% tumor cells, although sensitivity to detect mutations in samples containing > 10% tumor cells is strongly encouraged. Sensitizing EGFR mutations with a population frequency of at least 1% should be reported. IHC for total EGFR as well as EGFR copy number analysis by FISH (Fluorescence In Situ Hybridization) is not recommended.
6) What is the role of KRAS analysis in selecting patients for targeted therapy with EGFR TKIs?
KRAS mutations are common (30%) in lung adenocarcinomas and mutually exclusive with EGFR and ALK. Testing for KRAS may be performed initially to exclude KRAS mutated tumors from EGFR and ALK testing but KRAS mutation testing is not recommended as a sole determinant of EGFR-targeted therapy.
7) What additional testing considerations are important in the setting of secondary or acquired EGFR TKI resistance?
If a laboratory performs testing on specimens from patients with acquired resistance to EGFR kinase inhibitors, such tests should be able to detect the secondary EGFR T790M mutation in as few as 5% of cells.
8) What methods should be used for ALK testing?
ALK FISH assay using dual labeled break-apart probes should be used for selecting patients for ALK TKI therapy. ALK IHC, if carefully validated, may be considered as a screening methodology to select specimens for ALK FISH testing. RT-PCR (Reverse Transcription–Polymerase Chain Reaction) is not recommended as an alternative to FISH, for selecting patients for ALK inhibitor therapy.
9) Are other molecular markers suitable for testing in lung cancer?
Testing for EGFR should be prioritized over other molecular markers in lung adenocarcinoma followed by testing for ALK. Testing for ROS1 and RET rearrangements may soon become a part of the guidelines.
10) How should molecular testing of lung adenocarcinomas be implemented and operationalized?
Pathology departments should establish a process wherein tissue (blocks or unstained slides) is sent to outside molecular laboratories within 3 days of receiving a request and to in house molecular laboratories within 24 hours. Results should be available within 2 weeks and reported in a format that is easily understood by oncologists and nonspecialist pathologists.
Leighl NB, Rekhtman N, Biermann WA, et al. J Clin Oncol 2014;32:3673-3679
Screening for Lung Cancer US Preventive Services Task Force Recommendation Statement
SUMMARY: The Centers for Medicare & Medicaid Services (CMS) on November 14, 2014, proposed that the evidence is sufficient, to add a Lung cancer screening counseling and shared decision making visit for appropriate beneficiaries. Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 224,000 new cases of lung cancer will be diagnosed in the United States in 2014 and over 159,000 will die of the disease. Given the incidence and mortality related to Lung cancer, several studies were conducted dating back to the 1960’s and 1970’s in an attempt to find an appropriate screening test for Lung cancer. They included testing sputum cytology and chest radiography or a combination of both. However, these screening methodologies did not conclusively demonstrate improvements in health outcomes. The results of a NCI-sponsored National Lung Screening Trial (NLST) published in 2011, was more optimistic. In this federally funded U.S. study, 53,439 asymptomatic participants, 55 to 74 years of age, with at least 30 pack-year smoking history were enrolled and randomized to undergo annual screening with either Low dose CT scan (n=26,715) or a chest X-Ray (n=26,724), for three years. The use of Low Dose CT (LDCT) scans for 3 years in this high risk, healthy patients, resulted in a 20% reduction in Lung cancer mortality, compared to screening with a chest X-Ray. Based on these findings, Lung cancer screening was felt appropriate for the following groups of patients:
1) People 55-74 years of age with no signs or symptoms of Lung disease or lung Cancer
2) Current or former smoker with a 30 pack year smoking history (Number of years smoked multiplied by the number of packs of cigarettes per day with each pack containing 20 cigarettes)
3) Former smokers who has quit smoking within the past 15 years
The United States Preventive Services Task Force (USPSTF) recommended annual screening for lung cancer with Low Dose Computed Tomography in adult individuals, between ages 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. 
Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. This was a Grade: B recommendation which meant that the USPSTF recommends the service and there is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial. This therefore meant that clinicians offer or provide this service to these high risk individuals.
Based on this information the Centers for Medicare & Medicaid Services (CMS) on November 14, 2014, proposed that the evidence is sufficient, to add a Lung cancer screening counseling and shared decision making visit. CMS proposed, screening for Lung cancer with Low Dose Computed Tomography (LDCT), for appropriate beneficiaries, once per year, as an additional preventive service benefit under the Medicare program, only if all of the following criteria are met:
1. Age 55-74 years
2. Asymptomatic (no signs or symptoms of lung disease)
3. Tobacco smoking history of at least 30 pack-years (one pack-year = smoking one pack per day for one year; 1 pack = 20 cigarettes)
4. Current smoker or one who has quit smoking within the last 15 years
5. A lung cancer screening counseling and shared decision making visit which includes the use of one or more decision aids discussing the benefits, harms, follow-up diagnostic testing, over-diagnosis, false positive rate, and total radiation exposure
6. Counseling on the importance of adherence to annual LDCT lung cancer screening, impact of comorbidities and ability or willingness to undergo diagnosis and treatment
7. Counseling on the importance of maintaining cigarette smoking abstinence if former smoker, or smoking cessation if current smoker and, if appropriate, offering additional Medicare-covered tobacco cessation counseling services
Lung Cancer screening is performed using a non-contrast, Low Dose CT scan (LDCT) at an accredited advanced diagnostic imaging center with an effective radiation dose less than 1.5 mSv (the equivalent of 15 chest x-rays), compared to a standard chest CT with a median radiation dose of 8 mSv. The imaging center must collect and submit required data to a CMS-approved national registry for each LDCT lung cancer screening performed. Moyer VA, et al. on behalf of the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160:330-338.
Phase II study of nivolumab (Anti-PD-1, BMS-936558, ONO-4538) in patients with advanced, refractory squamous non-small cell lung cancer
SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 224,000 new cases of lung cancer will be diagnosed in the United States in 2014 and over 159,000 will die of the disease. Of the three main subtypes of Non Small Cell Lung Cancer (NSCLC), 25% are Squamous cell carcinomas, 40% are Adenocarcinomas and 10% are Large cell carcinomas. With a better understanding of the Immune checkpoints, the gates are now wide open for the development of various immunotherapies. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be to a significant extent related to their ability to escape immune surveillance by inhibiting T lymphocyte activation. The T cells of the immune system therefore play a very important role in modulating the immune system. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system, is an evolutionary mechanism and is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies are being developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By doing so, one would expect to unleash the T cells, resulting in T cell proliferation, activation and a therapeutic response. Checkmate -063 is a Phase II single arm, open label study designed to evaluate the efficacy of OPDIVO® (Nivolumab) in patients with advanced NSCLC with squamous histology, who had progressed on platinum based therapy as well as at least one additional systemic therapy. OPDIVO® is an immune checkpoint PD-1 (Programmed cell Death 1) targeted, fully human, immunoglobulin G4 monoclonal antibody, which demonstrated an objective response in 20% – 25% of patients with advanced Non Small Cell Lung Cancer, Melanoma and Renal Cell Carcinoma, with favorable toxicities, in previously published studies. This study enrolled 117 patients and two thirds of the patients had previously failed 3 or more treatments and three fourths of patients were within 3 months of completion of their most recent therapy. OPDIVO® was administered as a single agent at 3mg/kg by intravenous infusion every two weeks until disease progression or treatment discontinuation. The primary endpoint was Objective Response Rate (ORR) and exploratory endpoints were overall survival (OS), Progression Free Survival (PFS) and efficacy, based on PD-L1 expression status. With 11 months of minimum follow up, the Objective Response Rate (ORR) was 15% as assessed by an independent review committee and the median duration of response was not reached. These responses were independent of PD-L1 status for patients with quantifiable PD-L1 expression. The estimated one-year survival rate was 41% and median Overall Survival was 8.2 months. The authors noted that an additional 26% of patients had stable disease for a median duration of 6 months, resulting in a disease control rate (ORR+stable disease) of 41%. Approximately 17% of the patients experienced grade 3-4 adverse events which included fatigue, pneumonitis and diarrhea. The authors concluded that the high response rates, median duration of response and disease control rates for Squamous NSCLC, is very promising in this difficult to treat group of patients and phase III trials are underway evaluating OPDIVO® monotherapy in frontline and previously treated patients with Non Small Cell Lung cancer. Ramalingam SS, Mazieres J, Planchard D, et al. Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. LBA#3462
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors vs Conventional Chemotherapy in Non–Small Cell Lung Cancer Harboring Wild-Type Epidermal Growth Factor Receptor – A Meta-analysis
SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society estimates that over 224,000 new cases of lung cancer will be diagnosed in the United States in 2014 and over 159,000 will die of the disease. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, adenocarcinoma now is the most frequent histologic subtype of lung cancer.
In 2004, the discovery of Epidermal Growth Factor Receptor (EGFR) mutations in some advanced Non Small Cell Lung Cancer (NSCLC) cases with adenocarcinoma histology and the favorable responses with EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib) and IRESSA® (Gefitinib), changed the treatment paradigm in favor of targeted therapy, for this patient subset. It is estimated that approximately 10% of Western patient population and 50% of Asian patients with NSCLC, harbor EGFR activating mutations. EGFR Tyrosine Kinase Inhibitors have been shown to be superior to conventional chemotherapy in this patient group with improved Progression Free Survival (PFS) and Objective Response Rates. Patients with NSCLC should therefore be tested for the most common sensitizing mutations such as deletions in exon 19 and L858R point mutations in exon 21, as these patients clearly benefit from first line EGFR TKIs. EGFR expression by IHC (ImmunoHistoChemical) staining, EGFR gene copy by FISH (Fluorescence In Situ Hybridization) and blood based proteonomic testing by VERISTRAT® is currently not recommended for the selection of first line EGFR TKIs. There is presently no evidence indicating superiority of TKIs when compared with conventional chemotherapy for the second or third line treatment of EGFR Wild Type NSCLC. Nonetheless, TKIs are often recommended due to their acceptable toxicities. To address this treatment dilemma, the authors performed a systematic review and meta-analysis of randomized controlled trials, comparing first-generation EGFR TKIs (TARCEVA® and IRESSA®) treatment with conventional chemotherapy, in patients with advanced NSCLC, harboring Wild Type EGFR. This pooled analysis included 1605 patients from 11 clinical trials, with EGFR Wild Type NSCLC. The primary outcome measured was Progression Free Survival (PFS) and secondary outcomes were Objective Response Rate and Overall Survival. It was noted in this analysis that conventional chemotherapy was associated with longer PFS, compared with EGFR TKIs, among patients harboring Wild Type EGFR tumors. The authors noted that there was significant PFS benefit with chemotherapy, in trials using more sensitive EGFR mutation analysis platforms, than direct Sanger sequencing, and this may be the result of identifying the “true” Wild Type EGFR tumors. The objective response rate was higher at 16.8% with chemotherapy versus 7.2% for TKIs. There was however no statistically significant difference in the overall survival between the chemotherapy and TKI groups. When subgroups of patients in these trials were analyzed, outcomes were similar regardless of line of treatment, dominant ethinicity or EGFR mutation analysis method. The lack of improvement in Overall Survival in the chemotherapy group has been attributed to the large cross over rates in the trials that were analyzed. The authors concluded that conventional chemotherapy is associated with superior Progression Free Survival and Objective Response Rates, in patients with advanced NSCLC, harboring Wild Type EGFR tumors, compared with EGFR TKIs and the present guidelines recommending EGFR TKIs in this patient group has to be reevaluated. Lee J, Hahn S, Kim D, et al. JAMA 2014;311:1430-1437
Treatment of Advanced Non–Small-Cell Lung Cancer with Epidermal Growth Factor Receptor (EGFR) Mutation or ALK Gene Rearrangement Results of an International Expert Panel Meeting of the Italian Association of Thoracic Oncology
SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 27% of all cancer deaths. It is the leading cause of cancer death among both men and women. The American Cancer Society’s estimates that over 224,000 new cases of lung cancer will be diagnosed in the United States in 2014 and over 159,000 will die of the disease. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, adenocarcinoma now is the most frequent histologic subtype of lung cancer. In the mid 1990’s, following a meta-analysis of 52 randomized clinical trials, platinum based doublet chemotherapy became the accepted standard, for patients with Stage IV Non Small Cell Lung Cancer (NSCLC), after this combination demonstrated a 27% reduction in the risk of death compared to supportive care. Since then, significant advances have been made and it is now established that Platinum/Pemetrexed (ALIMTA®) combination results in superior survival in those with non squamous histology tumors whereas Platinum/ Gemcitabine (GEMZAR®) combination is superior in patients with squamous cell histology. In 2004, the discovery of Epidermal Growth Factor Receptor (EGFR) mutations in some advanced NSCLC cases with adenocarcinoma histology and the favorable responses with EGFR Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib) and IRESSA® (Gefitinib), changed the treatment paradigm in favor of targeted therapy for this patient subset. Subsequently, the discovery of rearrangements of the Anaplastic Lymphoma Kinase (ALK) gene in some patients with advanced NSCLC and adenocarcinoma histology, led to the development of agents such as XALKORI® (Crizotinib) and ZYKADIA® (Ceritinib), with promising results. It has become clear that appropriate, molecularly targeted therapy for tumors with a molecular abnormality, results in the best outcomes. This new paradigm lead to the development of evidence based recommendations by a panel of experts in thoracic oncology taking the “driver oncogenes and driver mutations” into consideration. According to the US Lung Cancer Mutation Consortium (LCMC), two thirds of patients with advanced adenocarcinoma of the lung, have a molecular driver abnormality. The most common oncogenic drivers in patients with advanced adenocarcinoma of the lung are, KRAS in 25%, EGFR in 21% and ALK in 8% as well as other mutations in BRAF, HER2, AKT1 and fusions involving RET and ROS oncogenes. These mutations are mutually exclusive and the presence of two simultaneous mutations, are rare. The following guidelines have been put together, to better manage patients with advanced adenocarcinoma of the lung. 
EGFR Mutations and EGFR TKIs
• All patients with advanced NSCLC with the exclusion of pure squamous cell carcinoma should be tested for EGFR mutations before first line treatment decision is made. Because EGFR mutations and ALK rearrangement are mutually exclusive, routine testing of the other is not required for those patients with one known genomic abnormality.
• Patients should be tested for the most common sensitizing mutations such as deletions in exon 19 and L858R point mutations in exon 21, as these patients clearly benefit from first line EGFR TKIs. EGFR expression by IHC (ImmunoHistoChemical) staining, EGFR gene copy by FISH (Fluorescence In Situ Hybridization) and blood based proteonomic testing by VERISTRAT® is currently not recommended for the selection of first line EGFR TKIs.
• Any one of the three available agents, TARCEVA® (Erlotinib), GILOTRIF® (Afatinib) or IRESSA® (Gefitinib) are recommended for first line treatment, as per the regulatory label, because of the absence of data on direct comparisons.
• Platinum based chemotherapy should be considered after EGFR TKI failure in eligible patients and there is no evidence to recommend a preferred chemotherapy regimen in EGFR mutation positive patients.
• If EGFR mutation positive results become available after commencement of first line chemotherapy, early interruption of chemotherapy is discouraged. However maintenance therapy with EGFR TKI should be considered after completion of first line chemotherapy.
• In patients with unknown EGFR mutational status, first line platinum based chemotherapy is the standard of care.
• Continuing EGFR TKI beyond disease progression after its use as first line treatment is not recommended.
ALK Rearrangements and Treatment Selection
• Currently, ALK status is determined by FISH technique although ALK testing by IHC analysis is gaining momentum.
• All patients with advanced NSCLC with the exclusion of pure squamous cell carcinoma should be tested for ALK rearrangement before decision about first line treatment is made. Because EGFR mutations and ALK rearrangements are mutually exclusive, routine testing of the other is not required for those patients with one known genomic abnormality.
• In the US, XALKORI® (Crizotinib) is approved for use in any line of treatment.
• Chemotherapy is allowed in any line of treatment although it is preferable to use it following treatment failure with XALKORI®.
• ZYKADIA® (Ceritinib) is approved in the US for treatment of patients with disease progression on or who are intolerant to XALKORI® (Crizotinib).
• If ALK positive results become available after commencement of first line chemotherapy, early interruption of chemotherapy is discouraged. In these patients, XALKORI® should be used as second line treatment following disease progression on chemotherapy. Maintenance therapy with XALKORI® is not recommended.
• In clinical practice, a repeat biopsy is not recommended at disease progression after treatment with EGFR TKIs or ALK inhibitors.
Gridelli C, de Marinis F, Cappuzzo F, et al. Clinical Lung Cancer 2014;15:173-181
ZYKADIA® (Ceritinib)
The FDA on April 29, 2014 granted accelerated approval to ZYKADIA® for the treatment of patients with Anaplastic Lymphoma Kinase (ALK)-positive, metastatic Non-Small Cell Lung Cancer (NSCLC), with disease progression on or who are intolerant to XALKORI® (Crizotinib). ZYKADIA® capsules are a product of Novartis Pharmaceuticals Corporation.
Ceritinib in ALK-Rearranged Non–Small-Cell Lung Cancer
SUMMARY: EML4-ALK (Echinoderm Microtubule associated protein Like 4) – (Anaplastic Lymphoma Kinase) is an aberrant fusion-type oncoprotein and is a tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma, who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplification of the respective genes, the associated tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). XALKORI® (Crizotinib) is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In an open label phase III trial involving 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum based regimen, treatment with XALKORI® significantly improved Progression Free Survival (PFS) and Response Rates (RR). In spite of this initial benefit, patients will however relapse within 12 months, with the average response duration of about 8 months. This has been attributed to acquired mutation within the ALK tyrosine kinase domain, amplification of the ALK fusion gene, subtherapeutic inhibition of ALK tyrosine kinase or activation of other pathways that can cause abnormal cell proliferation. Ceritinib (LDK378) is an oral, small molecule, second generation tyrosine kinase inhibitor of ALK and is 20 times as potent as XALKORI® against ALK. Unlike XALKORI®, Ceritinib does not inhibit MET kinase activity. Based on preclinical data supporting the efficacy of Ceritinib in both XALKORI® sensitive and resistant NSCLC tumors, the authors conducted a study to evaluate the antitumor activity of Ceritinib in patients with advanced NSCLC and other cancers harboring genetic alterations in ALK, in addition to determining the safety, MTD (maximum tolerated dose) and pharmacokinetics of Ceritinib. In this trial, patients who had received prior therapy with one or more ALK inhibitors as well as those with asymptomatic treated or untreated CNS metastases, were eligible to be enrolled. This study had 2 components – a dose escalation phase and an expansion phase. In the dose escalation phase, 59 patients were enrolled and the MTD of Ceritinib was determined to be 750 mg PO daily. In the expansion phase, 71 additional patients were treated for a total of 130 patients (N=59+71). Majority of these patients (94%) had advanced NSCLC. Patients with NSCLC who received at least 400mg of Ceritinib daily (N=114) had an overall response rate (RR) of 58% and median PFS was 7 months. Patients with advanced NSCLC who had received XALKORI® prior to enrollment (N=80) had a RR of 56%. The responses were noted both in patients with tumors harboring resistance mutations in the ALK tyrosine kinase domain as well as those in whom there was no new genetic alterations of ALK. Further, responses were seen in the untreated CNS lesions both in patients who had prior therapy with XALKORI® as well as those who did not. Adverse events were grade 1or 2 and GI related. These included vomiting, diarrhea, elevated aminotransferase levels and hypophosphatemia. The authors concluded that Cerifinib has marked antitumor activity in patients with advanced ALK rearranged NSCLC and in those who had progressed during XALKORI® treatment, regardless of the presence of resistance mutations in the ALK tyrosine kinase domain. Whether Cerifinib should be considered for the first line treatment of advanced ALK rearranged NSCLC, remains to be seen. Shaw AT, Kim D, Mehra R, et al. N Engl J Med 2014; 370:1189-1197
Safety and efficacy of weekly nab® paclitaxel in combination with carboplatin as first-line therapy in elderly patients with advanced non-small-cell lung cancer
SUMMARY: ABRAXANE® (Albumin-bound Paclitaxel or nab-Paclitaxel) is a solvent-free formulation of Paclitaxel with a superior therapeutic index and delivers higher concentrations of the drug’s active ingredient into the tumor cell. This is unlike solvent based taxanes such as TAXOL® (Paclitaxel) and TAXOTERE® (Docetaxel), which have delivery vehicles such as Cremaphor and Polysorbate 80 respectively. By virtue of being solvent free, ABRAXANE® can be administered over a shorter period of time without premedications and is associated with fewer side effects with possibly superior efficacy. In a phase III trial, 1052 treatment naive patients with Stage IIIB/IV Non Small Cell Lung Cancer (NSCLC) were randomly assigned to receive ABRAXANE® 100 mg/m2 weekly and PARAPLATIN® (Carboplatin) at Area Under the Concentration-time curve (AUC) 6, once every 3 weeks (nab-PC) or TAXOL® 200mg/m2 plus PARAPLATIN® AUC 6 once every 3 weeks (sb-PC). Patients were stratified by disease (Stage IIIB vs IV), age (< 70 vs ≥ 70 years), sex (male vs female), histology (squamous vs adenocarcinoma vs others). The primary end point was Overall Response Rate (ORR). Secondary end points included Progression Free Survival (PFS) and Overall Survival (OS). In their original report, the authors concluded that the study met its primary end point and ABRAXANE® combination (nab-PC) significantly improved ORR compared to TAXOL® combination (sb-PC) and was also associated with less neuropathy. In a sub-set analysis of patients 70 years or older (N=156), those in the ABRAXANE® group had a significantly longer median OS compared to the TAXOL® group (19.9 vs 10.4 months, HR=0.58, P=0.009). The PFS in this elderly group trended in favor of ABRAXANE® (8 vs 6.8 months, P=0.13). This survival benefit was not seen in the younger patients. Elderly patients with NSCLC usually tend to have other co-morbidities and treatment can be challenging. With lower incidence of toxicities such as neuropathy, neutropenia and arthralgias, ABRAXANE® combination therapy can be a valuable option for the first line treatment of elderly patients with advanced NSCLC of all histologies. Socinski MA, Langer CJ, Okamoto I, et al. Ann Oncol. 2013;24:314-321
Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer
SUMMARY: EML4-ALK (Echinoderm Microtubule associated protein Like 4) – ALK (Anaplastic Lymphoma Kinase) is an aberrant fusion-type oncoprotein and is a tyrosine kinase. This oncoprotein/tyrosine kinase is found in 2-7% of all Non Small Cell Lung Cancers (NSCLC) and is generated due to an inversion in the short arm of chromosome 2. This oncoprotein is more prevalent in patients with adenocarcinoma, who have little or no exposure to tobacco. Tyrosine kinases normally play an important role in cellular proliferation and differentiation. However with point mutations, translocation/rearrangement and amplification of the respective genes, the associated tyrosine kinases can potentially cause malignancy. Such is the case with mutations or translocations of the Anaplastic Lymphoma Kinase gene (ALK). Crizotinib (XALKORI®) is a small molecule Tyrosine Kinase Inhibitor that targets ALK, MET and ROS1 tyrosine kinases. In this open label phase III trial, 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum based regimen, were randomly assigned to receive XALKORI® 250 mg PO twice daily (N=173) or intravenous chemotherapy with either Pemetrexed (ALIMTA®) 500 mg/m2 or Docetaxel (TAXOTERE®) 75 mg/m2, every 3 weeks (N=174). The primary endpoint was Progression Free Survival (PFS) and secondary endpoints included Overall Survival (OS), Response Rate (RR) and safety. The median PFS was 7.7 months in the XALKORI® group as compared to 3 months in the chemotherapy group (HR=0.49; P<0.001). The Response Rates for XALKORI® and chemotherapy were 65% and 20% respectively (P<0.001). At the time of interim analysis, there was no significant difference in the OS between the XALKORI® and chemotherapy groups. The authors pointed out that this lack of OS benefit was due to the high cross over rate to the XALKORI® group from the chemotherapy group. Patients in the XALKORI® group had better quality of life, greater reduction in lung cancer symptoms and were on the study treatment longer, than with chemotherapy. The authors concluded that XALKORI® improves PFS, Response Rates as well as Quality Of Life in patients with previously treated, ALK positive advanced Non Small Cell Lung Cancer. This is remarkable, considering that the response rates in this patient population treated with second line chemotherapy is around 10-15%. As we move forward, it is very likely that tailored therapy based on molecular genotyping will become standard practice. Shaw AT, Kim D, Nakagawa K, et al. N Engl J Med 2013; 368:2385-2394