Tag: Lung Cancer: Non-Small Cell

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

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.

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