Boehringer Ingelheim has launched a campaign to educate healthcare providers about biomarker testing to personalize treatment for non-small cell lung cancer patients.
The "Let's Test" campaign comes as the drug maker prepares to launch afatinib, a new treatment option for NSCLC patients with EGFR-mutated tumors. In the recently reported LUX-Lung 3 trial, advanced adenocarcinoma patients with EGFR mutations treated with afatinib lived for 11.1 months without their tumors growing compared to 6.9 months for patients treated with best-in-class chemotherapy agents containing cisplatin and pemetrexed (PGx Reporter 6/6/2012).
Based on this data, Boehringer Ingelheim last month submitted a marketing authorization application for the drug with the European Medicines Agency. The company is moving toward filing a new drug application for afatinib with the US Food and Drug Administration in the coming months, but couldn't provide a specific timeline. The drug will be launched with a companion test, developed by Qiagen, which gauges EGFR mutations in patients.
With the Let's Test effort, Boehringer Ingelheim is laying the groundwork to encourage early tissue collection and broad biomarker testing for NSCLC patients before afatinib hits the market. The web-based educational effort also includes resources for healthcare providers to learn about what treatment guidelines say about such testing, the range of biomarkers that impact treatment response in NSCLC, and available personalized treatment options. Additionally, the website has resources specific to the various healthcare professionals who might interact with a lung cancer patient through the treatment cycle, such as oncologists, pulmonologists, interventional radiologists, thoracic surgeons, pathologists, and oncology nurse practitioners.
The Let's Test website focuses on EGFR mutations and ALK rearrangements. EGFR mutations occur in between 10 percent to 15 percent of the approximately 200,000 people diagnosed with advanced NSCLC each year in the US. ALK rearrangements are rarer, occurring in between 3 percent and 5 percent of advanced NSCLC patients.
According to available market research, however, not all these patients are receiving the right treatment due to limited testing adoption among healthcare providers. Data collected by Ipsos US Oncology Monitor suggest that only 50 percent of NSCLC patients are being tested for EGFR mutations. Even then, Boehringer's own research shows that many of these patients don't receive test results early enough to influence a personalized treatment strategy.
"We really want to do everything we can in the interest of advancing patient care to get the tissue taken, tested, and the results back to the oncologist in time for them to use that in the clinical decision about how they are going to treat the patient," Kevin Lokay, VP of the oncology business unit at Boehringer, told PGx Reporter. "As we are developing an agent that has been tested in the EGFR-mutation positive population, that agent will not be accessible to these patients if they haven't been tested."
Although PGx testing is gaining ground for cancer treatment, it is often limited to the academic setting. The majority of oncologists at community practices are not readily testing for genomic markers, particularly for lung cancer patients.
Lokay noted that PGx-based approaches are commonplace in breast cancer, where molecular profiling of tumors has become standard practice. Information such as HER2, ER, and PR status of breast tumors provides physicians guidance on crafting a personalized treatment strategy for their patients from the start.
However, in lung cancer, "we are a little bit behind in understanding the drivers," Lokay noted. And even as this understanding is on the rise, there are safety challenges associated with garnering sufficient tissue samples to facilitate biomarker testing.
"Unlike with breast cancer, pulmonologists and others taking tissue, such as thoracic surgeons and interventional radiologists, are taught to take as little tissue to be able to make the diagnosis and confirm histology, whether it's squamous or non-squamous," Lokay said. Taking large pieces of lung tissue could cause the lung to collapse. Moreover, 5 percent of stage IIIB and 2 percent of stage IV NSCLC patients have five-year survival rates after diagnosis.
As a result, physicians "didn't believe that there was a lot of benefit to doing [biomarker testing], because it was a pretty dismal outcome regardless of what they did," Lokay explained. However, with improving understanding of the molecular drivers of lung cancer, that perception shows signs of changing. For example, published studies suggest that NSCLC patients with EGFR-mutant tumors may have a better overall prognosis than those with EGFR wild-type tumors. As such, treating EGFR-positive advanced NSCLC patients with EGFR inhibitors sooner may yield better outcomes than waiting to treat until the disease has progressed.
Although the US Food and Drug Administration has not yet approved any drugs specifically for NSCLC patients with EGFR mutations, many physicians at academic cancer centers are already testing patients for these mutations and prescribing EGFR inhibitors, such as Roche/Genentech's Tarceva, to those who have a shot at response.
Last year, the FDA approved Xalkori, a new personalized treatment for NSCLC with ALK rearrangements, and recent survey data suggest that oncologists in private practices, hospital-affiliated outpatient clinics, community hospitals, and academia are increasingly performing the necessary genetic testing to gauge ALK mutations in patients to see if they would benefit from this drug. Six months after Xalkori's launch, BioTrends Research Group surveyed 80 oncologists and found that 82 percent were offering genetic testing in this setting. Meanwhile, 5 percent of respondents indicated it would take them six months or longer to offer such testing; 11 percent said they weren't sure when they would begin conducting such analysis; and 2 percent said they would never offer such testing (PGx Reporter 4/18/2012).
While these trends are encouraging, around half of NSCLC patients who should be tested for critical biomarkers such as ALK and EGFR aren't getting tested. Recognizing this, Boehringer's Let's Test campaign offers healthcare providers strategies for testing patients for key molecular markers as soon as they are diagnosed.
For example, the website includes a section encouraging doctors to provide reflex or automatic testing for ALK and EGFR mutations, and lists several labs that can facilitate this type of service. Reflex testing is testing that is automatically initiated for certain biomarkers once a patient is diagnosed with a particular disease and meets certain criteria. Boehringer points out that reflex testing to assess HER2 overexpression in women with certain breast cancer tumors types is part of standard practice.
"Reflex, or automatic, testing is an effective way to ensure that EGFR mutation and ALK rearrangement status are available to the oncologist as early in the treatment algorithm as possible," the company states on the website. "After establishing non-squamous histology, automatically testing for EGFR mutations first and ALK rearrangements if EGFR-negative promotes: efficiency and consistency in tissue acquisition, diagnostic procedures, and treatment decisions."
Generally, payors balk at broad biomarker screening programs, fearing such interventions will unnecessarily increase costs. However, with professional societies supporting early testing for certain subsets of lung cancer patients, insurers appear to be paying for diagnostic assessments that can be useful in the downstream care of patients.
For example, the National Comprehensive Cancer Network has issued guidelines, and the College of American Pathologists along with other groups have issued draft guidance recommending routine EGFR and ALK testing in patients with adenocarcinomas and other types of advanced non-squamous NSCLC. Due to the rarity of these markers in squamous cell cancer, treatment guidelines don't recommend testing in this setting.
"We have not seen payors not reimburse for tests at this point in time … for Tarceva and Xalkori," Lokay said. "In general, when we have advisory boards and discussions with payors, they are enthusiastic about targeted therapies that have companion diagnostics … and they generally like that they are paying for therapies that have a high percent of success. The biggest waste for a payor is a therapy that doesn't work."
New molecularly guided treatments are expensive. Xalkori costs more than $115,000 per year. The average Medicare reimbursement for the ALK mutation test is $440, according to Abbott, the company that markets the FDA-cleared companion test for the drug. As such, the cost of ensuring that the drug is prescribed only to those patients most likely to respond is miniscule compared to the price of the treatment.
The National Cancer Institute estimates that this year there will be more than 220,000 new cases of lung cancer, the majority of which, around 85 percent, will have disease affecting the non-small cells of the lung. Given the prevalence of the disease, economists have suggested that enrichment strategies may be necessary to cost-effectively administer biomarker testing.
Earlier this year, University of Colorado researchers Adam Atherly and Ross Camidge published a paper in the British Journal of Cancer reporting that broadly testing all advanced NSCLC patients in order to identify the small subset of ALK-positive individuals who should be treated with Xalkori did not meet a cost-effectiveness bar of less than $100,000 per quality-adjusted life year gained. However, by applying an enrichment strategy, where clinicians target testing to patients with certain characteristics that make them more likely to harbor ALK mutations, such as patients with adenocarcinomas, who have EGFR-negative mutations, and were low or non-smokers, the researchers found that oncologists could decrease the cost per QALY gained to around $4,756 (PGx Reporter 3/28/2012).
However, test makers and personalized drug developers have criticized this economic analysis on a number of fronts, most importantly pointing out that histology-driven or phenotype-based enrichment strategies would still miss patients who would benefit from targeted treatment. For example, in the Let's Test website, Boehringer highlights data from a Journal of Clinical Oncology paper that reported that 57 percent of all EGFR mutations in adenocarcinomas would be missed if doctors restricted testing to women who never smoked. Similarly, the company notes on the website that although ALK rearrangements are more common in non-smokers or those with a light smoking history, patients with a heavy smoking history have also been found to have ALK rearrangements.
"There may be more efficiency in not testing the broader population, but the problem is that there may be a significant number of patients that could still benefit from targeted treatments," Lokay said.
Although afatinib is not on the market yet, in September Boehringer announced an expanded access program through which patients with locally advanced or metastatic NSCLC with EGFR-mutated tumors can receive the investigational drug. The expanded access scheme will help provide the drug for patients who don't otherwise qualify for a clinical trial and don't have available alternative treatments.
However, healthcare providers who don't readily test NSCLC patients for biomarkers may not know which of their patients are eligible to receive afatinib through the expanded access program. Launching Let's Test ahead of afatinib's approval may encourage more physicians to consider how they can incorporate molecular profiling of lung cancer patients in their practices and allow them to identify patients who can receive the drug early.
Afatinib, once on the market, will compete with Tarceva and AstraZeneca's Iressa. Boehringer's drug is distinguished from these first-generation EGFR inhibitors in that it is an irreversible inhibitor, which means that the drug covalently binds to EGFR, HER2, and HER4 receptors that are overexpressed in certain cancers. Once the drug permanently attaches to the cell receptors, it blocks these receptors and inhibits cell signaling pathways that cause tumor cells to proliferate. In addition to NSCLC, Boehringer is exploring afatinib in breast and head and neck cancers.