Using a pharmacogenetic strategy to home in on a molecularly defined non-small cell lung cancer patient population, researchers have shown in a clinical trial that the investigational EGFR inhibitor afatinib significantly prolongs survival in patients with EGFR-mutated tumors.
Researchers from Boehringer Ingelheim and elsewhere presented data at the American Society of Clinical Oncology's annual meeting this week on the LUX-Lung 3 trial, which they heralded as the "largest and most robust" trial performed to date in the EGFR-mutation positive NSCLC population. Sponsor Boehringer Ingelheim will likely seek approval for afatinib as a first-line therapy for this subset of lung cancer patients.
The data, presented by lead study author James Chih-Hsin Yang of National Taiwan University Hospital, also showed that patients who harbor two of the most common EGFR mutations respond especially well to afatinib.
In the LUX-Lung 3 trial, study investigators enrolled 345 patients from 130 sites in 25 countries. Patients with Stage IIIB/IV adenocarcinoma and EGFR-positive tumors were randomized to receive either afatinib or the most effective chemotherapy regimen containing cisplatin and pemetrexed. The primary endpoint of the study was independent reviewer-assessed progression-free survival, or the period of time patients were alive without their disease advancing. Secondary endpoints included overall survival, disease control rate, tumor shrinkage, patient-reported outcomes, and safety. Study participants were previously untreated for advanced NSCLC.
The data from LUX-Lung 3 showed that patients receiving afatinib lived for a median of 11.1 months without their cancer progressing, while patients receiving cisplatin/pemetrexed lived for a median of 6.9 months. The overall survival data in the study are not yet mature.
After 12 months, "47 percent of patients in the study who received afatinib had not progressed, [while] 22 percent of people who received chemotherapy have not progressed," Yang said. "With this simple measurement, you can tell that the patients who received afatinib enjoyed a longer progression-free survival time compared with chemotherapy."
Patients on the afatinib arm had around a 40 percent less chance of dying than patients on the chemotherapy arm. According to an assessment by independent reviewers, tumors shrank in 56 percent of patients following treatment with afatinib, compared to 22.6 percent of patients in the chemo arm.
Between 30 percent and 40 percent of Asian adenocarcinoma patients and between 5 percent and 15 percent of Caucasian adenocarcinoma patients harbor EGFR mutations. Although this molecularly targeted population is small, the incidence of NSCLC is so high that many patients stand to potentially benefit from a personalized medicine treatment approach, Yang said during his presentation.
Throughout the world, there are approximately 1.6 million new cases of lung cancer each year, 85 percent of which are the non-small cell type. For the majority of lung cancer patients, their diagnosis comes too late for surgery to be an option. Chemotherapy regimens have shown to prolong survival for about one year. In the US, 15 percent of lung cancer patients survive for five years after diagnosis.
In LUX-Lung 3, study investigators enrolled NSCLC patients with a variety of EGFR mutations, including exon 19 deletions, L858R mutations, exon 20 insertions, G719X mutations, and S7681 mutations. Previously published data suggest that exon 19 deletions and L858R mutations comprise 90 percent of EGFR mutations in NSCLC patients. Exon 19 deletions have also been associated with resistance to first-generation EGFR inhibitors.
Previous studies have focused largely on studying the response of exon 19 deletions and L858R mutations on first-generation EGFR inhibitors. LUX-Lung 3 "is different in that we enrolled 10 percent of patients with uncommon mutations," Yang said.
There were 308 patients in LUX-Lung 3 with exon 19 deletions and L858R mutations. In the afatinib arm, 51 percent of the patients with these common mutations did not have disease progression at one year, compared to 21 percent of patients in the chemotherapy arm. The median progression-free survival time for patients in this subgroup was 13.5 months with afatinib treatment and 6.9 months for chemo-treated patients.
The fact that the overall study population with all the EGFR mutations responded similarly to the subgroup with common EGFR mutations when given chemotherapy further confirms the benefit of a personalized treatment strategy. What the data show is that "chemotherapy can suppress the tumors without knowing what type of tumors patients have, but targeted therapy is better at targeting the [EGFR-mutated] tumor," Yang said.
LUX-Lung investigators also have data on the response seen in NSCLC patients with less common EGFR mutations, but this information was not reported at ASCO.
However, "efficacy does come at a cost," Benjamin Solomon from the Peter MacCallum Cancer Center said at the meeting in a presentation reviewing the LUX-Lung 3 data. "The more potent inhibition of mutant EGFR seems to be related to toxicities [associated] with inhibition of normal EGFR in wild-type tissue."
Afatinib-treated patients experienced higher rates of diarrhea, rash, inflammation around the mouth, skin infection around the nails, and dry skin. Although there has been no direct comparison of toxicities seen with first-generation EGFR inhibitors against afatinib, "the impression I have is the [adverse event] rates seen here [with afatinib] are much higher than with the first-generation therapies."
Approximately 1 percent of patients stopped the treatment due to diarrhea. There were four deaths due to toxicities in the afatinib arm.
However, study investigators reported that afatinib-treated patients saw an improvement of existing conditions such as shortness of breath and chest pains. The drug also seemed to delay the onset of lung cancer-related symptoms, such as shortness of breath and cough, compared with chemotherapy. Based on patient-reported information, Yang said that overall, study participants indicated better physical functioning, health, and quality of life on afatinib.
In the trial, patients' EGFR tumor status was established via genetic testing performed at three central labs. "It is very important to do central laboratory testing," Yang said. "This is the age of personalized medicine, and one can make a wrong [decision about treatment] if the lab makes a wrong judgment."
Centralized genetic testing "is a way to ensure that the testing is standardized … and we know the sensitivity and the specificity of the tests," he said, adding that the genetic test kit that was used in the study can detect 29 different types of EGFR mutations.
Qiagen has a deal with Boehringer Ingelheim to develop an EGFR mutation-detecting companion test for afatinib (PGx Reporter 6/1/2011).
"It's clear that [LUX-Lung 3] establishes afatinib as another proven option for the first-line treatment of EGFR-mutation positive NSCLC patients, alongside [AstraZeneca's] Iressa and [Roche/Genentech's] Tarceva," Solomon said.
Initially, as the sponsor of a first-generation inhibitor, Roche subsidiary Genentech will likely capture the largest share of the EGFR-mutated NSCLC market.
Last year, the European Commission approved the use of Tarceva as a first-line treatment for NSCLC in patients with EGFR mutations (PGx Reporter 9/7/2012). Last month, UK's National Institute for Health and Clinical Excellence issued a draft guidance recommending that the country's National Health Service pay for Tarceva as an option for this patient population. The company is in discussions with the US Food and Drug Administration about launching Tarceva in this population (PGx Reporter 06/08/2011).
AstraZeneca's Iressa is also marketed outside of the US as a treatment for EGFR-mutation-positive NSCLC patients.
Previously, five randomized-controlled studies investigating the activity of Tarceva and Iressa have shown that EGFR-mutated NSCLC patients derive a significant benefit in terms of progression-free survival compared to chemotherapy regimens. The findings from LUX-Lung 3 are encouraging, according to Yang, because although in earlier trials investigators saw EGFR-mutated lung cancer patients benefit from afatinb treatment, none of those studies yielded such a robust progression-free survival advantage.
Afatinib is distinguished from first-generation EGFR inhibitors Tarceva and Iressa in that it is an irreversible inhibitor, which means that the drug covalently bonds to the receptor. Once the inhibitor binds to the cell receptor it will not detach, causing the cell to die. "Irreversible means that inhibition is stronger," Yang said.
Unlike first-generation inhibitors, afatinib also inhibits Erb4 and HER2, which has been linked to breast cancer and to some lung cancers. Afatinib is currently in Phase III clinical development for breast cancer and head and neck cancer.
As researchers begin to improve their understanding of EGFR-mutated NSCLC patients, there is also a pressing need to establish how patients with wild-type EGFR genes should be treated. In a separate presentation at ASCO, Marina Garassino from U.O. Oncologia Medica in Italy reported on the Phase III TAILOR trial, which compared Tarceva against docetaxel in the second-line setting for more than 200 EGFR wild-type NSCLC patients.
The study revealed that wild-type patients treated with chemotherapy fared better than those given Tarceva. Trial participants in the docetaxel arm experienced median progression-free survival of 3.4 months compared to 2.4 months for those in the Tarceva arm.
"We clearly need better treatments, but we also need to use our existing treatments in the best way possible," Solomon said during his presentation.
He cautioned, however, that just because this study showed wild-type patients didn't respond to the targeted agent, researchers shouldn't give up trying to personalize treatment strategies for this population.
"EGFR wild-type patients are not a homogenous population. It's important to recognize that these patients may have other actionable genetic changes in their tumors," Solomon reflected, highlighting the need to test for rearrangements in the ALK gene, which predicts response to the NSCLC cancer drug Xalkori.