EGFR-mutant NSCLC: Choice of First-Line Treatment May Get More Complicated

Medical guidelines for treatment of newly diagnosed non-small cell lung cancer (NSCLC) mandate upfront testing of tumor tissue for mutations in the EGFR gene (as well as ALK and ROS gene translocation). EGFR mutations are found in 10 to 15% of white patients, but in patients of East Asian origin such mutations are in encountered in approximately 48%. However, with new data and drugs entering the playing field, newly diagnosed patients’ treatment decisions could become more complex.

There is a good reason to test for EGFR mutations: the accumulated data show that, compared to first-line chemotherapy, treatment with drugs that inhibit the activity of EGFR in patients with activating EGFR mutations improves patients’ median progression-free survival (PFS) time from 4.6 to 6.9 months to 9.6 to 13.1 months, and has a higher objective response rate (ORR). Moreover, EGFR inhibitors are associated with a significantly lower incidence of adverse effects and better control of disease symptoms.

About 90% of EGFR mutations in EGFR are deletions in a portion of the gene known as exon 19 or a mutation in exon 21 (these mutations are known as del19 and L858R, respectively). The remaining mutations include alterations in exons 18 and 20, and these are associated with poor response to EGFR inhibitors.

The presence of the EGFR mutations del19 or L858R usually prompts doctors to prescribe one of the three EGFR inhibitors approved by the U.S. Food and Drug Administration (FDA) as a first-line treatment: erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif). Erlotinib and gefitinib are first-generation EGFR inhibitors, and afatinib is a second-generation drug. The first-generation inhibitors bind EGFR reversibly (they can attach and detach), whereas second generation inhibitors like afatinib bind to EGFR in an irreversible manner. All three inhibit not only the mutated EGFR protein, but also the normal EGFR that performs essential functions in some normal tissues. Afatinib also inhibits other members of the EGFR family of proteins (HER2 and HER4).

It is worth noting that none of these three drugs improve overall survival, with one exception, which I discuss later. The major side effects of EGFR inhibitors are skin rash and diarrhea, and the latter can be more severe with afatinib. In general, side effects are usually manageable and often transient, and by now, doctors have acquired much experience on how to alleviate them. Also, dose reductions to reduce side effects are possible with erlotinib and afatinib (but not with gefitinib). Gefitinib in general has lower risk of toxicities.

The choice between the three available inhibitors may depend on several factors: the oncologist’s preferences, the patient’s general condition, and importantly, the precise EGFR mutations identified in the patient’s tumor(s).

The del19 mutation is known to have the highest response rate to EGFR inhibitors amongst all EGFR mutations. A direct comparison in a large clinical trial showed an ORR of 72.5% with afatinib and 56% with gefitinib. There was no difference in PFS, but there was a trend in prolongation of overall survival with afatinib (27 versus 24 months).

Therefore, patients with del19 who are in a good overall condition should be given afatinib. The prevailing opinion is that gefitinib should be given to frail or older patients, or patients with other health concerns.

EGFR mutations other than L858R or del19, such as exon 20 insertions or exon 18 mutations, respond poorly to erlotinib and gefitinib. Patients whose tumors have these mutations do not have good treatment options, but are usually treated with afatinib, which has been shown to have better activity then first-generation inhibitors. There are now drugs in clinical trials specifically for patients with exon 20 insertions: a combination of poziotinib and AP32788, and osimertinib.

Obviously, the choice between the three FDA-approved first-line drugs requires careful consideration. However, it is apparently about to become a lot more difficult, with new contenders for first-line treatment in EGFR mutant NSCLC coming onto the scene. A combination of erlotinib with bevacizumab, a drug that limits blood supply to tumors, has already shown a superior PFS of 16 months versus 10 months with erlotinib alone. Another, and likely a stronger candidate, is osimertinib (Tagrisso), a third-generation inhibitor that does not bind to normal EGFR. Osimertinib is already FDA-approved for treatment of NSCLC with an EGFR mutation known as T790M.

T790M is very rarely found in untreated lung cancer, but arises during treatment with FDA-approved EGFR inhibitors in about 40 to 60% of patients, making them resistant to further treatment with first/second generation EGFR inhibitors. Osimertinib was developed to treat patients with T790M and has a reported ORR of 61%, which is very impressive. This is much higher than what is seen with chemotherapy in patients with resistance to first-line EGFR inhibitors: in a direct comparison in the AURA3 trial, a response rate of 71% was seen with osimertinib versus only 31% with chemotherapy. Moreover, osimertinib has activity (albeit much lower) even in the absence of a T790M mutation after resistance to erlotinib or gefitinb develops.

This latter feature led to testing of osimertinib as a first-line treatment in EGFR-mutant NSCLC. The trial included 60 patients who received two different doses of the drug, and the average ORR was 77%, with a median PFS of 20.5 months. These PFS data are much better than what is seen with any of the three FDA-approved first-line EGFR inhibitors (10 to 12 months).

There is a much larger trial ongoing, named FLAURA, which directly compares osimertinib with erlotinib or gefitinib in the frontline setting for patients with advanced EGFRmutant NSCLC. There is little doubt that the results, when published, would favor osimertinib, and this has been already announced in a press release issued by the trial sponsor.

It is possible that the FDA will approve osimertinib as the first-line treatment option for EGFR-positive NSCLC, which will make the choice of first-line drug difficult. What is better: sequence the available drugs, i.e., start with erlotinib followed by osimertinib when resistance develops (if T790M is identified), or give osimertinib outright?

Doing a simple calculation, erlotinib first may provide PFS of 9-13 months, followed by osimertinib (if T790M is present), adding another 10 months. Osimertinib given as first line can provide 20 months PFS. However, resistance to approved first-line EGFR inhibitors involves T790M in 40 to 60 % of patients, so perhaps it is more useful to use osimertinib right away? Not an easy question to answer. It would be wonderful if data could be somehow collected for the many patients who were treated with erlotinib, developed T790M mutation, and switched to osimertinib, rather than to conduct randomized trials. But this is unlikely to happen.

Super ASK Patient: Phil Kauffman Finds Peace in a Pragmatic Approach to Lung Cancer Treatment

In November of 2014, Phil Kauffman went to his primary care doctor with what he thought was a broken rib. The doctor advised him to let it heal on its own—a standard approach for such maladies.

Phil, a retired engineering consultant who lives near San Diego, California, with his wife (their two daughters are grown), went home and waited for his rib to heal, but the pain stuck around for months.

In March of 2015 his doctor ordered an X-ray, but instead of a broken rib, it revealed suspicious spots in Phil’s lung. A CT scan found five lesions characteristic of lung cancer. His rib pain was caused by pleural effusion (liquid) in his right lung, which was extracted, and an examination of that liquid confirmed a diagnosis of stage IV non-small cell lung cancer (NSCLC).

Phil remembers that during the first week after his diagnosis he was paralyzed with fear. His brother in law, a physician, helped him snap out of it, assuring him that his treatment options guaranteed a survival period of at least a few years or maybe more, and that cancer research was progressing at such a fast rate that the prospect of extending his lifetime beyond a couple of years was good. Continue reading…

The Trouble With KRAS

Mutations in the gene that encodes the KRAS protein are frequently encountered in various human cancers. They are found in about 30% of non-small cell lung cancers (NSCLCs), making KRAS the single most common gene mutated in this cancer. The rate of KRAS mutations in other cancers, such as pancreatic or colorectal, is even higher.

A mutant KRAS protein that is always in the “on” position activates many signaling pathways, many of which lead to unrestrained growth and proliferation of cancer cells. This makes KRAS an appealing treatment target. However, challenges abound, and researchers are exploring several different approaches to treating KRAS-mutant cancers.

Unlike mutations in proteins known as receptor tyrosine kinases, like EGFR or ALK, mutated KRAS is a very difficult protein to target with cancer drugs. (So much so that the National Institutes of Health (NIH) has undertaken a special effort to intensify the effort towards successful targeting of mutant KRAS, known as the RAS Initiative.) Continue reading…

Testing for Tumor Mutations: Liquid Biopsy Versus Traditional Biopsy

Liquid biopsies, virtually unknown even a year or two ago, are becoming common tools in precision diagnostics for cancer. Here, I will try to explain some of the more important differences between liquid and “traditional” tumor biopsies.

Biopsies of solid tumors (e.g., lung, breast, or brain tumors) involve surgically removing a small part of a tumor and sending it to pathology lab. In the last few years, doctors have also started to send some tumor samples to special service labs that analyze tumor DNA for the presence of cancer-related mutations.

By definition, regular biopsies can be intrusive and are sometimes associated with side effects, such as bleeding or infection. However, they provide some really essential information; i.e., the histology and grade of the tumor and other tumor characteristics necessary to determine the best choice of treatment. For lung cancer, for example, a biopsy determines the type of tumor—adenocarcinoma, squamous cancer, small-cell lung cancer, or another, less common type. For breast cancer, a routine test will determine if the tumor expresses estrogen, progesterone receptors, and a protein called HER2. These tests are critically important in guiding treatment choices. If mutational analysis of cancer-related genes is also performed (which doesn’t always happen, unfortunately), it may guide treatment with targeted drugs. Continue reading…

War of the Checkpoint Inhibitors: Anti-PD-1 Drugs Move into First-Line Treatment in NSCLC

Last year, the U.S. Food and Drug Administration (FDA) approved two anti-PD-1 checkpoint inhibitors, a type of immunotherapy, for treatment of non-small cell lung cancer (NSCLC) in patients whose cancer has progressed after first-line treatment with chemotherapy. Now, the manufacturers of both drugs, pembrolizumab (made by Merck) and nivolumab (made by Bristol-Myers Squibb; BMS) are intent on expanding the indications for use of their drugs. To this end, they have conducted clinical trials testing each as a first-line treatment (i.e., in previously untreated patients), comparing them to standard chemotherapy. Continue reading…

Super ASK Patient: Dyanne and Lars Push Far Beyond Standard Lung Cancer Treatment

In March of 2015, Dyanne Søraas was diagnosed with stage IV non-small cell lung cancer (NSCLC). She was 30 years old and otherwise healthy. Dyanne and her husband, Lars, began to research potential treatment options. Standard treatment seemed to provide little hope, and they gradually decided they would need to think outside the box in order to maximize the time their family would have together. Continue reading…

Lung Cancer Highlights from ASCO 2016

This year, the Annual Meeting of the American Society of Clinical Oncology (ASCO) did not produce any truly groundbreaking revelations about new treatments for lung cancer. However, researchers did report quite a few positive findings, and some disappointing ones. I have summarized some of the more prominent presentations below. Continue reading…

Super ASK Patient: Community Kindness Helps a Family Face Lung Cancer

Update:  We are deeply saddened to report that Michael passed away on July 20, 2016. It is a privilege to continue to share his story and keep his memory alive.

In October of 2014, Michael Hrabal’s wife Hazel urged him to go to the doctor for a small but persistent cough. The doctor prescribed cough medicine, but it didn’t help, and by the end of the month Michael had been diagnosed with stage IV non-small cell lung cancer.

“It was kind of shocking that this little cough turned out to be cancer,” says Michael, who was 57 years old at the time and living north of New York City with Hazel and their son Andrew. This was actually his second time facing cancer; he’d been treated for kidney cancer 15 years earlier, but had remained cancer-free until the new diagnosis. Continue reading…

Clinical Trial Versus Standard Protocol: Why and How to Enroll in a Trial

My job at Cancer Commons is to help cancer patients better understand and make decisions about their treatment. Through our Ask Cancer Commons service, I also strive to inform patients about new drugs in trials that they can discuss with their oncologists. Sometimes, I explain the rationale behind a patient’s current or upcoming treatment, and sometimes I try to convince patients to actually get treated, rather than hope that a vegetarian diet and herbal supplements will cure their metastatic disease. Continue reading…