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.


For Certain Asian NSCLC Patients, Afatinib Is Better than Chemotherapy

The gist: Certain Asian patients with non-small cell lung cancer (NSCLC) have better survival results when treated with the drug afatinib (Gilotrif) than with standard chemotherapy. In a clinical trial, these results were true for patients whose tumors had a particular mutation called del19 EGFR. But patients with the Leu858Arg EGFR mutation did just as well on Gilotrif as on standard chemotherapy.

“In an analysis of overall survival in the phase III LUX-Lung 3 and LUX-Lung 6 trials reported in The Lancet Oncology, Yang et al found no significant difference between afatinib (Gilotrif) vs pemetrexed (Alimta)-cisplatin (LUX-Lung 3) or vs gemcitabine-cisplatin (LUX-Lung 6) in previously untreated, predominantly Asian patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma. A significant difference favoring afatinib was found among patients with exon 19 deletion (del19) in both trials, with no difference observed among patients with the Leu858Arg mutation…

“The investigators concluded: ‘Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials.’ ”


Boehringer Reports Data from Afatinib Phase III LUX-Lung 3 Trial in Asian NSCLC Patients

The gist: Asian people with non-small cell lung cancer (NSCLC) whose tumors have a common mutation in the EGFR gene called del19 might have better survival when treated with the drug afatinib instead of chemotherapy. That was the conclusion of a recent clinical trial that tested afatinib in volunteer patients.

“Boehringer Ingelheim has reported positive data from a pre-specified subgroup-analysis of the pivotal Phase III LUX-Lung 3 trial of afatinib in Asian non-small cell lung cancer (NSCLC) patients.

“The trial showed that these patients with the most common type of EGFR mutation, (exon 19 deletion; del19), lived significantly longer after receiving first-line treatment with afatinib compared to chemotherapy.

“The company noted that overall survival results from this pre-specified Asian subgroup-analysis are consistent with the overall del19 population in LUX-Lung , and with the previously reported Asian Phase III LUX-Lung 6 trial, in which patients with the del19 mutation lived a median of more than one year longer if they started treatment with afatinib rather than standard chemotherapy…

“Guangdong Academy of Medical Sciences and Guangdong General Hospital vice-president and principal investigator of the LUX-Lung 6 trial Yi-Long Wu said: ‘Afatinib is the first treatment to demonstrate a significant overall survival benefit for NSCLC patients with the del19 mutation, the most common EGFR mutation.

” ‘More than half of the world’s lung cancer cases occur in Asia. Therefore, EGFR testing for NSCLC patients is important in order to identify the patients eligible for targeted therapy.’ “


MEDIA ALERT New Data Show Giotrif® (Afatinib) Provided More than One Year Additional Survival for Lung Cancer Patients with the Most Common Type of EGFR Mutation (del19) Compared to Chemotherapy

“Boehringer Ingelheim today announced results of the pre-specified individual, as well as the exploratory combined, analyses of two Phase III trials (LUX-Lung 3 and LUX-Lung 6). These data, to be presented at the 50th Annual Meeting of the American Society of Clinical Oncology (ASCO), demonstrated for the first time that patients with NSCLC with the most common epidermal growth factor receptor (EGFR) mutation (exon 19 deletions; del19) lived more than one year longer if treated with first-line afatinib compared to chemotherapy.”

Editor’s note: This article discusses the results of a clinical trial that tested a targeted drug called afatinib (aka Giotrif, or Gilotrif)  on volunteer patients with non-small cell lung cancer (NSCLC). The trial found that patients whose tumors had a particular mutation called del19 in the EGFR gene lived more than one year longer if treated with afatinib than if treated with chemotherapy. EGFR mutations and other mutations are detected via molecular testing, and can be used by oncologists to help develop personalized lung cancer treatment plans.