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.


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…


US Widens Use of Boehringer's Lung Cancer Drug Gilotrif

Excerpt:

“US health officials have expanded the approved indications for Boehringer Ingelheim’s Gilotrif, clearing its use in patients with squamous cell carcinoma of the lung.

“Gilotrif (afatinib), an oral, once-daily EGFR-directed therapy, is currently cleared in the US for the first-line treatment of specific types of EGFR mutation-positive non-small cell lung cancer.

“Approval for squamous cell carcinoma of the lung, a disease linked with a particularly bleak poor prognosis of one-year survival post diagnosis, was based on data from the head-to-head LUX-Lung 8 trial in patients whose tumours progressed after first-line chemotherapy.”

Go to full article.

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CHMP Recommends Afatinib for Second-Line NSCLC

“Afatinib (Giotrif, EU; Gilotrif, US) has received a positive recommendation from the Committee for Medicinal Products for Human Use (CHMP) as a treatment for patients with advanced squamous cell non–small cell lung cancer (NSCLC) following progression on platinum-based chemotherapy, according to Boehringer Ingelheim, the manufacturer of the irreversible EGFR inhibitor.

“The CHMP opinion, which recommends that the treatment should gain approval from the European Medicines Agency in this setting, is based on data from the phase III LUX-Lung 8 trial. In the study, second-line afatinib reduced the risk of both disease progression and death by 19%, compared with erlotinib (Tarceva) in patients with advanced squamous cell carcinoma of the lung.”


Mutation Status Guides Advanced NSCLC Therapy

“The presence or absence of mutations in advanced non-small cell lung cancer (NSCLC) should guide selection of first-line systemic therapy, according to an updated clinical guideline from the American Society of Clinical Oncology.

“Patients with squamous-cell tumors that have no gene alterations should begin treatment with combination platinum-based cytotoxic chemotherapy, so long as they have good performance status (0 or 1). Optionally, bevacizumab (Avastin) may be added when the platinum agent is carboplatin. For patients with performance status 2, either chemotherapy or palliative care alone is an acceptable option.

“In the presence of sensitizing EGFR mutations, appropriate first-line therapy is afatinib (Gilotrif), erlotinib (Tarceva), or gefitinib (Iressa). Treatment should begin with crizotinib (Xalkori) when patients have tumors with ALK or ROS1 rearrangements, as published online in the Journal of Clinical Oncology.”


Afatinib Improves Progression-Free Survival vs Erlotinib in Second-Line Treatment of Advanced Squamous Cell Carcinoma of the Lung

“In the phase III LUX-Lung 8 trial reported in The Lancet Oncology, Soria et al found that the irreversible ErbB-family inhibitor afatinib (Gilotrif) significantly improved progression-free and overall survival vs the EGFR tyrosine kinase inhibitor erlotinib as second-line treatment in patients with stage IIIB or IV squamous cell carcinoma of the lung who had disease progression after four or more cycles of platinum-based chemotherapy.

“In this open-label trial, 795 patients from 23 countries were randomly assigned between March 2012 and January 2014 to receive afatinib at 40 mg/d (n =398) or erlotinib at 150 mg/d (n = 397). The primary endpoint was progression-free survival on independent central review in the intent-to-treat population…

“The investigators concluded: ‘The significant improvements in progression-free survival and overall survival with afatinib compared with erlotinib, along with a manageable safety profile and the convenience of oral administration suggest that afatinib could be an additional option for the treatment of patients with squamous cell carcinoma of the lung.’ “


Boehringer's Giotrif Beats Roche's Tarceva on Lung Cancer Survival

“Boehringer Ingelheim’s Giotrif has shown a greater survival benefit than Roche’s Tarceva in previously-treated patients with advanced squamous cell carcinoma of the lung.

“According to data from the LUX-Lung 8 trial, published in The Lancet Oncology, Giotrif (afatinib) extended overall survival to a median of 7.9 months compared to 6.8 months on Tarceva (erlotinib), reducing the risk of death by 19%.

“The study also met its primary endpoint showing a significant improvement in progression-free survival over Tarceva, which is an approved and recommended treatment option for advanced SCC of the lung following treatment with first-line platinum-based chemotherapy.”


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.’ ”


Afatinib Works Best in Patients Whose Lung Cancer Has Specific Mutation in EGFR Gene

The gist: Afatinib (Gilotrif) works better than chemotherapy for people with non-small cell lung cancer (NSCLC) whose tumors have a specific mutation in the EGFR gene. This mutation is known as exon 19 deletion. In a recent clinical trial, some patients with exon 19 deletion were treated with Gilotrif and some with chemotherapy. The patients who received Gilotrif lived significantly longer than the patients who received chemotherapy. All patients had stage IIIB or IV lung adenocarcinoma.

“Patients with lung adenocarcinoma who harbored exon 19 deletion EGFR mutations experienced significantly longer OS when treated with first-line afatinib instead of chemotherapy, according to analyses of results from two phase 3 trials.

“However, researchers did not observe the survival benefit among patients with other types of EGFR mutations.

“ ‘These data provide important evidence about the use of afatinib in patients whose tumors have the del19 mutation and tell us that the standard treatments and approaches should no longer be assumed equivalent for every EGFR mutation,’ Lecia V. Sequist, MD, MPH, medical oncologist at Massachusetts General Hospital Cancer Center and associate professor of medicine at Harvard Medical School, said in a press release.”