Update Sustains Osimertinib Activity Against CNS Mets in NSCLC

Excerpt:

“New results again demonstrated the benefit of frontline osimertinib (Tagrisso) in patients with EGFR-positive advanced non–small cell lung cancer (NSCLC) and CNS metastases at baseline, according to data presented at the 2017 ESMO Asia Congress.

“The subgroup analysis from the phase III FLAURA trial included 128 patients with at least 1 measurable and/or nonmeasurable CNS lesion at baseline. Among 61 patients who received osimertinib, the CNS objective response rate (ORR) was 66%, compared to 43% (odds ratio, 2.5; 95% CI 1.2-5.2; P = .011) in 67 patients who received standard EGFR TKI therapy with erlotinib (Tarceva) or gefitinib (Iressa).”

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Jack West, MD: Top Five Lung Cancer Abstracts at ESMO 2017

Excerpt:

“The European Society for Medical Oncology (ESMO) 2017 Congress is just around the corner, and we can already say with confidence that there will be many provocative presentations, including several that are poised to change practice. At this point, we can only rely on the abstracts and press releases for several of these, but here are my early impressions on the top five presentations in lung cancer for ESMO 2017.”

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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.


Tagrisso Significantly Improves Progression-Free Survival in the Phase III FLAURA Trial for Lung Cancer

Excerpt:

“AstraZeneca today announced that the Phase III FLAURA trial showed a statistically-significant and clinically-meaningful progression-free survival (PFS) benefit with Tagrisso (osimertinib) compared to current 1st-line standard-of-care treatment (erlotinib or gefitinib) in previously-untreated patients with locally-advanced or metastatic epidermal growth factor receptor mutation-positive (EGFRm) non-small cell lung cancer (NSCLC).

“Sean Bohen, Executive Vice President, Global Medicines Development and Chief Medical Officer at AstraZeneca, said: ‘The strong results from the FLAURA trial are very exciting news for patients with EGFR mutation-positive non-small cell lung cancer, providing physicians with a potential new first-line treatment option to improve outcomes in this disease. We will now initiate discussions with global health authorities on the data and regulatory submissions.’ ”

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Adjuvant Gefitinib Delays Recurrence in EGFR-Positive NSCLC

Excerpt:

“Adjuvant therapy with gefitinib (Iressa), an epidermal growth factor receptor (EGFR)-targeted agent, was more successful at preventing recurrence than standard-of-care chemotherapy, in a phase III study of patients with EGFR-positive non–small cell lung cancer (NSCLC). Gefitinib extended recurrence-free survival by about 10 months in patients with stage II–IIIA NSCLC. These findings were presented at the 2017 ASCO Annual Meeting.”

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Targeted Therapy Can Delay Recurrence of Intermediate-Stage Lung Cancer

Excerpt:

“The targeted therapy gefitinib appears more effective in preventing recurrence after lung cancer surgery than the standard of care, chemotherapy. In a phase III clinical trial, patients with epidermal growth factor receptor (EGFR)-positive, stage II-IIIA non-small cell lung cancer (NSCLC) who received gefitinib went about 10 months longer without recurrence than patients who received chemotherapy. The study will be presented at the upcoming 2017 ASCO Annual Meeting in Chicago.

” ‘Adjuvant gefitinib may ultimately be considered as an important option for stage II-IIIA lung cancer patients with an active EGFR mutation, and we may consider routine EGFR testing in this earlier stage of lung cancer,’ said lead study author Yi-Long Wu, MD, a director of the Guangdong Lung Cancer Institute, Guangdong General Hospital, Guangzhou, China. ‘We intend to follow these patients until we can fully measure overall survival as opposed to disease-free survival, which just measures disease recurrence.’ ”

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Adding Pemetrexed to Gefitinib Improves PFS in EGFR-Mutated NSCLC

Excerpt:

“The combination of pemetrexed and gefitinib offered improved progression-free survival (PFS) over gefitinib alone in East Asian patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) and activating EGFR mutations, according to a new randomized, open-label study.

“EGFR tyrosine kinase inhibitors (TKIs) including gefitinib have been shown to improve outcomes in patients with EGFR-mutated NSCLC. ‘Given their different mechanisms of action, combination treatment with EGFR-TKIs and chemotherapy may further improve outcomes,’ wrote study authors led by James Chih-Hsin Yang, MD, PhD, of National Taiwan University Hospital in Taipei. Previous trials of such combinations have not shown clinical benefit, however, though this could have been because of antagonism between the agents used or because wild-type EGFR patients were included.”

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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…


Afatinib a Better Choice for EGFR-Mutated Lung Cancer in First-Line Treatment

“Patients with EGFR-activating mutations in advanced lung cancer seem to benefit more from afatinib than gefitinib as first-line treatment, researchers report at the first ESMO Asia 2015 Congress in Singapore.

“In the global, randomised, open-label Phase IIb LUX-Lung 7 (LL7) trial, the irreversible ErbB family blocker afatinib significantly improved efficacy versus gefitinib across a range of clinically relevant endpoints, such as progression-free survival, time-to- failure and objective response rate. ‘Based on these results I would consider afatinib as the EGFR (TKI) of choice for the first-line treatment for patients with EGFR mutation-positive non-small-cell (NSCLC),’ lead author, Professor Keunchil Park, head of the Division of Hematology/Oncology at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea, said.”