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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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.


Genprex Announces Positive Interim Data from Phase II Clinical Trial of Oncoprex™ for Late Stage Non-Small Cell Lung Cancer

Excerpt:

“Genprex, Inc. today announced positive interim data from an ongoing Phase II clinical trial (NCT01455389) evaluating its investigational immunogene therapy candidate Oncoprex™ in combination with the tyrosine kinase inhibitor (TKI) erlotinib (Tarceva®) for the treatment of late stage non-small cell lung cancer (NSCLC) patients.”

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Study Finds Cabozantinib Alone or With Erlotinib Improves Outcome in EGFR Wild-Type NSCLC

Excerpt:

“Treatment with the multikinase inhibitor cabozantinib (Cabometyx) alone or with erlotinib (Tarceva) improved progression-free survival vs erlotinib alone in second- or third-line treatment of advanced nonsquamous epidermal growth factor receptor (EGFR) wild-type non–small cell lung cancer (NSCLC), according to the phase II ECOG-ACRIN 1512 trial reported by Neal et al in The Lancet Oncology.”

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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…


Bevacizumab/Erlotinib Combo Approved in Europe for NSCLC

Excerpt:

“The European Commission approved bevacizumab (Avastin) in combination with erlotinib (Tarceva) as a frontline treatment for patients with unresectable advanced, metastatic, or recurrent EGFR-mutant non–small cell lung cancer (NSCLC).

“The approval was based on findings from the phase II JO25567 study, which showed a 46% reduction in the risk of progression or death with the combination versus single-agent erlotinib. The median progression-free survival (PFS) with the addition of bevacizumab was 16 versus 9.7 months with erlotinib alone (HR, 0.54; 95% CI, 0.36-0.79; P = .0015).

“ ‘The combination of Avastin and Tarceva represents a new standard of care for patients with this type of lung cancer,’ Sandra Horning, MD, chief medical officer and Global Head of Product Development at Roche, the company developing the combination, said in a statement. ‘This approval provides physicians in Europe with a powerful combination therapy that can significantly extend progression-free survival beyond 1 year, representing important progress for a group of patients who typically face a poor prognosis.’ ”

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CHMP Recommends EU Approval for Roche's Avastin in Combination With Tarceva for Patients With a Specific Type of Advanced Lung Cancer

Excerpt:

“Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today that the European Union’s Committee for Medicinal Products for Human Use (CHMP) has issued a positive opinion for the use of Avastin® (bevacizumab) in combination with Tarceva® (erlotinib) for the first-line treatment of adult patients with unresectable advanced, metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) activating mutations. NSCLC is the most common type of lung cancer, the leading cause of cancer-related death in Europe and across the world. Approximately 10-15 percent of Europeans with NSCLC will have tumours with EGFR-activating mutations, representing an estimated 33,000 cases in Europe per year or 90 every day.”

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Support for First-Line Erlotinib in NSCLC with EGFR Mutations

“For patients with non-small-cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations, erlotinib is active, and treatment beyond progression is feasible and may delay salvage therapy in selected patients, according to a study published online Dec. 30 in JAMA Oncology.

“Keunchil Park, M.D., from the Sungkyunkwan University School of Medicine in Seoul, South Korea, and colleagues examined the efficacy of first-line erlotinib therapy in  with NSCLC with activating EGFR mutations in the Asian Pacific trial of Tarceva as first-line in EGFR mutation (ASPIRATION). Patients received 150 mg/day erlotinib until ; after this point, therapy could be continued at the discretion of the patient and/or investigator. Patients were followed for a median of 11.3 months.”


Super Patient: Craig Blower Fights Lung Cancer with Knowledge—and Humor


Update:  We are deeply saddened to report that Craig passed away on March 16, 2016. It is a privilege to continue to share his story and keep his memory alive.

In 2010, Craig Blower had such a bad case of bronchitis that his doctor put him on steroids. Craig’s airways cleared up in a month or two, and he didn’t give it any more thought. Then, in late 2012, his throat began whistling slightly when he woke up. But Craig, who was 59 years old at the time, thought it was just part of getting older. “I basically ignored it,” he recalls. Continue reading…