‘FLAURA China cleared up doubts about Tagrisso’s effect on Asians’

AstraZeneca’s Tagrisso is the third-generation drug to treat non-small cell lung cancer (NSCLC) by targeting epidermal growth factor receptor (EGFR) mutations.

The treatment is the only EGFR tyrosine kinase inhibitor (TKI) that improved median overall survival for more than three years in the first-line treatment of advanced NSCLC, becoming the standard of care in the U.S. and Europe.

However, the sub-analysis of Asians in the FLAURA trial showed that the hazard ratio (HR) of the Tagrisso group was 1.00, which was no different from that of the control group. This made some critics question that Tagrisso as the first-line treatment might not improve survival compared to other EGFR TKIs.

In response, AstraZeneca released data of the FLAURA China trial to reconfirm Tagrisso’s effect on Asian patients. With the latest data, local lung cancer specialists start a new discussion over Tagrisso’s efficacy in Asians.

Korea Biomedical Review has met with Professor Ahn Hee-kyung of the Oncology Department at Gachon University Gil Medical Center to learn about the major issues of Tagrisso based on the FLAURA study.

Professor Ahn Hee-kyung of the Oncology Department at Gachon University Gil Medical Center speaks during an interview with Korea Biomedical Review.

Question: Can you briefly explain about recently released data of the FLAURA China trial?

Answer: The study took place in China to compare Tagrisso with the existing first-generation EGFR inhibitor Iressa, in the first-line treatment in 136 EGFR-mutated NSCLC patients.

The study had the same protocol in the previous FLAURA trial to allow cross-administration in the control group to switch to Tagrisso when the patient had T790M mutation.

The results showed that the Tagrisso-treated group (71 patients) had 17.8 months of median progression-free survival (mPFS) versus 9.8 months in the control group. This means that Tagrisso lowered the risk of disease progression and death by 44 percent.

Tagrisso also reduced the risk of mortality by 15 percent, as the Tagrisso group’s median overall survival (mOS) was 33.1 months, much longer than 25.7 months in the control group. This demonstrated Tagrisso’s therapeutic benefits in Chinese patients, which was consistent with the global FLAURA study results.

I think the FLAURA China data helped clear up doubts about Tagrisso’s efficacy in Asians. FLAURA China data was consistent with the global FLAURA data and met the expectation for Tagrisso in the first-line treatment.

Q: Many lung cancer specialists pointed out that a Japanese cohort was imbalanced in the sub-analysis of Asians in the FLAURA trial. Is that true?

A: Yes. The OS data sub-analysis from the global FLAURA study showed that OS benefits were not remarkable in Asians. So, some doctors said using a subsequent therapy might be better than Tagrisso as the first-line therapy in Asian patients and questioned whether Tagrisso was effective for the first-line treatment.

At the time, assumptions varied as to why Asians and non-Asians had different results, and one of them was data interpretation of Japanese patients who participated in the study.

Japanese patients accounted for the largest number of Asian patients in the FLAURA study. The analysis of Japanese data was similar to the sub-analysis of Asian patients.

Asian patients in the FLAURA trial had a higher proportion of those who relapsed after undergoing surgery rather than patients diagnosed with stage-four cancer, or a higher proportion of L858 mutation-positive patients, compared to patients worldwide. The imbalance might have affected the results. Also, Japan's unique treatment patterns, such as follow-up therapy after the first treatment failure, may have affected the results.

Q: Some said as EGFR inhibitors are as advanced as third-generation, PFS would be sufficient to evaluate the drug’s efficacy because OS is likely to cause bias. Do you agree with this?

A: Not really. It is clear that stage-four NSCLC is not curable no matter how various drugs appear and drug effects improve. So, a doctor’s best goal is to prolong the patient’s life as long as possible. We look at PFS data as a surrogate marker of OS. The ultimate goal is to improve OS. As various treatments have arrived, it has become very difficult to look at OS data and interpret them. But it is best to check OS data, and I do not doubt that there is no such strong indicator as OS.

Q: Tagrisso is very expensive, which cannot be ignored. Can you narrow down the patient group who must use Tagrisso for the first-line treatment?

A: For an NSCLC patient with a “burden” in the central nervous system, Tagrisso will be a very important option as the first-line treatment.

Generally, 20-30 percent of lung cancer patients accompany brain metastasis at the time of diagnosis, and the probability of brain metastasis is quite high.

NSCLC with brain metastasis is difficult to treat, and the prognosis is poor. Before the arrival of targeted therapy, NSCLC patients with brain metastasis used cytotoxic chemotherapy, but they had only about three months to live. Because cytotoxic chemotherapies do not penetrate the blood-brain barrier (BBB) well, they may be effective for the lungs but less effective for the brain.

So, surgery or radiation treatment was the main treatment option for patients with brain metastasis for a long time. However, it is difficult to repeat radiation therapy several times. If the brain metastasis progressed, it was difficult to control with chemotherapy, and there was not much the doctor could do.

Brain metastasis causes symptoms that lower life quality, such as headache, nausea, vomiting, and neurological symptoms. As NSCLC patients with brain metastasis have a low survival rate, researchers did not include them in clinical trials of investigational drugs.

However, the Tagrisso study considered its CNS effect because it improved BBB permeability in the previous data of drug concentration in cerebrospinal fluid. Later, Tagrisso demonstrated consistently low CNS progression, regardless of the underlying CNS metastasis in a clinical trial.

Therefore, patients with CNS burden at the time of diagnosis will benefit from Tagrisso.