Tagrisso (osimertinib), AstraZeneca’s third-generation EGFR (estimated glomerular filtration rate) tyrosine kinase inhibitor (TKI), has opened a new way for customized treatment of locally progressive or metastatic non-small cell lung cancer (NSCLC).

AZ has recently confirmed Tagrisso’s progression-free survival (PFS) benefits in combination with chemotherapies, widening options for NSCLC patients with various combo therapies based on third-generation EGFR TKI.

The U.K.-based pharma company announced Wednesday (local time) that Tagrisso produced positive results in the phase 3 clinical trial, the FLAURA2 study.

FLAURA2 was an open-label clinical study where researchers compared and evaluated the Tagrisso monotherapy with a combo therapy by adding it to chemotherapy (pemetrexed +cisplatin or carboplatin) in 586 people with locally progressive or metastatic EGFR-mutant NSCLC as the primary treatment, and the combination therapy significantly improved PFS, the primary endpoint.

“The safety results and the discontinuation rate due to adverse reactions were consistent with the established profile of each therapy,” the company said. “The overall survival (OS) data was immature at the time of the analysis, and we will officially evaluate it in a follow-up analysis.”

To sum up, the study indicated that if patients combine chemotherapies with Tagrisso, the global standard for the primary treatment of EGFR-mutant lung cancer, they can prolong PFS without concerns about unpredictable safety.

“Osimertinib monotherapy has provided opportunities to improve the survival rate for many patients by changing treatment environment as the global standard for EGFR-mutant NSCLC,” said Dr. Pasi A. Janne at Dana-Farber Cancer Institute, the study’s lead researcher. “The FLAURA2 study presented strong evidence to patients and medical professionals that adding chemotherapy to osimertinib could improve treatment results further compared to the monotherapy and delay treatment resistance and disease progression.”

Indeed, researchers have long sought various combination therapies based on TKI to treat EGFR-mutant NSCLC.

Based on the preclinical data that the double blocking of EGFR and VEGF (vascular endothelial growth factor) can create synergy, they have attempted the combination therapy of the first-generation EGFR TKI and VEGF inhibitor in various clinical trials. They improved PFS compared with the TKI monotherapy but could not prove clinical advantages in OS.

Most recently, the RELAY study, a phase 3 clinical trial where they assessed the combo therapy of the first-generation EGFR TKI, erlotinib (Taseba), and VEGF inhibitor, ramucirumab (Cyramza), attained the primary endpoint of PFS improvement by reducing disease progression and death risk by 41 percent. However, they are still awaiting results as its OS data remain immature.

Besides, they have continued to study combined uses with chemotherapies. Adding chemotherapies to TKI can cause additional problems of lowered quality of patients’ life and safety. Moreover, 20-30 percent of patients cannot survive until secondary treatment. Nevertheless, researchers continue the study because their combined use with chemotherapy can help to overcome cancer’s heterogeneity problem, offering another potential option.

Fox example, OS improvement has been confirmed in two phase 3 clinical trials – NEJ009 and CTRI/2016/08/007149 -where they evaluated first-generation EGFR TKI, gefitinib (Iressa), and chemotherapy.

In addition, the FLAURA2 study results have added the basis that combo therapies with chemotherapy could be an option that provided additional survival benefits compared to TKI monotherapies.

Accordingly, a new task has emerged for researchers – differentiating patients befitting the TKI plus chemotherapy method more from those who better suit the existing TKI monotherapies regarding the patients’ quality of life.

Besides, other various attempts are being made.

For instance, they combine the first and third-generation TKIs to overcome their resistance mechanism. Or they are delaying resistance by combining them with bispecific antibodies, like amivantamab (Rybrevant), which simultaneously target EGFR and NET (meteorology) routes.

AZ said it would announce the FLAURA study at the European Society for Medical Oncology’s annual conference (ESMO 2023) in October.