FLOWERS STUDY: EXPLORING COMBINATION STRATEGIES FOR PRIMARY RESISTANCE TO EGFR TKI

Although EGFR-TKIs have significant efficacy as first-line therapy, approximately 20% to 30% of patients develop primary resistance to EGFR-TKIs due to primary MET amplification/overexpression
.
In response to this practical clinical problem, the team of Professor Yang Genji of Guangdong Provincial People's Hospital designed a phase II prospective, dual-cohort, randomized multi-center FLOWERS clinical trial to evaluate the efficacy and safety of osimertinib ± sevotinib for first-line treatment in patients with primary MET amplification/overexpression, EGFR mutation-positive, and advanced non-small cell lung cancer (NSCLC
。 THE FLOWERS STUDY DESIGN WAS RECENTLY PUBLISHED
IN THE JOURNAL LUNG CANCER.

Study design background

In current clinical practice, treatment decisions for patients with advanced NSCLC are based on the molecular typing
of the tumor.
EGFR mutations are the most common genetic mutation in Asian NSCLC patients, occurring in 50% of patients
with non-squamous NSCLC.
EGFR-TKIs have shown superior efficacy compared with chemotherapy in patients with positive EGFR mutations, so EGFR TKIs are recommended as a first-line treatment
for these patients.
However, 20% to 30% of patients have primary resistance to EGFR TKI, resulting in patients being insensitive
to EGFR-TKI therapy.
Primary resistance can occur through a variety of mechanisms, such as inherent T790M mutations, or off-target genetic changes, including meta-MET amplification or hepatocyte growth factor (HGF) mutations
.

Multiple preclinical studies and clinical studies have confirmed that the coexistence of EGFR mutation and MET amplification or overexpression reduces the sensitivity
of tumor cells to EGFR-TKIs.
Servotinib is a potent and highly selective MET-TKI that has been shown to have antitumor activity
in cancers with MET-driven mutations.
The safety and tolerability of osimertinib + sevotinib has previously been evaluated
in the phase Ib TATTON study.
According to the data from Part D of the TATTON study, osimertinib (80 mg once daily) + sevotinib (300 mg once daily) showed good antitumor activity in patients with MET amplification/overexpression, positive EGFR mutation, prior first- or second-generation EGFR-TKI progression, and T790M-negative advanced NSCLC, with an ORR of 64%; The median progression-free survival (PFS) was 9.
1 months and a safe profile was acceptable
.

In addition, osimertinib plus sevotinib dual targeted therapy has shown effective antitumor activity in lung cancer organoid drug trials, suggesting that this may be a promising first-line treatment strategy
.
Based on the results of previous studies, Prof.
Yang's team designed this phase II prospective, dual-cohort, randomized multicenter FLOWERS clinical trial to evaluate the efficacy and safety
of osimertinib with or without sevotinib as first-line therapy in patients with primary MET amplification/overexpression, EGFR mutation positive, and advanced NSCLC.

Research methods

The FLOWERS study was a phase II, randomized, open-label, two-cohort multicenter trial
.
Approximately 44 patients will be randomized to osimertinib (80 mg once daily) monotherapy or osimertinib (80 mg once daily) and sevotinib (300 mg twice daily), and patients confirmed positive for MET after disease progression have the opportunity to receive cross-over combination therapy as second-line therapy (Figure 1).

The primary endpoint was objective response rate
.
Secondary endpoints were progression-free survival, duration of response, disease control rate, overall survival, and safety
.

Figure 1 Study design drawing

conclusion

Although EGFR-TKIs have significant efficacy as first-line therapy, approximately 20% to 30% of patients develop primary resistance to EGFR-TKIs due to primary MET amplification/overexpression
.
The results of the FLOWERS study will provide a better perspective on the efficacy and safety of osimertinib in combination with sevotinib as a first-line treatment for this subgroup of patients and provide meaningful guidance
in clinical practice.

References: Anna Li, Hua-Jun Chen, Jin-Ji Yang.
Design and rationale for a phaseII, randomized, open-label, two-cohort multicenter interventional study of osimertinib with or withoutsavolitinib in de novo MET aberrant, EGFR-mutant patients with advanced non-small-cell lung cancer:The FLOWERS Trial,Clinical Lung Cancer(2022), doi: https://doi.
org/10.
1016/j.
cllc.
2022.
09.
009