On September 11, 2023 AstraZeneca reported positive results from the FLAURA2 Phase III trial TAGRISSO (osimertinib) in combination with chemotherapy demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), compared to TAGRISSO alone for patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) (Press release, AstraZeneca, SEP 11, 2023, View Source [SID1234635086]).
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These results were presented today in a Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC) 2023 World Conference on Lung Cancer (WCLC) (abstract #PL03).
Results showed TAGRISSO plus chemotherapy reduced the risk of disease progression or death by 38% compared to TAGRISSO alone (based on a hazard ratio [HR] of 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). By investigator assessment, the combination extended median PFS by 8.8 months versus TAGRISSO alone. PFS results from blinded independent central review (BICR) were consistent, showing TAGRISSO plus chemotherapy extended median PFS by 9.5 months (based on HR of 0.62; 95% CI 0.48-0.80; p=0.0002). Importantly, a clinically meaningful PFS benefit was observed across all prespecified subgroups, including sex, race, type of EGFR mutation, age at time of diagnosis, smoking history and central nervous system (CNS) metastasis status at baseline.
At the time of this analysis, the overall survival (OS) data were immature however, a favorable trend was observed for TAGRISSO plus chemotherapy.
Pasi A. Jänne, MD, PhD, medical oncologist at Dana-Farber Cancer Institute and principal investigator for the FLAURA2 trial, said: "Patients received nearly nine additional months before their EGFR-mutated non-small cell lung cancer progressed as a result of the addition of chemotherapy to standard-of-care osimertinib, building on the strong efficacy we have already seen with osimertinib monotherapy. With these convincing data, patients may soon have a choice of two highly effective osimertinib-based treatment options in this advanced disease setting."
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "The compelling FLAURA2 results add to the extensive evidence supporting TAGRISSO as the backbone therapy in EGFR-mutated non-small cell lung cancer and establish a new benchmark for progression-free survival in this setting. We look forward to bringing this potential treatment regimen to patients with advanced lung cancer to further delay disease progression, especially for patients with the greatest unmet need including those with central nervous system metastasis at diagnosis."
Summary of results: FLAURA2
PFS by INV
PFS by BICR
TAGRISSO plus chemotherapy
(n=279)
TAGRISSO monotherapy
(n=278)
TAGRISSO plus chemotherapy
(n=279)
TAGRISSO monotherapy
(n=278)
Median PFS (in months)i
25.5
(24.7, NCii)
16.7
(14.1, 21.3)
29.4
(25.1, NCii)
19.9
(16.6, 25.3)
Hazard ratio (95% CI)
0.62 (0.49-0.79)
0.62 (0.48-0.80)
p-value
<0.0001
0.0002
Data maturity
51%
43%
i. Data cut-off date was 3 April 2023.
ii. NC: Not calculable
Safety results and discontinuation rates due to adverse events (AEs) were consistent with the established profiles of each medicine and no new safety concerns were reported. Grade 3 or higher AEs from all causes occurred in 64% of patients in the TAGRISSO plus chemotherapy arm versus 27% in the TAGRISSO monotherapy arm.
IMPORTANT SAFETY INFORMATION
There are no contraindications for TAGRISSO
Interstitial lung disease (ILD)/pneumonitis occurred in 3.8% of the 1479 TAGRISSO-treated patients; 0.3% of cases were fatal. Withhold TAGRISSO and promptly investigate for ILD in patients who present with worsening of respiratory symptoms which may be indicative of ILD (eg, dyspnea, cough and fever). Permanently discontinue TAGRISSO if ILD is confirmed
Heart rate-corrected QT (QTc) interval prolongation occurs in TAGRISSO-treated patients. Of the 1479 TAGRISSO-treated patients in clinical trials, 0.8% were found to have a QTc >500 msec, and 3.1% of patients had an increase from baseline QTc >60 msec. No QTc-related arrhythmias were reported. Conduct periodic monitoring with ECGs and electrolytes in patients with congenital long QTc syndrome, congestive heart failure, electrolyte abnormalities, or those who are taking medications known to prolong the QTc interval. Permanently discontinue TAGRISSO in patients who develop QTc interval prolongation with signs/symptoms of life-threatening arrhythmia
Cardiomyopathy occurred in 3% of the 1479 TAGRISSO-treated patients; 0.1% of cardiomyopathy cases were fatal. A decline in left ventricular ejection fraction (LVEF) ≥10% from baseline and to <50% LVEF occurred in 3.2% of 1233 patients who had baseline and at least one follow-up LVEF assessment. In the ADAURA study, 1.5% (5/325) of TAGRISSO-treated patients experienced LVEF decreases ≥10% from baseline and a drop to <50%. Conduct cardiac monitoring, including assessment of LVEF at baseline and during treatment, in patients with cardiac risk factors. Assess LVEF in patients who develop relevant cardiac signs or symptoms during treatment. For symptomatic congestive heart failure, permanently discontinue TAGRISSO
Keratitis was reported in 0.7% of 1479 patients treated with TAGRISSO in clinical trials. Promptly refer patients with signs and symptoms suggestive of keratitis (such as eye inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye) to an ophthalmologist
Postmarketing cases consistent with erythema multiforme major (EMM), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if EMM, SJS, or TEN is suspected and permanently discontinue if confirmed.
Postmarketing cases of cutaneous vasculitis including leukocytoclastic vasculitis, urticarial vasculitis, and IgA vasculitis have been reported in patients receiving TAGRISSO. Withhold TAGRISSO if cutaneous vasculitis is suspected, evaluate for systemic involvement, and consider dermatology consultation. If no other etiology can be identified, consider permanent discontinuation of TAGRISSO based on severity
Aplastic anemia has been reported in patients treated with TAGRISSO in clinical trials (0.07% of 1479) and postmarketing. Some cases had a fatal outcome. Inform patients of the signs and symptoms of aplastic anemia including but not limited to, new or persistent fevers, bruising, bleeding, and pallor. If aplastic anemia is suspected, withhold TAGRISSO and obtain a hematology consultation. If aplastic anemia is confirmed, permanently discontinue TAGRISSO. Perform complete blood count with differential before starting TAGRISSO, periodically throughout treatment, and more frequently if indicated
Verify pregnancy status of females of reproductive potential prior to initiating TAGRISSO. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with TAGRISSO and for 6 weeks after the final dose. Advise males with female partners of reproductive potential to use effective contraception for 4 months after the final dose
Most common (≥20%) adverse reactions, including laboratory abnormalities, were leukopenia, lymphopenia, thrombocytopenia, diarrhea, anemia, rash, musculoskeletal pain, nail toxicity, neutropenia, dry skin, stomatitis, fatigue, and cough
INDICATIONS
TAGRISSO is indicated as adjuvant therapy after tumor resection in adult patients with non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test
TAGRISSO is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test
TAGRISSO is indicated for the treatment of adult patients with metastatic EGFR T790M mutation-positive NSCLC, as detected by an FDA-approved test, whose disease has progressed on or after EGFR tyrosine kinase inhibitor (TKI) therapy
Please see complete Prescribing Information, including Patient Information for TAGRISSO.
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Notes
Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.1 Lung cancer is broadly split into NSCLC and small cell lung cancer.2 Each year, there are an estimated 2.2 million people diagnosed with lung cancer globally with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.1-3 Approximately 70% of people are diagnosed with advanced NSCLC.4
Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.5-7 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.8
FLAURA2
FLAURA2 is a randomized, open-label, multi-center, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with TAGRISSO 80mg once daily oral tablets in combination with chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)) every three weeks for four cycles, followed by TAGRISSO with pemetrexed maintenance every three weeks.
The trial enrolled 557 patients in more than 150 centers across more than 20 countries, including in the US, Europe, South America and Asia. This is the analysis of the primary endpoint of PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.
TAGRISSO
TAGRISSO (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastasis. TAGRISSO (40mg and 80mg once-daily oral tablets) has been used to treat nearly 700,000 patients across its indications worldwide and AstraZeneca continues to explore TAGRISSO as a treatment for patients across multiple stages of EGFRm NSCLC.
TAGRISSO, the only targeted therapy to improve survival in both early- and late-stages of EGFRm NSCLC, is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. These include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC (FLAURA), locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage (IB, II and IIIA) EGFRm NSCLC (ADAURA), where TAGRISSO recently demonstrated a statistically significant and clinically meaningful OS benefit.
AstraZeneca also has several ongoing Phase III trials focused on earlier stages of lung cancer including a trial in the Stage IA2-IA3 adjuvant resectable setting (ADAURA2), and in the Stage III locally advanced unresectable setting (LAURA).
The Company is also researching ways to address tumor mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test TAGRISSO plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new