SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.
Approximately 10-15% of Caucasian patients and 35-50% of Asian patients with Adenocarcinomas, harbor activating EGFR (Epidermal Growth Factor Receptor) mutations and 90% of these mutations are either Exon 19 deletions or L858R substitution mutation in Exon 21. Approximately 25% of patients with EGFR mutated NSCLC have brain metastases at diagnosis, increasing to approximately 40% within two years of diagnosis. The presence of brain metastases often reduces median survival to less than eight months. EGFR-Tyrosine Kinase Inhibitors (TKIs) such as TARCEVA® (Erlotinib), IRESSA® (Gefitinib) and GILOTRIF® (Afatinib), have demonstrated a 60-70% response rate as monotherapy when administered as first line treatment, in patients with metastatic NSCLC, who harbor the sensitizing EGFR mutations. However, majority of these patients experience disease progression within 9-14 months. This resistance to frontline EGFR TKI therapy has been attributed to the most common, acquired T790M “gatekeeper” point mutation in EGFR, identified in 50-60% of patients.
Osimertinib (TAGRISSO®) is a highly selective third-generation, irreversible Epidermal Growth Factor Receptor TKI, presently approved by the FDA, for the first-line treatment of patients with metastatic NSCLC, whose tumors have Exon 19 deletions or Exon 21 L858R mutations, as well as treatment of patients with metastatic EGFR T790M mutation-positive NSCLC, whose disease has progressed on or after EGFR-TKI therapy. Further, Osimertinib has higher CNS penetration and is therefore able to induce responses in 70-90% of patients with brain metastases.
In the Phase III FLAURA trial, among patients with metastatic, EGFR-mutant NSCLC, first-line treatment with Osimertinib significantly improved median Overall Survival, compared with Erlotinib and Gefitinib, and should therefore has been the preferred regimen in this patient group. The FLAURA2 trial builds on the favorable results observed in the Phase III FLAURA trial.
FLAURA2 is a randomized, open-label, multi-center, global, ongoing Phase III trial, in which 557 enrolled treatment naïve patients (N=557) with nonsquamous locally advanced (Stage IIIB-IIIC) or metastatic EGFR mutated NSCLC were randomly assigned 1:1 to receive Osimertinib plus chemotherapy (N=279) or Osimertinib monotherapy (N=278). Patients in the combination group received Osimertinib 80 mg oral tablets once daily in combination with chemotherapy consisting of Pemetrexed 500 mg/m2 IV plus Cisplatin 75 mg/m2 IV or Carboplatin (AUC5), every three weeks for four cycles, followed by Osimertinib with Pemetrexed maintenance every three weeks. The median patient age was 62 years, approximately 62% were women and 64% were Asian. Approximately 76% of patients completed four cycles of platinum therapy. The Primary end point was investigator-assessed Progression Free Survival (PFS). Secondary endpoints included Overall Survival (OS), Objective Response Rate (ORR) and Safety.
In this final analysis of the Primary endpoint of PFS, results from this study showed a significant improvement in Progression Free Survival (PFS) with the Osimertinib plus chemotherapy combination versus Osimertinib alone, with an 8.8-month improvement in median PFS with the combination regimen (HR=0.62; P<0.0001). This represented a 38% reduction in disease progression risk, compared to Osimertinib monotherapy. In addition, median PFS determined by blinded Independent Central Review showed a 9.5-month improvement with the combination regimen. The Objective Response Rate with the combination regimen was 83%, compared to 76%, in the Osimertinib monotherapy group. Grade 3 or higher hematologic adverse events occurred more frequently in the combination regimen group and were manageable. Data for Overall Survival were immature at the time of the analysis, and this ongoing trial will continue to assess the Secondary endpoint of Overall Survival.
The authors concluded that FLAURA2 provides compelling evidence that the addition of chemotherapy to Osimertinib in the first line treatment of nonsquamous, locally advanced or metastatic EGFR mutated NSCLC, can further improves outcomes, compared to Osimertinib alone, and can delay resistance to therapy and disease progression.
FLAURA2 results demonstrate osimertinib plus chemotherapy superior compared to osimertinib alone (press release). Available at: https://www.iaslc.org/iaslc-news/press-release/flaura2-results-demonstrate-osimertinib-plus-chemotherapy-superior. Published Sept.10, 2023.