In the battle for first-line EGFR mutant NSCLC patients, it all comes down to toxicity
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| Jun 4, 2012
Treatment of advanced non-small cell lung cancer (NSCLC) has become increasingly driven by tumor characteristics, with choice of systemic therapy now largely decided based on tumor histology, EGFR mutation status, and ALK translocation status, with several other drugs in new biomarker populations also under late-stage clinical development. In patients with EGFR mutations (18% of adenocarcinoma patients in the U.S.), 47% of patients are treated with the EGFR inhibitor Tarceva [erlotinib; OSI/Astellas/Roche] in first-line1. Boehringer Ingelheim is planning to launch afatinib, its irreversible dual EGFR/HER2 inhibitor, into this setting. If successful, it will be battling for patient share with Tarceva in the United States and both Tarceva (15% utilization)1 and Iressa [gefitinib; Astra Zeneca] (43% utilization)1 in Europe.
The LUX-Lung-3 trial randomized 345 patients (2:1) to single agent afatinib versus Alimta [pemetrexed; Eli Lilly] plus cisplatin as first-line therapy in patients with EGFR activating mutations. The study reached its primary endpoint of improved progression free survival (PFS), with mPFS of 11.1 months vs. 6.9 months (HR=0.58, p=0.0004). In common mutation patients (del19/L858R), the mPFS was even better (13.6 mos vs. 6.9 mos, HR=0.47, p<0.0001). A careful analysis of the subgroup reveals that this improved mPFS is driven by the 170 Del19 patients (HR=0.28). It is also important to note that this is the first trial to use Alimta/cisplatin as a comparator arm and because Alimta/cisplatin is a very active regimen in non-squamous patients, it was more difficult for afatinib to demonstrate superiority, yet it managed to do so, albeit at the cost of a higher Hazard Ratio. The most common adverse events were diarrhea and rash. Grade 3-5 adverse events occurred in 49% of patients, including 4 deaths.
LUX-LUNG-3 has ushered afatinib into first-line EGFR mutant NCSLC alongside Tarceva and Iressa. In the pivotal EURTAC trial, Tarceva produced a 9.7 month mPFS with a (HR=0.37, p<0.0001) in the ITT population and 10.4 month mPFS (HR=0.47) in 19del/L858R mutant patients. Iressa demonstrated similar results in this 19del/L858R population with the WJTOG, IPASS, and NEJ002 trials (9.2, 9.5, 10.8 month mPFS; HR 0.49, 0.48, 0.30, respectively). Afatinib performed slightly better than its competitors, which is encouraging. However, does potential increased efficacy outweigh additional toxicity? On comparing toxicity between the LUX-LUNG-3 (afatinib), EURTAC (Tarceva), and NEJ002 trials (Iressa), what stands out is not the difference in grade 3-5 events (49% vs 45% vs 41%) nor the overall rates of rash (89% vs 80% vs 71%), but the difference in rates of diarrhea (95% vs 57% vs 35%). Grade 3 and higher rash and diarrhea are also highest with afatinib (16.2% and 14.4% respectively) and lowest with Iressa (5% and 1%, respectively), which provides some explanation for the preference of European and Asian physicians for Iressa over Tarceva.
Despite the high utilization of Tarceva in the United States, it currently is not FDA approved in the first-line setting. This lack of approval created an opportunity for afatinib to enter this market without directly challenging the market leader in a head-to-head clinical trial. The LUX-LUNG-3 results might push Roche into finally filing for Tarceva approval in the US. Additionally, investigators are already calling for a head-to-head trial and LUX-LUNG-7 (NCT01466660) will compare afatinib to Iressa in 264 del19/L8585R mutant patients in an attempt to answer the question of which agent is superior.
1: CancerMPact, Treatment Architecture, United States, 2011