Onkologie 31. Jänner 2017
Notable advances in the field of anti-EGFR therapy
The irreversible ErbB family blocker afatinib and the reversible EGFR TKIs gefitinib and erlotinib have been approved as first-line therapies for treatment of NSCLC patients with EGFR-sensitising mutations. However, resistance frequently develops, which indicates the need for new agents. The EGFR T790M mutation has been identified as the most common resistance mutation.
AURA3: 70 % risk reduction with osimertinib
Osimertinib demonstrated statistically superior and clinically meaningful activity compared to the platinum-pemetrexed therapy. The primary endpoint of investigator-assessed PFS was highly significantly in favour of osimertinib (10.1 vs. 4.4 months; HR, 0.30; p < 0.001; Figure 1). Progression-free survival (PFS) benefits occurred across all of the subgroups. Patients with CNS metastases at baseline experienced similar reductions in the risk of progression or death (PFS, 8.5 vs. 4.2 months; HR, 0.32) as those without cerebral lesions (10.8 vs. 5.6 months; HR, 0.40). The objective response rate (ORR) was significantly higher with osimertinib (71 % vs. 31 %; p < 0.001), and the median duration of response was longer (9.7 vs. 4.1 months). Moreover, the tolerability of osimertinib surpassed that of chemotherapy, as possibly treatment-related grade ≥3 adverse events (AEs) occurred less frequently (6 % vs. 34 %). The investigators thus noted that osimertinib represents the new standard of care for patients with EGFR T790M-positive NSCLC following disease progression with first-line EGFR TKI therapy.
Figure 1: PFS according to investigator assessment in AURA3: pronounced advantage for osimertinib over chemotherapy
LUX-Lung 7: continued benefit with afatinib over gefitinib
The phase IIB LUX-Lung 7 trial was the first prospective, global, randomised study to compare two EGFR-directed therapies (afatinib and gefitinib) head-to-head in the first-line setting. A total of 319 patients with EGFR-positive stage IIIB/IV adenocarcinoma of the lung were randomised to either afatinib 40 mg OD or gefitinib 250 mg OD. In the primary analysis, afatinib significantly improved the co-primary endpoints of PFS and time to treatment failure (TTF) compared to gefitinib . The key secondary endpoint, ORR, was also significantly improved. At the WCLC, Park et al. presented the primary overall survival (OS) analysis as well as other updated outcomes .
Findings in elderly patients
As more than one third of patients with lung cancer are at least 75 years old, the efficacy and safety of new agents matters in this population. Treatment can be challenging due to poorer functional status and high comorbidity burden. According to post-hoc subgroup analyses of patients aged ≥ 75 and < 75 years in LUX-Lung 7, advanced age did not adversely affect the outcomes achieved with afatinib versus gefitinib . PFS and OS findings were consistent across age subgroups (Figure 2).
Figure 2: Median OS obtained with afatinib vs. gefitinib in various age groups in the LUX-Lung 7 trial
Predictors of long-term response in LUX-Lung 8
The randomised, open-label phase III LUX-Lung 8 study compared afatinib 40 mg OD and erlotinib 150 mg OD in patients with squamous-cell carcinoma (SCC) of the lung who had progressed after ≥ 4 cycles of platinum-doublet chemotherapy. Here, afatinib significantly improved PFS and OS (HR, 0.81 for both) , which prompted its approval for this indication. A group of 15 long-term responders (LTRs) who derived prolonged benefit from afatinib treatment was identified in the LUX-Lung 8 trial. In this cohort, the median treatment duration was 16.6 months. Goss et al. investigated molecular and clinical biomarkers that might be indicative of long-term response to afatinib .
CSF penetration of afatinib
The CNS is a common site for tumour recurrence, probably due to the low penetration of some therapeutic agents through the blood-brain barrier. Patients with brain metastases arising from NSCLC have poor prognosis. Results from the LUX-Lung 3 and 6 studies suggest that afatinib is effective for the treatment of EGFR-positive NSCLC patients with brain metastases .
Afatinib in medically unfit patients
As the LUX-Lung 3 and 6 trials solely included patients suitable for platinum-based doublet chemotherapy, the efficacy and toxicity of afatinib in patients not eligible for this kind of treatment remained unknown. One study suggested that TKIs can benefit medically unfit EGFR-mutant East Asian patients . The single-arm, phase II TIMELY trial was the first on this issue to be conducted in a western population . Thirty-nine patients with NSCLC who were deemed unsuitable for radical treatment or chemotherapy, or who declined the latter, participated in the study. They had either confirmed activating EGFR mutation or showed clinical characteristics that were indicative of EGFR mutations when no tissue was suitable for genotyping, or genotyping had failed/ was not available. Treatment consisted of afatinib 40 mg OD until progression.
Icotinib is superior to brain irradiation
Whole-brain irradiation (WBI) has been a standard of care for NSCLC patients with brain metastases. The randomised phase III BRAIN trial evaluated the EGFR TKI icotinib at 125 mg three times daily compared to WBI with or without chemotherapy in EGFR-TKI–naïve patients with EGFR-mutant, advanced NSCLC and brain metastases at ≥ 3 sites . In both arms, more than 80 % of the patients did not experience any symptoms related to their cranial lesions. Eighty-five and 73 patients received icotinib and WBI, respectively. Intracranial PFS was defined as the primary endpoint. BRAIN represents the first phase III trial to compare an EGFR TKI with WBI.
Figure 3: Intracranial PFS with icotinib vs. whole-brain irradiation ± chemotherapy
A significant benefit was also observed for PFS (6.8 vs. 3.4 months; HR, 0.44; p < 0.001). Six-month PFS rates achieved with icotinib and WBI were 55.0 % and 22.0 %, while at 1 year, 19.0 % versus 9.0 % of patients were alive and progression free. The OS analysis did not reveal any difference between the two arms. The icotinib treatment gave rise to significant benefits regarding intracranial ORR (67.1 % vs. 40.9 %; p < 0.001) and intracranial DCR (84.7 % vs. 67.1 %; p = 0.014). This was also true for overall ORR (55.0 % vs. 11.1 %; p < 0.001) and overall DCR (78.8 % vs. 54.8 %; p = 0.001). With respect to treatment-related toxicity, patients in the icotinib arm did better than the control group, with significant differences in favour of the EGFR TKI noted for AEs of all grades. Based on these data, the authors concluded that icotinib should be used in first-line treatment of advanced EGFR-mutant NSCLC patients with brain metastases.
Clinical significance of p53 mutation
Griesinger et al. reported the first data obtained in a homogeneously TKI-treated patient population with EGFR-activating mutations, to show that when classified as pathogenic versus nonpathogenic/ wild-type, p53 mutation is a negative predictive marker for PFS and OS . Usually, p53 mutations are classified as either disruptive or nondisruptive. Here, the DNA-contact mutations R273C, R273G and R248Q were reclassified as pathogenic, as were missense mutations located inside loops L1-L3 of p53, along with sequence substitutions that reached a score of C65 according to the missense analysis programme Align-GVGD. All other p53 mutations located outside loops L1-L3 were scored as non-pathogenic.
1 Papadimitrakopoulou VA et al., Randomised phase III study of osimertinib vs platinum-pemetrexed for EGFR T790-positive advanced NSCLC (AURA3). WCLC 2016, PL03.03
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