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EGFR-mutant advanced non-small-cell lung carcinoma: Afatinib in TKI-naïve patients


Afatinib ( Giotrif ) was compared with standard Platinum-based doublet chemotherapy in two large, randomized phase III studies, ie, LUX-Lung 3 and LUX-Lung 6, in patients with EGFR-mutant advanced non-small-cell lung carcinoma ( NSCLC ).
Cisplatin / Pemetrexed was used in LUX-Lung 3 as the control arm whereas Gemcitabine / Cisplatin was used as the control arm in the LUX-Lung 6 study.

LUX-Lung 6 was conducted in East Asia and LUX-Lung 3 recruited patients globally.

Progression-free survival ( PFS ) was 11.1 months versus 6.9 months ( hazard ratio [ HR ] 0.58, 95% confidence interval [CI] 0.43–0.78, P=0.001 ) in LUX-Lung 3 when Afatinib was compared with the Platinum doublet in all of the EGFR-mutant disease population.
This difference in progression-free survival was greater ( 13.6 months versus 6.9 months; HR=0.47, 95% CI 0.34–0.65, P=0.001 ) in patients whose tumors had exon 19 deletion or L858R EGFR mutations.

LUX-Lung 6 reported a progression-free survival of 11.0 months with Afatinib versus 5.6 months with the Platinum doublet-containing arm ( HR=0.28, P less than 0.0001 ).

Both trials failed to show an overall survival ( OS ) benefit; however, a pooled analysis of these two studies, presented at the American Society of Clinical Oncology ( ASCO ) meeting in Chicago in 2014,34 showed a survival advantage of 3 months for patients treated with Afatinib compared with the chemotherapy arm.
In total, 631 of 709 patients enrolled in the two trials with common EGFR mutations ( exon 19 deletions or L858R ) were studied in the pooled analysis.
Overall survival in the Afatinib arm was 27.3 months as opposed to 24.3 months in the chemotherapy arm ( HR=0.81, P=0.037 ) and this was supposedly statistically significant.
Also, interestingly, in both trials, the median overall survival was higher amongst patients with exon 19 deletion.

Afatinib was compared with Erlotinib ( Tarceva ) in LUX-Lung 8, a randomized phase III study in patients with [ tyrosine-kinase inhibitor ] TKI-naïve with relapsed / refractory squamous cell lung cancer ( total patients at the time of analysis, n=669; Afatinib n=335, Erlotinib n=334 ) who had failed a Platinum doublet.
Although the trial was powered for both progression-free survival and overall survival, progression-free survival was the primary end point.
Median progression-free survival was significantly higher for Afatinib than for Erlotinib, both by independent radiological review ( 2.4 versus 1.9 months; P=0.0427 ) and by investigator review ( 2.7 versus 1.9 months; P=0.0053 ).
The ORR was not different in the two groups ( 4.8% versus 3.0%; P=0.233 ), but the disease control rate was significantly higher with Afatinib than with Erlotinib ( 45.7% versus 36.8%; P=0.020 ).
However, a higher incidence of grade 3 drug-related toxicities, ie, diarrhea ( 9.7% versus 2.4% ) and stomatitis ( 3.3% versus 0.0% ), was reported with Afatinib despite grade 3 rash / acne being greater in the Erlotinib arm ( 5.5% versus 9.0% ). ( Xagena )

Joshi M et al, Cancer Manag Res 2015; 7: 75–82

XagenaMedicine_2015



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