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First-line afatinib extended OS in exon 19 deletion-positive lung adenocarcinoma
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Patients with lung adenocarcinoma who harbored exon 19 deletion EGFR mutations experienced significantly longer OS when treated with first-line afatinib instead of chemotherapy, according to analyses of results from two phase 3 trials.
However, researchers did not observe the survival benefit among patients with other types of EGFR mutations.
Lecia V. Sequist
“These data provide important evidence about the use of afatinib in patients whose tumors have the del19 mutation and tell us that the standard treatments and approaches should no longer be assumed equivalent for every EGFR mutation,” Lecia V. Sequist, MD, MPH, medical oncologist at Massachusetts General Hospital Cancer Center and associate professor of medicine at Harvard Medical School, said in a press release.
Sequist and colleagues evaluated data from 345 patients enrolled on the LUX-Lung 3 trial and 364 patients enrolled on the LUX-Lung 6 trial. All patients had EGFR mutation-positive stage IIIB or IV lung adenocarcinoma.
Researchers had randomly assigned patients in those trials 2:1 to receive afatinib (Gilotrif, Boehringer Ingelheim) or chemotherapy.
Median follow-up was 41 months (interquartile range [IQR], 35-44) in LUX-Lung 3 and 33 months (IQR, 31-37) in LUX-Lung 6. By this time, 62% of patients from LUX-Lung 3 and 68% from LUX-Lung 6 had died.
Median OS did not differ among patients who received afatinib vs. chemotherapy in the overall populations of LUX-Lung 3 (28.2 months vs. 28.2 months; HR=0.88; 95% CI, 0.66-1.17) and LUX-Lung 6 (23.1 months vs. 23.5 months; HR=0.93; 95% CI, 0.72-1.22).
However, results of both trials showed patients with exon 19 deletion (del19)-positive tumors demonstrated significantly prolonged median OS after afatinib treatment. In LUX-Lung 3, median OS in this subset of patients was 33.3 months in the afatinib arm vs. 21.1 months in the chemotherapy arm (HR=0.54; 95% CI, 0.36-0.79). In LUX-Lung 6, median OS was 31.4 months in the afatinib arm vs. 18.4 months in the chemotherapy arm (HR=0.64; 95% CI, 0.44-0.94).
Researchers did not observe a similar survival benefit with afatinib among patients with Leu858Arg EGFR mutations. In LUX-Lung 3, median OS among the subset of patients with this form of EGFR mutation was 27.6 months in the afatinib arm and 40.3 months in the chemotherapy arm (HR=1.3; 95% CI, 0.8-2.11). In LUX-Lung 6, median OS was 19.6 months in the afatinib arm and 24.3 months in the chemotherapy arm HR=1.22; 95% CI, 0.81-1.83).
The most common grade 3 to grade 4 adverse events associated with afatinib were rash or acne (16% in LUX-Lung 3; 15% in LUX-Lung 6) and diarrhea (14% in LUX-Lung 3 and 5% in LUX-Lung 6). Grade 3 to grade 4 paronychia occurred in 11% of patients on the LUX-Lung 3 trial, and stomatitis or mucositis occurred in 5% of patients on the LUX-Lung 6 trial.
The findings warrant a comparison of afatinib with the first-generation EGFR inhibitors gefitinib (Iressa, AstraZeneca) and erlotinib (Tarceva; Genentech, Astellas), Antonio Rossi, MD, of S.G. Moscati Hospital in Avellino, Italy, and Massimi Di Maio, MD, of the University of Turin in Turin, Italy, wrote in an accompanying editorial.
“Are these data sufficient to address whether afatinib is better than first-generation EGFR inhibitors?” Rossi and Maio wrote. “Only head-to-head trials can definitively answer this question. and LUX-Lung 7 (NCT01466660) — a phase 2b randomized trial comparing afatinib with gefitinib for first-line treatment of lung adenocarcinoma with EGFR common mutations — should provide the first comparative evidence of efficacy and safety in this setting. In the absence of direct comparisons, for each patient the choice among the available EGFR inhibitors should take into account all of the clinically relevant endpoints, including disease control, survival prolongation, tolerability and quality of life.”
For more information:
Yang JC. Lancet Oncol. 2015;doi:10.1016/S1470-2045(14)71173-8.
Rossi A. Lancet Oncol. 2015;doi:10.1016/S1470-2045(14)71196-9.
Disclosure: The study was funded by Boehringer Ingelheim. Sequist reports research funding from Boehringer Ingelheim and non-compensated consultant roles with AstraZeneca, Boehringer Ingelheim, Clovis Oncology, Genentech, Merrimack, Novartis and Taiho. Rossi and Maio report personal fees from AstraZeneca and Boehringer Ingelheim. See the study for the remaining researchers’ relevant financial disclosures.
Perspective
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Tarek Mekhail, MD, MSc, FRCSI, FRCSEd
Does front-line treatment with EGFR tyrosine kinase inhibitors prolong survival in patients who harbor activating EGFR mutations — such as exon 19 deletion (del19) or Leu858Arg (L858A) — compared with chemotherapy? The answer to this question has lingered for many years. Many randomized clinical trials and one meta-analysis failed to show a survival benefit for front-line TKIs despite a very robust improvement in PFS. This is generally thought to be due to a crossover effect with patients progressing on chemotherapy being ultimately “saved” by receiving a TKI as a second line.Many oncologists concluded that “It does not really matter when you give it, as long as you give it,” referring to the TKIs! Notwithstanding the emergence of other molecularly defined subgroups of patients, like those harboring the EML4-ALK and ROS1 mutations, some oncologists even argued that molecular testing may not be as important as claimed. They base their argument on the fact that erlotinib (Tarceva; Genentech, Astellas) can be given as a second-line therapy, regardless of mutation status.
Again, despite a significant improvement in PFS, both LUX-Lung 3 and LUX-Lung 6 failed to show an OS benefit for patients who harbor the activating mutations when the analysis included both types of the mutations together.
In a subgroup analysis, however, a significant improvement in OS with afatinib (Gilotrif, Boehringer Ingelheim) compared with chemotherapy was noted — in both LUX-Lung 3 and LUX-Lung 6, as well as in the combined analysis using individual patient data — in patients who harbored the del19 mutation but not the L858A EGFR mutation.
This survival improvement occurred despite a crossover rate from chemotherapy to a TKI — most commonly to erlotinib or gefitinib (Iressa, AstraZeneca) — at progression in 75% of patients in LUX-Lung 3 and 56% of patients in LUX 6. Crossover rates in LUX-Lung 3 are not dissimilar to crossover rates in other randomized trials.
These results clearly demonstrate that del19 and L858A EGFR mutations are two distinct subtypes with different behavior and outcomes.
Two questions remain unanswered.
First, is the survival benefit observed in del19 limited to afatinib or does it apply to the other TKIs, erlotinib and gefitinib? The answer to that question is currently unknown. LUX-Lung 7, a phase 2b randomized trial designed to compare front-line afatinib to gefitinib in patients with activating mutations, may shed some light on this issue.
Second, how should we interpret the negative survival results for the L858A patients, with numerically — albeit not statistically significant — inferior outcome with front-line afatinib? Afatinib compared with chemotherapy did result in superior PFS or objective response rates in patients with L858A EGFR mutations. Furthermore, third-generation TKIs soon will be available for patients with the T790M mutation leading to resistance to first- and second-generation TKIs. Thus, a large proportion of patients with activating EGFR mutations now will receive chemotherapy as third line or beyond. In view of this, despite LUX-Lung 3 and LUX-Lung 6, I still consider front-line TKI the standard of care for patients with L858A mutation, as well as those with del19.
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