Acquired resistance after front-line treatment (tx) with 1st-/2nd-generation EGFR TKIs necessitates further therapies for pts with EGFRm+ NSCLC. We explored the outcome of subsequent therapies, including other EGFR TKIs and chemotherapy (CT) after 1st-line afatinib in the LL3, 6 and 7 randomised trials.
We retrospectively assessed subsequent therapy outcomes in pts with common EGFR mutations, who were randomised to 1st-line afatinib in the LL3/6/7 trials. Data had been prospectively collected as study follow-up information. Tx duration was assessed by descriptive medians or KM estimates. Biopsies at afatinib resistance were not required in LL3/6/7.
Of the 553 pts with common EGFR mutations who received 1st-line afatinib and later discontinued it, 2nd-line therapy was given in 394 (71%) pts and consisted of platinum-based CT for 252 (46%), single agent CT for 39 (7%), 1st-generation EGFR TKI for 49 (9%) and other tx for 54 (10%) pts. Median time on 2nd-line tx was 2.9 months for platinum-based and 1.4 months for single-agent CT, with no relevant difference between Del19 and L858R mutation subgroups. Among 186 (34%) pts who received 1st-generation EGFR TKIs post-afatinib, median time on tx was 3.9 months. Of 212 pts randomised to 1st-line CT in LL3 and LL6, 117 (55%) received 1st-generation EGFR TKI monotherapy as 2nd-line tx, with a median time on tx of 11.2 months. Interestingly, 34 pts received osimertinib after 1st-line afatinib, the majority in ≥ 3rd line; median time on osimertinib tx was 31.5 months (95% CI 16.8–31.5 months). Median OS for osimertinib-treated pts is not yet evaluable.
The majority (71%) of pts who received 1st-line afatinib were fit enough to receive subsequent therapies and there was no relevant difference in 2nd-line tx duration by Del19/L858R EGFR mutation subgroup. Introduction of a different TKI was common, with good outcome. Time on tx with osimertinib after afatinib was unexpectedly long among 34 pts; this should be examined in a larger cohort. Overall, these findings suggest that pts treated with 1st-line afatinib are well suited for subsequent therapies, including CT, 1st-generation EGFR TKIs and osimertinib.
Clinical trial identification
LUX-Lung 3, NCT00949650; LUX-Lung 6, NCT01121393; LUX-Lung 7, NCT01466660
Legal entity responsible for the study
L. Sequist: Advisory boards for Boehringer Ingelheim, AstraZeneca, Novartis, Clovis, Genentech, Merrimack, Ariad, BMS. M. Schuler: Advisory boards for AZ, BI, Celgene, Eli Lilly, Novartis; corporate-sponsored research for BI, BMS, Novartis; honoraria from AZ, BI, BMS, Celgene, Eli Lilly, Novartis, Roche, MSD, Alexion; patents with University Duisburg-Essen. T. Kato: Lecturer fees from AstraZeneca, BI, Chugai, Eli Lilly, MSD, Ono; donations/contributions from BI; research expenses from Taiho, Chugai, AstraZeneca, Eli Lilly, Abbvie, Pfizer, MSD, BMS, BI, Kirin Kyowa, Ono, Merck Serono. H. Tanaka: Advisory board: AstraZeneca; honoraria: Boehringer, Ono pharma, Chugai pharma, Eli Lilly, MSD. T. Hida: Research expenses from Chugai Pharmaceutical, Novartis, Taiho Pharmaceutical, AstraZeneca, Nippon Boehringer Ingelheim, Pfizer, Clovis Oncology, Astellas Pharma. K. Park: Advisory boards for Astellas, AZ, BI, Clovis, Eli Lilly, Hanmi, LOXO, MSD, Novartis, ONO, Roche J. Bennouna: Received honoraria from Roche, Boehringer Ingelheim, Novartis, AstraZeneca and Pierre Fabre and has consulting/advisory roles for Roche, Boehringer Ingelheim, Novartis and Pierre Fabre Medicament. D. Moro Sibilot: Advisory board: Lilly, Roche, BMS, MSD, Novartis, Pfizer, Ariad, AstraZeneca, Boehringer Ingelheim. A.Märten, B. Peil, E. Ehrnrooth: Employee of Boehringer Ingelheim. N. Yamamoto: Ad boards: AZ, BI, Chugai, Eli Lilly, MSD, Novartis, ONO, Taiho Corporate-sponsored research: BI, Chugai, Eli Lilly, MSD Honoraria: AZ, BI, Chugai, Eli Lilly, MSD, Novartis, ONO, Taiho. K. Nakagawa: Advisory board: Astellas Pharma Inc./Eli Lilly Japan K.K./Ono Pharmaceutical Co., Ltd. Corporate-sponsored research: GlaxoSmithKline K.K./AstraZeneca K.K./Kyowa Hakko Kirin Co.,Ltd./Pfizer Japan Inc./AbbVie Inc./Novartis Pharma K.K./Nippon Boehringer Ingelheim Co.,Ltd./Daiichi Sankyo Co., Ltd./Eli Lilly Japan K.K./MSD K.K./Quintiles Inc./Ono Pharmaceutical Co., Ltd./Yakult Honsha Co., Ltd./PAREXEL International Corp/Otsuka Pharmaceutical Co., Ltd./Astellas Pharma Inc./AC MEDICAL INC./Taiho Pharmaceutical Co.,Ltd./Merck Serono Co., Ltd./EPS International Co., Ltd./Covance Inc./Chugai Pharmaceutical Co.,Ltd./Bristol Myers Squibb Company/Eisai Co., Ltd. Honoraria: Astellas Pharma Inc./AstraZeneca K.K./Novartis Pharma K.K./Pfizer Japan Inc./Chugai Pharmaceutical Co.,Ltd./Eli Lilly Japan K.K./MSD K.K./Ono Pharmaceutical Co.,Ltd./Nippon Boehringer Ingelheim Co.,Ltd./Bristol Myers Squibb Company/Kissei Pharmaceutical Co., Ltd./Daiichi Sankyo Co., Ltd./Taiho Pharmaceutical Co.,Ltd./AYUMI Pharmaceutical Corporation. All other authors have declared no conflicts of interest.