128O Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with untreated EGFRm advanced NSCLC: FLAURA post-progression outcomes

Background: In the FLAURA phase 3 study, the third-generation EGFR-TKI osimertinib significantly improved progression-free survival (PFS) vs SoC EGFR-TKIs (gefitinib or erlotinib) in pts with previously untreated Ex19del/L858R (EGFRm) advanced NSCLC (hazard ratio [HR] 0.46 [95% CI 0.37, 0.57]; p < 0.001). Interim overall survival (OS) data was encouraging but not formally statistically significant (HR 0.63 [95% CI 0.45, 0.88]; p = 0.007). Here we report exploratory post-progression outcomes. Methods: Pts were randomised 1:1 to receive osimertinib (80 mg orally [PO], once daily [QD]) or SoC (gefitinib 250 mg PO QD or erlotinib 150 mg PO QD). Treatment beyond disease progression was allowed if the investigator judged continued clinical benefit; investigators determined subsequent therapy. Pts receiving SoC could cross over to osimertinib after objective disease progression with documented post-progression T790M-positive mutation status. Results: At data cutoff, 12 June 2017, 138/279 (49%) and 213/277 (77%) pts discontinued osimertinib and SoC, respectively; 82 (29%) and 129 (47%) received a subsequent treatment: EGFR-TKI-containing, 29 (10%) and 97 (35%; 55 [20%] osimertinib); platinum chemotherapy-containing, 46 (16%) and 27 (10%). Median time (mths) to discontinuation of study treatment or death: osimertinib 20.8 (95% CI 17.2, 24.1) vs SoC 11.5 (10.3, 12.8). Median time (mths) to discontinuation of any EGFR-TKI (study treatment and subsequent EGFR-TKI, not interrupted by non-EGFR-TKI therapy) or death: osimertinib 23.0 (19.5, not calculable [NC]) vs SoC 16.0 (14.8, 18.6). Time-to-event post-progression endpoints all favoured osimertinib (Table).Tabled 1Osimertinib (n= 279)SoC (n = 277)Disease progression or death, n (%)136 (49)206 (74)Remained on study treatment for at least 7 days post investigator assessed progression, n/N (%)91/136 (67)145/206 (70)Median duration on study treatment post-progression (95% CI), wksaCalculated using the Kaplan-Meier method.TFST8.1 (6.3, 12.3)7.0 (5.9, 8.1)Pts who started FST or died, n (%)115 (41)175 (63)Started FST, n (%)82 (29)129 (47)Died, n (%)33 (12)46 (17)Median TFST or death (95% CI), mthsaCalculated using the Kaplan-Meier method.23.5 (22.0, NC)13.8 (12.3, 15.7)HR (95% CI)bHR and CI were obtained directly from the U and V statistics. The analysis was performed using a log rank test stratified by race (Asian versus non-Asian) and mutation type (Ex19del vs L858R). 2-sided p-value. CI, confidence interval; FST, first subsequent therapy (second-line treatment); HR, hazard ratio; NC, not calculable; PFS2, second progression-free survival (or death) post initiation of second-line treatment (i.e. time from randomisation to second progression on subsequent treatment); TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death; SST, second subsequent therapy; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1.0.51 (0.40, 0.64), p < 0.0001PFS2 (investigator assessed)Second progression or death, n (%)73 (26)106 (38)Median PFS2 (95% CI), mthsaCalculated using the Kaplan-Meier method.NC (23.7, NC)20.0 (18.2, NC)HR (95% CI)bHR and CI were obtained directly from the U and V statistics. The analysis was performed using a log rank test stratified by race (Asian versus non-Asian) and mutation type (Ex19del vs L858R). 2-sided p-value. CI, confidence interval; FST, first subsequent therapy (second-line treatment); HR, hazard ratio; NC, not calculable; PFS2, second progression-free survival (or death) post initiation of second-line treatment (i.e. time from randomisation to second progression on subsequent treatment); TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death; SST, second subsequent therapy; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1.0.58 (0.44, 0.78), p = 0.0004TSSTPts who started SST or died, n (%)74 (27)110 (40)Started SST, n (%)24 (9)39 (14)Died, n (%)50 (18)71 (26)Median TSST or death (95% CI), mthsaCalculated using the Kaplan-Meier method.NC (NC, NC)25.9 (20.0, NC)HR (95% CI)bHR and CI were obtained directly from the U and V statistics. The analysis was performed using a log rank test stratified by race (Asian versus non-Asian) and mutation type (Ex19del vs L858R). 2-sided p-value. CI, confidence interval; FST, first subsequent therapy (second-line treatment); HR, hazard ratio; NC, not calculable; PFS2, second progression-free survival (or death) post initiation of second-line treatment (i.e. time from randomisation to second progression on subsequent treatment); TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death; SST, second subsequent therapy; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1.0.60 (0.45, 0.80), p = 0.0005a Calculated using the Kaplan-Meier method.b HR and CI were obtained directly from the U and V statistics. The analysis was performed using a log rank test stratified by race (Asian versus non-Asian) and mutation type (Ex19del vs L858R). 2-sided p-value. CI, confidence interval; FST, first subsequent therapy (second-line treatment); HR, hazard ratio; NC, not calculable; PFS2, second progression-free survival (or death) post initiation of second-line treatment (i.e. time from randomisation to second progression on subsequent treatment); TFST, time to first subsequent therapy or death; TSST, time to second subsequent therapy or death; SST, second subsequent therapy; RECIST, Response Evaluation Criteria In Solid Tumors version 1.1. Open table in a new tab Conclusions: PFS benefit with osimertinib was preserved throughout time-to-event post-progression endpoints. Step-wise increase of the statistically significant HRs (PFS 0.46, TFST 0.51, PFS2 0.58, TSST 0.60) provides confidence in the interim OS data. Clinical trial identification: ClinicalTrials.gov NCT02296125 Legal entity responsible for the study: AstraZeneca Funding: AstraZeneca Disclosure: D. Planchard: Advisory boards: Astrazeneca, Boehringer, BMS, Pfizer, Novartis, MSD, Roche M. Boyer: Research funding and/or honoraria for advisory board work or talks, paid to my institution, from: AstraZeneca, Roche, Merck Sharpe and Dohme, Pfizer, Amgen, Bristol-Myers Squibb. P. Cheema: Advisory board/Honorarium: AstraZeneca Research grant: AstraZeneca T. Takahashi: Honoraria: AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Ono Pharmaceutical, Grants: AstraZeneca KK, Pfizer Japan Inc., Eli Lilly Japan K.K., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., MSD K.K. A. Todd: Employee of AstraZeneca but own no stocks or shares, and am not a member of any board. I am not aware of any other conflicts of interest or opportunities for financial gain. A. McKeown: Employee of, and shareholder in, AstraZeneca. Y. Rukazenkov: Employee of and shareholder in AstraZeneca. Y. Ohe: Grants and personal fees from AstraZeneca, during the conduct of the study; grants and personal fees from AstraZeneca, grants and personal fees from Ono, grants and personal fees from BMS, grants and personal fees from Chougai, grants and personal fees from Pfizer, grants and personal fees from MSD, grants and personal fees from Novartis, grants from Kyorin, grants from Dainippon-Sumitomo, personal fees from Daiichi-Sankyo, personal fees from Nipponkayaku, personal fees from Boehringer Ingelheim, personal fees from Bayer, grants and personal fees from Lilly, outside the submitted work. All personal fees were honoraria for consulting or lectures. All other authors have declared no conflicts of interest.