1241MO - Osimertinib (osi) after definitive chemoradiotherapy (CRT) in unresectable (UR) stg III EGFRm NSCLC: Analyses of CNS and distant progression from the phase III LAURA study

Background

Distant metastases (mts) in NSCLC are a poor prognostic factor, which can negatively impact quality of life. The CNS is a common site of distant progression in EGFRm NSCLC. Osi, a 3rd-gen CNS-active EGFR-TKI, is recommended as tx for EGFRm advanced NSCLC and adjuvant tx for resected EGFRm NSCLC. In LAURA (NCT03521154), osi demonstrated statistically significant and clinically meaningful progression-free survival (PFS) benefit in pts with UR stg III EGFRm NSCLC without progression after definitive CRT. CNS efficacy and time to death/distant mts (TTDM) analyses are reported here.

Methods

After definitive platinum-based CRT with no progression, pts (≥18 yrs) with UR stg III EGFRm NSCLC were randomised 2:1 to osi 80 mg or placebo (PBO) QD until BICR-confirmed progression/discontinuation. Imaging, including brain MRI, was mandated at baseline, every 8 wks to wk 48, then every 12 wks until progression. Primary endpoint was PFS by BICR per RECIST v1.1. CNS PFS by neuroradiologist BICR and TTDM by BICR, per RECIST v1.1, were secondary endpoints. DCO: 5 Jan 2024.

Results

Overall, 216 pts were randomised: osi n=143, PBO n=73. Median CNS PFS by BICR (95% CI): not reached (NC, NC) with osi vs 14.9 mo (7.4, NC) with PBO (Table). CNS PFS HR (95 CI%): 0.17 (0.09, 0.32). Risk of CNS progression per investigator assessment was consistent with BICR assessment. Cumulative incidence of CNS progression at 12 mo (95% CI): osi 9% (5, 14), PBO 36% (24, 47). There was also a clinically meaningful improvement in TTDM with osi vs PBO (HR 0.21; 95% CI 0.11, 0.38). Cumulative incidence of TTDM at 12 mo (95% CI): osi 11% (6, 17), PBO 37% (26, 48). Table: 1241MO

∗Death in the absence of CNS progression

†Patients with distant mts or death in the absence of distant mts BICR, blinded independent central review; CI, confidence interval; CNS, central nervous system; HR, hazard ratio; mts, metastases; NC, not calculable; NR, not reached; PFS, progression-free survival; TTDM, time to death/distant mts

Conclusions

Osi demonstrated clinically meaningful improvements in CNS PFS and TTDM vs PBO, with an 83% reduction in risk of CNS progression/death. This protective effect of osi against CNS progression and prolonged TTDM, together with significant PFS improvement, reinforces osi after CRT as the new SoC for UR stg III EGFRm NSCLC.

Clinical trial identification

NCT03521154.

Editorial acknowledgement

The authors would like to acknowledge Rachel Gater, PhD, of Ashfield MedComms, an Inizio Company, for medical writing support that was funded by AstraZeneca in accordance with Good Publications Practice (GPP) guidelines.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

S. Lu: Financial Interests, Personal, Advisory Role: AstraZeneca, Pfizer, Hutchinson MediPharma, Zai Lab, G Novarti, Yuhan Corporation, Menarini, Mirati Therapeutics, Inc., Daiichi Sankyo, D3 Bio, Ltd., Simcere; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Hansoh; Non-Financial Interests, Personal, Member of Board of Directors, Independent director: Innovent Biologics, Inc.; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca; Financial Interests, Personal, Research Grant: AstraZeneca, Hutchinson, Bristol Myers Squibb, Heng Rui, BeiGene, Hansoh, Boehringer Ingelheim; Financial Interests, Personal, Speaker, Consultant, Advisor: AstraZeneca, Pfizer, Bristol Myer Squibb, Hutchinson MediPharma, Zai Lab, Yuhan Corporation, Menarini, InventisBio Co., Ltd., Shanghai Fosun Pharamceutical (Group) Co., Ltd., Simcere Zaiming Pharmaceutical Co., Ltd.; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Roche, Hansoh; Financial Interests, Personal, Steering Committee Member: AstraZeneca, Bristol Myers Squibb, Yuhan Corporation, Menarini, GSK. M. Ahn: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Merck Sharp & Dohme, Takeda, Daiichi Sankyo, Merck, Amgen, Roche, Pfizer, Lilly, Yuhan; Financial Interests, Personal, Advisory Role: AstraZeneca, Merck Sharp & Dohme, Takeda, Daiichi Sankyo, Merck, Amgen, Roche, Pfizer, Lilly, Yuhan; Financial Interests, Personal and Institutional, Research Funding: Yuhan. T.R. Baisamut: Financial Interests, Personal, Advisory Board, Honorarium: AstraZeneca, Yuhan, Roche, Amgen, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Takeda, Bristol Myers Squibb; Financial Interests, Institutional, Coordinating PI, Research fund: AstraZeneca, Yuhan, Roche, Merck Sharp & Dohme, Novartis; Financial Interests, Personal, Invited Speaker, Honorarium: AstraZeneca, Yuhan, Roche, Amgen, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Takeda, Bristol Myers Squibb; Financial Interests, Institutional, Local PI, Research fund: AstraZeneca, Yuhan, Roche, Merck Sharp & Dohme, Novartis; Financial Interests, Institutional, Principal Investigator, Research fund: AstraZeneca, Yuhan, Roche, Merck Sharp & Dohme, Novartis; Financial Interests, Institutional, Research Funding: AstraZeneca, Yuhan, Roche, Merck Sharp & Dohme, Novartis; Financial Interests, Personal, Speaker, Consultant, Advisor, Honorarium: AstraZeneca, Yuhan, Roche, Amgen, Johnson & Johnson, Merck Sharp & Dohme, Pfizer, Takeda, Bristol Myers Squibb; Financial Interests, Personal, Steering Committee Member, Honorarium: AstraZeneca, Roche, Yuhan. M. Ozguroglu: Financial Interests, Personal, Advisory Board: Merck Sharp & Dohme Oncology, Regeneron/Sanofi, Astellas; Financial Interests, Personal, Advisory Role: Merck Sharp & Dohme Oncology, AstraZeneca; Non-Financial Interests, Personal, Invited Speaker: Regeneron; Financial Interests, Personal, Local PI: Merck Sharp & Dohme, AstraZeneca, Regeneron, Bristol Myers Squibb, Pfizer, BeiGene, Daiichi Sankyo, Roche; Other, Personal, Membership or affiliation: ESMO, ASCO; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Financial Interests, Personal, Steering Committee Member: AstraZeneca; Financial Interests, Personal, Other, Travel, accommodations, expenses: AstraZeneca; Financial Interests, Personal, Other, Honoraria: Astellas Pharma, Novartis, Janssen Oncology. T. Kato: Financial Interests, Personal, Full or part-time Employment, Family member: Lilly; Financial Interests, Personal, Advisory Role: AstraZeneca, Merck Sharp & Dohme, Pfizer, BeiGene, Novartis, Daiichi Sankyo, Janssen, Merck KGaA, Amgen; Financial Interests, Personal, Other, Honoraria: Chugai Pharmaceutical, Ono Pharmaceutical, Lilly, AstraZeneca, Taiho Pharmaceutical, Pfizer, Merck Sharp & Dohme, Novartis, Daiichi Sankyo, GSK, Merck KGaA, Takeda, BeiGene, Boehringer Ingelheim, Janssen, Bristol Myers Squibb Japan, Roche, Amgen; Financial Interests, Institutional, Research Funding: Chugai Pharmaceutical, Merck Sharp & Dohme, Pfizer, AstraZeneca, Lilly, AbbVie, Regeneron, Novartis, Amgen, Merck KGaA, Takeda, Haihe Biopharma, Blueprint Medicines, Turning Point Therapeutics, Daiichi Sankyo, BeiGene, Gilead Sciences, Bayer, GSK, Janssen. J.C. Yang: Financial Interests, Personal and Institutional, Advisory Board: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, Merck KGaA, Darmstadt, Germany, Merck Sharp & Dohme, Novartis, Ono Pharmaceuticals, Pfizer, Roche/Genentech, Takeda, Yuhan Pharmaceuticals, Janssen Pharmaceuticals, Gilead Sciences, Inc., GSK, BeiGene, Regeneron Pharmaceutical, Taiho Pharmaceutical, ArriVent, AnHeart Therapeutics; Non-Financial Interests, Personal, Coordinating PI: AstraZeneca, Merck Sharp & Dohme, Dizal Pharmaceuticals; Financial Interests, Institutional, Funding: AstraZeneca, Roche; Other, Personal, Invited Speaker: AstraZeneca, Merck Sharp & Dohme, Roche/Genentech, Takeda Oncology, Janssen; Non-Financial Interests, Personal and Institutional, Local PI: Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eli Lilly, Merck KGaA Darmstadt, Germany, Merck Sharp & Dohme, Roche/Genentech, Takeda, Yuhan Pharmaceuticals, Janssen Pharmaceuticals, Gilead Sciences, Inc., ArriVent, AnHeart Therapeutics; Non-Financial Interests, Personal, Membership or affiliation: AACR, ASCO, WCLC; Non-Financial Interests, Personal, Steering Committee Member: AstraZeneca, Daiichi Sankyo, Eli Lilly, Merck KGaA, Darmstadt, Germany, Merck Sharp & Dohme, Takeda, Yuhan Pharmaceuticals, Janssen Pharmaceuticals, ArriVent. F.K. Fujiki: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb; Non-Financial Interests, Personal and Institutional, Local PI, LAURA Local PI: AstraZeneca; Financial Interests, Personal, Speaker, Consultant, Advisor: Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca. T. Inoue: Financial Interests, Personal, Speaker’s Bureau: Ono Pharmaceutical, Merck Sharp & Dohme K.K., Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., Eli Lilly Japan K.K. V.Q. Le: Financial Interests, Personal, Advisory Role: AstraZeneca, Roche; Financial Interests, Personal, Other, Honoraria: AstraZeneca, Roche, Merck Sharp & Dohme, Pfizer, Novartis. V. Sriuranpong: Financial Interests, Personal, Advisory Role: Astellas, AstraZeneca, Merck Sharp & Dohme, Roche, Novartis, Takeda; Financial Interests, Personal, Invited Speaker: Astellas, AstraZeneca, Merck Sharp & Dohme, Roche, Novartis, Takeda, Pfizer, Eisai; Financial Interests, Institutional, Research Funding: Astellas, AstraZeneca, Daiichi Sankyo, Merck Sharp & Dohme, Novartis, Roche, Takeda; Financial Interests, Personal, Speaker, Consultant, Advisor: Astellas, AstraZeneca, Merck Sharp & Dohme, Roche, Novartis, Takeda, Pfizer, Eisai. D. Vicente: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche/Genentech, Lilly, Daiichi, Pfizer, Novartis, Takeda, Merck Sharp & Dohme, Bristol Myers Squibb, Gilead; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche/Genentech, Lilly, Daiichi, Pfizer, Novartis, Takeda, Merck Sharp & Dohme, Bristol Myers Squibb, Gilead; Financial Interests, Personal, Member of Board of Directors: Daiichi; Financial Interests, Personal, Principal Investigator: AstraZeneca, Roche/Genentech, Lilly, Daiichi, Pfizer, Novartis, Takeda, Merck Sharp & Dohme, Bristol Myers Squibb, Gilead; Financial Interests, Personal, Steering Committee Member: Daiichi, Pfizer. L. Poole: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca, Lilly, Takeda. E. Armenteros Monterroso: Financial Interests, Personal and Institutional, Full or part-time Employment: AstraZeneca. T. van der Gronde: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. Y. Rukazenkov: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S.S. Ramalingam: Other, Personal and Institutional, Coordinating PI: AstraZeneca; Financial Interests, Institutional, Funding: AstraZeneca, Bristol Myers Squibb, Merck, Pfizer, Amgen; Financial Interests, Institutional, Research Funding: Amgen, AstraZeneca, GSK, Pfizer, Bristol Myers Squibb; Financial Interests, Personal, Other, Travel, accommodation, expenses: AbbVie. All other authors have declared no conflicts of interest.