1O - Osimertinib (osi) + datopotamab deruxtecan (Dato-DXd) in patients (pts) with EGFR-mutated (EGFRm) advanced NSCLC (aNSCLC) whose disease progressed on first-line (1L) osi: ORCHARD

Background

Osi, a 3rd-generation EGFR-TKI, is preferred 1L treatment (tx) for EGFRm aNSCLC. Acquired resistance eventually leads to disease progression, and subsequent tx options are limited. Dato-DXd, a TROP2-directed antibody-drug conjugate, was recently granted FDA breakthrough therapy designation for pts with pretreated EGFRm aNSCLC based on findings from the TROPION-Lung05 (TL05) and TL01 studies. ORCHARD (NCT03944772) is a Phase II, non-randomised platform study evaluating novel tx combinations in pts with EGFRm aNSCLC who progressed on 1L osi. We report the latest data from module 10, the first-in-human study of osi + Dato-DXd.

Methods

Pts received oral osi (80 mg QD) + IV Dato-DXd (4 or 6 mg/kg Q3W in two cohorts). Enrolment started in the 4 mg cohort and was extended to the 6 mg cohort, followed by simultaneous enrolment to both dose levels. Primary endpoint: ORR (RECIST v1.1; by investigator). Secondary endpoints: DoR, PFS, OS, and safety. DCO: 12 Oct 2024.

Results

Overall, 69 pts received osi + Dato-DXd. Median tx duration was 9.0 and 9.8 mo for the 4 mg (n=35) and 6 mg (n=34) cohorts, respectively; median duration of follow-up was 13.4 and 13.8 mo, respectively. Among 68 evaluable pts, ORR was similar between the cohorts (4/6 mg: 43/36%); DoR (4/6 mg: 15/64% remaining in response at 9 mo) and PFS (4/6 mg: median, 9.5/11.7 mo) favoured the 6 mg cohort (Table). OS was immature (37% maturity). More pts in the 6 mg cohort had grade ≥3 AEs related to any tx (4/6 mg: 34/56%), AEs leading to Dato-DXd dose reduction (4/6 mg: 23/59%), and adjudicated ILD/pneumonitis (4/6 mg: any grade, 3/15%; grade ≥3, 3/6%).

*Estimated by Kaplan–Meier method. CI, confidence interval; DoR, duration of response; ILD, interstitial lung disease; mo, months; NC, not calculable; ORR, objective response rate; OS, overall survival; PFS, progression-free survival.

Conclusions

Osi + Dato-DXd showed promising efficacy and manageable safety in pts with EGFRm aNSCLC who progressed on 1L osi. There were no new safety signals. Considering the overall benefit/risk profile, 6 mg/kg should be the preferred Dato-DXd starting dose for combination with 80 mg osi. Longer-term follow-up data are awaited.

Clinical trial identification

NCT03944772; release date: 08/05/2019.

Editorial acknowledgement

The authors would like to acknowledge Aaron Korpal, PhD, of Ashfield MedComms, an Inizio company, for medical writing support that was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

X. Le: Financial Interests, Institutional, Other, Research funding: Eli Lilly, EMD Serono, ArriVent, Dizal, Teligene, Regeneron, Janssen, ThermoFisher, Takeda, and Boehringer Ingelheim; Financial Interests, Personal, Other, Speaker, consultant, advisor: Eli Lilly, EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Novartis, Regeneron, Boehringer Ingelheim, Hengrui Therapeutics, Bayer, Teligene, Taiho, Daiichi Sankyo, Janssen, Blueprint Medicines, Sensei Biotherapeutics, SystImmune, ArriVent, A. L. Hendriks: Financial Interests, Institutional, Advisory Board: Amgen, Boehringer Ingelheim, Lilly, Novartis, Pfizer, Takeda, Merck, Janssen, MSD, Anheart, AbbVie, BMS, Daiichi, Pierre Fabre, Roche, Summit, AstraZeneca; Financial Interests, Institutional, Invited Speaker, for educational webinar and satellite symposium: AstraZeneca; Financial Interests, Institutional, Invited Speaker, educational webinar/interview: Bayer; Financial Interests, Institutional, Invited Speaker, for educational webinar: Lilly; Financial Interests, Institutional, Invited Speaker, educationals: MSD; Financial Interests, Personal, Invited Speaker, for webinars: Medtalks; Financial Interests, Personal, Invited Speaker, payment for post ASCO round table discussion: VJOncology; Financial Interests, Personal, Invited Speaker, payment for post ASCO/ESMO/WCLC presentations, educational committee member: Benecke; Financial Interests, Institutional, Invited Speaker, payment for post ESMO/ASCO discussion: high5oncology; Financial Interests, Institutional, Other, podcast on brain metastases: Takeda; Financial Interests, Institutional, Other, educational webinar: Janssen; Financial Interests, Institutional, Invited Speaker, satellite symposium at conference: GSK, Sanofi; Financial Interests, Personal, Invited Speaker, presentation guideline: Medimix; Financial Interests, Institutional, Invited Speaker, podcast and educational: Pfizer; Financial Interests, Personal, Other, member of the committee that revised these guidelines: Dutch guidelines NSCLC, brain metastases and leptomeningeal metastases; Financial Interests, Institutional, Research Grant, for IIS: Roche, Boehringer Ingelheim, AstraZeneca, Takeda, Novartis; Financial Interests, Institutional, Research Grant, donation for health care improvement project: Merck; Financial Interests, Institutional, Research Grant, funding for healthcare improvement project: Pfizer; Financial Interests, Institutional, Research Grant, for IIS, under negotiation: Gilead; Financial Interests, Institutional, Invited Speaker: AstraZeneca, GSK, Novartis, Merck Serono, Roche, Takeda, Blueprint Medicines, Mirati, MSD, Gilead, Amgen, Boehringer Ingelheim, Pfizer; Financial Interests, Institutional, Invited Speaker, and local PI for same trial: AbbVie; Non-Financial Interests, Personal, Other, Chair metastatic NSCLC for lung cancer group: EORTC; Non-Financial Interests, Personal, Other, secretary NVALT studies foundation: NVALT; Non-Financial Interests, Personal, Other, vice chair scientific committee: Dutch Thoracic Group. A. Morabito: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Lilly, BMS, MSD, Pfizer, Takeda, Novartis, Sanofi, Pierre Fabre; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, MSD, Takeda, Pierre Fabre. L. Bonanno: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Roche, Novartis, MSD, Janssen; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, MSD, BMS, Lilly, Novartis; Financial Interests, Personal, Other, Local PI: AstraZeneca, Roche, BMS, MSD, Oseimmunotherapeutics, Arcus Biosciences PharmaMar; Financial Interests, Personal, Research Grant: AstraZeneca; Non-Financial Interests, Personal, Other, Steering Committee Member: AstraZeneca. I. Okamoto: Financial Interests, Institutional, Funding: Daiichi Sankyo, Chugai Pharma, Lilly, Bristol Myers Squibb, MSD Oncology, AstraZeneca, Taiho Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Chugai Pharmaceutical Co., Ltd. Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd, Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, Novartis Pharma K.K., Daiichi Sankyo; Financial Interests, Personal, Other, Steering Committee Member: AstraZeneca, Daiichi Sankyo. J.W. Goldman: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Lilly, Pfizer, Boehringer Ingelheim, AbbVie, Genentech; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: AstraZeneca; Financial Interests, Personal, Other, Research Funding: Lilly, Genentech/Roche, Bristol Myers Squibb, AstraZeneca/MedImmune, AbbVie, Corvus Pharmaceuticals, Spectrum Pharmaceuticals, Advaxis, Pfizer. H.A. Yu: Financial Interests, Personal, Other, Honoraria: AstraZeneca, Janssen, Blueprint Medicine, C4 Therapeutics, Daiichi; Financial Interests, Personal, Other, Research Funding: AstraZeneca, Pfizer, Lilly, Cullinan, Novartis, Daiichi. O.T. Brustugun: Financial Interests, Institutional, Advisory Board: AstraZeneca, MSD, Roche; Financial Interests, Institutional, Other, Coordinating PI: AstraZeneca, Amgen, MSD, Novartis, Takeda, Ultimovacs; Financial Interests, Institutional, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Other, Steering Committee Member: Novartis. T.O. Halvorsen: Financial Interests, Personal, Advisory Board: AstraZeneca; Non-Financial Interests, Personal, Other, Coordinating PI: AstraZeneca; Non-Financial Interests, Personal, Other, Collaboration on artificial intelligence histopathological research in SCLC. Collaboration on development of MDT meetings: AstraZeneca; Non-Financial Interests, Personal, Principal Investigator: AstraZeneca; Financial Interests, Personal, Other, Speaker, Consultant, Advisor: AstraZeneca. K. Marrone: Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Regeneron, Janssen, Bristol Myers Squibb, Amgen, AstraZeneca; Financial Interests, Personal, Funding: Bristol Myers Squibb. B.C. Cho: Financial Interests, Personal, Advisory Board: KANAPH Therapeutic Inc, Bridgebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc, J INTS Bio, Therapex Co., Ltd, Gilead, Amgen; Financial Interests, Personal, Full or part-time Employment: Yonsei University Health System; Financial Interests, Personal, Invited Speaker: AstraZeneca, Guardant, Roche, Korean Cancer Association, Korean Society of Medical Oncology, Korean Society of Thyroid-Head and Neck Surgery, Korean Cancer Study Group, Novartis, MSD, The Chinese Thoracic Oncology Society, Pfizer; Financial Interests, Personal, Licensing Fees: Champions Oncology, Crown Bioscience, Imagen, PearlRiver Bio GmbH; Financial Interests, Personal, Member of Board of Directors: J INTS BIO; Financial Interests, Personal, Other, Founder: DAAN Biotherapeutics; Financial Interests, Institutional, Research Grant: MOGAM Institute, LG Chem, Oscotec, Interpark Bio Convergence Corp, GIInnovation, GI-Cell, Abion, AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Champions Oncology, CJ Bioscience, CJ Blossom Park, Cyrus, Dizal Pharma, Genexine, Jans; Financial Interests, Personal, Other, Speaker, Consultant, Advisor: Abion, BeiGene, Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, CJ, CureLogen, Cyrus Therapeutics, Ono, Onegene Biotechnology, Yuhan, Pfizer, Eli Lilly, GI-Cell, Guardant, HK Inno-N, Imnewrun Biosciences Inc., Janssen, Takeda, MSD, Janssen, Medp; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, Bridgebio therapeutics, KANAPH Therapeutic Inc, Cyrus therapeutics, Interpark Bio Convergence Corp., J INTS BIO. J.W. Riess: Financial Interests, Personal, Advisory Board: Catalyst, Amgen, Roche/Genentech, Regeneron, Janssen, BMS, EMD Serano, Merck, Merus NV, Oncohost; Non-Financial Interests, Personal, Other, Coordinating PI: IO Biotech, Summit; Financial Interests, Institutional, Other, Research Funding: Nuvalent, Summit, Merck, Novartis, Revolution Medicines, AstraZeneca, Pfizer, SeaGen, Boehringer Ingelheim; Non-Financial Interests, Personal, Other, Steering Committee Member: IO Biotech, AstraZeneca, GSK, Summit; Non-Financial Interests, Personal, Other, Trial Chair: IO Biotech, Summit, SeaGen. A.J. De Langen: Financial Interests, Personal, Advisory Role: AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, Pfizer, Roche, Lilly, MSD; Financial Interests, Personal, Research Grant: AstraZeneca, Bristol Myers Squibb, Boehringer-Ingelheim, MSD. Z. Piotrowska: Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Taiho, Janssen, Bayer, Black Diamond Therapeutics, AstraZeneca, Blueprint Medicines, Daiichi Sankyo, Merck, Sanofi, Takeda, C4 Therapeutics; Non-Financial Interests, Institutional, Other, Coordinating PI: AstraZeneca, Cullinan Oncology; Financial Interests, Personal, Invited Speaker: Eli Lilly, Boehringer Ingelheim, Janssen, AstraZeneca; Financial Interests, Personal, Other, Local PI: Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, Blueprint Medicines; Financial Interests, Institutional, Other, Research Funding: Novartis, Takeda, Spectrum, AstraZeneca, Tesaro/GSK, Cullinan Oncology, Daiichi Sankyo, AbbVie, Janssen, Blueprint Medicines; Financial Interests, Personal, Other, Steering Committee Member: AstraZeneca; Financial Interests, Personal, Other, Member of data safety monitoring committee: Genentech. H. Ambrose: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. J.M. Lehman: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. P.G. Fraenkel: Financial Interests, Personal, Full or part-time Employment: AstraZeneca; Financial Interests, Personal, Stocks/Shares: AstraZeneca. S.B. Goldberg: Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Janssen, Summit Therapeutics, Merck, Regeneron, Eli Lilly; Financial Interests, Personal, Other, Research Funding: AstraZeneca, Boehringer Ingelheim, Mirati. All other authors have declared no conflicts of interest.