180O - IMpassion132 double-blind randomised phase III trial of chemotherapy (CT) ± atezolizumab (atezo) for early-relapsing unresectable locally advanced or metastatic triple-negative breast cancer (aTNBC)

Background

Immune checkpoint inhibitors (ICIs) improve efficacy of first-line CT for some patients (pts) with aTNBC but data in early relapse are limited.

Methods

IMpassion132 (NCT03371017) enrolled pts with aTNBC relapsing <12 mo after the last of any anthracycline- and taxane-containing (neo)adjuvant CT or primary TNBC surgery. PD-L1 status was centrally assessed by SP142 before randomisation. Initially pts were enrolled irrespective of PD-L1 status. In Aug 2019 the protocol was amended to enrich for PD-L1+ (tumour immune cell ≥1%) aTNBC. Stratification factors were investigator-selected CT (capecitabine 1000 mg/m² bid d1–14 q21d [X] or carboplatin AUC2 + gemcitabine 1000 mg/m² d1 & 8 q21d [CG]), visceral (lung and/or liver) metastases and (until Aug 2019) PD-L1 status. Pts were randomised 1:1 to placebo or atezo 1200 mg q21d with chosen CT until progression or unacceptable toxicity. Crossover was not allowed. The primary endpoint was overall survival (OS), tested hierarchically first in PD-L1+ pts then, if positive, in the modified intent-to-treat (mITT*) population. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety.

Results

Among 354 PD-L1+ pts (of 595 pts enrolled), 68% had a disease-free interval <6 mo and 73% received CG. The primary objective was not met (Table); subgroup results were consistent. PFS was similar across treatment arms and populations (median ∼4 mo). ORRs were 28% with placebo + CT vs 40% with atezo + CT. Adverse events (predominantly haematological) were broadly similar between arms and as expected with atezo + CG or X in early-relapsing aTNBC. Table: 180O

Final OS analysis (prespecified after ∼247 deaths in the PD-L1+ population); median follow-up 9 months

*All-comer pts randomised before Aug 2019.

Conclusions

Pts with early-relapsing aTNBC have a dismal prognosis that is not improved with atezo.A biology-based definition of intrinsic resistance to ICIs in aTNBC is urgently needed to optimally treat these pts and design next-generation (combination) clinical trials.

Clinical trial identification

EudraCT 2016-005119-42.

Editorial acknowledgement

Jennifer Kelly (Medi-Kelsey Ltd).

Legal entity responsible for the study

F. Hoffmann-La Roche Ltd.

Funding

F. Hoffmann-La Roche Ltd.

Disclosure

R.A. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Pfizer, Merck, Lilly, Eisai; Financial Interests, Personal, Invited Speaker: AstraZeneca, Roche, Pfizer, Merck, Lilly, AstraZeneca; Financial Interests, Personal and Institutional, Invited Speaker: Roche; Financial Interests, Personal and Institutional, Research Grant, Investigator Initiated Trial: AstraZeneca. F. André: Financial Interests, Personal, Advisory Board: Lilly FRANCE; Financial Interests, Institutional, Advisory Board: AstraZeneca, Daiichi Sankyo, Roche, Lilly, Pfizer, OWKIN, Novartis, Guardant Health, N-Power Medicine, Servier, Gilead, Boston Pharmaceutics; Financial Interests, Institutional, Research Grant: AstraZeneca, Lilly, Novartis, Pfizer, Roche, Daiichi, Guardant Health, OWKIN. A. Gonçalves: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, MSD, innate pharma, Parexel, Gilead; Financial Interests, Institutional, Invited Speaker: Novartis, Roche, MSD, AstraZeneca, Daiichi Sankyo; Other, travel accommodation meeting registration: Mylan; Other, travel accommodation meeting registration: Novartis; Other, travel, accommodation, meeting registration: Roche, Menarini. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo, Menarini-Stemline; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, PUMA; Non-Financial Interests, Member of Board of Directors: TRIO; Non-Financial Interests, Leadership Role: GEICAM; Non-Financial Interests, Member: ASCO; Non-Financial Interests, Affiliate: SEOM. P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Gilead, Eisai, MSD, Seagen, Amgen, Celgene, Lilly; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Genentech, Novartis, Oncogenex, Roche, Medivation. F. Schütz: Financial Interests, Personal, Speaker’s Bureau: Amgen, AstraZeneca, Daiichi Sankyo, Exact Science, Gilead, Lilly, MSD, Pfizer, Novartis, OnkoZert, Roche; Financial Interests, Personal, Advisory Board: Atheneum, FuxWinter, Lilly, MSD, Gilead, Onkowissen.de, Oncologics; Financial Interests, Personal, Full or part-time Employment: Diakonissen-Stiftungs-Krankenhaus Speyer, Germany. S. Kummel: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Lilly, MSD, Novartis, Seagen, Pfizer, Pfizer, Roche, Somatex, Gilead, Sanofi, Hologic, PINK; Financial Interests, Personal, Invited Speaker: Exact Science, MSD, Lilly, Gilead, Roche, Sanofi, Daiichi Sankyo; Financial Interests, Personal, Ownership Interest, Minority Ownership: WSG Study Group; Financial Interests, Personal and Institutional, Invited Speaker: Roche, Novartis; Financial Interests, Institutional, Invited Speaker: Roche, Novartis, Lilly, Somatex, AstraZeneca, MSD. S.M. Swain: Financial Interests, Personal, Advisory Board, Advisory Boards and non-promotional speaking and in kind travel to Paris for Advisory board 9/2022: Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory Boards, IDMC through BIG for Olympia, in kind third party writing: AstraZeneca; Financial Interests, Personal, Invited Speaker, Non Promotional speaking and advisory boards, Travel for speaking or poster for investigator meeting for INAVO 122,: Roche/Genentech; Financial Interests, Personal, Invited Speaker, In kind, for several papers and I do not know the cost of each one attributed to me: Roche/Genentech; Financial Interests, Personal, Other, I hour consultation: Molecular Templates; Financial Interests, Personal, Advisory Board: Biotheranostics, Natera; Financial Interests, Personal, Advisory Board, Advisory Board and travel(in kind hotel): Sanofi; Financial Interests, Personal, Member of Board of Directors, BOD 11/9/22 to 12/14/23. Seagen sold to Pfizer and BOD dissolved on 12/14/23: Seagen; Financial Interests, Personal, Other, Member of Scientific Advisory Board: Napo Pharmaceuticals; Financial Interests, Personal, Stocks/Shares: Seagen; Financial Interests, Institutional, Research Grant, Grant to institution to perform clinical trial in Pharmacogenomics: Kailos Genetics; Financial Interests, Institutional, Invited Speaker, Grant to perform HALT D clinical trial: Genentech Inc; Financial Interests, Personal, Invited Speaker, Steering committee of Kaitlin, IMPASSION 132 and INAVO 122: Genentech Inc; Financial Interests, Institutional, Funding, Research projects with NSABP and Georgetown investigator initiated clinical trial: BCRF; Non-Financial Interests, Member of Board of Directors, 2021 to present, travel to NRG meeting in Chicago 7/2022 in kind: NSABP Foundation; Non-Financial Interests, Member of Board of Directors, CCF and Chair of Women Who Conquer Cancer, in kind travel to Austin Texas for WWCC fundraising event: ASCO Conquer Cancer Foundation; Non-Financial Interests, Project Lead, Inavolisib study steering committee chair WO442663: Roche; Non-Financial Interests, Personal, Proprietary Information: Seagen. D. Loirat: Financial Interests, Personal, Advisory Board: MSD, AstraZeneca, Pfizer, Novartis, Exact Sciences; Financial Interests, Personal, Other, Travel/congress: MSD; Financial Interests, Personal, Other, Travel/Congress: Roche, AstraZeneca, Gilead, Novartis; Financial Interests, Personal, Invited Speaker: Gilead, Lilly; Financial Interests, Personal, Other, Travel/Congres: Pflizer. R. Villalobos Valencia: Financial Interests, Personal, Advisory Board, Only as speaker and advisory board: AstraZeneca, Novartis; Financial Interests, Personal, Advisory Board, Speaker and Advisory Board: Pfizer; Non-Financial Interests, Principal Investigator, Principal investigator in phase II and III clinical research protocols and with personal payment in private practice: AstraZeneca, Roche, Amgen, Merck. S. Im: Financial Interests, Personal, Advisory Board, no payment: AstraZeneca, Novartis, Eisai, Roche, Hanmi, Pfizer, Lilly, MSD, GSK, Daiichi Sankyo; Financial Interests, Institutional, Advisory Board: Bertis; Financial Interests, Personal, Advisory Board: Idience; Financial Interests, Institutional, Research Grant: AstraZeneca, Pfizer, Roche, Eisai, Dae Woong; Financial Interests, Institutional, Invited Speaker, Clinical Trial Budget: AstraZeneca, Eisai, Hanmi, Novartis, Roche, Pfizer, Daiichi Sankyo, MSD, Lilly; Financial Interests, Institutional, Research Grant, Clinical Trial Budget: Boryung Pharm. Y.H. Park: Financial Interests, Personal, Advisory Board: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Roche, Novartis, MSD, Daiichi Sankyo; Financial Interests, Institutional, Other, Research Grant: AstraZeneca, Pfizer, Roche, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer; Non-Financial Interests, Principal Investigator: AstraZeneca, Pfizer, Novartis, MSD, Lilly, Roche, Daiichi Sankyo. Z.K. Machackova: Financial Interests, Personal, Full or part-time Employment: Hoffmann-La Roche; Financial Interests, Personal, Stocks/Shares: Hoffmann-La Roche. J.-. Mouta: Financial Interests, Personal, Full or part-time Employment, Employer of F. Hoffman - La Roche: Roche; Financial Interests, Personal, Stocks/Shares: Roche. R.J. Deurloo: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann - La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann - La Roche Ltd.; Non-Financial Interests, Leadership Role: F. Hoffmann - La Roche Ltd. X. Gan: Financial Interests, Personal, Full or part-time Employment: Roche (China) Holding Ltd. M. Fan: Financial Interests, Personal, Full or part-time Employment: Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: Hoffmann-La Roche Ltd. A. Swat: Financial Interests, Personal, Full or part-time Employment: F. Hoffmann-La Roche Ltd.; Financial Interests, Personal, Stocks/Shares: F. Hoffmann-La Roche Ltd. J. Cortés: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Lilly, MSD, LEUKO, Bioasis, Clovis oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Jazz Pharmaceuticals, AbbVie, Scorpion Therapeutics, Biocon; Financial Interests, Personal, Invited Speaker: Roche, Novartis, Eisai, Pfizer, Lilly, MSD, Daiichi Sankyo; Financial Interests, Personal, Other, Consulting/advisor: Expres2ion Biotechnologies; Financial Interests, Personal, Other, consulting: Bridgebio; Financial Interests, Personal, Stocks/Shares: MAJ3 Capital; Financial Interests, Personal, Stocks/Shares, (relative): Leuko; Financial Interests, Institutional, Research Grant: Roche, Ariad Pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, Guardant health, MSD, Pfizer, Piqur Therapeutics, Queen Mary University of London; Other, Travel cost and expenses: Roche, Novartis, Eisai, Daiichi Sankyo, Pfizer, Gilead, AstraZeneca, Stemline Therapeutics; Other, travel cost and expenses: MSD. All other authors have declared no conflicts of interest.