Studies evaluating adjuvant CDK4/6i provided contradictory results thus far and further characterization of the biological effect of CDK4/6i in residual disease (RD) after neoadjuvant chemotherapy (NAC) is needed. Here we report the primary analysis of the PROMETEO II trial.
Patients (pts) with HR+/HER2- BC and RD after completing anthracycline/taxane-based NAC were included. RD was confirmed with an ultrasound showing a tumor diameter ≥ 10 mm and a core-biopsy detecting the presence of invasive tumor with Ki67% ≥ 5% by local IHC. Before surgery (SUR), patients received palbociclib 125mg for 21 days and letrozole until SUR. The primary endpoint was complete cell cycle arrest (CCCA) rate determined by Ki67 ≤2.7%, centrally assessed, at SUR. Secondary endpoints include residual cancer burden (RCB) and safety. Tumor samples collected at 3 timepoints (before NAC, during screening (SCR) period and at SUR) were mandatory to assess gene expression, sTILs and PD-L1 IHC (SP142).
22 pts were enrolled: median age 56y (41-69), 45% premenopausal and histologic grade 2/3 63%. The rate of CCCA at SUR was 59% (Table). Between SCR and SUR, Ki67% decreased by a geometric mean change of 44.2%. One patient achieved RCB-I. Intrinsic subtype changes at SUR occurred in 58% of cases, mostly (38.1%) Luminal A/B converting to Normal-like. After palbociclib, immune genes were induced and proliferation genes were suppressed (FDR<5%). Interestingly, immune genes were upregulated in tumors with CCCA after palbociclib compared to tumors with non-CCCA. 9 patients (41%) experienced grade 3 AEs (all neutropenia). Biomarkers according with the 3 timepoints by central assessment
PRE_NAC SCR SUR CCCA, n(%) 1 (4) 6 (27) 13(59) Mean %ki67 22.5 7.2 4.2 sTILs, median (r) 2.5 (<1-35) 2.5 (0-40) 4 (1-20) PDL1+, n(%) NA 0 3 (14) IgG high group, n(%) 2 (9) 7 (32) 13 (59)
In chemo-resistant residual disease in pts with HR+/HER2- BC, palbociclib induce a potent anti-proliferative effect. A direct relationship between immune infiltration and anti-proliferative response exists, where immune infiltration is increased in residual tumors with CCCA.
EudraCT 2019-001275-36, NCT04130152 First posted: October 17, 2019.
SOLTI.
Sponsor: SOLTI Cancer Research Group. This study was funded by Pfizer.
S. Pernas Simon: Financial Interests, Personal, Advisory Board: Seagen, AstraZeneca- Daiichi Sankyo, Pierre-Fabre, Pfizer; Financial Interests, Personal, Invited Speaker: Lilly, Novartis, Eisai, Roche; Financial Interests, Institutional, Invited Speaker: Astra-Zeneca, Novartis, Daiichi Sankyo; Non-Financial Interests, Invited Speaker: SOLTI. G. Villacampa: Financial Interests, Personal, Invited Speaker, Invited speaker in a course: MSD; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Invited speaker in an internal training: Pierre Fabrer, GSK; Financial Interests, Personal, Invited Speaker, Internal discussion about the interpretation of some published results: Pfizer; Financial Interests, Personal, Other, Collaborations with specific projects: Reveal Genomics. T. Pascual: Financial Interests, Personal, Invited Speaker: Pfizer/ AstraZeneca / Veracyte / Novartis; Financial Interests, Personal, Advisory Board: Roche/Genentech. A. Prat: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker, Lecture fees: Novartis, Daiichi Sankyo; Financial Interests, Personal, Advisory Board, Advisory role/consultancy: Novartis, Pfizer, Oncolytics Biotech, Guardant Health, Peptomyc; Financial Interests, Institutional, Invited Speaker, Clinical trials: Daiichi Sankyo; Financial Interests, Institutional, Other, Contracted research: Boehringer, Medica Scientia inno. Research; Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker, Leadership role: Reveal Genomics, SL.; Financial Interests, Personal, Stocks/Shares: Reveal Genomics, Oncolytics Biotech; Financial Interests, Personal, Royalties: Reveal Genomics; Financial Interests, Institutional, Invited Speaker: Roche, AstraZeneca, Novartis; Financial Interests, Personal and Institutional, Invited Speaker: Daiichi Sankyo; Non-Financial Interests, Institutional, Other, Leadership roles: Patronage committee: SOLTI Foundation, Actitud Frente al Cáncer Foundation; Non-Financial Interests, Personal, Other, Asociación Española de Investigación sobre el Cáncer: ASEICA. E.M. Ciruelos: Financial Interests, Personal, Other, Speakers Bureau. Educational activities: Roche; Financial Interests, Personal, Invited Speaker, Symposia and Educational activities: Roche; Financial Interests, Personal, Advisory Board, Non-permanent advisor: Roche, Lilly, Novartis, Pfizer, Daiichi Sankyo, MSD; Financial Interests, Personal, Invited Speaker, Symposia and Education: Lilly; Financial Interests, Personal, Invited Speaker, Educational activities: Pfizer; Financial Interests, Personal, Advisory Board, Non-permanent advisor, Travel accommodation: AstraZeneca; Financial Interests, Personal, Other, Advisory Board: Gilead; Financial Interests, Personal, Other, Advisory Board, Invited speaker: Seagen; Financial Interests, Institutional, Funding, PI for Patricia 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for Prometeo 2 trial (sponsor: SOLTI Group): Pfizer; Financial Interests, Institutional, Funding, PI for TATEN trial (sponsor: SOLTI Group): MSD; Financial Interests, Institutional, Funding, PI for ATREZZO trial (sponsor: SOLTI Group): Roche; Non-Financial Interests, Invited Speaker, Non-profit organization dedicated to breast cancer research: SOLTI Cooperative Group; Non-Financial Interests, Advisory Role, Scientific Evaluator at ISCIII (Spanish Government Academic Research Platform): Instituto de Salud Carlos III. All other authors have declared no conflicts of interest.