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Randomized Controlled Trial
. 2022 Jul 1;8(7):1010-1018.
doi: 10.1001/jamaoncol.2022.1059.

Effect of Denosumab Added to 2 Different nab-Paclitaxel Regimens as Neoadjuvant Therapy in Patients With Primary Breast Cancer: The GeparX 2 × 2 Randomized Clinical Trial

Jens-Uwe Blohmer  1 , Theresa Link  2   3   4   5 , Mattea Reinisch  6 , Marianne Just  7 , Michael Untch  8 , Oliver Stötzer  9 , Peter A Fasching  10 , Andreas Schneeweiss  11 , Pauline Wimberger  2   3   4   5 , Sabine Seiler  12 , Jens Huober  13   14 , Marc Thill  15 , Christian Jackisch  16 , Kerstin Rhiem  17 , Christine Solbach  18 , Claus Hanusch  19 , Fenja Seither  12 , Carsten Denkert  20 , Knut Engels  21 , Valentina Nekljudova  12 , Sibylle Loibl  12   22   23 ; GBG and AGO-B
Collaborators, Affiliations
Randomized Controlled Trial

Effect of Denosumab Added to 2 Different nab-Paclitaxel Regimens as Neoadjuvant Therapy in Patients With Primary Breast Cancer: The GeparX 2 × 2 Randomized Clinical Trial

Jens-Uwe Blohmer et al. JAMA Oncol. .

Abstract

Importance: Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)-positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear.

Objective: To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting.

Design, setting, and participants: The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)-positive BC.

Interventions: Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m2 (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy).

Main outcomes and measures: The primary outcome was pCR rates between arms for each randomization.

Results: A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004).

Conclusions and relevance: In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m2 weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity.

Trial registration: ClinicalTrials.gov Identifier: NCT02682693.

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Conflict of interest statement

Conflict of Interest Disclosures: Blohmer reported personal fees from Amgen during the conduct of the study; and personal fees from AstraZeneca, Merck Sharp & Dohme (MSD), Roche, and Seagen outside the submitted work. Link reported personal fees from Novartis, Pfizer, Roche, Tesaro, MSD, Amgen, Clovis, Lilly, Myriad, Eisai, GSK, and Gilead and nonfinancial support from MSD, Celgene, Clovis, and Daiichi Sankyo outside the submitted work. Reinisch reported personal fees from Roche, Lilly, AstraZeneca, Daiichi Sankyo, Pfizer, Seagen, Somatex, and Novartis and travel from Novartis and Celgene outside the submitted work. Untch reported personal fees (advisor; all fees to employer) from AbbVie, Eisai, and Seagen and personal fees (advisor, speaker; all fees to employer) from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Gilead, GlaxoSmithKline (GSK), Lilly, MSD Merck, Mylan, Myriad, Novartis, Pierre Fabre, Pfizer, Sanofi Aventis, and Roche outside the submitted work. Fasching reported grants from BioNTech and Cepheid and personal fees from Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Eisai, MSD, Lilly, Pierre Fabre, Seagen, Roche, Hexal, Agendia, Gilead, and Sanofi Aventis during the conduct of the study. Schneeweiss reported personal fees (honoraria) from Amgen, AstraZeneca, Celgene, Gilead, GSK, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Teva, and Tesaro, and travel support from Celgene, Pfizer, and Roche outside the submitted work. Wimberger reported personal fees from Amgen, AstraZeneca, MSD, Novartis, Pfizer, Lilly, Roche, TEVA, Eisai, Clovis, and GSK outside the submitted work. Seiler reported travel costs from Novartis and personal fees from Roche, Mundipharma, Amgen, and AbbVie outside the submitted work. Huober reported grants from Hexal; grants and personal fees from Lilly; grants, personal fees, and travel expenses from Celgene; personal fees from Novartis, MSD, AstraZeneca, Gilead, Seagen, and Eisai; and personal fees and travel expenses from Roche, Pfizer, and Daiichi Sankyo outside the submitted work. Thill reported personal fees and nonfinancial support from Amgen; personal fees from AstraZeneca, Celgene, Pfizer, Roche, Hexal, Organon, Viatris, Vifor, Servier, Exact Sciences, Sysmex, Clearcut, PFM Medical, Daiichi Sankyo, Eisai, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Clovis, and Seagen; and trial funding from Endomag and Exact Sciences outside the submitted work. Jackisch reported personal fees from Roche, AstraZeneca, Pfizer, and Amgen during the conduct of the study. Hanusch reported personal fees from Roche, Novartis, Pfizer, Celgene, Lilly, and AstraZeneca outside the submitted work. Denkert reported grants from the German Breast Group during the conduct of the study; personal fees from Novartis, Roche, MSD Oncology, Daiichi Sankyo, Molecular Health, AstraZeneca, Merck, and Lilly; grants from Myriad Genetics and Roche; and other (cofounder) from Sividon outside the submitted work; in addition, Denkert had a patent for Company: VMscope digital pathology software with royalties paid. Loibl reported honorarium for advisory boards (paid to institute) from AbbVie, Amgen, Bayer, Celgene, EirGenix, GSK, Lilly, Merck, Puma, Seagen; honorarium for advisory boards and lectures from AstraZeneca, Daiichi Sankyo, Novartis, Pierre Fabre, Prime/Medscape, and Pfizer; nonfinancial support and honorarium for advisory boards (paid to institute) from Bristol Myers Squibb; personal fees (lecture) from Chugai; other (paid to institute) from Ipsen; grants (honorarium for advisory boards and lectures from Roche; honorarium (lecture, paid to institute) from Samsung; nonfinancial support (paid to institute) from Vifor; and nonfinancial support (paid to institute/medical writing) from Gilead outside the submitted work; in addition, Loibl had a patent for EP14153692.0 pending, Immunsignature in TNBC; a patent for EP21152186.9 pending, CDK 4/6 Inhibitor Therapy; a patent for EP15702464.7 pending, Predicting response to an anti-HER2–containing therapy; and a patent for VMscope with royalties paid to VMscope GmbH. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. GeparX Study Design
AUC indicates area under the curve; BC, breast cancer; Dmab, denosumab; EC, epirubicin and cyclophosphamide; nP, nab-paclitaxel; pCR, pathological complete response; SC, subcutaneously; sTILs, stromal tumor-infiltrating lymphocytes; TNBC, triple-negative BC; wk, weekly.
Figure 2.
Figure 2.. CONSORT Diagram of the GeparX Study
AE indicates adverse event; CT, chemotherapy; Dmab, denosumab; EC, epirubicin and cyclophosphamide; nP, nab-paclitaxel; wk, weekly. aThree patients did not start Dmab and were analyzed for safety and adherence in no Dmab arm; in 7 patients of nP d1,8 q3 wk arm, there was no pause at day 15 in at least 2 cycles, and they were analyzed for safety and adherence in the nP weekly arm. bIncludes patients who completed both nP and EC. cOf patients “as randomized.”
Figure 3.
Figure 3.. Forest Plot of Univariate Logistic Regression for pCR (ypT0 ypN0) in Subgroups for the Denosumab Randomization and the nab-Paclitaxel Randomization
Dmab indicates denosumab; EC, epirubicin and cyclophosphamide; HR, hormone receptor; LPBC, lymphocyte-predominant breast cancer; nP, nab-paclitaxel; pCR, pathological complete response; TNBC, triple-negative breast cancer; wk, weekly.
See this image and copyright information in PMC

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