Background

IMpassion130 is a Ph 3 study evaluating atezolizumab (A) + nab-paclitaxel (nP) vs placebo (P) + nP as 1L treatment for patients (pts) with mTNBC. A+nP significantly improved PFS in PD-L1+ pts (PD-L1 positivity defined as PD-L1–stained immune cells [IC] ≥ 1% of the tumour area by VENTANA PD-L1 SP142 assay). PD-L1+ pts also had clinically meaningful OS benefit with A+nP (25 vs 18 mo; HR 0.71 [95% CI: 0.54, 0.93]; median follow-up, 18 mo; Schmid, ASCO 2019). In this exploratory post-hoc analysis, we evaluated the analytical concordance of SP142 with 2 other PD-L1 IHC assays, and their ability to predict clinical activity.

Methods

Available samples from IMpassion130 were evaluated for PD-L1 status using VENTANA SP142 or SP263 IHC assay (IC ≥ 1%, SP142+ or SP263+) or Dako PD-L1 IHC 22C3 assay (combined proportion score [CPS] ≥ 1, 22C3+) by central laboratory in a biomarker-evaluable population (BEP).

Results

A BEP of 614 pts (68% of ITT) was evaluable for PD-L1 status using the 3 assays. PD-L1+ prevalence was 46% for SP142+, 81% for 22C3+, and 75% for SP263+. The overall percentage agreement (OPA) of SP142 with 22C3 and SP263 was 69% and 63%, respectively. PPAs of 98% for both assays suggest that SP142+ pts are captured by the other two tests, while NPAs were < 45%. The PFS HR (95% CI) was 0.60 (0.47, 0.78) in SP142+ pts, 0.68 (0.56, 0.82) in 22C3+ pts, and 0.64 (0.53, 0.79) in SP263+ pts. The OS HR (95% CI) was 0.74 (0.54, 1.01) in SP142+ pts, 0.78 (0.62, 0.99) in 22C3+ pts, and 0.75 (0.59, 0.96) in SP263+ pts. Subgroup outcomes of SP142+ and SP263+ or 22C3+ indicate that the PFS and OS benefit with A+nP in SP263+/SP142– or 22C3+/SP142– subgroups was smaller than in double-positive subgroups (table).Table:

LBA20

Conclusions

At the evaluated cutoffs, 22C3 and SP263 assays identified more pts with PD-L1+ tumours. The pts in the SP142 PD-L1+ population, which is nested within the 22C3 and SP263 PD-L1+ populations, derived the greatest clinical benefit with A+nP.

Clinical trial identification

NCT02425891.

Editorial acknowledgement

Medical writing assistance was provided by Steffen Biechele, PhD, of Health Interactions and funded by F. Hoffmann-La Roche, Ltd.

Legal entity responsible for the study

F. Hoffmann-La Roche, Ltd.

Funding

F. Hoffmann-La Roche, Ltd.

Disclosure

H.S. Rugo: Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): OBI; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution), Travel / Accommodation / Expenses: Genentech/Roche; Research grant / Funding (institution), Travel / Accommodation / Expenses: MacroGenics; Travel / Accommodation / Expenses: PUMA; Travel / Accommodation / Expenses: Mylan; Research grant / Funding (self): Immunomedics; Research grant / Funding (self), Travel / Accommodation / Expenses: Daiichi Sankyo; Honoraria (self): Celltrion. S. Loi: Research grant / Funding (institution), Non-remunerated activity/ies, Non-remunerated consultant: Novartis; Research grant / Funding (institution), Non-remunerated activity/ies, Non-remunerated consultant: BMS; Research grant / Funding (institution), Non-remunerated activity/ies, Non-remunerated consultant: Roche/Genentech; Research grant / Funding (institution), Non-remunerated activity/ies, Non-remunerated consultant: Merck; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution): Eli Lilly; Non-remunerated activity/ies, Non-remunerated consultant: Seattle Genetics; Non-remunerated activity/ies, Non-remunerated consultant: Pfizer; Advisory / Consultancy: Aduro Biotechnology. S. Adams: Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Celgene. P. Schmid: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Research grant / Funding (institution): Oncogenex; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Astellas; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Puma biotechnology. A. Schneeweiss: Honoraria (self), Research grant / Funding (institution): Celgene; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Molecular Partners; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Eli Lilly; Honoraria (self), Travel / Accommodation / Expenses: Pfizer. C.H. Barrios: Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy, Research grant / Funding (institution): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advisory / Consultancy, Research grant / Funding (institution): Roche/Genentech; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Taiho Pharmaceutical; Research grant / Funding (institution): Mylan; Research grant / Funding (institution): Merrimack; Advisory / Consultancy, Research grant / Funding (institution): Merck; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): BioMarin; Research grant / Funding (institution): BMS; Research grant / Funding (institution): Daiichi Sankyo; Advisory / Consultancy: Bayer; Advisory / Consultancy: Eisai. H. Iwata: Honoraria (self), Advisory / Consultancy: Chugai; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Eli Lilly; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo. V.C. Dieras: Honoraria (self): Roche/Genentech; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly; Honoraria (self): Novartis; Honoraria (self): Daiichi Sankyo; Honoraria (self): AstraZeneca; Honoraria (self): AbbVie; Honoraria (self): Odonate. E.P. Winer: Honoraria (self): Eli Lilly; Honoraria (self), Advisory / Consultancy: Leap; Honoraria (self): Roche/Genentech; Honoraria (self): Infinite MD; Honoraria (self): Carrick Therapeutics; Honoraria (self): GlaxoSmithKline; Honoraria (self): Jounce; Honoraria (self): Genomic Health; Honoraria (self): Merck; Honoraria (self): Seattle Genetics. M. Kockx: Shareholder / Stockholder / Stock options, Full / Part-time employment: HistoGeneX. D. Peeters: Full / Part-time employment: HistoGeneX. S.Y. Chui: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche Ltd.. J.C. Lin: Full / Part-time employment: F. Hoffmann-La Roche Ltd.. A. Nguyen Duc: Full / Part-time employment: F. Hoffmann-La Roche Ltd.. G. Viale: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Roche/Genentech. L. Molinero: Shareholder / Stockholder / Stock options, Full / Part-time employment: F. Hoffmann-La Roche Ltd.. L.A. Emens: Honoraria (self): AbbVie; Honoraria (self): Amgen; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Honoraria (self): Celgene; Advisory / Consultancy, Non-remunerated activity/ies, Non-remunerated consulting/advisory board: eTHeRNA; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self): Gritstone; Honoraria (self): MedImmune; Honoraria (self): Molecuvax; Honoraria (self), Travel / Accommodation / Expenses: Macrogenics; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self): Peregrine; Honoraria (self), Travel / Accommodation / Expenses: Replimune; Honoraria (self): Syndax; Honoraria (self), Travel / Accommodation / Expenses: Vaccinex; Research grant / Funding (institution), Licensing / Royalties: Aduro Biotech; Research grant / Funding (institution): Breast Cancer Research Foundation; Research grant / Funding (institution): Corvus.

Background

Pembro showed promising antitumor activity and manageable safety in mTNBC in KEYNOTE-012 and 086. KEYNOTE-119 (NCT02555657) is a randomized, open-label phase III study of pembro monotherapy vs single-agent chemo in participants (pts) with previously treated mTNBC.

Methods

Pts with centrally confirmed TNBC, 1-2 prior systemic treatments for mTNBC, PD on latest therapy and a prior anthracycline or taxane were randomized 1:1 to pembro 200 mg Q3W or physician’s choice of capecitabine, eribulin, gemcitabine, or vinorelbine (60% enrollment cap for each). Pts were stratified by PD-L1 + vs - and prior (neo)adjuvant therapy vs mTNBC at first diagnosis. Primary end points were OS in pts with PD-L1 combined positive score (CPS) ≥10, pts with CPS ≥1, and all pts. Secondary end points were PFS, ORR, DOR, DCR and safety. OS superiority of pembro vs chemo was tested in all pts only if superiority was shown in pts with CPS ≥1.

Results

As of 11 APR 2019, median follow-up was 9.9 mo for pembro (n = 312) and 10.9 mo for chemo (n = 310). Pembro did not significantly improve OS in pts with CPS ≥10 (P = .0574) or CPS ≥1 (P = .0728) or in all pts, although the pembro treatment effect increased as CPS increased (HR 0.78, 0.86, and 0.97, respectively; Table); in an exploratory analysis of pts with CPS ≥20, median OS was 14.9 mo with pembro vs 12.5 mo with chemo (HR 0.58, 95% CI 0.38-0.88). Pembro did not improve PFS (Table). DOR was longer with pembro vs chemo (Table). Grade 3-5 treatment-related AE rates were 14% with pembro (1 death) vs 36% with chemo (2 deaths). Rates of grade 3-4 immune-mediated AEs and infusion reactions were 3.2% vs 1.0%, with no deaths.Table:

LBA21

Conclusions

Pembro monotherapy did not significantly improve OS as 2/3L treatment for mTNBC vs chemo, although the pembro treatment effect increased as PD-L1 enrichment increased. Pembro was generally well tolerated and had less high-grade toxicity than chemo.

Clinical trial identification

NCT02555657.

Editorial acknowledgement

Writing assistance was provided by Christine McCrary Sisk and funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

J. Cortés: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Samsung; Advisory / Consultancy: Cellestia; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biothera Pharmaceutical; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Research grant / Funding (institution): Ariad Pharmaceuticals; Research grant / Funding (institution): Baxalta; Research grant / Funding (institution): GMBH/Servier Affaires; Research grant / Funding (institution): Bayer Healthcare; Research grant / Funding (institution): F. Hoffman-La Roche; Research grant / Funding (institution): Guardanth Health; Research grant / Funding (institution): Merck Sharp & Dohme; Research grant / Funding (institution): Piqor Therapeutics; Research grant / Funding (institution): Puma C; Research grant / Funding (institution): Queen Mary University of London; Shareholder / Stockholder / Stock options: MedSIR. S. Im: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Ildong; Advisory / Consultancy: MediPactor; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Roche. A. Gonçalves: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Celgene. K.S. Lee: Advisory / Consultancy: Roche; Advisory / Consultancy: Lilly; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Research grant / Funding (institution), (support of drug): Dong-A Pharm. P. Schmid: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Roche; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: BI; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Esai; Honoraria (self), Advisory / Consultancy: Puma; Honoraria (self), Advisory / Consultancy: Celgene; Research grant / Funding (institution): Genetech; Research grant / Funding (institution): Oncogenex; Research grant / Funding (institution): Astellas; Spouse / Financial dependant, Spouse is a consultant for Genetech/Roche: Genetech/Roche. K. Tamura: Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Cyugai; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Eisai; Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Eli Lilly; Research grant / Funding (self), Research grant / Funding (institution): Daiich-Sankyo; Research grant / Funding (self), Research grant / Funding (institution): MSD; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self), Research grant / Funding (institution): Ono; Research grant / Funding (self), Research grant / Funding (institution): Kyowa Hakko; Research grant / Funding (self), Research grant / Funding (institution): Novartis; Research grant / Funding (self), Research grant / Funding (institution): Clovis; Research grant / Funding (self), Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Boehringer Ingelheim; Research grant / Funding (institution): Taiho. L. Testa: Advisory / Consultancy, Research grant / Funding (institution): Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Roche; Travel / Accommodation / Expenses: Libbs; Travel / Accommodation / Expenses: Pfizer. I. Witzel: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Daichi Sankyo; Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Hexal Biosimilars; Research grant / Funding (institution): MSD. S. Ohtani: Honoraria (institution): Chugai; Honoraria (institution): Eizai; Honoraria (institution): Pfizer; Honoraria (institution): AstraZeneca. N. Harbeck: Advisory / Consultancy: Agendia; Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy, Speaker Bureau / Expert testimony: Daiichi Sankyo; Advisory / Consultancy: Genomic Health; Advisory / Consultancy, Speaker Bureau / Expert testimony: Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy: Odonate; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony: Amgen; Advisory / Consultancy: Sandoz/Hexal; Advisory / Consultancy: Seattle Genetics; Speaker Bureau / Expert testimony: Nanostring; Shareholder / Stockholder / Stock options, Spouse / Financial dependant, Co-director of West German Study Group (self): West German Study Group; Full / Part-time employment: LMU Munich. F. André: Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution): Lilly; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Daiichi; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: GlaxoSmithKline. R. Dent: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche. X. Zhou: Full / Part-time employment: Merck & Co., Inc.. V. Karantza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc.. J.A. Mejia: Full / Part-time employment: Merck & Co., Inc.. E.P. Winer: Advisory / Consultancy: Genentech, Lilly, Carrick Therapeutics, GSK, Seattle Genetics, LEAP. All other authors have declared no conflicts of interest.

Background

T-DM1 is indicated for the treatment of HER2+ metastatic BC previously treated with trastuzumab and a taxane, separately or in combination. Atezo is an anti-PD-L1 antibody that inhibits PD-L1 binding to PD-1 and B7.1 thereby restoring antitumor immunity. In a phase 3 study, the addition of atezo to nab-paclitaxel significantly improved PFS in PD-L1+ pts with metastatic triple negative BC. In KATE2 (NCT02924883), adding atezo to T-DM1 in pts with HER2+ BC did not significantly increase PFS compared to T-DM1+pbo in the ITT population, but PFS was numerically longer in PD-L1+ pts. Here, we present OS and updated safety data from KATE2.

Methods

Pts with advanced HER2-positive BC that had progressed after treatment with trastuzumab and a taxane were randomized 2:1 to atezo 1200 mg or pbo, + T-DM1 3.6 mg/kg IV q3w. Pts were grouped by tumor infiltrating PD-L1+ immune cell (IC) status: IC0 vs IC1/2/3 (<1% vs ≥ 1%, respectively) using VENTANA SP142. The preplanned OS analysis in the ITT population was a secondary endpoint with 30% power to detect an effect. OS in PD-L1 subgroups was analyzed post-hoc.

Results

As of the cutoff date (11 Dec 2018), median follow-up was 19.5 mo in the atezo+T-DM1 arm and 18.2 mo in the pbo+T-DM1 arm. With 52 OS events reported, median OS was not reached in either arm. In the ITT population, 1-year OS was similar in both arms. In the PD-L1+ subgroup, 1-year OS was greater in the atezo+T-DM1 arm. The safety profile was consistent with the known safety profile of each drug. Grade ≥3 AEs (52.6% vs 44.8%) and serious AEs (36.1% vs 20.9%)—primarily pyrexia—were more frequent in the atezo+T-DM1 arm than in the T-DM1+pbo arm.

Conclusions

These data suggest a possible OS benefit with atezo+T-DM1 in PD-L1+ pts. However, given the small number of OS events, the short follow-up and lack of statistical power, further study is necessary.Table:

305O

Clinical trial identification

NCT02924883.

Editorial acknowledgement

Medical writing assistance was provided by Katherine Stevens-Favorite, PhD and Holly Strausbaugh, PhD of Twist Medical LCC and funded by F. Hoffmann-La Roche.

Legal entity responsible for the study

F. Hoffmann - La Roche.

Funding

F. Hoffmann - La Roche.

Disclosure

L.A. Emens: Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Bayer; Advisory / Consultancy, Travel / Accommodation / Expenses: Bristol Meyers Squibb; Honoraria (self), Advisory / Consultancy: Celgene; Advisory / Consultancy: eTHeRNA; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche/Genentech; Honoraria (self), Advisory / Consultancy: Gristone; Honoraria (self), Advisory / Consultancy: Medimmune; Advisory / Consultancy: Molecuvax; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Macrogenics; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy: Peregrine; Honoraria (self), Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Replimune; Honoraria (self), Advisory / Consultancy: Syndax; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Vaccinex; Research grant / Funding (institution): Aduro; Research grant / Funding (institution), Same dislosure for Corvus, Dept of Defense, EMD Serono, HeritX Inc, Maxcyte, Merck: Breast Cancer Research Foundation; Research grant / Funding (institution), Licensing / Royalties, IND Licensing vaccine <25k: Aduro. F.J. Esteva: Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Novartis. C. Saura: Research grant / Funding (institution): Roche-Genentech; Research grant / Funding (institution): Macrogenics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution): Piqur therapeutics; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Puma biotechnology; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Synthon biopharmaceuticals; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Genomyc Health; Advisory / Consultancy, Travel / Accommodation / Expenses: Pierre Fabre. M. De Laurentiis: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Celgene; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Eli Lilly; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen. S. Kim: Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Sanofi-Genzyme; Research grant / Funding (institution): Dongkook Inc. S. Im: Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Roche; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Pfizer; Research grant / Funding (institution): Novartis. Y. Wang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche (China) Holding Ltd. A. Mani: Full / Part-time employment: Roche/Genentech; Shareholder / Stockholder / Stock options: Roche/Genentech. J. Shah: Shareholder / Stockholder / Stock options, Full / Part-time employment: Genentech. H. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. S. de Haas: Shareholder / Stockholder / Stock options, Full / Part-time employment: Roche. M. Patre: Shareholder / Stockholder / Stock options, Licensing / Royalties, Full / Part-time employment, Methods of treating her2 - positive metastatic breast cancer A61K47/6855: F. Hoffman-La Roche. S. Loi: Research grant / Funding (institution), Non-remunerated activity/ies: Novartis; Research grant / Funding (institution), Non-remunerated activity/ies: Bristol Meyers Squibb; Research grant / Funding (institution), Non-remunerated activity/ies: Roche-Genentech; Research grant / Funding (institution): Puma Biotechnology; Research grant / Funding (institution), Non-remunerated activity/ies: Pfizer; Non-remunerated activity/ies: Seattle Genentics; Non-remunerated activity/ies: Merck; Research grant / Funding (institution): Eli Lilly. All other authors have declared no conflicts of interest.

Background

Trilaciclib (T) is an IV cyclin dependent kinase (CDK) 4/6 inhibitor and first-in-class myelopreservation agent. Previous results from this phase II trial demonstrated that adding T to GC in mTNBC resulted in: 1) a longer duration and higher administered total dose of chemotherapy, 2) higher response rates and longer PFS, and 3) reduction in the frequency of some myelosuppression events. We now report preliminary OS and updated PFS.

Methods

This randomized, phase II, open-label study enrolled mTNBC patients with 0-2 prior chemotherapy regimens for recurrent/metastatic disease. Patients were randomized to GC alone on day 1, 8 (Group 1) or T + GC (Group 2) or T + GC (Group 3) using an alternative schedule (T D1, 2, 8, 9 + GC D2, 9) every 21 days until disease progression or unacceptable toxicity. The primary endpoint was reduction in GC-related neutropenia. PFS and OS were secondary endpoints.

Results

Among 102 enrolled patients, 98 were treated. 52% had ECOG PS 0 and 37.3% received prior chemotherapy for mTNBC. Median follow-up is 10.5 months; 3 patients remain on treatment. There have been no SAEs related to T. Drug exposure in Group 2/3 patients receiving T (median 168 days, 8 cycles) is longer than with GC alone (median 101 days, 4 cycles). PFS and OS in the intent to treat (ITT) population are summarized in the table below. Groups 2 + 3 (receiving T) had longer PFS compared with GC alone, HR of 0.59, p = 0.0628, and OS was statistically improved with HR of 0.37 and 0.39 in Groups 2 and 3, p = 0.0411 and p = 0.0044, respectively. ORR were 36.7%, 50.0%, and 33.3% in Groups 3, 2, and 1, respectively.Table:

LBA22

Conclusions

The addition of T to GC resulted in a significant increase in OS in both T groups. Previously observed PFS benefit with T was also confirmed.

Clinical trial identification

NCT02978716.

Legal entity responsible for the study

G1 Therapeutics, Inc.

Funding

G1 Therapeutics, Inc.

Disclosure

J. O’Shaughnessy: Honoraria (self): AbbVie Inc; Honoraria (self): Agendia; Honoraria (self): Amgen Biotechnology; Honoraria (self): AstraZeneca; Honoraria (self): Bristol-Myers Squibb; Honoraria (self): Celgene Croporation; Honoraria (self): Eisai; Honoraria (self): Genentech; Honoraria (self): Genomic Health; Honoraria (self): GRAIL; Honoraria (self): Immunomedics; Honoraria (self): Heron Therapeutics; Honoraria (self): Ipsen Biopharmaceuticals; Honoraria (self): Jounce Therapeutics; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Myriad; Honoraria (self): Novartis; Honoraria (self): Ondonate Therapeutics; Honoraria (self): Pfizer. G.S. Wright: Honoraria (self): Total Health Conferencing; Shareholder / Stockholder / Stock options: Roche Holdings Ltd; Shareholder / Stockholder / Stock options: Odonate Therapeutics; Shareholder / Stockholder / Stock options: Puma Biotech; Research grant / Funding (institution), Shareholder / Stockholder / Stock options, PI does not receive direct research funding; institution received payment for conduct of trials: Macrogenics ; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AbbVie; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Incyte; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Janssen; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Astellas; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Celgene; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: AstraZeneca; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Bristol-Myers Squibb; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Boehringer Ingelheim; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Medivation; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Merrimack; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer. A. Thummala: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Comprehensive Cancer Centers of Nevada. H.S. Han: Advisory / Consultancy: Lilly; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Novartis; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Pfizer; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: TapImmune; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Seattle Genetics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: BMS Prescient; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Horizon; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Karyopharm. S. Wilks: Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: US Oncology. J.A. Sorrentino: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. Z. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics. J.K. Horton: Shareholder / Stockholder / Stock options, Full / Part-time employment: G1 Therapeutics; Honoraria (self), Research grant / Funding (self): Varian Medical Systems; Honoraria (self): Qfix; Leadership role: International Journal of Radiation Oncology, Biology, Physics; Leadership role: American Board of Radiology; Leadership role: ASTRO. A.R. Tan: Advisory / Consultancy: Celgene; Advisory / Consultancy: Immunomedics; Advisory / Consultancy, Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Genentech; Advisory / Consultancy: Novartis; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Research grant / Funding (self): Merck; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: G1 Therapeutics; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Roche; Research grant / Funding (institution), PI does not receive direct research funding; institution received payment for conduct of trials: Tesaro; Leadership role, Breast Cancer Leader: Caris Precision Oncology Alliance. All other authors have declared no conflicts of interest.

Background

Abemaciclib, an oral selective inhibitor of CDK4 & 6, showed efficacy & tolerability in patients (pts) with HR+, HER2- ABC. In preclinical models, inhibition of CDK4 & 6 by abemaciclib enhanced the activity of HER2-directed agents and re-sensitized resistant tumors to HER2 blockade, suggesting a crosstalk between HER2 signaling and the cyclin D1/CDK4 signaling pathways in HR+ tumors only.

Methods

monarcHER (NCT02675231), a phase II study, compared 3 treatment arms in pts with HR+, HER2+ ABC; arm A (abemaciclib 150mg PO Q12H Days 1-21 of a 21-day cycle + trastuzumab [T] IV infusion Day 1 of 21-day cycle + fulvestrant 500 mg IM Cycle 1 D1 and D15 and Cycle 2 D8, then Q4W), arm B (abemaciclib + T), vs arm C (T + investigator’s choice chemotherapy, 21-day cycle). Eligible pts were postmenopausal women, ≥2 HER2-directed therapies for ABC, prior T-DM1 and taxane, ECOG PS ≤ 1. 237 pts were randomized 1:1:1 and stratified by number of prior systemic regimens for ABC (2 to 3 vs > 3) and measurable vs nonmeasurable disease. The gated primary objective was to compare investigator assessed PFS of Arm A to C and, if positive, then B to C. Secondary objectives include: OS, objective response rate (ORR), safety, patient reported outcomes, and pharmacokinetics. Primary analysis was planned after approximately 165 PFS events, providing 80% power to detect superiority of Arm A over C, assuming a HR of .667 at 1-sided α = .1.

Results

Analysis was performed at 169 events. Median PFS was longer in Arm A vs C (HR [95% CI], 0.673 [0.451 – 1.003]; p = 0.0253; 8.3 vs 5.7 mo). No difference in Arm B vs C (HR [95% CI], 0.943 [0.643 – 1.383]; p = 0.385; 5.7 vs 5.7 mo). ORR was 35.4%, 16.5% and 22.8% in arms A, B, and C respectively. Most common grade 3/4 adverse events (AEs) in Arms A, B, and C were neutropenia (26.9%, 22.1%, and 26.4%), leukopenia (10.3%, 2.6%, and 9.7%), thrombocytopenia (10.3%, 6.5%, and 2.8%), and diarrhea (9.0%, 6.5%, and 2.8%). AE-on treatment related deaths: 2 in arm A, 1 in B, and 1 in C.

Conclusions

The study met its primary endpoint of improved PFS in the ITT population in Arm A over Arm C. Safety data was similar to the known safety profile of abemaciclib.

Clinical trial identification

NCT02675231.

Editorial acknowledgement

Writing assistance was provided by Rachel Richardson.

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

S.M. Tolaney: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement: AstraZeneca; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement : Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement : Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement : Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Institutional Research Funds; honorarium; travel expense reimbursement: Genentech/Roche; Honoraria (self), Advisory / Consultancy, Honorarium; travel expense reimbursement: Immunomedics ; Research grant / Funding (institution), Institutional Research Funds : Exelixis; Research grant / Funding (institution), Institutional Research Funds : Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institutional Research Funds; honorarium; travel expense reimbursement: Eisai; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Institutional Research Funds; honorarium; travel expense reimbursement: Nanostring; Advisory / Consultancy, Honorarium; travel expense reimbursement : Puma; Research grant / Funding (institution), Institutional Research Funds: Cyclacel; Honoraria (self), Advisory / Consultancy, Honorarium: Sanofi; Honoraria (self), Advisory / Consultancy, Honorarium: Tesaro; Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses, Honorarium; travel expense reimbursement: Celldex . A.M. Wardley: Advisory / Consultancy, Speaker Bureau / Expert testimony, Sponsorship for meetings: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZenaca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Eli Lilly and Company; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Pfizer; Honoraria (self), Advisory / Consultancy: Pierre Fabre; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: NAPP; Honoraria (self), Advisory / Consultancy: ACCORD; Honoraria (self), Advisory / Consultancy: Athenex; Advisory / Consultancy: Gerson Lehman Group Guidepoint Global ; Advisory / Consultancy: Coleman Expert Network; Travel / Accommodation / Expenses, Sponsorship for meetings: Daiichi Sankyo; Officer / Board of Directors: Andrew Wardley LTD. J. Hilton: Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Officer / Board of Directors: BMS. T. Troso-Sandoval: Research grant / Funding (institution): Eli Lilly and Company. S. Im: Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy: Eisai; Advisory / Consultancy: Amgen; Advisory / Consultancy: Roche; Advisory / Consultancy: Hanmi. S. Kim: Research grant / Funding (institution): Norvartis; Research grant / Funding (institution): Sanofi-Genzyme; Research grant / Funding (institution): Dingkook Inc. S.R.D. Johnston: Advisory / Consultancy, Research grant / Funding (institution): Astrazeneca; Advisory / Consultancy: Eli Lilly and Company; Advisory / Consultancy, Speaker Bureau / Expert testimony: Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Puma Biotechnology; Speaker Bureau / Expert testimony: Eisai. S. Goel: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, Lab funding and Clinical trial research support : Eli Lilly and Company; Advisory / Consultancy, Research grant / Funding (institution), Clinical trial research support: Novartis; Advisory / Consultancy: G1 therapeutics. K. Catron: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. Z. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. C. Gainford: Shareholder / Stockholder / Stock options, Full / Part-time employment: Eli Lilly and Company. F. André: Research grant / Funding (institution): Eli Lilly and Company; Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: GlaxoSmithKline; Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Research grant / Funding (institution): Pfizer. All other authors have declared no conflicts of interest.