Background

Abemaciclib demonstrated a sustained benefit in invasive disease-free survival and a tolerable safety profile in monarchE at 42 months (mo) median follow-up (mFU). At 19 mo mFU, initial patient (pt)-reported outcome (PRO) findings supported a tolerable profile with most pts remaining on treatment (tx). With all pts now off abemaciclib, we report data including the full 2-year tx period and follow-up to evaluate long-term impact on PROs.

Methods

Pts completed PROs including FACT-B, FACT-ES, and FACIT-Fatigue at baseline, 3, 6, 12, 18, 24 mo, and 1, 6, 12 mo after tx discontinuation (dc). Mixed effects repeated measures model estimated changes from baseline within and between arms for summary scores and individual items. Meaningful change was defined as 0.5 standard deviation of baseline summary scores and 1 point for individual items. Additional analyses included frequencies of responses to items associated with adverse events (AEs; e.g., diarrhea, fatigue) and tx bother.

Results

For the 5591 treated pts, PRO completion rates were >90% on tx and ∼80% during follow-up. Within- and between-arms, differences in mean changes from baseline for all PROs were less than prespecified thresholds for meaningful difference, except for diarrhea, with worse scores in abemaciclib plus ET at 3 and 6 mo. During tx, most pts reported being bothered “a little bit” or “not at all” by side effects in both arms and most pts (79-85%) on abemaciclib reported “not at all” to “somewhat” for diarrhea (Table). During post-tx follow-up, PROs in both arms were similar to baseline, with ≥80% of pts on abemaciclib arm reporting “not at all” for diarrhea.Table: 93MO

Distribution of responses to key PRO items at selected assessments**

Conclusions

Adjuvant abemaciclib added to ET did not result in meaningful differences in PROs, except for diarrhea,which is considered clinically manageable. Long-term findings suggest reversibility of these effects after tx dc and can help inform pt risk/benefit assessment.

Clinical trial identification

NCT0315599.

Editorial acknowledgement

Medical writing support was provided by Trish Huynh (Eli Lilly and Company, IN, USA).

Legal entity responsible for the study

Eli Lilly and Company.

Funding

Eli Lilly and Company.

Disclosure

N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Seagen, Medscape, Art Tempi, Onkowissen, Gilead, Sanofi, Exact Sciences; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Roche, Sandoz-Hexal, Seagen, Aptitude Health, Gilead, Sanofi; Financial Interests, Personal, Other, Husband: WSG (Husband); Financial Interests, Personal, Ownership Interest: West German Study Group; Financial Interests, Institutional, Funding: AstraZeneca, BMS, Daiichi Sankyo, Lilly, MSD, Novartis, Pierre Fabre, Roche, Palleos, Seagen, TRIO, WSG; Non-Financial Interests, Member, Member German AGO Breast Guideline Committee: AGO Breast Committee; Non-Financial Interests, Member, Breast Cancer Educational Programs: ESO/ESCO; Other, Founding Editor: BreastCare Journal. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Sanofi, Merck Serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Personal, Expert Testimony: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, GlaxoSmithKline, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. J. Cruz Jurado: Financial Interests, Personal, Advisory Board: PharmaMar, Roche, Lilly, Pfizer, Novartis, Gilead, AstraZeneca, Daiichi, Seagen, GSK, Bayer; Financial Interests, Personal, Invited Speaker: PharmaMar, Roche, Lilly, Pfizer, Novartis, Eisai, Gilead, AstraZeneca, Daiichi, Seagen, Esteve, Roche. M. Takahashi: Financial Interests, Personal, Other: AstraZeneca, Eli Lilly and Company, Eisai, MSD, Daiichi Sankyo, Pfizer. C.H. Barrios: Financial Interests, Personal, Advisory Board, Consulting Scientific Presentations: GSK, Novartis, Pfizer, Roche, Eisai, Bayer, MSD, AstraZeneca, Zodiac, Lilly, Sanofi; Financial Interests, Personal, Advisory Board, Consultation: Boehringer; Financial Interests, Personal, Advisory Board, Scientific Presentations Consulting AD Board: Daiichi Sankyio; Financial Interests, Personal, Ownership Interest, Virtual APP: THUMMI; Financial Interests, Personal, Stocks/Shares, Clinical Research Company: Medsir; Financial Interests, Institutional, Research Grant, Research Funding To The Institution: Pfizer, Amgen, GSK, Lilly, Sanofi, Merk, Biomarin, BMS, Medivation, Exelixis, Merck KGAA, Shangai Henlius Biothech, Polyphor, PharmaMar; Financial Interests, Institutional, Research Grant, Research Funding to the institution steering Committee: Novartis, AstraZeneca, Daiichi; Financial Interests, Institutional, Research Grant, Research Funding to the institution steering committee: ROCHE; Financial Interests, Institutional, Invited Speaker, Research funding to the institution: Nektar, Regeneron, Janssen, OBI Pharma, Seagen, Checkpoint Therapeutics, Novocure, Aveo Oncology, Takeda, Celgene, TRIO, PPD, Syneos health, DOCS, Labcorp, IQIVIA, Parexel, Nuvisan, PSI, Medplace; Financial Interests, Institutional, Invited Speaker, Research funding to the institution Steering committee: Myovant; Non-Financial Interests, Invited Speaker, Member of Executive Board: BIG International Group; Non-Financial Interests, Leadership Role, Latin American Cooperative Oncology Group: LACOG; Non-Financial Interests, Other, Chair, International Educational Steering Group: ASCO; Non-Financial Interests, Advisory Role, Member Compliance Committee: ESMO. R.J. Wei: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. B. San Antonio: Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company; Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company. A.M. Liepa: Financial Interests, Personal, Full or part-time Employment: Eli Lilly and Company; Financial Interests, Personal, Stocks/Shares: Eli Lilly and Company. M. Martin Jimenez: Financial Interests, Personal, Advisory Board: AstraZeneca, Lilly, Roche/Genentech, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: Pfizer, AstraZeneca, Lilly, Novartis, Roche/Genentech; Financial Interests, Institutional, Research Grant: Novartis, Roche, Puma; Non-Financial Interests, Invited Speaker: TRIO; Non-Financial Interests, Leadership Role: GEICAM. S.R.D. Johnston: Financial Interests, Institutional, Research Grant, Research funding to institute for laboratory studies and clinical trials: Pfizer, Puma Biotechnology, Eli Lilly and Company, AstraZeneca, Novartis, Roche/Genentech; Financial Interests, Other, Consulting or advisory role: Eli Lilly and Company, AstraZeneca, Puma Biotechnology, Pfizer, Novartis, Sanofi Genzyme; Other, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Pfizer, Eisai, AstraZeneca, Roche/Genentech. S.M. Tolaney: Other, Institutional, Other, Funding for study: Eli Lilly and Company; Other, Personal, Other, Honorariums: Eli Lilly and Company; Financial Interests, Institutional, Research Grant: AstraZeneca, Merck , Nektar, Novartis, Pfizer, Genentech/Roche, Gilead, Exelixis, BMS, Eisai, Nanostring, Cyclacel, Sanofi, Seagen; Other, Personal, Advisory Board, Honorarium: AstraZeneca, Eli Lilly and Company, Merck, Novartis, Pfizer, Genentech/Roche, Gilead, BMS; Other, Personal, Advisory Board: Eisai, Sanofi, Seagen, Daiichi Sankyo, Athenex, OncoPep, Kyowa Kirin Pharma, Cytomx, Certara, Mersana Therapeutics, Ellipses Pharma, 4D Pharma, OncoSec, Infinity Therapeutics, BeyondSpring Pharma, OncXerna, Zymeworks, Zentalis, ARC Therapeutics, Reveal Genomics, Blueprint Medicines, Myovant, Umoja Biopharma, Menarini/Stemline. All other authors have declared no conflicts of interest.

Background

This study determines the prognostic and predictive effect of body mass index (BMI) on the disease-free survival (DFS) of postmenopausal hormone receptor-positive (HR+) breast cancer patients who received (extended) endocrine therapy.

Methods

Patients with a BMI of ≥18.5 kg/m² were identified from the randomised, phase III DATA trial (NCT00301457), which evaluated the use of six versus three years of anastrozole in postmenopausal women with HR+ breast cancer who were disease-free after two to three years of adjuvant tamoxifen. Patients were categorised as normal weight (18.5-24.9 kg/m²), overweight (25-29.9 kg/m²), or obese (≥30 kg/m²). The primary endpoint was DFS. Multivariable Cox regression analyses were performed. The prognostic impact of BMI was evaluated from date of randomisation, whereas the predictive impact of BMI on the efficacy of extended anastrozole was evaluated from three years after randomisation, i.e. treatment divergence (adapted DFS).

Results

Overall, 1,781 patients were included: 678 (38%) normal weight, 712 (40%) overweight, and 391 (22%) obese patients. After a median follow-up of 13.1 years, overweight and obese patients had a worse DFS when compared with normal weight patients (hazard ratio (HR)=1.16; 95% confidence interval (CI) 0.97-1.38, p=0.10; and HR=1.26; 95% CI 1.03-1.54, p=0.03, respectively). In women aged <60 years, overweight was associated with a worse DFS (HR=1.29; 95% CI 1.00-1.67, p=0.05) as was obesity (HR=1.83; 95% CI 1.36-2.46, p<0.001), but this was not observed in women aged ≥60 years (HR=1.04; 95% CI 0.82-1.33, p=0.72; and HR=0.94; 95% CI 0.72-1.23, p=0.63, respectively) (p-interaction = 0.009). The effect of extended anastrozole on adapted DFS did not differ between normal weight (HR=1.00; 95% CI 0.74-1.35, p=1.00), overweight (HR=0.74; 95% CI 0.56-0.98, p=0.04), and obese patients (HR=0.97; 95% CI 0.69-1.36, p=0.85) (p-interaction=0.24).

Conclusions

In HR+ breast cancer patients aged <60 years at randomisation, overweight and obesity were adverse prognostic factors for DFS. In patients aged ≥60 years, this adverse prognostic effect was not observed. The effect of extended anastrozole on adapted DFS did not differ between BMI classes.

Clinical trial identification

NCT00301457.

Legal entity responsible for the study

MUMC+.

Funding

AstraZeneca.

Disclosure

S.W.M. Lammers: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Eli Lilly. S.M.E. Geurts: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, Pfizer, Novartis, Eli Lilly, Daiichi Sankyo, Gilead; Financial Interests, Personal, Invited Speaker: AstraZeneca. A.C.P. Swinkels: Financial Interests, Institutional, Funding: AstraZeneca. C.H. Smorenburg: Financial Interests, Institutional, Leadership Role: Board of Dutch national breast cancer guidelines. J.R. Kroep: Financial Interests, Institutional, Advisory Board: AstraZeneca, MSD, Eisai, Eli Lilly, GSK; Financial Interests, Institutional, Invited Speaker: MSD; Financial Interests, Institutional, Research Grant: AstraZeneca. A.H. Honkoop: Financial Interests, Institutional, Research Grant: Dutch Breast Cancer Research Group; Financial Interests, Institutional, Advisory Board: Eli Lilly; Financial Interests, Personal, Other, Support to attend the ESMO 2022 congress: Pfizer. S.C. Linn: Financial Interests, Institutional, Research Grant: AstraZeneca, Eurocept Plaza, Roche, Genentech, Gilead Sciences, Tesaro, Novartis, Dutch Cancer Society, ZonMW, A Sister's Hope, [Z]aan de Wandel, Agendia; Financial Interests, Institutional, Other, Consulting fees: AstraZeneca, ERC (EU), NWO (Dutch Research Council); Financial Interests, Institutional, Other, Payment or honoraria: Daiichi Sankyo; Financial Interests, Institutional, Other, Support for attending meetings: ESMO, Daiichi Sankyo, ERC (EU), NWO (Dutch Research Council); Non-Financial Interests, Institutional, Product Samples, Drug: Genentech, Roche, Gilead Sciences, Novartis, AstraZeneca; Non-Financial Interests, Institutional, Product Samples, Gene expression tests: Agendia; Other, Institutional, Ownership Interest: Patent (UN23A01/P-EP) pending on a method for assessing homologous recombination deficiency in ovarian cancer cells; Other, Institutional, Leadership Role, Chair: Trial Steering Committee of the PIONEER trial (Cambridge University); Other, Institutional, Advisory Role, Member: Health Council of the Netherlands - Independent scientific advisory body for government and parliament. A.L.T. Imholz: Financial Interests, Institutional, Funding: AstraZeneca. M.M. Smidt: Financial Interests, Institutional, Research Grant: Dutch Cancer Society, Servier Pharma, Nutricia, Kankeronderzoekfonds Limburg, ZonMw, The Jules Coenegracht Foundation, Academische Alliantie, NWA-ORC, TKI. I.J.H. Vriens: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Research Grant: Pfizer, Eli Lilly. V.C.G. Tjan-Heijnen: Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Personal and Institutional, Research Grant: Novartis, Eli Lilly, AstraZeneca; Financial Interests, Institutional, Research Grant: Roche, Pfizer, Daiichi Sankyo, Gilead; Financial Interests, Personal, Advisory Role: AstraZeneca, Eli Lilly, Novartis. All other authors have declared no conflicts of interest.

Background

The present study investigated the long-term Quality of Life (QoL) and sexual health of premenopausal women, on average 9.5 (range 5-15) years after being diagnosed with a HR-positive breast cancer (BC) registered in the ABCSG 22 registry.

Methods

Between April 2008 and January 2022, ABCSG collected Patient Reported Outcome (PRO) data from a registry of premenopausal women with HR-positive BC receiving endocrine therapy with tamoxifen and goserelin for five years (± chemotherapy). After a median follow up of 9 (IQR 8-11) years, a cross-sectional PRO assessment targeting QoL, sexual health and fertility issues was conducted at 11 Austrian centres. PRO was assessed using the EORTC QLQ C30, QLQ-BR45, EORTC QLQ-SHQ22, SABIS, MENQOL and fertility questionnaire. All scores are presented descriptively. Differences between subgroups scores and between register scores and values from reference population were evaluated using MANOVA.

Results

Overall, 469 women were included; the median age was 46 years at BC diagnosis, 55 years at the time of the PRO assessment. 30% of the women had chemotherapy before the start of hormonal therapy. Compared to the general population, women with a history of BC have statistically significant worse score in the emotional and social functional scales of the EORTC C30 as well as more insomnia, constipation, and more financial difficulties. Interestingly, women with a history of BC reported better global health status than the general population (mean 76.9 vs 71.2). Women who had received prior chemotherapy had a statistically significant worse score in the cognitive (mean 80.6 vs 85.8) and social functioning (mean 73.6 vs 80.2) scales of the EORTC C30, more nausea/vomiting, as well as more financial problems compared to the women with endocrine therapy alone. Analyses regarding sexual health, MENQOL and fertility issues is currently ongoing and will also be presented at the meeting.

Conclusions

The long-term side effects of BC therapy and their impact on QoL in premenopausal women are persistent after 10 years of the diagnosis and most pronounced in women who had received additional chemotherapy.

Legal entity responsible for the study

ABCSG, Austrian Breast and Colorectal Cancer Study Group.

Funding

Has not received any funding.

Disclosure

V. Bjelic-Radisic: Non-Financial Interests, Principal Investigator, PI of the EORTC Follow Up 16-17 studyPI of EORTC QLQ BR Update study: EORTC. D. Egle: Financial Interests, Personal, Advisory Board: AstraZeneca, Gilead, Pfizer, Novartis, Lilly, Seagen, Pierre-Fabre, MSD; Financial Interests, Personal, Invited Speaker: Roche, Sirius Medical; Financial Interests, Personal, Expert Testimony: Daiichi Sankyo. F. Haslbauer: Financial Interests, Personal, Invited Speaker: Amgen, AbbVie, Gilead, BMS, Merck Serono; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Servier. F. Fitzal: Financial Interests, Personal, Other, Editor editor for Oncoplastic Surgery part I and II: Springer; Financial Interests, Personal, Other, Mentor: Comena; Financial Interests, Personal, Other, Travel support and scientific support: Roche, AstraZeneca, Pfizer, Myriad, Nanostring, Bondimed (Polytech, Integra), Lilly; Financial Interests, Personal, Advisory Board: Pfizer, AstraZeneca, Lilly, Roche. R. Greil: Financial Interests, Personal, Advisory Board: Celgene, Novartis, Roche, BMS, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead, Daiichi Sankyo, Sanofi; Financial Interests, Personal and Institutional, Funding: Celgene, Roche, Merck, Takeda, AstraZeneca Novartis, Amgen, BMS, MSD, Sandoz, AbbVie, Gilead, Daiichi Sankyo. M. Balic: Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Daiichi Sankyo, MSD, Pierre Fabre, Pfizer, Roche, Gilead; Financial Interests, Personal, Advisory Board: AstraZeneca, Daiichi Sankyo, Eli Lilly, Eli Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Gilead; Financial Interests, Personal and Institutional, Invited Speaker: AstraZeneca; Financial Interests, Personal, Invited Speaker, Steering Committee Member, Coordinating PI, Advisory role: Roche; Financial Interests, Institutional, Invited Speaker: Roche, Austrian Breast and Colorectal Cancer Study Group, MSD, Qiagen, Amgen, Pierre Fabre, Novartis, Pfizer, Gilead. R. Bartsch: Financial Interests, Personal, Invited Speaker: AstraZeneca, Seagen, Roche, Novartis, Eli Lilly, Pierre-Fabre, Daiichi, Gilead, MSD, Pfizer, Eisai, Gruenenthal; Financial Interests, Personal, Advisory Board: Daiichi, AstraZeneca, Roche, Novartis, Eli Lilly, Pierre-Fabre, MSD, Gilead, Seagen, Eisai, Gruenenthal; Financial Interests, Institutional, Funding, Investigator Initiated Trial: Daiichi; Financial Interests, Institutional, Invited Speaker, Drug support for investigator initiated trial: MSD. M.I. Gnant: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Novartis, Pierre Fabre; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, Eli Lilly, Menarini-Stemline; Financial Interests, Personal, Expert Testimony: Veracyte; Financial Interests, Invited Speaker: Pfizer; Other, Spouse is employed by Sandoz: Sandoz. All other authors have declared no conflicts of interest.

Background

In the phase III, randomized, open-label KEYNOTE-119 (NCT02555657) study, second- or third-line treatment with pembro monotherapy did not significantly improve OS vs single-agent chemo treatment of physician’s choice (TPC) in patients (pts) with mTNBC, although the pembro treatment effect increased with increasing PD-L1 enrichment. In this exploratory analysis, we evaluated the association of T-cell-inflamed gene expression profile (GEP) with clinical outcomes from KEYNOTE-119.

Methods

Pts with centrally confirmed mTNBC, ECOG PS ≤1, and 1-2 prior systemic treatments for metastatic breast cancer were randomized 1:1 to pembro 200 mg Q3W for up to 35 cycles or TPC (capecitabine, eribulin, gemcitabine, or vinorelbine) per local guidelines. Tumor RNA profiling was conducted on the RNA-seq platform (Illumina, San Diego, CA). Association of GEP with clinical outcomes was evaluated by logistic regression (best objective response [BOR] per RECIST v1.1) and Cox proportional hazards models (PFS and OS) with baseline adjustment for ECOG PS; 95% CIs for BOR were estimated using the Clopper and Pearson method.

Results

As of April 11, 2019, GEP data for 333 pts (pembro, n=177; TPC, n=156) were available for analysis. GEP was significantly associated with improved BOR, PFS, and OS in pts treated with pembro but not TPC (Table). HR for OS was 0.77 (95% CI, 0.58–1.04) in pts with GEP non-low (≥1^st tertile) and 1.72 (1.15–2.55) in pts with GEP low (<1^st tertile). No association was seen between BRCA/HRD status and treatment response.

Conclusions

These findings suggest a positive association between GEP and clinical outcomes in pts with mTNBC who are treated with pembro, with a more favorable treatment effect in the GEP-enriched population. Results may help inform future analyses of outcomes by biomarker status in this population.

Table: 190MO

Clinical trial identification

NCT02555657.

Editorial acknowledgement

Medical writing assistance was provided by Sonia Mohinta, PhD, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

J. Cortés: Financial Interests, Personal and Institutional, Other, Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Financial Interests, Personal, Other, Honoraria (self), Travel / Accommodation /Expenses: Novartis; Financial Interests, Personal, Other, Honoraria (self), Advisory /Consultancy: Celgene, Eisai; Financial Interests, Personal and Institutional, Other, Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Financial Interests, Personal, Other, Honoraria (self): Samsung; Financial Interests, Personal, Other, Advisory / Consultancy: Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Financial Interests, Personal, Other, Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Financial Interests, Institutional, Other, Research grant / Funding (institution): Ariad Pharmaceuticals, Baxalta, GMBH/Servier Affaires, Bayer Healthcare, F. Hoffman-La Roche, Guardanth Health, Merck Sharp & Dohme, Piqor Therapeutics, Puma C, Queen Mary University of London; Financial Interests, Personal, Other, Shareholder / Stockholder / Stock options: MedSIR. S. Im: Financial Interests, Personal, Other, Advisory / Consultancy, Research grant / Funding (self): AstraZeneca, Pfizer; Financial Interests, Personal, Other, Advisory / Consultancy: Amgen, Eisai, Hanmi, Ildong, MediPactor, Novartis, Roche. A. Gonçalves: Financial Interests, Institutional, Other, Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Novartis; Financial Interests, Institutional, Other, Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): MSD; Financial Interests, Institutional, Other, Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Financial Interests, Institutional, Other, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Roche; Financial Interests, Personal, Invited Speaker, Travel / Accommodation / Expenses: Celgene. K.S. Lee: Financial Interests, Personal, Invited Speaker, Advisory / Consultancy: Roche, Lilly, Pfizer, Novartis; Financial Interests, Personal and Institutional, Invited Speaker, Research grant / Funding (institution), (support of drug): Dong-A Pharm. P. Schmid: Financial Interests, Personal, Other, Honoraria (self), Advisory / Consultancy: Pfizer, Merck, BI, Bayer, Esai, Puma, Celgene; Financial Interests, Personal and Institutional, Other, Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AZ, Novartis, Roche; Financial Interests, Institutional, Other, Research grant / Funding (institution): Genentech, Oncogenex, Astellas; Financial Interests, Personal, Other, Spouse / Financial dependant, Spouse is a consultant for Genentech/Roche: Genentech/Roche. K. Tamura: Financial Interests, Personal and Institutional, Other, Advisory / Consultancy, Research grant / Funding (self), Research grant / Funding (institution): Pfizer, Cyugai, Eisai, Eli Lilly; Financial Interests, Personal and Institutional, Other, Research grant / Funding (self), Research grant / Funding (institution): Daiich-Sankyo, MSD, AstraZeneca, Ono, Kyowa Hakko, Novartis, Clovis, Sanofi; Financial Interests, Institutional, Other, Research grant / Funding (institution): Takeda, Bristol Myers Squibb, Boehringer Ingelheim, Taiho. L. Testa: Financial Interests, Institutional, Other, Advisory / Consultancy, Research grant / Funding (institution): Lilly, Novartis; Financial Interests, Institutional, Other, Research grant / Funding (institution): Roche; Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Libbs, Pfizer. S. Ohtani: Financial Interests, Institutional, Other, Honoraria (institution): Chugai, Eisai, Pfizer, AstraZeneca. N. Harbeck: Financial Interests, Personal, Other, Advisory / Consultancy: Agendia, Celgene, Genomic Health, Odonate, Sandoz/Hexal, Seattle Genetics; Financial Interests, Personal, Other, Advisory / Consultancy, Speaker Bureau / Expert testimony: AstraZeneca, Daiichi Sankyo, Lilly, MSD, Novartis, Pfizer, Roche; Financial Interests, Personal, Other, Speaker Bureau / Expert testimony: Amgen, Nanostring; Financial Interests, Personal, Other, Shareholder / Stockholder / Stock options, Spouse / Financial dependant, Codirector of West German Study Group (self): West German Study Group; Financial Interests, Personal, Other, Full / Part-time employment: LMU Munich. S. Loi: Financial Interests, Institutional, Other, Consulting or Advisory Role: Aduro Biotech, AstraZeneca/MedImmune, Bristol Myers Squibb, G1 Therapeutics, Merck Sharp & Dohme, Novartis, Pfizer, Roche/Genentech, and Seattle Genetics; Financial Interests, Institutional, Other, Research Funding: Bristol Myers Squibb, Eli Lilly, Merck, Novartis, Puma Biotechnology, Roche/Genentech, and Seattle Genetics. J. Lunceford, V. Karantza, J.A. Mejia, R. Cristescu, M. Nebozhyn, P. Jelinic, L. Huang: Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA. E.P. Winer: Financial Interests, Personal, Other, Advisory / Consultancy: Genentech, Lilly, Carrick Therapeutics, GSK, Seattle Genetics, LEAP. All other authors have declared no conflicts of interest.

Background

The recommended cut-off of <1% positive cells to define estrogen receptor (ER) negative status in breast cancer (BC) is highly debated. We compared the tumor immune microenvironment (TME) of HER2-neg BC according to ER status (ER-neg: 0% vs ER-low: 1-9%).

Methods

This multicentric study included patients with stage I-III HER2-neg BC from centers across Italy and France: Istituto Oncologico Veneto IOV; Montpellier Cancer Institute MCI; Istituto Nazionale Tumori Milano; Istituto Europeo di Oncologia. Tumor samples were reviewed for ER: ER-neg and ER-low pts were eligible, pts with ER intermediate expression (ER-int: 10-50%) were included in a control cohort. Tumor-infiltrating lymphocytes (TILs) were evaluated on full-face H&E slides. CD8, FOXP3 and PD-L1 (SP142) status was assessed by IHC and quantified by digital pathology in samples from IOV (full-face slides) and MCI (tissue-microarray).

Results

Of 753 pts included, 613 had ER-neg BC, 80 had ER-low BC, and 60 had ER-int disease. TME characterization in these tumor specimens is summarized in the table. TILs levels were similar in ER-neg and ER-low tumors, and in both subgroups significantly higher than in ER-int samples. Compared to ER-neg, ER-low BC had significantly higher levels of CD8+ and FOXP3+ cells, with a similar CD8/FOXP3 ratio. The rate of PD-L1 -positive tumors was similar between ER-neg and ER-low BC pts. At the validated ≥30% cut-off, higher TILs were associated with better relapse-free survival in ER-neg (5-yr rates: 89% vs 71%, p<0.001) and ER-low BC pts (93% vs 58%, p=0.047), but not in the ER-int group, where we found an opposite trend (43% vs 69%, p=0.114). Table: 1MO

Table: 1MO

Conclusions

TME composition is similar in ER-neg vs ER-low HER2-neg BC tumors and TILs have a similar prognostic role in these cohorts. Our results support the claim that HER2-neg/ER-low BC pts should be granted access to drugs developed for triple-negative BC, including immune checkpoint inhibitors. Gene expression analysis will be presented at the meeting.

Legal entity responsible for the study

The authors.

Funding

Funding from Merck KGaA, Darmstadt, Germany and Institutional funding from Istituto Oncologico Veneto - Ricerca Corrente.

Disclosure

D. Massa: Financial Interests, Personal, Sponsor/Funding, Travel Support: Eli Lilly. C. Vernieri: Financial Interests, Personal, Advisory Role: Novartis, Daiichi Sankyo, Pfizer; Financial Interests, Personal, Invited Speaker: Novartis, Eli Lilly, Istituto Gentili; Financial Interests, Personal, Research Grant: Roche; Financial Interests, Personal, Other, Travel Grant: Novartis, Daiichi Sankyo, Pfizer, Eli Lilly, Istituto Gentili. C. Criscitiello: Financial Interests, Personal, Invited Speaker: Pfizer, Novartis, Eli Lilly, Roche, Gilead; Financial Interests, Personal, Advisory Board: MSD, Seagen, AstraZeneca, Daiichi Sankyo. G. Griguolo: Financial Interests, Personal, Advisory Board: Gilead; Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis; Financial Interests, Personal, Other, Travel Support: Gilead, Eli Lilly, Pfizer, Novartis, Daiichi Sankyo, Amgen. F. Miglietta: Financial Interests, Personal, Sponsor/Funding: Roche, Novartis, Gilead. A. Vingiani: Financial Interests, Personal, Invited Speaker: Roche, Eli Lilly. R. Lobefaro: Financial Interests, Personal, Advisory Role: Pfizer, Lilly, Daiichi Sankyo, AstraZeneca. G. Pruneri: Financial Interests, Personal, Advisory Board: ADS Biotec; Financial Interests, Personal, Other, Honoraria: Exact Sciences, Novartis, Eli Lilly, AstraZeneca; Financial Interests, Personal, Research Grant: Roche. M. Fassan: Financial Interests, Personal, Advisory Role: Astellas Pharma, Pierre Fabre, MSD, AstraZeneca, Janssen, GlaxoSmithKline, Amgen, Novartis , Roche; Financial Interests, Personal, Research Grant: Astellas Pharma, QED Therapeutics, Diaceutics and Macrophage Pharma. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Officer, ESMO Clinical Practice Guidelines Chair: ESMO. V. Guarneri: Financial Interests, Personal, Invited Speaker: Eli Lilly, Novartis, Amgen, GSK; Financial Interests, Personal, Advisory Board: Eli Lilly, Novartis, MSD, Gilead, Sanofi, Merck Serono, Exact Sciences, Eisai, Olema Oncology; Financial Interests, Personal, Expert Testimony: Eli Lilly; Financial Interests, Institutional, Invited Speaker: Eli Lilly, Roche, BMS, Novartis, AstraZeneca, MSD, Synton Biopharmaceuticals, Merck, Glaxo Smith Kline, Daiichi Sankyo, Nerviano; Non-Financial Interests, Member: ASCO. W. Jacot: Financial Interests, Personal, Advisory Board: AstraZeneca, Eisai, Novartis, Roche, Pfizer, Eli Lilly, MSD, BMS, Chugai, Seagen, Daiichi Sankyo; Financial Interests, Personal, Invited Speaker: AstraZeneca, Pfizer, Seagen, Daiichi Sankyo; Financial Interests, Institutional, Research Grant: AstraZeneca, Daiichi Sankyo; Financial Interests, Invited Speaker: Roche, Novartis, Daiichi Sankyo, Daiichi Sankyo. M.V. Dieci: Financial Interests, Personal, Advisory Role: Eli Lilly, Pfizer, Novartis, Seagen, Gilead, MSD, Exact Sciences, AstraZeneca, Roche, Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

IC markers against which inhibitors are currently used/evaluated clinically, have not yet been studied in detail in metastases (M) from patients with primary HR+/HER2- BC. In this study, we examined expression levels of these IC markers in multiple M and primary tumors (P) from primary HR+/HER2- BC patients who enrolled in our postmortem tissue donation program UPTIDER (NCT04531696).

Methods

326 samples (23 untreated P and 290 postmortem M samples) from 10 UPTIDER patients with primary HR+/HER2- BC underwent bulk RNA sequencing (Lexogen). Quality control (QC) was set for 500000 assigned reads and gene counts were normalized using variance stabilizing transformation. We selected IC markers being clinically investigated in BC (BTLA, CD40, CD47, CD86, CD137, CD137L, CD158A, CD226, CTLA4, ICOS, LAG3, OX40, PD-1, PD-L1, TIM3, TIGIT) from literature and clinicaltrials.gov. Available matched FFPE samples were evaluated for histology (invasive lobular, ILC, and BC of no special type, NST) and ER-status. Associations between sample status (outcome: M vs P/ ER+ vs ER- for M) and individual gene expression were assessed by logistic linear regressions with data clustering by patient using the generalized estimating equation method. We studied the association between sample specific postmortem interval (ssPMI) and gene expression by repeated sampling (at 1.5h intervals) of the same M in 7 patients.

Results

324/326 samples passed QC (289 M and 22 P) and the IC expression was stable with increasing ssPMI. TIM3was highly expressed, and PD-1 was among the least expressed in M. Intra-patient inter-M heterogeneity was observed for all markers. M showed lower expression of PD-1, PD-L1, CTLA4, LAG3, OX40 and TIGIT (Odds ratio (OR) range: 0.27-0.53, p<0.05) and higher expression of TIM3 and BTLA (OR range:1.37-6.19, p<0.05) compared to P. BTLA, CD86, CTLA4, OX40 and TIM3 were more expressed in NST M compared to ILC M (OR range: 1-1.43). PD-L1, CD47, LAG3, CD40 and TIGIT were found more expressed in ER+ vs ER- M in both NST and ILC (OR NST: 1.02-1.37, OR ILC: 1.12-5.52).

Conclusions

This study sheds light on the expression of IC markers in M from patients with HR+/HER2- primary BC as well as on the impact of histology and ER-expression.

Clinical trial identification

NCT04531696.

Legal entity responsible for the study

Laboratory for Translational Breast Cancer Research.

Funding

KU Leuven, Leuven, Belgium.

Disclosure

K. Punie: Financial Interests, Institutional, Advisory Board: AstraZeneca, Novartis, Roche, Vifor Pharma, Eli Lilly, Pierre Fabre, McCann Health, Roularta, Teva, Gilead Sciences, Pfizer, Gilead, MSD; Financial Interests, Institutional, Invited Speaker: Pfizer, Roche, Novartis, Eli Lilly, Mundi Pharma, MSD, Medscape, MSD; Financial Interests, Institutional, Other, Consultancy: Roche; Financial Interests, Personal, Other, Consultancy: Gilead, Novartis, MSD, Roche; Financial Interests, Personal, Invited Speaker: AstraZeneca, Sanofi; Financial Interests, Personal, Advisory Board: Seagen; Financial Interests, Institutional, Funding: Sanofi; Non-Financial Interests, Principal Investigator: EORTC 1745-ETF-BCG trial; Non-Financial Interests, Other, Committee member: ESMO Young Oncologists Committee; Non-Financial Interests, Invited Speaker: BSMO; Non-Financial Interests, Other, Committee Member: ESMO Resilience Task Force; Non-Financial Interests, Advisory Role: Commission Personalized Medecine Federal Government Belgium; Non-Financial Interests, Advisory Role, External Scientific Advisor: European Medicine Agency. H. Wildiers: Financial Interests, Institutional, Advisory Board: Roche, Lilly, AstraZeneca, Daiichi Sankyo, PSI Cro AG, KCE, MSD, MSD, E Squared Communications LLC; Financial Interests, Institutional, Invited Speaker: Eisai, AstraZeneca; Financial Interests, Institutional, Other, Consultancy fee: AbbVie, Immutep Pty; Financial Interests, Institutional, Expert Testimony: Daiichi Sankyo; Financial Interests, Institutional, Other, Consultancy: Daiichi Sankyo; Financial Interests, Institutional, Research Grant, Grant to the Leuven Breast Center to support the research database: Roche; Financial Interests, Institutional, Research Grant, Grant to institute to perform a multicentric national academic trial: Novartis; Other, Travel & accomodations: Pfizer; Other, Travel & accomodation: Roche; Other, Subscription fee: Gilead. G. Floris: Financial Interests, Institutional, Advisory Board: AstraZeneca. All other authors have declared no conflicts of interest.

Background

In the phase III KEYNOTE-355 study (NCT02819518), first-line treatment with pembro + chemo resulted in statistically significant and clinically meaningful improvements in PFS and OS versus placebo + chemo in patients (pts) with advanced TNBC with PD-L1 combined positive score (CPS) ≥10. We report efficacy outcomes from the KEYNOTE-355 final analysis for pts who had disease control and discontinued chemo before pembro and for pts who experienced immune-mediated AEs.

Methods

Pts with untreated locally recurrent inoperable or metastatic TNBC were randomized 2:1 to pembro (200 mg Q3W) or placebo for 35 cycles in combination with chemo (nab-paclitaxel, paclitaxel, or gemcitabine/carboplatin). Treatment continued until progression, intolerable toxicity, or (for pembro/placebo) completion of 35 cycles; pts could discontinue chemo independently of pembro/placebo (and vice versa). In this analysis, PFS per RECIST v1.1 by BICR and OS were evaluated in (a) pts who received pembro + chemo, achieved a best objective response of CR, PR, or SD lasting ≥24 wk, and received their last dose of chemo >21 days before their last dose of pembro, and (b) pts who received pembro + chemo and experienced ≥1 immune-mediated AEs (per a list of preferred terms compiled from the CTCAE v4.0).

Results

Pts were randomized to pembro + chemo (n=566) or placebo + chemo (n=281). At data cutoff (June 15, 2021), 317 pts in the pembro + chemo group had CR, PR, or SD ≥24 wk. Among these pts, discontinutation of chemo before pembro was associated with similar efficacy to that in the overall population, irrespective of tumor PD-L1 CPS (Table). Similarly, there was evidence of antitumor activity in pts who had immune-mediated AEs, overall and by tumor PD-L1 CPS (Table).

Conclusions

In this analysis of outcomes among pts who received pembro + chemo in the KEYNOTE-355 study, there was evidence for efficacy of pembro + chemo regardless of discontinuation of chemo before pembro or occurrence of immune-mediated AEs.

Table: 191MO

Clinical trial identification

NCT02819518.

Editorial acknowledgement

Medical writing assistance was provided by Sonia Mohinta, PhD, of ICON plc (Blue Bell, PA, USA). This assistance was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Funding

Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.

Disclosure

H.S. Rugo: Financial Interests, Institutional, Research Grant: Pfizer, Novartis, Lilly, Roche/Genentech, Macrogenics, OBI, Merck, Eisai, Immunomedics, Daiichi Sankyo, Seattle Genetics, and Odonate; Financial Interests, Personal, Other, Consultant: Samsung and Puma; Financial Interests, Personal, Speaker’s Bureau: Daiichi Sankyo, Mylan, Pfizer, Merck, AstraZeneca, Novartis, and Macrogenics. D.W. Cescon: Financial Interests, Personal, Advisory Role: AstraZeneca, Exact Sciences, Eisai, Gilead, GlaxoSmithKline, Merck, Novartis, Pfizer and Roche; Financial Interests, Institutional, Funding: GlaxoSmithKline, Inivata, Merck, Pfizer and Roche; Financial Interests, Personal, Other, member of a trial steering committee: AstraZeneca, Merck and GlaxoSmithKline. S. Im: Financial Interests, Personal, Other, Advisory / Consultancy, Research grant / Funding (self): AstraZeneca, Pfizer; Financial Interests, Personal, Other, Advisory / Consultancy: Amgen, Eisai, Hanmi, Ildong, MediPactor, Novartis, Roche. M. Md Yusof: Financial Interests, Personal, Other, Received honoraria: AstraZeneca, Bayer, Boehringer Ingelheim, Merck, MSD, Specialised Therapeutics, Zuellig Pharma, Novartis, Pfizer, Roche, Eisai, Celgene; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Arcus, Genentech, Mundi Pharma, Novartis, Pfizer, Roche. C.E. Gallardo Araneda: Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Speaker’s Bureau: Bristol Myers Squibb; Financial Interests, Personal, Funding: Novartis pharma SAS; Roche; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: MSD; Roche. C.H. Barrios: Financial Interests, Personal, Advisory Role: Boehringer Ingelheim; Eisai Europe Ltd.; GlaxoSmithKline; Novartis pharma SAS; Pfizer Pharmaceuticals Israel; Roche/Genentech; Financial Interests, Personal, Funding: AB Science; Abraxis BioScience; Amgen; Asana Biosciences; Astellas Pharma; AstraZeneca; Biomarin; Boehringer Ingelheim; Bristol Myers Squibb; Daiichi Sankyo; Exelixis; GlaxoSmithKline; ImClone Systems; Investigator in AbbVie-sponsored cl. trials; LEO Phar. N. Turner: Financial Interests, Personal, Other, Received honoraria: Pfizer Inc.; Financial Interests, Personal, Advisory Role: Pfizer Inc.; Financial Interests, Personal, Funding: Servier, Pfizer Inc., Eil Lilly, Roche, and AstraZeneca. V. Karantza, W. Pan, Z. Guo: Financial Interests, Personal, Full or part-time Employment: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc., Rahway, NJ, USA. J. Cortés: Financial Interests, Personal, Other, Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Financial Interests, Personal, Other, Honoraria (self), Travel / Accommodation /Expenses: Novartis; Financial Interests, Personal, Other, Honoraria (self), Advisory / Consultancy: Celgene; Financial Interests, Personal, Other, Honoraria (self), Advisory /Consultancy: Eisai; Financial Interests, Personal, Other, Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Financial Interests, Personal, Other, Honoraria (self): Samsung; Financial Interests, Personal, Other, Advisory / Consultancy: Cellestia, Biothera Pharmaceutical, Merus, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex; Financial Interests, Institutional, Other, Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Financial Interests, Institutional, Other, Research grant / Funding (institution): Ariad Pharmaceuticals, Baxalta, GMBH/Servier Affaires, Bayer Healthcare, F. Hoffman-La Roche, Guardanth Health, Merck Sharp & Dohme, Piqor Therapeutics, Puma C, Queen Mary University of London; Financial Interests, Personal, Other, Shareholder / Stockholder / Stock options: MedSIR. All other authors have declared no conflicts of interest.