Background

The predictive value of tumor mutatio1nal burden (TMB), alone or in combination with an immune gene expression profile (GEP), for response to neoadjuvant therapy in early triple negative breast cancer (TNBC) is currently not known, neither for immune checkpoint blockade (ICB) nor conventional chemotherapy.

Methods

We obtained both whole exome sequencing and RNA-Seq data from pre-treatment samples of 149 TNBC of the recent neoadjuvant ICB trial GeparNuevo. In a predefined analysis we assessed the predictive value of TMB and a previously developed immune GEP for pathological complete remission (pCR).

Results

Median TMB was 1.52 mut/Mb (range 0.02-7.65) and was significantly higher in patients with pCR (median 1.87 vs. 1.39; P=0.005). In multivariate analysis odds ratios for pCR per mut/Mb were 2.06 (95% CI 1.33-3.20, P=0.001) among all patients, 1.77 (95% CI 1.00-3.13, P=0.049) in the durvalumab treatment arm, and 2.82 (95% CI 1.21-6.54, P=0.016) in the placebo treatment arm, respectively. We also found that both continuous TMB and immune GEP (or tumor infiltrating lymphocytes) independently predicted pCR. When we stratified patients in groups based on the upper tertile of TMB and median GEP, we observed a pCR rate of 82% (95% CI 60%-95%) in the group with both high TMB and GEP, in contrast to only 28% (95% CI 16%-43%) in the group with both low TMB and GEP.

Conclusions

TMB and immune gene expression profile add independent value for pCR prediction. Our results recommend further analysis of TMB in combination with immune parameters to individually tailor therapies in breast cancer.

Clinical trial identification

NCT02685059.

Legal entity responsible for the study

The authors.

Funding

H.W. & J. Hector-Stiftung.

Disclosure

C. Denkert: Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honoraria (self): Amgen; Honoraria (self): MSD; Honoraria (self): Celgene; Honoraria (self): AstraZeneca; Shareholder/Stockholder/Stock options: Sividon Diagnostics. K.E. Weber: Shareholder/Stockholder/Stock options, Licensing/Royalties: Sividon Diagnostics. C. Hanusch: Honoraria (self): Roche; Honoraria (self): Novartis; Honoraria (self): Lilly; Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Pfizer. B. Higgs: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. J. Huober: Honoraria (self), Research grant/Funding (self): Celgene; Honoraria (self), Research grant/Funding (self): Novartis; Honoraria (self), Research grant/Funding (self): Hexal; Honoraria (self): Lilly; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): MSD; Honoraria (self): Eisai; Honoraria (self): AbbVie; Honoraria (self): Daiichi. J-U. Blohmer: Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Honoraria (self): MSD Oncology; Honoraria (self): Myriad Genetics; Honoraria (self): Novartis/Pfizer; Honoraria (self): Roche; Honoraria (self): Sonoscape. W.D. Schmitt: Honoraria (self): AstraZeneca. S. Wu: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. M. van Mackelenbergh: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Genomic Health; Non-remunerated activity/ies: Novartis; Non-remunerated activity/ies: Lilly. C. Jackisch: Honoraria (self): Roche; Honoraria (self): Celgene. M. Untch: Honoraria (institution), Non-remunerated activity/ies: AbbVie; Honoraria (institution), Non-remunerated activity/ies: Amgen; Honoraria (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution): BMS; Honoraria (institution), Non-remunerated activity/ies: Celgene GmbH; Honoraria (institution), Non-remunerated activity/ies: Daiji Sankyo; Honoraria (institution), Non-remunerated activity/ies: Eisai GmbH; Honoraria (institution): Lilly Deutschland; Honoraria (institution), Non-remunerated activity/ies: Lilly Int.; Honoraria (institution), Non-remunerated activity/ies: MSD Merck; Honoraria (institution), Non-remunerated activity/ies: Mundipharma; Honoraria (institution), Non-remunerated activity/ies: Myriad Genetics; Honoraria (self), Non-remunerated activity/ies: Odonate; Honoraria (institution), Non-remunerated activity/ies: Pfizer GmbH; Honoraria (self): Puma; Honoraria (institution), Non-remunerated activity/ies: Roche Pharma AG; Honoraria (institution): Sanofi Aventis; Honoraria (institution), Non-remunerated activity/ies: Teva; Honoraria (institution), Non-remunerated activity/ies: Novartis; Honoraria (institution): Pierre Fabre. A. Schneeweiss: Honoraria (self), Research grant/Funding (self): Roche; Honoraria (self): Celgene; Honoraria (self): Pfizer; Honoraria (self): AstraZeneca; Honoraria (self): Novartis; Honoraria (self): MSD; Honoraria (self): Tesaro; Honoraria (self): Lilly. S. Loibl: Honoraria (institution), Research grant/Funding (institution), Non-remunerated activity/ies: AstraZeneca; Honoraria (institution), Research grant/Funding (institution), Non-remunerated activity/ies: Celgene; Honoraria (institution), Research grant/Funding (institution): AbbVie; Honoraria (institution), Research grant/Funding (institution): Amgen; Honoraria (institution), Research grant/Funding (institution): Novartis; Honoraria (institution), Research grant/Funding (institution): Pfizer; Honoraria (institution), Research grant/Funding (institution): Roche; Honoraria (institution): Seattle Genetics; Honoraria (institution): PriME/Medscape; Honoraria (self): Chugai; Research grant/Funding (institution): Teva; Research grant/Funding (institution): Vifor; Honoraria (institution), Research grant/Funding (institution): Daiichi-Sankyo; Honoraria (institution): Lilly; Honoraria (institution): Samsung; Honoraria (institution): Eirgenix. All other authors have declared no conflicts of interest.

Background

PD(L)1 inhibitor have shown efficacy for limited sub population of patients (pts) with HER2 negative metastatic breast cancer (MBC). The main predictive marker of efficacy to date are the absence of ER and PR receptor, and pdl1 positivity by IHC. We investigated copy number alteration (CNA) of the PDL1 gene (also named CD274) located at 9p24.1 in the SAFIR02 Breast Immuno randomized phase II trial (NCT02299999).

Methods

SAFIR02 BREAST IMMUNO randomized 199 pts presenting a MBC without actionable genomic alterations, responding to 6 months standard chemotherapy, either on durvalumab (10 Mg/kg every two weeks) or on maintenance chemotherapy with a 2:1 ratio. Eighty-two (43%) pts had a triple negative (TN) MBC. Using metastatic tumor samples, PDL1 CNA were characterized from array CGH analysis (Affymetrix CytoscanHD or Oncoscan). A gain of copy number was defined as 3–4 copies and an amplification ≥ 5 copies. Treatment effect was estimated in each subgroup using a cox proportional hazard model.

Results

For PDL1 CNA were available for 153 pts (101 immuno, 52 chemotherapy). PDL1 copy loss, neutral, or copy gain/amplification were reported on 30 (20%), 93 (61%) and 30 (20%) of pts, respectively. Pts with TN MBC had a higher proportion of gain/amplification (23/65 pts, 35% for TN tumors; vs 7/82, 8.5% for non-TN). Improvement of OS with durvalumab was limited to the PDL1 CNA gain/amplification subgroup (HR = 0.17, 95% CI 0.05-0.55) with a median OS of 9 months (95%CI 4-18) in maintenance arm and not reached in durvalumab arm. Among pts with TN tumors, durvalumab was associated to a better OS in the gain/amplification subgroup (HR 0.18, 95%CI 0.05-0.71 ), compared to the neutral/loss subgroup (HR 1.1, 95%CI 0.47-2.6 ).

Conclusions

This exploratory subgroups analysis of the first randomized trial comparing a PDL1 inhibitor to chemotherapy in the maintenance setting shows that PDL1 CNA could be an important predictive marker for PD(L)1 inhibitors efficacy. If confirmed on larger series, it could have an important implication on the development of immunotherapy for MBC pts, in particular for subgroups with low immunogenicity such as the luminal subtype.

Clinical trial identification

NCT02299999; 2013-001652-36.

Editorial acknowledgement

This research was conducted with support from an "Investigator Sponsored Study¨Programme by AstraZeneca".

This research was conducted with support from Fondation ARC.

Legal entity responsible for the study

Unicancer.

Funding

Fondation ARC, AstraZeneca.

Disclosure

T. Bachelot: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Seattle Genetic; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca. F. Dalenc: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Eisai; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca. F. André: Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Lilly; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution), Travel/Accommodation/Expenses: Daiichi Sankyo; Leadership role, Founder: Pegacsy. All other authors have declared no conflicts of interest.

Background

ET plus RIB (CDK4/6 inhibitor) or ALP (PI3Kα inhibitor) provides consistent improvement in progression-free survival (PFS) and/or overall survival compared to ET alone. LSZ102 (LSZ), an oral SERD, demonstrated synergistic activity with RIB and ALP in preclinical models of ER+ BC. Here, we describe the dose escalation data from phase 1/1b, open-label study of single agent LSZ (arm A), and LSZ+RIB (arm B) or LSZ+ALP (arm C).

Methods

Study enrolled pre/post-menopausal patients (pts) (≥18 yrs; ECOG PS ≤1) with histologically confirmed ER+ BC who had progressed after ET for advanced disease or had a recurrence while on, or within 12 months (mo) from the end of adjuvant therapy. Prior PI3K, mTOR or AKT inhibitors were not allowed in arm C. The primary objective was to characterize safety and tolerability of LSZ alone or in combination with RIB or ALP and identify recommended dose(s) for expansion (RDE). Secondary objectives included preliminary antitumor activity and PK/PD properties of LSZ alone and combinations.

Results

Safety data are shown in the table. The RDEs were determined to be: 450 mg QD LSZ ± 400 mg QD RIB and 300 mg LSZ QD with 250 mg QD ALP. Overall response rate [CR or PR] and median PFS were: 1.3% and 1.8 mo (1.7-2.0), 15.8% and 6.2 mo (4.4-6.4), 5.4% and 3.5 mo (1.8-5.5) for Arm A, B and C, respectively. Paired biopsies showed downregulation of ER upon treatment (tx) with LSZ or in combination. cfDNA analysis across all arms identified commonly observed genetic alterations, and longitudinal analysis showed that ESR1 Y537S mutations were not enriched after tx. Table: LBA1

Safety data

Conclusions

LSZ plus RIB or ALP showed manageable safety and encouraging clinical activity in heavily pre-treated ER+ BC pts, regardless of ESR1 and PIK3CA mutations. This is the first report of an oral SERD in combination with both CDK4/6 and PI3Kα inhibitors.

Clinical trial identification

NCT02734615.

Editorial acknowledgement

Avinash Yerramsetti (Novartis Healthcare Pvt. Ltd.) for medical editorial assistance with this abstract.

Legal entity responsible for the study

Novartis Pharmaceuticals

Funding

Novartis Pharmaceuticals

Disclosure

K. Jhaveri: Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Spectrum pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution): ADC Therapeutics; Advisory/Consultancy, Research grant/Funding (institution): Pfizer; Advisory/Consultancy: BMS; Advisory/Consultancy: Jounce Therapeutics; Advisory/Consultancy: Taiho Oncology; Advisory/Consultancy: Synthon; Advisory/Consultancy: Lily Pharmaceuticals; Research grant/Funding (institution): Clovis Oncology; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): Debio Pharmaceuticals; Research grant/Funding (institution): Zymeworks. D. Juric: Advisory/Consultancy, Research grant/Funding (institution): Genentech; Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy, Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): EMD Serono; Advisory/Consultancy: Ipsen; Research grant/Funding (institution): Celgene; Research grant/Funding (institution): Placon Therapeutics; Research grant/Funding (institution): Syros; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Takeda. Y. Yap: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Novartis; Advisory/Consultancy: Pfizer; Travel/Accommodation/Expenses: Eisai; Travel/Accommodation/Expenses: Astra Zeneca; Advisory/Consultancy: Roche. R.M. Layman: Research grant/Funding (institution): Novartis. F.P. Duhoux: Advisory/Consultancy, Research grant/Funding (institution), Consulting fees paid to my institution: Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses, Consulting fees paid to my institution: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses, Consulting fees paid to my institution: Pfizer; Advisory/Consultancy, Consulting fees paid to my institution: AstraZeneca; Advisory/Consultancy, Consulting fees paid to my institution: Lilly; Advisory/Consultancy, Travel/Accommodation/Expenses, Consulting fees paid to my institution: Amgen; Travel/Accommodation/Expenses: Teva. S. De Vita: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. N. Kundamal: Shareholder/Stockholder/Stock options, Full/Part-time employment: Novartis. W. He: Full/Part-time employment: Novartis. A. Balbin: Full/Part-time employment: Novartis. Q. Sheng: Full/Part-time employment: Novartis. G. Curigliano: Advisory/Consultancy: Merck; Advisory/Consultancy: Pfizer; Research grant/Funding (institution): Astra Zeneca; Speaker Bureau/Expert testimony: Daichi Sankyo; Speaker Bureau/Expert testimony: Roche.