Novel biomarkers predict benefit with immunotherapy in metastatic breast cancer

Lugano, Switzerland, 22 May 2020 - Two novel biomarkers have been found to correlate with improved outcomes with immunotherapy in metastatic breast cancer and may help to identify the patients most likely to benefit from this treatment, according to exploratory studies reported at the ESMO Breast Cancer Virtual Meeting 2020 (1,2). The biomarkers are an increase in the number of programmed death ligand-1 (PDL1/CD274) genes measured by copy number alteration (CNA) and the PD-L1 combined positive score (CPS), which assesses PD-L1 expression on both tumour and immune cells.

"Metastatic breast cancer remains incurable, with many unmet needs and challenges. Triple negative breast cancer has the poorest prognosis among breast cancer subtypes and limited treatment options, mainly involving chemotherapy," said Prof. Sherene Loi, Medical Oncologist and Head of Translational Breast Cancer Genomics and Therapeutics at the Peter MacCallum Cancer Centre, Melbourne, Australia, commenting on the relevance of the new studies. "Immunotherapy has resulted in long durations of disease control and even cures with improved quality of life compared with chemotherapy in other cancers. We are hoping this might also be applicable for some breast cancer patients".

"Previous studies show that not all patients with metastatic breast cancer benefit from immunotherapy. Pre-existing immunity, which can be detected by PD-L1 expression, is required for response to PD-1 or PD-L1 targeting immunotherapy agents. The key question is whether we can identify further patients with metastatic breast cancer that respond to immunotherapy using biomarkers other than just PD-L1 expression."

To explore new potential biomarkers for immunotherapy in advanced breast cancer, researchers assessed the predictive value of copy number alteration (CNA) for the PDL1 gene, which measures whether the gene number has decreased, remained the same (2 copies, one on each chromosome) or increased. (1) They measured CNA values in tumour tissue collected from 126 patients with metastatic breast cancer taking part in the SAFIR-IMMUNO study, the first randomised trial comparing immunotherapy with durvalumab to maintenance chemotherapy in this setting.

"The main predictive markers of immunotherapy efficacy in metastatic breast cancer to date are the absence of hormone receptors and PD-L1 positivity on immune cells," said lead author Prof. Thomas Bachelot, Director of the Breast Cancer Unit, Leon Berard Centre, Lyon, France. But he warned, "Immunohistochemistry analysis of PDL1 expression is not standardised and a more robust predictor of response to immunotherapy is needed."

Results showed that nearly one in four (23.8%) of the patients had copy gain (3 or 4 copies) or amplification (> 4 copies) of the PDL1 gene. Improvement of overall survival with durvalumab was limited to this group, with a median overall survival of 9 months (95% confidence interval [CI] 4-18) in the chemotherapy arm and not reached in the durvalumab arm (hazard ratio 0.17, 95% CI 0.05-0.55).

"This exploratory translational analysis suggested a higher efficacy of durvalumab as maintenance treatment for patients with PDL1 copy gain or amplification," said Bachelot. He suggested: "PDL1 copy number alteration could be an important predictive marker for PD-L1 inhibitor efficacy. If confirmed in larger series, this could have important implications for the development of immunotherapy in patients with metastatic breast cancer, enabling us to better identify patients that are sensitive to PD-L1 inhibitors than current testing for PD-L1 positivity on immune cells."

"At the moment patients with ER-positive breast cancer are not treated with immunotherapy because results of trials were poor. But maybe if we can select the subpopulation that will benefit - the 10% of patients with CNA abnormalities - and show immunotherapy is beneficial for them too, then this would be important," he explained.

Commenting on the potential relevance of the data, Loi said, "The study suggests that PD-L1 amplification may be a predictor for benefit to durvalumab monotherapy, interestingly in all subtypes as well as in triple negative breast cancer." But she cautioned, "It was an unplanned, retrospective analysis so requires further validation in larger studies. There was no analysis presented of whether PD-L1 amplification was associated with overexpression at the protein level, which would be important to understand the underlying biological mechanism of this observation."

Improved health-related quality of life

A second study looked at health-related quality of life (HRQOL) in patients with metastatic triple negative breast cancer randomised to the PD-L1 inhibitor pembrolizumab or chemotherapy in the KEYNOTE-119 trial. (2) Efficacy results for the trial showed no significant difference in overall survival (3) but this analysis described patient reported outcomes for patients by their PD-L1 combined positive score (CPS). CPS is a novel biomarker that assesses PD-L1 expression on both tumour cells and immune cells in contrast to PD-L1 tumour proportion score (TPS), which has been used as a biomarker for immunotherapy in other cancers but fails to take account of immune cell PD-L1 expression. (4)

"The benefit of pembrolizumab versus chemotherapy was observed in nearly all prespecified patient reported outcome endpoints," said lead author Prof. Peter Schmid, Lead of the Centre for Experimental Medicine at Barts Cancer Institute, Queen Mary University of London, UK. "Importantly, time to deterioration score for global health status/QoL scale was longer for patients treated with pembrolizumab compared to those treated with chemotherapy," he reported. The median time to deterioration was 4.3 months for pembrolizumab versus 1.7 months with chemotherapy (hazard ratio 0.70, 95% CI 0.46, 1.05). Scores for symptom scales for fatigue, nausea and vomiting, pain, dyspnoea and loss of appetite all increased with chemotherapy but remained stable or improved slightly with immunotherapy.

"In this CPS-enriched population of patients with metastatic triple negative breast cancer receiving second- and third-line treatments, health-related quality of life was better for patients receiving pembrolizumab than those receiving chemotherapy," said Schmid.

He added: "We are still learning a lot about immunotherapy in metastatic breast cancer. Trials for single agent immunotherapy in the first-line setting have not been positive. But these results clearly show there is a group of patients who do at least as well with single agent immunotherapy as chemotherapy in terms of survival and probably better in terms of quality of life."

Loi commented: "Patients who expressed high levels of PD-L1 protein according to their CPS score had better overall survival with pembrolizumab compared with chemotherapy, and pembrolizumab was far better tolerated than chemotherapy according to HRQOL measures. This underscores the importance of PD-L1 testing in the advanced setting as well as identifying other biomarkers that can help identify those who do best with pembrolizumab monotherapy given its favourable HRQOL impact."

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO Breast Cancer Virtual Meeting 2020

Official Congress Hashtag: #ESMOBreast20

Disclaimer

This press release contains information provided by the authors of the highlighted abstracts and reflects the content of these abstracts. It does not necessarily reflect the views or opinions of ESMO who cannot be held responsible for the accuracy of the data. Commentators quoted in the press release are required to comply with the ESMO Declaration of Interests policy and the ESMO Code of Conduct.

References

1 Abstract 128O 'PDL1/CD274 gain/amplification as a predictive marker of checkpoint blockade inhibitor efficacy in metastatic breast cancer: exploratory analysis of the SAFIR02-IMMUNO randomized phase II trial.' will be presented by Thomas Bachelot during the Best Abstracts session on Sunday 24 May 2020 12:45 to 14:15 (CET) on Channel 1. Annals of Oncology, Volume 31, Supplement 2, May 2020

2 The poster of abstract 141P 'Impact of Pembrolizumab Versus Chemotherapy on Health-Related Quality of Life in Patients with Metastatic Triple Negative Breast Cancer' by Peter Schmid will be on display in the e-Poster section of the Virtual Meeting Platform throughout the Congress days. Annals of Oncology, Volume 31, Supplement 2, May 2020

3 Cortes J, Lipatov O, Im S-A et al. KEYNOTE-119: Phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metatastatic triple negative breast cancer (mTNBC). ESMO 2019. Abstract LBA21. Annals of Oncology 2019 doi:10.1093/annonc/mdz394

4 Kulangara K, Zhang N, Corigliano E et al. Clinical utility of the combined positive score for programmed death ligand-1 expression and the approval of pembrolizumab for treatment of gastric cancer. Arch Pathol Lab Med 2019; 143: 330-337

About the European Society for Medical Oncology (ESMO)

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128O - PDL1/CD274 gain/amplification as a predictive marker of checkpoint blockade inhibitor efficacy in metastatic breast cancer: exploratory analysis of the SAFIR02-IMMUNO randomized phase II trial

T. Bachelot1, T. Filleron2, F. Dalenc3, I. Bieche4, I. Gaberis5, E. Rouleau6, A. Tran-Dien5, J. Adam7, A. Lusque8, M. Jimenez9, A. Jacquet9, F. Andre;10

1Centre Leon Berard, Lyon, France, 2Biostatistics, Centre Claudius-Regaud, Toulouse, CEDEX 3, France, 3Centre Claudius-Regaud, Centre Claudius-Regaud, Toulouse, CEDEX 3, France, 4Institut Curie, Institut Curie, Paris, France, 5Gustave Roussy, Gustave Roussy - Cancer Campus, Villejuif, France, 6Gustave ROUSSY, Gustave Roussy - Cancer Campus, Villejuif, CEDEX 5, France, 7Pathology, Institut Gustave Roussy, Villejuif, France, 8Biostatistics, Centre Claudius-Regaud, Toulouse, France, 9R&D, UNICANCER, Paris, France, 10Breast Cancer Unit, Medical Oncology Department, Gustave Roussy - Cancer Campus, Villejuif, France

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: ClinicalTrials.gov ID: NCT02299999 N┬░EudraCT : 2013-001652-36

Editorial acknowledgement: This research was conducted with support from an "Investigator Sponsored Study┬ĘProgramme 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: ASTRA ZENECA. 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. Andre: 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.

141P- Impact of Pembrolizumab Versus Chemotherapy on Health-Related Quality of Life in Patients with Metastatic Triple Negative Breast Cancer

P. Schmid1, A. Haiderali2, J. Mejia3, Z. Guo4, X. Zhou4, A. Martin-Nguyen2, J. Corts5, E. Winer6

1Centre of Experimental Cancer Medicine, Barts Cancer Institute-Queen Mary University of London, London, UK, 2Center for Observation and Real-World Evidence, MSD-Merck Sharp & Dohme, Kenilworth, USA, 3Clinical Research, MSD-Merck Sharp & Dohme, Kenilworth, USA, 4Biostatistics and Research Decision Science, MSD-Merck Sharp & Dohme, Kenilworth, USA, 5IOB Institute of Oncology, Quironsalud Group, Madrid & Barcelona, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain, 6Breast Oncology Center, Dana Farber Cancer Institute, Boston, MA, USA

Background: KEYNOTE-119 (NCT02555657), an open-label, randomized, phase 3 trial for metastatic triple-negative breast cancer (mTNBC), evaluated IV Pembrolizumab (P) 200?mg Q3W for up to 2 years vs investigator's choice of chemotherapy (CT) as second-line or third-line treatment. In the primary analysis populations (all-comers, PD-L1 CPS?1, PD-L1 CPS?10), OS was not significantly different between P and CT. We present results of prespecified health-related quality of life (HRQoL) analyses in this study.

Methods: The EORTC QLQ-C30 and QLQ-BR23 were completed at baseline, various time points during treatment cycles up to 2 years or until end of treatment, and 30-day safety follow-up visit. Data were analyzed from patients receiving ?1 dose of study treatment and completing ?1 HRQoL assessment. Least-squares mean (LSM) change from baseline, 95% CIs, and nominal P values were calculated. Time to deterioration (TTD; ?10-point worsening from baseline) was assessed by Kaplan-Meier method and Cox regression model. No formal hypothesis testing was performed.

Results: The HRQoL population included all-comers (P, n?=?306; CT, n?=?288), subjects with PD-L1 positive CPS?1 tumors (P, n?=?188; CT, n?=?183), and subjects with PD-L1 positive CPS?10 tumors (P, n?=?86; CT, n?=?91). Compliance for QLQ-C30 and QLQ-BR23 at week 6 was ?90% in both arms for all patient populations. The benefit of P vs CT was observed in nearly all pre-specified PRO endpoints, particularly in CPS?10 population. In this CPS-enriched population, the difference in LSM between arms in pre-specified systemic therapy side effects scale (-9.14; 95%CI, -13.16, -5.11; p

Conclusions: In this CPS-enriched population of patients with mTNBC receiving second and third-line treatments, HRQoL was better for patients receiving P than those receiving CT.

Clinical trial identification: NCT02555657 EudraCT : 2015-00100-27

Legal entity responsible for the study: MSD-Merck, Sharp and Dohme

Funding: MSD-Merck, Sharp and Dohme

Disclosure: P. Schmid: Honoraria (self), Research grant/Funding (institution), Spouse/Financial dependant: Roche; Honoraria (self), Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): Oncogenex; Honoraria (institution), Research grant/Funding (self): Novartis; Research grant/Funding (self): Astellas; Honoraria (self): Merck; Honoraria (self): Pfizer; Honoraria (self): Eisai; Honoraria (self): Bayer. A. Haiderali: Full/Part-time employment: MSD-Merck Sharp & Dohme.

J. Mejia: Full/Part-time employment: MSD-Merck Sharp & Dohme. Z. Guo: Full/Part-time employment: MSD-Merck Sharp & Dohme. X. Zhou: Full/Part-time employment: MSD-Merck Sharp & Dohme. A. Martin-Nguyen: Full/Part-time employment: MSD-Merck Sharp & Dohme. J. Cortes: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): Roche; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self): Eisai; Honoraria (self): Pfizer; Advisory/Consultancy: Samsung; Honoraria (self), Advisory/Consultancy: Celgene; Advisory/Consultancy: AstraZeneca; Shareholder/Stockholder/Stock options, Licensing/Royalties: MedSIR. E. Winer: Honoraria (self), Advisory/Consultancy: Genenteche/Roche; Honoraria (institution), Advisory/Consultancy: Carrick Therapeutics; Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Genomic Health; Honoraria (self), Advisory/Consultancy: GlaxoSmithKline; Honoraria (self), Advisory/Consultancy: Jounce; Honoraria (self), Advisory/Consultancy: Leap; Honoraria (self), Advisory/Consultancy: Lilly; Honoraria (self), Advisory/Consultancy: Seattle Genetics.



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