Immune therapy eliminates tumour cells in early triple negative breast cancer

Barcelona, Spain 29 September 2019 – Immune therapy added to chemotherapy improves pathological complete response in patients with early triple negative breast cancer, according to late breaking results from the KEYNOTE-522 trial presented at the ESMO Congress 2019 in Barcelona, Spain. (1,2) Interim results from the study, which is the first phase III trial of immunotherapy in early breast cancer, also indicated an improvement in event-free survival.

“The data suggest that the improved pathological complete response with pembrolizumab translates into fewer recurrences,” said study author Prof Peter Schmid, Barts Cancer Institute, Queen Mary University of London, UK.

Triple negative breast cancer is the most aggressive subtype of breast cancer and more often affects young women. Patients typically receive chemotherapy, followed by surgery to remove the tumour. This provides the best chance of pathological complete response, meaning no cancerous cells remaining on the resected tumour. Women with a pathological complete response have an 85-90% likelihood of being cured, while those with residual viable tumour tissue have a 40-50% probability of recurrence, which often occurs within three years.

KEYNOTE-522 tested whether adding immune therapy to chemotherapy prior to surgery could improve pathological complete response and event-free survival in women with early triple negative breast cancer. A total of 1,174 patients were randomly allocated at a 2:1 ratio to pembrolizumab or placebo, both added to preoperative chemotherapy with anthracyclines, taxanes, and platinum, for five to six months. After surgery, patients continued their allocated treatment of pembrolizumab or placebo for nine cycles.

The analysis presented at the ESMO Congress 2019 was performed after a median follow-up of 15.5 months. Pathological complete response, assessed in the first 602 patients, significantly increased from 51.2% (95% confidence interval [CI] 44.1-58.3) in the placebo group to 64.8% (95% CI 59.9-69.5) in the pembrolizumab group (p=0.00055). “We found a 13.6% difference which is a clinically meaningful benefit,” said Schmid.

Because triple negative breast cancer is aggressive and recurrences often occur early on, the investigators conducted an interim analysis of event-free survival. There was a favourable trend for the pembrolizumab group with a hazard ratio of 0.63 (95% CI 0.43-0.93), Schmid said: “These are preliminary data, but they provide a strong sign that the addition of immune therapy to neoadjuvant chemotherapy prevents breast cancer recurrence. If we prevent recurrence, we cure more patients, but we need longer-term data for confirmation.”

Grade 3 or higher treatment-related adverse events occurred in 78.0% and 73.0% of the pembrolizumab and placebo groups, respectively. Schmid noted that many of the side-effects were driven by the intensive chemotherapy regimen. Side-effects with a potential link to immune therapy occurred in 42% of study participants taking pembrolizumab versus 21% on placebo. “Immune therapy added some side-effects to chemotherapy but there were no new safety signals,” he said.

Commenting on the results for ESMO, Prof Fabrice Andre, Institut Gustave Roussy, Villejuif, France, said: “Triple negative breast cancer accounts for 15% of breast cancers. It represents an unmet medical need, since the only approved medical therapy at early stages of the disease is chemotherapy. This study could have a major impact on treatment for these patients.”

Andre noted that pathological complete response is a valid endpoint for US Food and Drug Administration (FDA) approval. “This is a good situation to test whether the FDA will approve a drug for triple negative breast cancer based on pathological complete response. The combination of the anti-PD-1 monoclonal antibody pembrolizumab plus chemotherapy could become a standard of care if approved,” he said.

While a large benefit in response rates was expected, the poor predictive value of PD-L1 was surprising. “This is probably because most early stage triple negative breast cancers express some degree of PD-L1, sometimes below the predefined cut-off of positivity. The role of chemotherapy as a sensitiser for anti-PD-1 in PD-L1-low early stage triple negative breast cancer should also be explored,” said Andre. “The next step will be to define which patients are resistant and prioritise which targets should be hit in this population. We also have to determine the impact of this new class of drug on survivorship issues.”

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Notes to Editors

Please make sure to use the official name of the meeting in your reports: ESMO Congress 2019

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2 LBA8_PR ‘KEYNOTE-522: Phase 3 study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo (pbo) + chemo as neoadjuvant treatment, followed by pembro vs pbo as adjuvant treatment for early triple-negative breast cancer (TNBC)’ will be presented by Peter Schmid during the Presidential Symposium II on Sunday 29 September 2019, 16:30-18:00 (CEST) in Barcelona Auditorium.

Annals of Oncology

, Volume 30, Supplement 5, October 2019

About the European Society for Medical Oncology (ESMO)

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LBA8_PR – KEYNOTE-522: Phase 3 study of pembrolizumab + chemotherapy vs placebo + chemotherapy as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early-stage high-risk triple-negative breast cancer

P. Schmid1, J. Cortes2, R. Dent3, L. Pusztai4, H.L. McArthur5, S. Kuemmel6, J. Bergh7, C. Denkert8, Y.H. Park9, R. Hui10, N. Harbeck11, M. Takahashi12, T. Foukakis7, P.A. Fasching13, F. Cardoso14, L. Jia15, V. Karantza16, J. Zhao17, G. Aktan18, J. O’Shaughnessy19

1 Centre For Experimental Cancer Medicine, Barts Cancer Institute-Queen Mary University of London, London, United Kingdom, 2Oncology Department, Vall d’Hebron University Hospital, Barcelona, Spain, 3Medical Oncology, National Cancer Centre Singapore, Singapore, 4Medical Oncology, Yale University School of Medicine, New Haven, United States of America, 5Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, United States of America, 6Breast Center, Clinics Essen-Mitte, Essen, Germany, 7Oncology, Karolinska University Hospital, Stockholm, Sweden, 8Institute Of Pathology, Universitatsklinikum Marburg, Marburg, Germany, 9Hematology-oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, 10Westmead Hospital, University of Sydney, Sydney, Australia, 11Breast Center, Ludwig Maximilians University – Grosshadern, Munich, Germany, 12Department Of Breast Surgery, Hokkaido Cancer Center, Sapporo, Japan, 13Gynecology And Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany, 14Breast Unit, Champalimaud Foundation Cancer Center, Lisbon, Portugal, 15Biostatistics, Merck & Co., Inc., Kenilworth, United States of America, 16Department Of Oncology, Merck & Co., Inc., Kenilworth, United States of America, 17Biostatistics And Re-search Decision Sciences, Merck & Co Inc, North Wales, United States of America, 18Department Of Oncology, Merck Sharp & Dohme Corp. USA, Whitehouse Station, United States of America, 19Medical Oncology, Texas Oncology – Baylor Sammons Cancer Center, Dallas, United States of America

Background: Neoadjuvant pembro + chemo had manageable safety and promising antitumor activity in participants (pts) with early TNBC in KEYNOTE-173 and I-SPY 2. KEYNOTE-522 (NCT03036488) is a pbo controlled phase 3 study of neoadjuvant pembro + chemo followed by adjuvant pembro in pts with early TNBC.

Methods: Pts with previously untreated, non-metastatic, centrally confirmed TNBC (stage T1c N1-2 or T2-4 N0-2 per AJCC) were randomized 2:1 to pembro 200 mg Q3W or pbo, both given with 4 cycles of paclitaxel + carboplatin, then with 4 cycles of doxorubicin or epirubicin + cyclophosphamide (neoadjuvant phase). After definitive surgery, pts received pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity (adjuvant phase). Pts were stratified by nodal status (+ vs -), tumor size (T1/T2 vs T3/T4), and carboplatin schedule (Q3W vs QW). Dual primary endpoints were pCR defined as ypT0/Tis ypN0 and event-free survival (EFS). Secondary end-points included pCR defined as ypT0 ypN0 and ypT0/Tis, OS, and efficacy in the PD-L1+ population.

Results: Median follow-up was 15.5 mo (range, 2.7-25.0). 784 pts were randomized to pembro, 390 to pbo. Among 602 pts evaluable for the definitive pCR analysis, pembro + chemo showed a statistically significant improvement in pCR (ypT0/Tis ypN0) vs pbo + chemo: 64.8% (95% CI, 59.9-69.5) vs 51.2% (95% CI, 44.1-58.3), P = 0.00055; results were consistent for the secondary pCR definitions, ypT0 ypN0 (59.9% vs 45.3%) and ypT0/Tis (68.6% vs 53.7%). For pembro vs pbo, pCR (ypT0/Tis ypN0) was 68.9% vs 54.9% in the PD-L1+ population and 45.3% vs 30.3% in the PD-L1- population. The addition of pembro to chemo followed by pembro showed a favorable trend in EFS (HR 0.63 [95% CI, 0.43-0.93]). Across phases, grade 3 or higher treatment-related AE rates were 78.0% in the pembro + chemo group and 73.0% in the pbo + chemo group (death incidence, 0.4% vs 0.3%, respectively).

Conclusions: Addition of pembro to neoadjuvant chemo significantly increased the pCR rate in pts with early TNBC. Neoadjuvant pembro + chemo followed by adjuvant pembro showed a favorable trend in EFS. AEs were consistent with the known safety profiles of each agent.

Clinical trial identification: ClinicalTrials.gov: NCT03036488

Editorial acknowledgement: Writing assistance was provided by Christine McCrary Sisk. This assistance was 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: P. Schmid: Honoraria (self): Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Advisory / Consultancy: Pfizer, AZ, Novartis, Roche, Merck, BI, Bayer, Eisai, Puma, Celgene; Research grant / Funding (institution): AZ, Genetech, Roche, Oncogenex, Novaris, Astellas; Spouse / Financial dependant: Spouse is a consultant for Genetech/Roche.

J. Cortes: 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), Research grant / Funding (institution), Travel / Accommodation / Expenses: Eisai; Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Honoraria (self): Samsung Bioepis; Honoraria (self), Advisory / Consultancy: Lily; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Merck Sharpe & Dohme; Advisory / Consultancy: Cellestia; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Biothera Pharmaceuticals; Advisory / Consultancy: Merus; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: Erytech; Advisory / Consultancy: Athenex; Advisory / Consultancy: Polyphor; Advisory / Consultancy: Servier; Research grant / Funding (institution): Ariad Pharmaceuticals; Research grant / Funding (institution): Baxalta GMBH/Servier Affaires; Research grant / Funding (institution): Bayer Healthcare; Research grant / Funding (institution): Guardian Health; Research grant / Funding (institution): Piqur Therapeutics ; Research grant / Funding (institution): Puma C; Research grant / Funding (institution): Queen Mary University of London; Research grant / Funding (institution): Seagen; Shareholder / Stockholder / Stock options: MedSIR.

R. Dent: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Advisory / Consultancy, Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Novartis; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche.

L. Pusztai: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: AstraZeneca; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Eisai; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Pieris; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Seattle Genetics; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Almac; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Syndax.

H.L. McArthur: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy, Travel / Accommodation / Expenses: Spectrum Pharm; Advisory / Consultancy, Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Travel / Accommodation / Expenses: Immunomedics; Advisory / Consultancy, Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Genentech; Advisory / Consultancy, Re-search grant / Funding (institution), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Puma Biotechnology.

S. Kuemmel: Advisory / Consultancy: F. Hoffmann-La Roche Ltd; Advisory / Consultancy: Genomic Health; Advisory / Consultancy: Novartis; Advisory / Consultancy: Amgen; Advisory / Consultancy: Celgene; Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Somatex; Advisory / Consultancy: MSD; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Puma Biotechnology; Advisory / Consultancy: PFM Medical; Advisory / Consultancy: Lilly; Research grant / Funding (institution): WSG; Travel / Accommodation / Expenses: Roche Pharma.

J. Bergh: Research grant / Funding (institution): Amgen; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Sanofi Aventis.

C. Denkert: Honoraria (self): Teva; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Roche; Honorar-ia (self), Advisory / Consultancy: Amgen ; Advisory / Consultancy: MSD; Advisory / Consultancy: Daiichi Sankyo; Share-holder / Stockholder / Stock options: Sividon (Myriad); Licensing / Royalties: VmScope.

Y.H. Park: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy, Research grant / Funding (self): Roche; Speak-er Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck; Research grant / Funding (self): AstraZeneca.

R. Hui: Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Eli Lilly.

N. Harbeck: Honoraria (institution): only research grants; 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; Advisory / Consultancy: Sandoz/Hexal; Advisory / Consultancy: Seattle Genetics; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Nanostring; Leadership role: German AGO Breast Committee; Research grant / Funding (institution): several phase II-III trials; Shareholder / Stockholder / Stock options: CO-Director West German Study Group; Full / Part-time employment: LMU Munich; Spouse / Financial dependant: West German Study Group.

M. Takahashi: Honoraria (self): AstraZeneca; Honoraria (self): Pfizer; Honoraria (self): Eli Lilly ; Honoraria (self), Re-search grant / Funding (self): Eisai; Research grant / Funding (self): Taiho; Research grant / Funding (self): Kyowa-Hakko Kirin; Research grant / Funding (self): Nippon Kayaku .

T. Foukakis: Honoraria (self), Honoraria (institution), Research grant / Funding (institution): Roche; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (institution), Research grant / Funding (institution): Pfizer; Licensing / Royalties: Wolters Kluwer Health (UpToDate).

P.A. Fasching: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Daiichi-Sankyo; Honoraria (self), Advisory / Consultancy: TEVA; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultan-cy: Merck Sharp&Dohme; Honoraria (self), Advisory / Consultancy: Myelo Therapeutics; Honoraria (self), Advisory / Consultancy: Macrogenics; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Puma; Honoraria (institution), Research grant / Funding (institution): Biontech; Honoraria (institution), Research grant / Funding (institution): Cepheid.

F. Cardoso: Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy: Astellas/Medivation; Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca; Advisory / Consultancy: Celgene; Advisory / Consultancy, Research grant / Funding (institution): Daiichi-Sankyo; Advisory / Consultancy, Re-search grant / Funding (institution): Eisai; Advisory / Consultancy: GE Oncology; Advisory / Consultancy, Research grant / Funding (institution): Genentech; Advisory / Consultancy, Research grant / Funding (institution): GlaxoSmithKline; Advi-sory / Consultancy, Research grant / Funding (institution): Macrogenics; Advisory / Consultancy: Medscape; Advisory / Consultancy, Research grant / Funding (institution): MSD; Advisory / Consultancy: Merus BV; Advisory / Consultancy: Mylan; Advisory / Consultancy: Mundipharma; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Pierre-Fabre; Advisory / Consultancy: prIME Oncology; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Sanofi; Advisory / Consultancy: Seat-tle Genetics; Advisory / Consultancy: Teva; Research grant / Funding (institution): Boehringer-Ingelheim; Research grant / Funding (institution): Bristol-Myers-Squibb; Research grant / Funding (institution): Fresenius GmbH; Research grant / Funding (institution): Ipsen; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Nektar Therapeutics; Research grant / Funding (institution): Nerviano; Research grant / Funding (institution): Medigene; Re-search grant / Funding (institution): MedImmune; Research grant / Funding (institution): Millenium; Research grant / Funding (institution): Sonus; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Tigris; Research grant / Funding (institution): Wilex; Research grant / Funding (institution): Wyeth; Officer / Board of Directors: ESMO Board of Directors.

L. Jia: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc..

V. Karantza: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc..

J. Zhao: Full / Part-time employment: Merck & Co., Inc..

G. Aktan: Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck & Co., Inc..

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 Corporation; Honoraria (self): Eisai; Honoraria (self): Genentech; Honoraria (self): Genomic Health; Honoraria (self): GRAIL; Honoraria (self): Immunomedics; Honoraria (self): Heron Therapeautics; Honoraria (self): Ipsen Biopharmaceuticals; Honoraria (self): Jounce Therapeutics; Honoraria (self): Lilly; Honoraria (self): Merck; Honoraria (self): Myriad; Honoraria (self): Novartis; Honoraria (self): Novartis; Honoraria (self): Pfizer; Honoraria (self): Puma Biotechnology; Honoraria (self): Prime Oncol-ogy; Honoraria (self): Roche; Honoraria (self): Seattle Genetics; Honoraria (self): Syndax Pharmaceuticals.