Abstract

R. Soo1, J-Y. Han2, G. Dimopoulou3, B.C. Cho4, C.M. Yeo5, E. Nadal6, E. Carcereny7, J. de Castro8, M.A. Sala9, R. Bernabe10, L. Coate11, M. Provencio12, R. Garcia Campelo13, S. Cuffe14, S. Hashemi15, M. Früh16, B. Ruepp17, H. Roschitzki-Voser17, R. Stahel18, S. Peters19
1Medical Oncology, National University Hospital, Singapore, 2Medical Oncology, Goyang National Cancer Center, Goyang, Republic of Korea, 3Statistical Office, Frontier-Science Foundation Hellas, Athens, Greece, 4Medical Oncology, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea, 5Medical Oncology, Tan Tock Seng Hospital, Singapore, 6Medical Oncology, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain, 7Medical Oncology, Hospital Universitari Germans Trial i Pujol, Badalona, Spain, 8Medical Oncology, Hospital la Paz, Madrid, Spain, 9Medical Oncology, Hospital Basurto, Bilbao, Spain, 10Medical Oncology, Hospital Virgen del Rocio, Seville, Spain, 11Medical Oncology, University Hospital Limerick, Limerick, Ireland, 12Medical Oncology, Hospital Puerta de Hierro, Madrid, Spain, 13Medical Oncology, Hospital Teresa Herrera, La Coruña, Spain, 14St James’s Hospital and Cancer Trials Ireland, Dublin, Ireland, 15Amsterdam UMC, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands, 16Medical Oncology, Kantonsspital St. Gallen, St. Gallen, Switzerland, 17Coordinating Center, European Thoracic Oncology Platform (ETOP), Bern, Switzerland, 18European Thoracic Oncology Platform (ETOP), Bern, Switzerland, 19Multidisciplinary Oncology Center, Centre Hospitalier Universitaire Vaudois - CHUV, Lausanne, Switzerland

Background: Whilst Osi is the standard treatment (TX) in patients (pts) with advanced NSCLC with sensitising EGFR-mt and acquired T790M-mt, progression inevitably occurs. Preclinical studies suggest the angiogenic pathway is implicated in EGFR tyrosine kinase inhibitor (TKI) resistance. The study objective was to determine the efficacy and safety of combined Osi/Bev versus Osi in pts with NSCLC with EGFR-mt (exon 19 del or L858R) and T790M-mt at progression on prior EGFR TKI.

Methods: BOOSTER is an open-label randomized phase II trial. Eligible pts were equally randomized to Osi (80 mg QD) and Bev (15 mg/kg i.v. Q3W) versus Osi. Primary end point was investigator assessed progression free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), and adverse events (AEs). The trial was designed to detect an increase in the median PFS from 11 months (m) with Osi to 17.2m with Osi/Bev (HR 0.64, at 5% 1-sided alpha and 80% power, 126 PFS events; 154 pts).

Results: Between 05/2017-02/2019, 155 pts were randomized: 78 Osi/ Bev, 77 Osi. The median age was 67 years, 62% females, 40% current-former (c-f) smokers, 30% ECOG PS 0, stage IIIb-c/IVa/IVb: 1%/70%/28%, 59% non-Asians. At a median follow-up of 34m, the median PFS was 15.4m (95% CI 9.2-18.0) and 12.3m (6.2-17.2) (PFS events: 64 & 65) in the Osi/Bev and Osi arm respectively (HR 0.96; 0.68- 1.37; p=0.83). Median OS was 24.0m (17.8-32.1) in Osi/Bev and 24.3m (16.9-37.0) in Osi arm (deaths: 46 & 43) (HR 1.03; 0.67-1.56; p=0.91). ORR was 55% in both arms. Smoking history exhibits significant TX interaction for both PFS and OS (adjusted p= 0.0052 & 0.029); PFS HR 0.52/1.47, OS HR 0.59/1.54, for c-f/never smokers, respectively. Median time to TX discontinuation was 12.4m/8.2m in Osi/Bev and 10.8m in Osi. Grade≥3 TX-related AEs occurred in 47% pts in Osi/Bev (Grade 5: 0 pt) and 18% in Osi (Grade 5: 3 pts).

Conclusions: No difference in PFS was observed between Osi/Bev and Osi. A significant TX interaction with smoking history is identified in subgroup analysis, indicating superiority of Osi/Bev vs. Osi for c/f smokers.

Clinical trial identification: NCT03133546.

Legal entity responsible for the study: European Thoracic Oncology Platform (ETOP).

Funding: AstraZeneca (study drug and study support) and Roche (study drug).

Disclosure:
R. Soo: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda, Yuhan; Financial Interests, Personal, Research Grant: AstraZeneca, Boehringer Ingelheim; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Lilly, Merck, Novartis, Otsuka, Pfizer, Roche, Synthorx, Taiho, Takeda, Yuhan.
J. Han: Financial Interests, Personal and Institutional, Other, Honoraria: Roche, AstraZeneca, Takeda; Financial Interests, Personal and Institutional, Advisory Role: AstraZeneca, Lilly, MSD, BMS, Pfizer, Medpacto; Financial Interests, Personal and Institutional, Research Grant: Roche, Pfizer, Ono, Takeda.
B.C. Cho: Financial Interests, Personal, Research Grant: Novartis, Bayer, AstraZeneca, MOGAM Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono, Dizal Pharma, MSD, AbbVie, Medpacto, GIInnovation, Eli Lilly, Blueprint Medicines, Interpark Bio Convergence Corp.; Financial Interests, Personal, Advisory Role: Novartis, AstraZeneca, Boehringer-Ingelheim, Roche, BMS, Ono, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, MSD, Medpacto, Blueprint Medicines; Financial Interests, Personal, Stocks/Shares: TheraCanVac Inc, Gencurix Inc, Bridgebio Therapeutics, Kanaph Therapeutic Inc, Cyrus Therapeutics, Interpark Bio Convergence Corp.; Financial Interests, Personal, Advisory Board: Kanaph Therapeutic Inc, Brigebio Therapeutics, Cyrus Therapeutics, Guardant Health, Oscotec Inc.; Financial Interests, Personal, Member of the Board of Directors: Interpark Bio Convergence Corp.; Financial Interests, Personal, Royalties: Champions Oncology; Financial Interests, Personal, Other, Founder: DAAN Biotherapeutics.
E. Nadal: Financial Interests, Personal, Funding: Roche, Pfizer, Merck-Serono, BMS; Financial Interests, Personal, Advisory Board: Roche, BMS, MSD, Merck-Serono, Pfizer, Lilly, Amgen, Boehringer-Ingelheim, AstraZeneca, Takeda.
E. Carcereny: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Roche, Takeda; Financial Interests, Personal, Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal, Expert Testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Pfizer, Roche, Takeda; Financial Interests, Personal, Other, Travel / Accommodation / Expenses: Bristol-Myers Squibb, Pfizer, Roche, Takeda.
J. de Castro: Financial Interests, Personal and Institutional, Other, Educational fees: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis, F. Hoffmann-La Roche; Financial Interests, Personal and Institutional, Advisory Board: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, GlaxoSmithKline, Janssen, Lilly, Merck Sharp and Dohme, Novartis, Pfizer, F. Hoffmann-La Roche, Sanofi, Takeda; Financial Interests, Personal and Institutional, Speaker’s Bureau: AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, F. Hoffmann-La Roche.
M.A. Sala: Non-Financial Interests, Institutional, Other, Travel grants: Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, MSD, Mylan, Pfizer, Pharma Mar, Pierre Fabre, Roche; Non-Financial Interests, Institutional, Speaker’s Bureau: Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, MSD, Mylan, Pfizer, Pharma Mar, Pierre Fabre, Roche; Non-Financial Interests, Institutional, Advisory Board: Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, MSD, Mylan, Pfizer, Pharma Mar, Pierre Fabre, Roche.
L. Coate: Financial Interests, Personal, Advisory Board: AstraZeneca, Roche, Daiichi.
M. Provencio: Financial Interests, Personal and Institutional, Advisory Board: BMS, AstraZeneca, Roche, MSD, Lilly.
R. Garcia Campelo: Financial Interests, Personal, Advisory Board: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen; Financial Interests, Personal, Invited Speaker: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen; Financial Interests, Personal, Advisory Role: MSD, Bristol-Myers, Roche, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, Lilly, Takeda, Janssen.
S. Cuffe: Financial Interests, Personal, Other, travel grants: MSD, Pfizer, Roche.
S. Hashemi: Financial Interests, Personal and Institutional, Invited Speaker: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, GSK, Janssen, MSD, Novartis, Roche, Takeda, Xcovery; Financial Interests, Personal and Institutional, Research Grant: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, GSK, Janssen, MSD, Novartis, Roche, Takeda, Xcovery; Financial Interests, Personal and Institutional, Principal Investigator: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, GSK, Janssen, MSD, Novartis, Roche, Takeda, Xcovery; Financial Interests, Personal and Institutional, Advisory Role: AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, GSK, Janssen, MSD, Novartis, Roche, Takeda, Xcovery.
M. Früh: Financial Interests, Personal, Advisory Role: BMS, MSD, AstraZeneca, Boehringer Ingelheim, Roche, Takeda, Pfizer; Non-Financial Interests, Institutional, Research Grant: BMS; AstraZeneca.
R. Stahel: Financial Interests, Personal, Advisory Role: AstraZeneca, BMS, Janssen, MSD, Pfizer, Regeneron, Roche, Seattle Genetics, Takeda; Financial Interests, Personal, Invited Speaker: Amgen, AstraZeneca, Blueprint, Eli Lilly, GSK, MSD, Novartis, Roche, Sandoz; Financial Interests, Institutional, Research Grant: Roche, AstraZeneca, BMS, MSD, Pfizer.
S. Peters: Financial Interests, Personal and Institutional, Advisory Role: AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffman-La Roche, Foundation Medicine, Illumina, Janssen, Novartis , PharmaMar, Pfizer, Regeneron, Sanofi, Seat; Financial Interests, Personal and Institutional, Speaker’s Bureau: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Novartis, Pfizer, Sanofi, Takeda, Merck Sharp and Dohme, Medscape, Imedex; Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, F. Hoffman-La Roche, Illumina, Novartis, Pfizer, Merck Sharp and Dohme, Merck Serono; Financial Interests, Personal, Expert Testimony: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, F. Hoffman-La Roche, Novartis, Pfizer, Sanofi, Takeda, Merck Sharp and Dohme, Medscape.
All other authors have declared no conflicts of interest.

Abstract

P. Schmid¹, J. Cortes², R. Dent³, L. Pusztai⁴, H. McArthur⁵, S. Kümmel⁶, J. Bergh⁷, C. Denkert⁸, Y.H. Park⁹, R. Hui¹⁰, N. Harbeck¹¹, M. Takahashi¹², M. Untch¹³, P.A. Fasching¹⁴, F. Cardoso¹⁵, Y. Ding¹⁶, K. Tryfonidis¹⁷, G. Aktan¹⁷, V. Karantza¹⁷, J. O’Shaughnessy^18
1Centre for Experimental Cancer Medicine, Barts Cancer Institute, Queen Mary University London, London, UK, ²International Breast Cancer Center, Quirón Group, Madrid and Barcelona, Spain, and Vall d'Hebron Institute of Oncology, Barcelona, Spain, ³National Cancer Center Singapore, Duke–National University of Singapore Medical School, Singapore, ⁴Yale School of Medicine, Yale Cancer Center, New Haven, CT, USA, ⁵Breast Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA, ⁶Breast Unit, Kliniken Essen-Mitte, Essen, Germany, ⁷Department of Oncology-Pathology, Karolinska Institutet and Breast Cancer Centre, Cancer Theme, Karolinska University Hospital, Solna, Sweden, ⁸Institute of Pathology, Philipps-University Marburg and University Hospital Marburg (UKGM), Marburg, Germany, ⁹Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea, ¹⁰Westmead Breast Cancer Institute, Westmead Hospital and the University of Sydney, Sydney, NSW, Australia, ¹¹Breast Center, LMU University Hospital, Munich, Germany, ¹²Department of Breast Surgery, Hokkaido Cancer Center, Sapporo, Japan, ¹³Breast Cancer Center, Helios Klinikum Berlin-Buch, Berlin, Germany, ¹⁴University Hospital Erlangen, Comprehensive Cancer Center Erlangen-EMN, Erlangen, Germany, ¹⁵Breast Unit, Champalimaud Clinical Center/Champalimaud Foundation, Lisbon, Portugal, ¹⁶Biostatistics, Merck & Co., Inc., Kenilworth, NJ, USA, ¹⁷Merck Research Laboratories, Merck & Co., Inc., Kenilworth, NJ, USA, ¹⁸Baylor University Medical Center, Texas Oncology, US Oncology, Dallas, TX, USA

Background: KEYNOTE-522 (NCT03036488) is a phase III study of neoadjuvant pembrolizumab (pembro) + chemotherapy (chemo) vs. placebo (pbo) + chemo followed by adjuvant pembro vs. pbo in patients (pts) with early-stage TNBC. In prior interim analyses, pembro + chemo showed a significant improvement in pCR and a favorable trend in EFS. We present results from a prespecified interim analysis of KEYNOTE-522.

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 neoadjuvant pembro 200 mg Q3W or pbo, both given with 4 cycles of paclitaxel + carboplatin, then with 4 cycles of doxorubicin or epirubicin + cyclophosphamide. After definitive surgery, pts received adjuvant pembro or pbo for 9 cycles or until recurrence or unacceptable toxicity. Pts were stratified by nodal status (+ vs. -), tumor size (T1/T2 vs. T3/T4), and carboplatin schedule (Q3W vs. QW). Dual primary endpoints are pCR (ypT0/Tis ypN0) and EFS.

Results: 1174 pts were randomized to pembro (n=784) or pbo (n=390). At the March 23, 2021 data cutoff (median follow-up, 37.8 mo [range, 2.7-48.0]), 123 pts (15.7%) in the pembro group and 93 pts (23.8%) in the pbo group had an EFS event, defined as disease progression that precluded definitive surgery, a local/distant recurrence, a second primary cancer, or death from any cause (HR 0.63 [95% CI, 0.48-0.82]; P=0.0003). The 36-mo EFS rate was 84.5% (95% CI, 81.7-86.9) in the pembro group vs. 76.8% (95% CI, 72.2-80.7) in the pbo group; median was not reached in either group. The most common EFS event was distant recurrence, in 60 pts (7.7%) in the pembro group vs. 51 pts (13.1%) in the pbo group. Pembro showed a favorable trend in OS (HR 0.72 [95% CI, 0.51-1.02]); follow-up is ongoing. Grade ≥3 treatment-related AE rates were 77.1% in the pembro group and 73.3% in the pbo group (death incidence, 0.5% vs. 0.3%, respectively); immune-mediated AEs of any grade occurred in 43.6% vs. 21.9%, respectively.

Conclusions: Neoadjuvant pembro + chemo followed by adjuvant pembro showed a statistically significant and clinically meaningful improvement in EFS compared with neoadjuvant chemotherapy alone in pts with early-stage TNBC.

Clinical trial identification: NCT03036488.

Editorial acknowledgement: Medical writing and/or editorial 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: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure:
P. Schmid: Financial Interests, Personal, Advisory Board: AstraZeneca; Bayer; Boehringer Ingelheim; Merck; Novartis; Pfizer; Puma; Roche; Eisai; Celgene; Financial Interests, Personal, Other, Spouse: Roche; Financial Interests, Institutional, Research Grant: Astellas; AstraZeneca; Genentech; Novartis; Oncogenex; Roche; Medivation.
J. Cortes: Financial Interests, Personal, Invited Speaker: Roche; Novartis; Celgene; Eisai; Pfizer; Samsung Bioepis; Lilly; Merck Sharp & Dohme; Daiichi Sankyo; Financial Interests, Personal, Advisory Board: Roche; Celgene; Cellestia; AstraZeneca; Biothera Pharmaceutical; Merus; Seattle Genetics; Daiichi Sankyo; Erytech; Athenex; Polyphor; Lilly; Servier; Merck Sharp & Dohme; GSK; Leuko; Bioasis; Clovis Oncology; Boehringer Ingelheim; Kyowa Kirin; Financial Interests, Personal, Stocks/Shares: MedSIR; Financial Interests, Institutional, Research Grant: Roche; Ariad Pharmaceuticals; AstraZeneca; Baxalta GMBH/Servier Affaires; Bayer Healthcare; Merck Sharp & Dohme; Pfizer; Piqur Therapeutics; Puma C; Queen Mary University of London; F. Hoffman-La Roche; Guardant Health; Eisai; Financial Interests, Personal, Other, Travel, Accommodation, Expenses: Roche; Novartis; Eisai; Pfizer; Daiichi Sankyo.
R. Dent: Financial Interests, Personal, Advisory Board: AstraZeneca; Eisai; Eli Lilly; Genentech; Merck; Novartis; Pfizer; Financial Interests, Personal, Other, Consultant: Genentech; Financial Interests, Personal, Other, Travel expenses: Genentech; Merck; Pfizer.
L. Pusztai: Financial Interests, Personal, Advisory Board: Seagen; Pfizer; AstraZeneca; Merck; Novartis; Bristol-Myers Squibb; Genentech; Eisai; Pieris; Immunomedics; Clovis; Syndax; H3Bio; Radius Health; Daiichi; Non-Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; Non-Financial Interests, Institutional, Principal Investigator: Merck; Pfizer; AstraZeneca; Seagen.
H. McArthur: Financial Interests, Personal, Advisory Board: Amgen; Bristol-Myers Squibb; Eli Lilly; Genentech/Roche; Immunomedics; Merck; Pfizer; Puma; Daiichi Sankyo; Seattle Genetics; AstraZeneca; Financial Interests, Institutional, Research Grant: Bristol-Myers Squibb; MedImmune; AstraZeneca; BTG; Merck.
S. Kümmel: Financial Interests, Personal and Institutional, Invited Speaker: Roche; Genomic Health; Exact Science; Seagen; Novartis; Amgen; Celgene; Daiichi Sankyo; AstraZeneca; Somatex/Hologic; MSD; Pfizer; PFM Medical; Lilly; Financial Interests, Personal and Institutional, Advisory Board: Roche; Genomic Health; Exact Science; Seagen; Novartis; Amgen; Celgene; Daiichi Sankyo; AstraZeneca; Somatex/Hologic; MSD; Pfizer; PFM Medical; Lilly; Non-Financial Interests, Personal, Member of the Board of Directors: WSG - Westdeutsche Studiengruppe - co Director; Financial Interests, Institutional, Research Grant: Somatex/Hologic; Financial Interests, Personal and Institutional, Principal Investigator: Roche; Novartis; Somatex/Hologic; Non-Financial Interests, Personal, Member: ESMO; ASCO; DGS; DGGG; WSG; AGO; AGImed; Non-Financial Interests, Personal, Member of the Board of Directors: AGO.
J. Bergh: Other, Institutional, Invited Speaker, Agreement with Karolinska Institutet: AstraZeneca; Roche; Non-Financial Interests, Institutional, Member of the Board of Directors: Karolinska Comprehensive Cancer Center; Cancer Core Europe; Cancer Research Karolinska Institutet; Financial Interests, Personal, Full or part-time Employment: Karolinska Institutet; Karolinska University Hospital, Karolinska CCC; Financial Interests, Personal and Institutional, Ownership Interest: Asklepios Medicin HB; Financial Interests, Institutional, Royalties, For participation in writing for UpToDate: Asklepios Medicin HB; Financial Interests, Institutional, Research Grant, Prior to last 3 years: AstraZeneca; Amgen; Bayer; Merck; Pfizer; Roche; Sanofi-Aventis; Financial Interests, Institutional, Funding: Swedish Cancer Society; Cancer Society in Stockholm; Knut and Alice Wallenberg Society; Swedish Research Council; Financial Interests, Institutional, Principal Investigator: Prospective academic studies; Non-Financial Interests, Personal and Institutional, Member: ASCO; AACR; ESMO; Nobel Assembly; Non-Financial Interests, Personal and Institutional, Member, Founding member: ECCO Academy; Non-Financial Interests, Personal and Institutional, Member, Fellow: Royal College of Physicians; Non-Financial Interests, Personal and Institutional, Member, Adjunct member: Nobel Committee; Non-Financial Interests, Personal and Institutional, Affiliate, Visiting Professor: Oxford University; Non-Financial Interests, Personal and Institutional, Advisory Role: European Medicines Agency; Swedish Medicine Products Agency; Non-Financial Interests, Institutional, Leadership Role: Cancer Research KI.
C. Denkert: Financial Interests, Personal, Advisory Board, (Oncology): MSD; Daiichi Sankyo; Molecular Health; AstraZeneca; Merck; Novartis; Roche; Financial Interests, Personal, Ownership Interest, (until 2016): Sividon Diagnostics; Financial Interests, Personal, Royalties: VMscope digital pathology software; Financial Interests, Institutional, Funding: Myriad; Roche; GBG.
Y.H. Park: Non-Financial Interests, Personal, Advisory Board: AstraZeneca; Pfizer; Roche; Novartis; Merck; Financial Interests, Institutional, Research Grant: AstraZeneca; Pfizer; Roche; Merck; Non-Financial Interests, Institutional, Principal Investigator: AstraZeneca; Pfizer; Roche; Daiichi Sankyo; Novartis; Merck; Financial Interests, Personal, Other, Speaker fee: Roche; Novartis; Non-Financial Interests, Personal, Other, Medical writing support: F. Hoffmann-La Roche Ltd.
R. Hui: Financial Interests, Personal, Invited Speaker: MSD; Novartis; AstraZeneca; Roche; Non-Financial Interests, Personal, Writing Engagements: Novartis; Financial Interests, Personal, Advisory Board: AstraZeneca; BMS; Eli Lilly; Merck; MSD; Novartis; Oncosec; Pfizer; Roche; Seagen.
N. Harbeck: Financial Interests, Personal, Invited Speaker: AstraZeneca; Daiichi Sankyo; Lilly; MSD; Novartis; Pfizer; Pierre Fabre; Roche; Seagen; Financial Interests, Personal, Advisory Board: AstraZeneca; Daiichi Sankyo; Lilly; MSD; Novartis; Pfizer; Pierre Fabre; Roche; Sandoz/Hexal; Seagen; Non-Financial Interests, Personal, Officer: ESMO Guideline Committee; Financial Interests, Personal, Full or part-time Employment: LMU University Hospital; Financial Interests, Personal, Ownership Interest: WSG; Non-Financial Interests, Personal, Member: AGO, Germany; ESO/ESCO.
M. Takahashi: Financial Interests, Personal, Speaker’s Bureau: AstraZeneca; Eli Lilly; Eisai; Pfizer.
M. Untch: Financial Interests, Institutional, Invited Speaker: AstraZeneca; Celgene; Amgen; Pfizer; Roche; Lilly; Daiichi Sankyo; Mylan; Novartis; MSD; Seagen; Pierre Fabre; GSK; Financial Interests, Personal, Writing Engagements: AstraZeneca GmbH; Daiichi Sankyo; Exact Sciences Deutschland; Lilly; Mylan Germany; Pierre Fabre; Veracyte, Inc; Financial Interests, Institutional, Advisory Board: AbbVie; AstraZeneca; Celgene; Amgen; Pfizer; Roche; Lilly; GSK; Daiichi Sankyo; Novartis; MSD; Seagen; Celgene; Pierre Fabre; Agendia; Mylan; Financial Interests, Institutional, Advisory Role: AbbVie; AstraZeneca; Celgene; Amgen; Pfizer; Roche; Lilly; GSK; Daiichi Sankyo; Novartis; MSD; Seagen; Pierre Fabre; Agendia.
P.A. Fasching: Financial Interests, Personal, Advisory Board: Agendia; AstraZeneca; Daiicho Sankyo; Eisai; Hecal; Lilly; Merck Sharp & Dohme; Novartis; Pfizer; Pierre Fabre; Roche; Seagen; Financial Interests, Personal, Invited Speaker: AstraZeneca; Daiichi Sankyo; Eisai; Lilly; Merck Sharp & Dohme; Novartis; Seagen; Non-Financial Interests, Institutional, Principal Investigator: BionTech; Cepheid; Non-Financial Interests, Personal, Member: Arbeitsgemeinschaft für Gynäkologische Onkologie e.v.; ASCO; Deutsche Gesellschaft für Senologie e.v.; Translational Research in Oncology.
F. Cardoso: Financial Interests, Personal, Advisory Board: Amgen; Astellas/Medivation; AstraZeneca; Celgene; Daiichi Sankyo; Eisai; GE Oncology; Genentech; GlaxoSmithKline; Macrogenics; Medscape; Merck Sharp & Dohme; Merus BV; Mundipharma; Mylan Pharmaceuticals Inc.; Novartis Pharma; Pfizer; Pierre Fabre; prIME Oncology; Roche; Samsung Bioepis; Sanofi; Seattle Genetics; Teva Pharmaceutical Industries.
Y. Ding: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
K. Tryfonidis: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
G. Aktan: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
V. Karantza: Financial Interests, Personal, Full or part-time Employment: Merck & Co., Inc.; Financial Interests, Personal, Stocks/Shares: Merck & Co., Inc.
J. O’Shaughnessy: Financial Interests, Personal, Speaker’s Bureau: Lilly; Pfizer; Seagen; Financial Interests, Personal, Advisory Board: AbbVie Inc.; Agendia; Amgen Biotechnology; Aptitude Health; AstraZeneca; Bayer; Bristol-Myers Squibb; Celgene Corporation; Clovis Oncology; Daiichi Sankyo; Eisai; G1 Therapeutics; Genentech; Gilead Sciences; GRAIL; Halozyme Therapeutics; Heron Therapeutics; Immunomedics; Ipsen Biopharmaceuticals; Lilly; Merck; Myriad; Nektar Therapeutics; Novartis; Pfizer; Pharmacyclics; Pierre Fabre Pharmaceuticals; Puma Biotechnology; Prime Oncology; Roche; Samsung Bioepis; Sanofi; Seagen; Syndax Pharmaceuticals; Taiho Oncology; Takeda; Synthon.

Abstract

S. Peters¹, U. Dafni², M. Perol³, E. Felip⁴, L. Polito⁵, N. Pal⁶, T.G.N. Ton⁶, D. Merritt⁷, S. Morris⁸, R.A. Stahel^9
1Multidisciplinary Oncology, Centre Hospitalier Universitaire Vaudois – CHUV, Lausanne, Switzerland; ²ETOP Statistical Center, Frontier-Science Foundation—Hellas, Athens, Greece; ³Medical Oncology, Centre Léon Bérard, Lyon, France; ⁴Medical Oncology Service (Lung Cancer Unit), Vall d'Hebron University Hospital, Barcelona, Spain; ⁵Product Development Personalized Healthcare, F. Hoffmann-La Roche, Ltd, Basel, Switzerland; ⁶Product Development Personalized Healthcare, Genentech, Inc., South San Francisco, CA, USA; ⁷Product Development Medical Affairs, F. Hoffmann-La Roche, Ltd, Basel, Switzerland; ⁸Product Development Medical Affairs Oncology, F. Hoffmann-La Roche, Ltd, Basel, Switzerland; ⁹Foundation Council, European Thoracic Oncology Platform (ETOP), Berne, Switzerland

Background: Anti−PD-(L)1 therapy alone (cancer immunotherapy [CIT]-mono) or combined with platinum-based chemotherapy (CIT-chemo) is used as 1L treatment for patients with metastatic Nsq-NSCLC with a PD-L1 tumor proportion score (TPS) ≥50% (high expression). Our study compared clinical outcomes with CIT-mono vs CIT-chemo in this specific clinical scenario.

Methods: This was a retrospective cohort study using the nationwide Flatiron Health Electronic Health Record-derived de-identified US database. Patients with metastatic Nsq-NSCLC with high PD-L1 expression initiating 1L CIT-mono or CIT-chemo between 24 Oct 2016 and 28 Feb 2019 were followed until study end (28 Feb 2020). We compared overall survival (OS) and real-world progression-free survival (rwPFS) using Kaplan-Meier methodology. Hazard ratios (HR) were adjusted (aHR) for differences in baseline characteristics.

Results: Patients with PD-L1−high Nsq-NSCLC treated with CIT-mono (n=351) had higher proportions of poor prognostic baseline characteristics (notably, age and metastatic disease type) than patients treated with CIT-chemo (n=169; Table). With a median follow-up of 19.9 mo for CIT-chemo vs 23.5 mo for CIT-mono, median OS and rwPFS did not differ between the two groups (median OS: CIT-chemo, 21.0 mo vs CIT-mono, 22.1 mo, aHR=1.03, 95% CI 0.77-1.39, P=0.83; median rwPFS: CIT-chemo, 10.8 mo vs CIT-mono, 11.5 mo, aHR=1.04, 95% CI 0.78-1.37, P=0.81). CIT-chemo only showed significant and meaningful improvement in OS and rwPFS vs CIT-mono in the never-smoker subgroup, albeit a small sample of patients (n=50; OS HR=0.25, 95% CI 0.07-0.83, interaction P=0.02; rwPFS HR=0.40, 95% CI 0.17-0.95, interaction P=0.04).

Conclusions: Except in a subgroup of patients with no smoking history, sparing the chemotherapy in 1L CIT treatment does not appear to impact survival outcomes. Table: Baseline Characteristics

Variable
Categories
CIT-chemo
CIT-mono

N
169
351

Age group, n (%)
<65 y
77 (45.6)
109 (31.1)

≥65 y
92 (54.4)
242 (68.9)

Sex, n (%)
F
75 (44.4)
183 (52.1)

M
94 (55.6)
168 (47.9)

Smoking status, n (%)
Former/current
153 (90.5)
317 (90.3)

No history
16 (9.5)
34 (9.7)

ECOG performance status, n (%)
0
77 (45.6)
138 (39.3)

1
92 (54.4)
213 (60.7)

Metastatic disease type, n (%)
De novo stage IV
157 (92.9)
271 (77.2)

Recurrent
12 (7.1)
80 (22.8)

Brain metastasis, n (%)
Yes
50 (30.0)
91 (25.9)

Liver metastasis, n (%)
Yes
28 (16.6)
43 (12.3)


Editorial acknowledgement: Medical writing support was provided by Kia C. E. Walcott, PhD, of Health Interactions.

Legal entity responsible for the study: F. Hoffmann-La Roche, Ltd.

Funding: F. Hoffmann-La Roche, Ltd.

Disclosure:
S. Peters: Financial Interests: AbbVie, Amgen, AstraZeneca, Bayer, BeiGene, Biocartis, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Foundation Medicine, Illumina, Incyte, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merri; Financial Interests, Talk in a company’s organized public event: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, ecancer, Eli Lilly, Illumina, Medscape, Merck Sharp and Dohme, Novartis, Pfizer, Prime, Roche/Genentech, Sanofi, Takeda; Financial Interests, (Sub)investigator in trials (institutional financial support for clinical trials): Amgen, AstraZeneca, Biodesix, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, GSK, Illumina, Lilly, Merck Sharp and Dohme, Merck Serono, Mirati, Novartis, and Pfizer, Phoshoplatin Therapeutics, Roche/Genentech.
U. Dafni: Financial Interests, Advisory/Consultancy: Roche.
M. Perol: Financial Interests, Advisory/Consultancy: Roche, AstraZeneca, Lilly, Pfizer, MSD, Bristol Myers Squibb, Boehringer Ingelheim, Novartis, Sanofi, Gritstone, Illumina, Takeda; Financial Interests: Amgen, Chugai; Financial Interests: Amgen, Chugai.
E. Felip: Financial Interests, Honoraria: AbbVie, Amgen, AstraZeneca, Bayer, Blue Print Medicines, Boehringer-Ingelheim, Bristol-Myers Squibb, Eli Lilly, GSK, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Roche, Peervoice, Pfizer, prIME Oncology, Puma Biotechnology, Roche, Sanofi ; Financial Interests: Grant for Oncology Innovation (GOI), Fundación Merck Salud; and Office/Board of Directors for Grífols.
L. Polito: Financial Interests: Roche.
N. Pal: Financial Interests: Genentech, Inc.; Financial Interests: Roche/Genentech.
T.G.N. Ton: Financial Interests: Genentech; Financial Interests: Roche.
D. Merritt: Financial Interests: Roche; Financial Interests: Roche.
S. Morris: Financial Interests: Roche; Financial Interests: Roche.
R.A. Stahel: Financial Interests: Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, Eli Lilly, GSK, MSD, Novartis, Roche; Financial Interests: AstraZeneca, BMS, Janssen, MSD, Pfizer, Regeneron, Roche, Sandoz, Seattle Genetics, Takeda; Financial Interests, DMC: Genentech/Roche, Takeda; Financial Interests, Editor: CTR; Financial Interests, Editor in Chief: Lung Cancer; Financial Interests: AstraZeneca; Financial Interests, ETOP Study: BMS; Financial Interests, IBCSG Study: Ipsen; Financial Interests, ETOP Study, IBCSG Study: MSD; Financial Interests, IBCSG Study: Novartis; Financial Interests, IBCSG Study, ETOP Study: Pfizer; Financial Interests, IBCSG Study: Pierre Fabre; Financial Interests, ETOP Study, IBCSG Study: Roche; Financial Interests, President Foundation Council: ETOP; Financial Interests, President Foundation Council: IBCSG.

Abstract

K.S. Tewari¹, B.J. Monk², I. Vergote³, A. Miller⁴, A.C. de Melo⁵, H.S. Kim⁶, Y.M. Kim⁶, A. Lisyanskaya⁷, V. Samouëlian⁸, D. Lorusso⁹, F. Damian¹⁰, C-L. Chang¹¹, E.A. Gotovkin¹², S. Takahashi¹³, D. Ramone¹⁴, J. Pikiel¹⁵, J. Li¹⁶, M. Mathias¹⁶, M.G. Fury¹⁶, A. Oaknin^17
1Department of Obstetrics & Gynecology, University of California Irvine, Orange, CA, USA, ²Arizona Oncology (US Oncology Network) University of Arizona, Creighton University, Division of Gynecologic Oncology, Arizona, AZ, USA, ³Department of Obstetrics and Gynecology and Gynecologic Oncology, University Hospitals, Leuven, Belgium, ⁴Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA, ⁵Division of Clinical Research, Brazilian National Cancer Institute, Rio de Janeiro, Brazil, ⁶Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul, Republic of Korea, ⁷Department of Gynaecological Oncology, St. Petersburg State Budgetary Institution of Healthcare, St. Petersburg, Russian Federation, ⁸Gynecology Oncology, CHUM, CRCHUM, Université de Montréal, Montreal, QC, Canada, ⁹Gynaecology Oncology Unit, Fondazione Policlinico Universitario A Gemelli IRCCS and Catholic University of Sacred Heart, Rome, Italy, ¹⁰Gynaecology, Hospital Sao Lucas PUCRS, Porto Alegre, Brazil, ¹¹Gynaecology, MacKay Memorial Hospital, Taipei, Taiwan, ¹²Gynaecology, State Budget Healthcare Institution Ivanovo Regional Oncology Dispensary, Ivanovo, Russian Federation, ¹³Department of Medical Oncology, The Cancer Institute Hospital of JFCR, Tokyo, Japan, ¹⁴Clinical Research Department, Barretos Cancer Hospital (Pio XII Foundation), Barretos, Brazil, ¹⁵Gynaecology, Szpitale Pomorskie, Gdynia, Poland, ¹⁶Clinical Sciences Oncology, Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA, ¹⁷Gynaecologic Cancer Programme, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d’Hebron, Vall d’Hebron Barcelona Hospital Campus, Barcelona, Spain
Background: Salvage chemo is ineffective for patients (pts) with R/M cervical cancer following progression on first-line (1L) platinum-based chemo + bevacizumab.
Methods: EMPOWER-Cervical 1/GOG-3016/ENGOT-cx9 is an open-label, randomised (1:1), multi-centre, phase III trial of anti-programmed cell death (PD)-1 cemiplimab vs. IC single agent chemo in R/M cervical cancer that has progressed after 1L platinum-based treatment (tx). Pts were enrolled regardless of PD-L1 expression; received cemiplimab 350 mg IV every 3 wks or IC chemo (pemetrexed, vinorelbine, gemcitabine, irinotecan or topotecan), up to 96 wks; and were stratified by histology (squamous cell carcinoma [SCC] / adenocarcinoma or adenosquamous [AC]). Primary endpoint was overall survival (OS), analysed hierarchically in pts with SCC followed by total population (SCC + AC). Additional endpoints included progression-free survival (PFS), objective response rate (ORR), quality of life (QoL) and safety. Interim analysis was scheduled when 85% events occurred among SCC pts.
Results: 608 pts were randomised: median age, 51 years [range, 22‒87]; 477 SCC, 131 AC; ECOG performance score: 0 [46.5%], 1 [53.5%]. Median cemiplimab exposure was 15 wks (range, 1.4‒100.7). At interim analysis, OS (Table), PFS, ORR in overall and SCC populations, and mean change from baseline QoL in SCC, favoured cemiplimab. Most common tx emergent adverse events (AEs) of any grade for cemiplimab vs. IC chemo were anaemia (25% vs. 45%), nausea (18% vs. 33%) and vomiting (16% vs. 23%). Discontinuation due to AEs occurred in 8% (cemiplimab) and 5% (IC chemo).
Conclusions: Cemiplimab significantly improves OS over single agent chemo for pts with R/M cervical cancer after 1L platinum-based tx regardless of PD-L1 status or histology. No new safety signals were observed.
Cemiplimab median OS months (n)
IC chemo median OS months (n)
Hazard ratio for death (95% confidence interval)
P value

Total population
12.0 (n=304)
8.5 (n=304)
0.69 (0.56‒0.84)
P<0.001

SCC population
11.1 (n=239)
8.8 (n=238)
0.73 (0.58‒0.91)
P=0.003

AC population
13.3 (n=65)
7.0 (n=66)
0.56 (0.36‒0.85)
P<0.005
(nominal P value, not adjusted for multiplicity)


Clinical trial identification: NCT03257267.
Editorial acknowledgement: Writing support was provided by Randall Janairo, PhD, of Prime, Knutsford, UK, funded by Regeneron Pharmaceuticals, Inc. and Sanofi.
Legal entity responsible for the study: Regeneron Pharmaceuticals, Inc., Sanofi, and GOG and ENGOT.
Funding: Regeneron Pharmaceuticals, Inc. and Sanofi.
Disclosure:
K.S. Tewari: Financial Interests, Personal, Other, Honoraria: Tesaro, Clovis Oncology; Financial Interests, Personal, Advisory Role, Consulting or advisory roles: Genentech, Tesaro, Clovis, AstraZeneca; Financial Interests, Personal, Speaker’s Bureau: Genentech, AstraZeneca, Merck, Tesaro, Clovis; Financial Interests, Institutional, Research Grant: AbbVie, Genentech, Morphotek, Merck, Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Other, Travel, accommodations, expenses: Genentech.
B.J. Monk: Financial Interests, Personal, Other, Consulting honoraria: Aravive, Asymmetric Therapeutics, Boston Biomedical, ChemoCare, ChemoID, Circulogene, Conjupro Biotherapeutics, Eisai, Geistlich, Genmab/Seattle Genetics, Gynecologic Oncology Group Foundation, ImmunoGen, Immunomedics, Incyte, Laekna Health Care; Financial Interests, Personal, Other, Consulting honoraria: Mateon/Oxigene, Merck, Mersana, Myriad, Nucana, Oncomed, Oncoquest, Oncosec, Perthera, Pfizer, Precision Oncology, Puma, Regeneron, Samumed, Takeda, VBL, Vigeo; Financial Interests, Personal, Speaker’s Bureau, Consulting/speaker honoraria: AstraZeneca, Clovis, Janssen/Johnson & Johnson, Roche/Genentech, Tesaro/GSK.
I. Vergote: Financial Interests, Personal, Other, Consulting fees: AstraZeneca, Elevar Therapeutics, Genmab, GlaxoSmithKline, Immunogen, Merck Sharp & Dohme, Oncoinvent; Financial Interests, Personal, Research Grant: Genmab, F. Hoffmann-La Roche.
A.C. de Melo: Financial Interests, Personal, Advisory Board: MSD, BMS, Libbs; Financial Interests, Personal, Other, Support for travel or accommodation: AstraZeneca, MSD, BMS,d Roche; Financial Interests, Institutional, Research Grant: Clovis Oncology, BMS, Roche, Novartis, Amgen, MSD, Lilly, Pierre Fabre, Sanofi, Pfizer.
Y.M. Kim: Financial Interests, Personal, Stocks/Shares: Johnson & Johnson, Genolution; Financial Interests, Personal, Advisory Role: MSD; Financial Interests, Personal, Research Grant: Regeneron Pharmaceuticals, Inc., Roche.
D. Lorusso: Financial Interests, Personal, Advisory Board: Amgen, AstraZeneca, Clovis Oncology, Genmab, Immunogen, Merck Serono, MSD, PharmaMar, Roche, GSK; Financial Interests, Institutional, Research Grant: Clovis Oncology, MSD, PharmaMar, Roche, GSK; Financial Interests, Personal, Expert Testimony: Clovis Oncology; Financial Interests, Personal, Principal Investigator: AstraZeneca, Clovis Oncology, Genmab, Immunogen, MSD, PharmaMar, Roche, GSK; Financial Interests, Personal, Other, Travel support: AstraZeneca, PharmaMar, Roche, GSK; Non-Financial Interests, Personal, Other, Nonfinancial member interests: European Network for Gynaecological Oncological Trial groups (ENGOT), European Society of Gynaecological Oncology (ESGO), European Society for Medical Oncology (ESMO), Gynecologic Cancer Intergroup (GCIG; Board of Directors); Non-Financial Interests, Personal, Other, Nonfinancial member interests: Italian Association of Medical Oncology (AIOM), Multicenter Italian Trials in Ovarian Cancer (MITO).
S. Takahashi: Financial Interests, Personal, Other, Honoraria: Daiichi Sankyo, Eisai, Bayer, Taiho Pharmaceutical, MSD, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb Japan, Ono Pharmaceutical, Nihonkayaku, Pfizer, Lilly Japan; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Research Grant: Daiichi Sankyo, Sanofi, Eisai, Bayer, Taiho Pharmaceutical, MSD, Novartis, Chugai Pharma, AstraZeneca, Bristol-Myers Squibb, Lilly, Ono Pharmaceutical, PharmaMar, Pfizer/EMD Serono; Financial Interests, Personal, Other, Travel, accommodation, and expenses: Daiichi Sankyo, Novartis.
J. Li: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.
M. Mathias: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.
M.G. Fury: Financial Interests, Personal, Full or part-time Employment: Regeneron Pharmaceuticals, Inc.; Financial Interests, Personal, Stocks/Shares: Regeneron Pharmaceuticals, Inc.
A. Oaknin: Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen, Genmab, Mersana Therapeutic, GSK, Deciphera Pharmaceuticals; Financial Interests, Personal, Other, Support for travel or accommodation: Roche, AstraZeneca, PharmaMar.
All other authors have declared no conflicts of interest.