Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial—PEARL

ORIGINAL ARTICLE Palbociclib in combina ion wi h endoc ine he apy e sus capeci abine in ho monal ecep o -posi i e, human epide mal g ow h ac o 2-nega i e, a oma ase inhibi o - esis an me as a ic b eas cance : a phase III andomised con olled ialdPEARL 5 M. Ma in 1,2,3*y , C. Zielinski 4,5y , M. Ruiz-Bo ego 3,6 , E. Ca asco 3 , N. Tu ne 7 , E. M. Ci uelos 3,8,9,10 , M. Muñoz 3,11,12 , B. Be mejo 2,3,13,14 , M. Ma geli 3,15 , A. An on 2,3,16 , Z. Kahan 17 , T. Csöszi 18 , M. I. Casas 3 , L. Mu illo 3,19 , S. Mo ales 3,20 , E. Alba 2,3,21 , E. Gal-Yam 22 , A. Gue e o-Zo ano 3,23 , L. Cal o 3,24 , J. de la Haba-Rod iguez 2,3,25 , M. Ramos 3,26 , I. Al a ez 3,27 , A. Ga cia-Palomo 3,28 , C. Huang Ba le 29 , M. Koehle 29,30 , R. Caballe o 3 , M. Co sa o 31 , X. Huang 29 , J. A. Ga cia-Sáenz 3,32 , J. I. Chacón 3,33 , C. Swi 34 , C. Thallinge 5,35 & M. Gil-Gil 3,36 1 Medical Oncology, Ins i u o de In es igación Sani a ia G ego io Ma añón, Medicine Depa men , Uni e sidad Complu ense, Mad id; 2 Oncology Biomedical Resea ch Na ional Ne wo k (CIBERONC-ISCIII), Mad id; 3 GEICAM Spanish B eas Cance G oup, Mad id, Spain; 4 Medical Oncology, Cen al Eu opean Cance Cen e , Wiene P i a klinik Hospi al, Vienna; 5 CECOG Cen al Eu opean Coope a i e Oncology G oup, Vienna, Aus ia; 6 Medical Oncology, Hospi al Uni e si a io Vi gen del Rocio, Se illa, Spain; 7 Ins i u e o Cance Resea ch and Royal Ma sden, London, UK; 8 Medical Oncology, Hospi al Uni e si a io 12 de Oc ub e, Mad id; 9 Medical Oncology, HM Hospi ales Mad id, Mad id; 10 SOLTI G oup on B eas Cance Resea ch, Ba celona; 11 Medical Oncology, Hospi al Clinic de Ba celona, Ba celona; 12 T ansla ional Genomics and Ta ge ed The apeu ics in Solid Tumo s (IDIBAPS), Ba celona; 13 Medical Oncology, Hospi al Clínico Uni e si a io de Valencia, Valencia; 14 Biomedical Resea ch Ins i u e INCLIVA, Valencia; 15 B-ARGO G oup, Ca alan Ins i u e o Oncology, Hospi al Uni e si a i Ge mans T ias i Pujol, Badalona; 16 Medical Oncology, Hospi al Uni e si a io Miguel Se e , Za agoza, Spain; 17 Depa men o Onco he apy, Uni e si y o Szeged, Szeged; 18 Depa men o Oncology, Jasz-Nagykun-Szolnok Megyei He enyi Geza Ko haz-Rendel} oin eze , Szolnok, Hunga y; 19 Medical Oncology, Hospi al Clínico de Za agoza Lozano Blesa, Za agoza; 20 Medical Oncology, Hospi al Uni e si a io A nau de Vilano a, Lleida; 21 UGCI Medical Oncology, Hospi ales Regional y Vi gen de la Vic o ia, IBIMA, Málaga, Spain; 22 Depa men o Oncology, Ins i u e o Oncology, Sheba Medical Cen e , Tel-Hashome , Is ael; 23 Medical Oncology, Ins i u o Valenciano de Oncología, Valencia; 24 Medical Oncology, Complejo Hospi ala io A Co uña, Co uña; 25 Medical Oncology, Hospi al Uni e si a io Reina Sofia, Có doba; Ins i u o Maimonides de In es igación Biomédica (IMIBIC); Uni e sidad de Có doba, Có doba; 26 Cen o Oncológico de Galicia, A Co uña, Co uña; 27 Medical Oncology, Hospi al Uni e si a io Donos ia-Biodonos ia, San Sebas ián; 28 Medical Oncology, Hospi al de León, León, Spain; 29 Pfize , New Yo k, USA; 30 Repa e The apeu ics, Camb idge, USA; 31 Pfize , Milano, I aly; 32 Medical Oncology, Hospi al Clínico Uni e si a io San Ca los, Mad id; 33 Medical Oncology, Hospi al Vi gen de la Salud, Toledo, Spain; 34 Ralph Lau en Cen e o B eas Cance Resea ch, Royal Ma sden, London, UK; 35 Depa men o Oncology, Medical Uni e si y o Vienna, Depa men o Oncology, Vienna, Aus ia; 36 Ins i u Ca alà d’Oncologia (ICO) & IDIBELL, L’Hospi ale , Ba celona, Spain A ailable online XXX Backg ound: Palbociclib plus endoc ine he apy (ET) is he s anda d ea men o ho mone ecep o -posi i e and human epide mal g ow h ac o ecep o 2-nega i e, me as a ic b eas cance (MBC). Howe e , i s e ficacy has no been compa ed wi h ha o chemo he apy in a phase III ial. Pa ien s and me hods: PEARL is a mul icen e, phase III andomised s udy in which pa ien s wi h a oma ase inhibi o (AI)- esis an MBC we e included in wo consecu i e coho s. In coho 1, pa ien s we e andomised 1 : 1 o palbociclib plus exemes ane o capeci abine. On disco e ing new e idence abou es ogen ecep o -1 (ESR1) mu a ions inducing esis ance o AIs, he ial was amended o include coho 2, in which pa ien s we e andomised 1 : 1 be ween palbociclib plus ul es an and capeci abine. The s a ifica ion c i e ia we e disease si e, p io sensi i i y o ET, p io chemo he apy o MBC, and coun y o o igin. Co-p ima y endpoin s we e p og ession- ee su i al (PFS) in coho 2 and in wild- ype ESR1 pa ien s (coho 1 þcoho 2). ESR1 ho spo mu a ions we e analysed in baseline ci cula ing umou DNA. Resul s: F om Ma ch 2014 o July 2018, 296 and 305 pa ien s we e included in coho 1 and coho 2, espec i ely. Palbociclib plus ET was no supe io o capeci abine in bo h coho 2 [median PFS: 7.5 e sus 10.0 mon hs; adjus ed *Co espondence o: P o esso Miguel Ma ín, Medical Oncology, Ins i u o de In es igación Sani a ia G ego io Ma añón, CIBERONC-ISCIII GEICAM Spanish B eas Cance G oup, Doc o Esque do, 46, Mad id, Spain, 28007. Tel: þ34-91659-28-70 E-mail: [email p o ec ed] (M. Ma in). y These au ho s con ibu ed equally o his s udy. 5 This s udy has been p e iously p esen ed a San An onio B eas Cance Symposium; 10-14 Decembe 2019; San An onio, TX. Philadelphia (PA): AACR; Published a Cance Res 2020;80(4 Suppl): Abs ac numbe GS2-07. Cance Res Feb ua y 14 2020;80 (4 Supplemen ) GS2-07-GS2-07; h ps://doi.o g/10.1158/1538-7445. SABCS19-GS2-07 Published Feb ua y 2020. Final PFS esul s we e p esen ed as a pos e discussion a he Ame ican Socie y o Clinical Oncology (ASCO) i ual mee ing and he quali y-o -li e da a has been p esen ed as a pos e a he i ual Eu opean Socie y o Medical Oncology (ESMO) B eas Cance Mee ing. 0923-7534/© 2020 The Au ho (s). Published by Else ie L d on behal o Eu opean Socie y o Medical Oncology. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). Volume xxx -Issue xxx -2021 h ps://doi.o g/10.1016/j.annonc.2020.12.013 1 haza d a io (aHR): 1.13; 95% confidence in e al (CI): 0.85-1.50] and wild- ype ESR1 pa ien s (median PFS: 8.0 e sus 10.6 mon hs; aHR: 1.11; 95% CI: 0.87-1.41). The mos equen g ade 3-4 oxici ies wi h palbociclib plus exemes ane, palbociclib plus ul es an and capeci abine, espec i ely, we e neu openia (57.4%, 55.7% and 5.5%), hand/ oo synd ome (0%, 0% and 23.5%), and dia hoea (1.3%, 1.3% and 7.6%). Palbociclib plus ET o e ed be e quali y o li e (aHR o ime o de e io a ion o global heal h s a us: 0.67; 95% CI: 0.53-0.85). Conclusions: The e was no s a is ical supe io i y o palbociclib plus ET o e capeci abine wi h espec o PFS in MBC pa ien s esis an o AIs. Palbociclib plus ET showed a be e sa e y p ofile and imp o ed quali y o li e. Key wo ds: palbociclib, capeci abine, me as a ic b eas cance , ho mone ecep o -posi i e, HER2-nega i e, endoc ine he apy INTRODUCTION Un il ecen ly, single-agen endoc ine he apy (ET) was he ecommended choice o ea men o mos women wi h ho mone ecep o -posi i e and human epide mal g ow h ac o ecep o 2 (HER2)-nega i e me as a ic b eas cance (MBC). Un o una ely, no all pa ien s espond o ET due o p ima y o acqui ed esis ance. In he pas decade, new a ge ed he apies, mainly cyclin-dependen kinase 4/6 (CDK4/6) inhibi o s, in combina ion wi h ET ha e signifi- can ly imp o ed p og ession- ee su i al (PFS) 1-7 and o e all su i al (OS) 8-10 compa ed wi h ET alone in pa ien s wi h ea men -nai e o p e ea ed MBC. The PALOMA-3 ial 4 showed ha palbociclib plus ul- es an significan ly imp o ed PFS as opposed o ul es- an plus placebo [haza d a io (HR): 0.46; P<0.0001] in pa ien s who expe ienced cance elapse o p og ession du ing o wi hin 12 mon hs o comple ing adju an ET o while hey we e on ET o wi hin 1 mon h o p io ET o MBC. Consequen ly, palbociclib plus ul es an was app o ed by he Food and D ug Adminis a ion and he Eu opean Medicines Agency o hese pa ien s. Tha ial showed ha adding palbociclib o ul es an significan ly delayed disease p og ession compa ed wi h ul es an alone in pa ien s esis an o a oma ase inhibi o s (AIs). Howe e , we s ill conside ed i necessa y o analyse he e ficacy di e ences be ween palbociclib plus ET and o he cu en s anda ds o ca e in MBC pa ien s esis an o AIs, such as chemo he apy. In 2014, he GEICAM Spanish B eas Cance G oup s a - ed he PEARL ial in collabo a ion wi h he Cen al Eu o- pean Coope a i e Oncology G oup (CECOG). This ial compa ed palbociclib plus ET wi h capeci abine in a popu- la ion o pos menopausal pa ien s e y simila o hose in he PALOMA-3 ial. We selec ed capeci abine as he chemo he apy agen as i is conside ed o be one o he mos ac i e d ugs a ailable o MBC, wi h median PFS anging om 2.8 o 5.9 mon hs (which was e en highe in pa ien s wi h ho mone ecep o -posi i e disease) and OS imes o 9.3-18.1 mon hs in p e iously ea ed MBC pa- ien s. 11-14 We combined palbociclib wi h exemes ane in he ini ial s udy design; howe e , a e he eme ging e i- dence ha pa ien s p e ea ed wi h AIs may de elop ESR1 mu a ions ha gene a e esis ance o AIs, we in oduced a second coho in which palbociclib was combined wi h ul es an . 15,16 METHODS S udy design The PEARL ial (clinical ial egis a ion numbe : ClinT ials. go e e ence NCT02028507), a mul icen e, in e na ional, open-label, con olled, andomised phase III s udy wi h wo successi e coho s o simila cha ac e is ics, was ca ied ou in ou coun ies (37 si es): Spain (GEICAM), Aus ia, Hunga y, and Is ael (CECOG). Coho 1 pa ien s we e andomised 1 : 1 o ecei e palbociclib (125 mg/day o 3 weeks ollowed by 1 week o ) plus exemes ane (25 mg/ day) o capeci abine [acco ding o he app o ed label: 2500 mg/m 2 /day (2000 mg/m 2 /day in pa ien s aged >70 yea s old) o 2 weeks ollowed by 1 week o ]. The s udy hy- po hesis endo sed he supe io i y o palbociclib plus exemes ane o e capeci abine (expec ed PFS, HR: 0.686, wi h a 5% significance le el). In Decembe 2015, new da a sugges ed ha exemes ane in pa ien s who ha e p o- g essed on AIs could be a subop imal op ion because ESR1 mu a ions may con e AI he apy esis ance in pa ien s p e iously exposed o AIs (wi h a equency o mu a ions o 29%-37%). 15-17 One o he s udies sugges ed ha ul es- an may be e ec i e in pa ien s wi h ESR1 mu a ion- posi i e umou s. 16 In May 2016, a p o ocol amendmen wi h a modifica ion o ial design and objec i es was app o ed be o e any e ficacy da a we e a ailable. The e o e, a subsequen coho 2 was in oduced, in which pa ien s we e andomised 1 : 1 o ecei e palbociclib (same schedule as coho 1) plus ul es an (500 mg in amuscula injec- ion on days 1 and 15 o cycle 1; hen on day 1 o subse- quen 28-day cycles) o capeci abine (same schedule as coho 1). A ha ime, 296 pa ien s we e al eady ec ui ed in coho 1 ( om an ini ial planned sample o 348 pa ien s). The new s udy hypo heses endo sed he supe io i y o palbociclib plus ul es an o e capeci abine and palboci- clib plus ET o e capeci abine in pa ien s wi h wild- ype ESR1 (expec ed PFS, HR: 0.667, wi h a 5% significance le el) (Supplemen a y Ma e ial S1, a ailable a h ps://doi. o g/10.1016/j.annonc.2020.12.013). Randomisa ion was ca ied ou cen ally a he GEICAM headqua e s. In bo h he coho s, s a ifica ion c i e ia we e disease si e ( isce al/non- isce al), sensi i i y o p io ET [ elapse a e 24 mon hs o adju an ET o esponse (comple e o pa ial) o s abilisa ion a e 24 weeks o he mos ecen ET in he con ex o ad anced disease (yes/ Annals o Oncology M. Ma in e al. 2h ps://doi.o g/10.1016/j.annonc.2020.12.013 Volume xxx -Issue xxx -2021 no)], p io chemo he apy o MBC (yes/no), and coun y o o igin. The ea men con inued un il ei he objec i e dis- ease p og ession, acco ding o he RECIST 1.1, 18 symp- oma ic de e io a ion, unaccep able oxici y, dea h, o wi hd awal o consen , whiche e occu ed fi s . As-pe - p o ocol dose educ ions o palbociclib and capeci abine we e allowed in case o oxici y. Upon comple ion o he s udy ea men , pa ien s we e moni o ed o su i al e e y 6 mon hs. Resea ch p o ocol was app o ed by e e y si e’s ins i u- ional e iew boa d and e e y coun y’s egula o y agency. All he pa ien s signed w i en in o med consen s. Sa e y and e ficacy da a we e con inuously e alua ed by an inde- penden da a moni o ing commi ee. The da a we e ana- lysed by a s a is ician employed by GEICAM. Pa ien s Pos menopausal women wi h ho mone ecep o -posi i e and HER2-nega i e AI- esis an MBC (defined as ecu - ence: while on o wi hin 12 mon hs a e he end o adju an ea men o p og ession; while on o wi hin 1 mon h a e he end o ea men o ad anced disease) we e included. Pa ien s had o ha e measu able disease assessable by compu ed omog aphy (CT)/magne ic imaging esonance (MRI) acco ding o RECIST 1.1 o a leas one ly ic o mixed bone lesion. One chemo he apy line o MBC was pe mi ed. Addi ional inclusion c i e ia included Eas e n Coope a i e Oncology G oup pe o mance s a us (ECOG) o 0 o 1, li e expec ancy o 12 weeks o mo e, and adequa e o gan unc ion. Pa ien s who ecei ed p io ea men wi h CDK4/6, mammalian a ge o apamycin (mTOR) o phosphoinosi- ide 3-kinase (PI3K) inhibi o s, capeci abine, o pa ien s wi h isce al c isis we e excluded. Pa ien s we e equi ed o ha e a co ec ed QT in e al (QTc) <480 ms and no amily o pe sonal his o y o long o sho QT synd ome, B ugada synd ome, To sade de Poin es, o known his o y o QTc p olonga ion. T ial assessmen s Baseline disease assessmen s (ca ied ou wi hin 4 weeks be o e andomisa ion), equi ed a CT o MRI scan o he ches , abdomen, and pel is. Assessmen s we e ca ied ou e e y 8 weeks o 120 weeks and hen e e y 12 weeks un il documen ed p og essi e disease, ini ia ion o a new an i- cance he apy, o pa ien d opou . Pa ien s who dis- con inued s udy ea men o easons o he han p og essi e disease had umou assessmen s e e y 12 weeks. Haema ology and biochemis y es s we e ca ied ou be o e each cycle; haema ology es ing was addi ionally ca ied ou on day 14 o cycles 1 and 2 in he palbociclib a ms. Ad e se e en s (AEs) we e assessed and g aded a each cycle acco ding o Na ional Cance Ins i u e common e minology c i e ia o ad e se e en s (NCI-CTCAE) e sion 4.0. Pa ien s comple ed he Eu opean O ganiza ion o Resea ch and T ea men o Cance co e quali y-o -li e (EORTC QLQ-C30; 3.0), 19 BC-specific (EORTC QLQ-BR23; 1.0), 20 and he Eu oQoL Heal h U ili ies Index EQ-5D-3L 21 ques ionnai es a baseline, a e e y wo cycles o he fi s se en cycles, hen a e e y h ee cycles un il he end o ea men , and once again a he isi a e ea men . Pa ien s we e equi ed o ha e a manda o y plasma sample d awn o explo a o y bioma ke analyses in ci cu- la ing umou DNA (c DNA) ob ained be o e ea men onse . Wi h he p o ocol amendmen o include coho 2, he ESR1 mu a ional s a us assessmen was a p edefined analysis equi ed o e alua e he p ima y objec i e o he s udy. The esul s we e blinded o pa ien s and in es iga o s (Supplemen a y Ma e ial S2, a ailable a h ps://doi.o g/ 10.1016/j.annonc.2020.12.013). In addi ion, o malin-fixed pa a fin-embedded umou samples we e collec ed be o e s udy en y o gene ically iden i y in insic BC sub ypes (Luminal A and B, HER2- en iched, basal-like, and no mal-like) using he HTG Edge- Seq Oncology Bioma ke Panel (Supplemen a y Ma e ial S3, a ailable a h ps://doi.o g/10.1016/j.annonc.2020.12.013). Objec i es and endpoin s The ini ial p ima y objec i e was o compa e PFS wi h pal- bociclib plus exemes ane and ha wi h capeci abine ea - men . A e he p o ocol amendmen o include coho 2, he wo new co-p ima y objec i es we e o compa e PFS o pa ien s ea ed wi h (i) palbociclib plus ul es an e sus capeci abine ega dless o ESR1 mu a ional s a us and (ii) palbociclib plus ET (exemes ane o ul es an ) e sus capeci abine in pa ien s wi h wild- ype ESR1 in c DNA a s udy en y. PFS was defined as he ime om andom- isa ion o he fi s documen a ion o p og essi e disease based on in es iga o s’assessmen s acco ding o RECIST 1.1 o o dea h om any cause. Seconda y objec i es included, among o he s, PFS wi h palbociclib plus ET e sus capeci abine ega dless o ESR1 mu a ional s a us, objec i e esponse a e (ORR), clinical benefi a e (CBR) (defined as ORR plus s able disease a e o a leas 24 weeks du a ion), esponse du a ion (RD), OS, sa e y, and pa ien - epo ed ou comes (PROs). Conce ning PROs, we epo ed he ime o de e io a ion o he global heal h s a us om he EORTC QLQ-C30, defined as he ime om andomisa ion o fi s de ec ion o a de e io a ion e en (ma ked wi h a dec ease o 10 poin s om he baseline). Addi ionally, we explo ed he independen p ognos ic and p edic i e alue o in insic sub ypes. S a is ical analysis A o al o 193 PFS e en s we e equi ed in coho 2 o ha e 80% powe o de ec a di e ence be ween capeci abine (es ima ed median PFS o 6 mon hs) and palbociclib plus ul es an (median PFS o 9 mon hs 4 ), o an HR o 0.667, wi h a 5% significance le el. The a ge sample size was 300 pa ien s. To de ec he same di e ence be ween M. Ma in e al. Annals o Oncology Volume xxx -Issue xxx -2021 h ps://doi.o g/10.1016/j.annonc.2020.12.013 3 capeci abine and palbociclib plus ET in pa ien s wi h wild- ype ESR1 and assuming an 80% c DNA collec ion/de ec- ion a e and 30% o he pa ien s wi h ESR1 mu a ions, he equi ed sample size was also 300 pa ien s. The s udy was designed o ha e wo in e im analyses and a final analysis. The final PFS analysis was planned when 193 e en s in coho 2 we e obse ed. A modifica ion o Hochbe g’s me hod 22 was used o wo p ima y ea men compa isons o p o ide he con ol o expe imen -wise ype 1 e o a e a a wo-sided 5% significance le el. The KaplaneMeie me hod was used o es ima e he median PFS; 95% confidence in e als (CIs) we e p o ided o es ima es o in e es . The Cox p opo ional-haza ds model was used o calcula e he unadjus ed and adjus ed HR (aHR) (by s a ifica ion ac o s and numbe o in ol ed si es) and 95% CI. E ficacy analyses we e based on wo popula ions: all andomised pa ien s [in en ion- o- ea (ITT) popula ion] and all andomised pa ien s wi h wild- ype ESR1 in c DNA a s udy en y (wild- ype ESR1 popu- la ion). Sa e y analysis was ca ied ou on all pa ien s who ecei ed one o mo e dose o s udy he apy. PROs analysis was ca ied ou on pa ien s wi h baseline and one o mo e quali y o li e (QoL) ques ionnai es comple ed. Time o de e io a ion was analysed using Cox eg ession models. RESULTS Pa ien s and ea men A o al o 601 pa ien s we e included in his s udy om Ma ch 2014 o July 2018. Coho 1 included 296 pa ien s (153 on palbociclib plus exemes ane and 143 on capeci a- bine) and coho 2 included 305 pa ien s (149 on palbociclib plus ul es an and 156 on capeci abine). E ficacy analyses included all pa ien s, bu sa e y analyses excluded 13 pa- ien s (10 on capeci abine and 3 on palbociclib plus ET) ne e ecei ing s udy ea men . ESR1 mu a ions we e assessed in 557 pa ien s (92.7%), 91% o who we e om he capeci abine a ms and 94% we e om he palbociclib plus ET a ms; 164 o hem (29%) had ESR1 mu a ions (Figu e 1). All he baseline demog aphics and disease cha ac e is ics we e balanced be ween he a ms ac oss bo h he coho s, excep o he numbe o in ol ed si es (g ea e in he capeci abine a m in coho 2) (Table 1). Coho 1 N = 296 Randomised N = 601 Coho 2 N = 305 Palbociclib + exemes ane N = 153 Capeci abine N = 143 Palbociclib + ul es an N = 149 Capeci abine N = 156 Sc eening ailu e N = 92 No ea men N = 3 No ea men N = 6 No ea men N = 4 Regis e ed N = 693 Mu an N = 48 (32.9%) WT N = 98 (67.1%) Mu an N = 38 (27.1%) WT N = 102 (72.8%) Mu an N = 37 (29.4%) WT N = 89 (70.6%) Mu an N = 41 (28.3%) WT N = 104 (71.7%) Sa e y N = 150 (98.0%) Sa e y N = 137 (95.8%) ESR1a N = 145 (94.8%) ESR1b N = 126 (88.1%) Sa e y N = 149 (100%) ESR1c N = 140 (94%) Sa e y N = 152 (97.4%) ESR1d N = 146 (93.6%) Figu e 1. Conso diag am. ESR1, es ogen ecep o 1; WT, wild- ype ESR1. a No ea men n¼2 and sample no a ailable n¼6. b No ea men n¼6 and sample no a ailable n¼11. c Sample no a ailable n¼9. d No ea men n¼3 and sample no a ailable n¼7. Annals o Oncology M. Ma in e al. 4h ps://doi.o g/10.1016/j.annonc.2020.12.013 Volume xxx -Issue xxx -2021 Table 1. Pa ien s’baseline cha ac e is ics (in en ion- o- ea popula ion) Va iables Coho 1 Coho 2 Palbociclib plus exemes ane Capeci abine Palbociclib plus ul es an Capeci abine n¼153 n¼143 P alue n¼149 n¼156 P alue Demog aphics and disease cha ac e is ics Median age, yea s ( ange) 60 (31-89) 60 (38-87) 0.5574 62 (38-86) 60 (33-85) 0.2618 ECOG pe o mance s a us c ,n(%) 0 85 (55.6) 84 (58.7) 0.5800 90 (60.4) 93 (59.6) 0.8884 1 68 (44.4) 59 (41.3) 59 (39.6) 63 (40.4) Visce al disease, n(%) Yes 103 (67.3) 94 (65.7) 0.8379 97 (65.1) 102 (65.4) 0.9585 No 50 (32.7) 48 (33.6) 52 (34.9) 54 (34.6) Mos equen disease si es, n(%) Bone 107 (69.9) 101 (70.6) 0.8960 97 (65.1) 114 (73.1) 0.1316 Li e 67 (43.8) 61 (42.7) 0.8441 60 (40.3) 68 (43.6) 0.5569 B eas /skin/subcu aneous/lymph node 62 (40.5) 72 (50.3) 0.0896 63 (42.3) 84 (53.8) 0.0433 a,b Lung 44 (28.8) 38 (26.6) 0.6747 40 (26.8) 44 (28.2) 0.7905 Pleu a 19 (12.4) 20 (14.0) 0.6903 12 (8.1) 23 (14.7) 0.0669 Numbe o in ol ed si es, n(%) 1 47 (30.7) 32 (22.4) 0.2196 56 (37.6) 35 (22.4) 0.0147 a 2 62 (40.5) 59 (41.3) 48 (32.2) 60 (38.5) 3 44 (28.8) 51 (35.7) 45 (30.2) 61 (39.1) Tumou cha ac e is ics Ho mone ecep o s a us, n(%) d ERþPRþ114 (74.5) 103 (72.0) 114 (76.5) 118 (75.6) ERþPRe36 (23.5) 38 (26.6) 33 (22.2) 33 (21.2) ERePRþo ERþPR no a ailable e 2 (1.3) 2 (1.4) 2 (1.3) 5 (3.2) ESR1 mu a ional s a us, n(%) Wild- ype 104 (68.0) 89 (62.2) 0.8434 102 (68.5) 98 (62.8) 0.2905 Mu an 41 (26.8) 37 (25.9) 38 (25.5) 48 (30.8) No a ailable 8 (5.2) 17 (11.9) 9 (6.0) 10 (6.4) Sensi i i y o p io endoc ine he apy, n(%) Yes 107 (69.9) 104 (72.7) 0.5956 119 (79.9) 122 (78.2) 0.7218 No 46 (30.1) 39 (27.3) 30 (20.1) 34 (21.8) Genomic sub ype, n(%) g n[117 n[107 n[112 n[119 Luminal A 61 (52.1) 61 (57.0) 58 (51.8) 52 (43.7) Luminal B 49 (41.9) 42 (39.3) 43 (38.4) 58 (48.7) HER2-en iched 5 (4.3) 4 (3.7) 11 (9.8) 9 (7.6) Basal-like 2 (1.7) 0 0 0 P io he apy Numbe o p io lines o endoc ine he apy o MBC, n(%) No p io endoc ine he apy o MBC 30 (19.6) 31 (21.7) 38 (25.5) 44 (28.2) 1 82 (53.6) 70 (49.0) 85 (57.0) 90 (57.7) 2 35 (22.9) 34 (23.8) 12 (8.1) 9 (5.8) 3 3 (2.0) 4 (2.8) 1 (0.7) 1 (0.6) Main enance a e chemo he apy 3 (2.0) 4 (2.8) 12 (8.1) 12 (7.7) P io endoc ine he apy o MBC, n(%) A oma ase inhibi o 106 (69.3) 105 (73.4) 0.4308 111 (74.5) 109 (69.9) 0.3679 Ful es an 44 (28.8) 35 (24.5) 0.4052 0 1 (0.6) 0.3276 O he selec i e es ogen ecep o deg ade 0 0 - 2 (1.3) 1 (0.6) 0.5350 Tamoxi en 16 (10.5) 17 (11.9) 0.6960 12 (8.1) 16 (10.3) 0.5054 Lu einising ho mone- eleasing ho mone analogues 10 (6.5) 11 (7.7) 0.6986 8 (5.4) 14 (9.0) 0.2238 P io chemo he apy o MBC, n(%) Yes 48 (31.4) 41 (28.7) 0.6125 41 (27.5) 41 (26.3) 0.8079 No 105 (68.6) 102 (71.3) 108 (72.5) 115 (73.7) Line a s udy en y, h n(%) 1s line 27 (17.6) 31 (21.7) 0.5498 38 (25.5) 43 (27.6) 0.8477 2nd line 61 (39.9) 50 (35.0) 76 (51.0) 79 (50.6) 3 d line 62 (40.5) 62 (43.3) 35 (23.5) 34 (21.8) Con inued M. Ma in e al. Annals o Oncology Volume xxx -Issue xxx -2021 h ps://doi.o g/10.1016/j.annonc.2020.12.013 5 A he cu -o da e o he p ima y analysis (14 Janua y 2019), 80 pa ien s we e s ill on he s udy ea men : 10 (6.7%) we e on palbociclib plus exemes ane, 37 (24.8%) on palbociclib plus ul es an , and 33 (11%) on capeci abine. The median ela i e dose-in ensi y in coho 1 was 82.6% o capeci abine, 100% o exemes ane, and 95.2% o pal- bociclib, and ha in coho 2 was 79.5% o capeci abine, 100% o ul es an , and 92.9% o palbociclib. The median ime on s udy he apy in coho 1 was highe o capeci- abine, 7.9 mon hs ( ange: 0.2-50.5), han o palbociclib plus exemes ane, 6.3 mon hs ( ange: 0.5-52.3). Howe e , in coho 2 he median ime on s udy he apy was 6.3 mon hs o capeci abine ( ange: 0.2-26.4) and 7.8 mon hs o pal- bociclib plus ul es an ( ange: 0.8-31.1). The main eason o pe manen discon inua ion o he ea men was dis- ease p og ession. In bo h coho s, he p opo ion o pa- ien s who discon inued due o p og essi e disease was smalle in he capeci abine a m (65.7% in coho 1, 58.6% in coho 2) han in he palbociclib plus exemes ane (81.3%) and palbociclib plus ul es an a ms (68.5% in coho 2) (Supplemen a y Table S1, a ailable a h ps://doi.o g/10. 1016/j.annonc.2020.12.013). E ficacy The median ollow-ups o coho 2 and he wild- ype ESR1 popula ion we e 13.5 mon hs ( ange: 0.0-30.7) and 18.9 mon hs ( ange: 0.0-56.3), espec i ely. The median PFS in coho 2 was 7.5 mon hs (95% CI: 5.7-10.9) in he palbo- ciclib plus ul es an a m and 10.0 mon hs (95% CI: 6.3- 12.9) in he capeci abine a m (aHR: 1.13; 95% CI: 0.85-1.50; P¼0.398). The median PFS in he wild- ype ESR1 popula- ion was 8.0 mon hs (95% CI: 6.5-10.9) in he palbociclib plus ET a m and 10.6 mon hs (95% CI: 7.4-13.0) in he capeci abine a m (aHR: 1.11; 95% CI: 0.87-1.41; P¼0.404) (Figu e 2). PFS subg oup analyses by s a ifica ion ac o s and o he baseline cha ac e is ics in coho 2 and in he wild- ype ESR1 popula ion (Figu e 3), as well as in he o e all popula ion ega dless o ESR1 mu a ional s a us (Supplemen a y Figu e S1, a ailable a h ps://doi.o g/10. 1016/j.annonc.2020.12.013) confi med he non-supe io i y o palbociclib plus ET o e capeci abine. Rega ding he s udy’s seconda y endpoin s o e ficacy, he median PFS in all pa ien s om coho 1 and coho 2 was 7.4 mon hs (95% CI: 5.9-9.3) in he palbociclib plus ET a m and 9.4 mon hs (95% CI: 7.5-11.3) in he capeci abine a m (aHR: 1.11; 95% CI: 0.92-1.34; P¼0.380) (Supplemen a y Figu e S2, a ailable a h ps://doi.o g/10. 1016/j.annonc.2020.12.013). The aHR o PFS in he mu an ESR1 popula ion was 1.12 (95% CI: 0.78-1.60; P¼ 0.540) as shown in Supplemen a y Figu e S3, a ailable a h ps://doi.o g/10.1016/j.annonc.2020.12.013. The ORR in coho 2 was 26.7% o palbociclib plus ul es an e sus 33.3% o capeci abine. In pa ien s wi h ESR1 wild- ype, ORR was 27.8% o palbociclib plus ET e sus 36.9% o capeci abine. The CBR was e y simila be ween he a ms in coho 2 and he pa ien s wi h ESR1 wild- ype. The median RD in coho 2 was 9.4 mon hs in he palbociclib plus ul- es an a m and 12.9 mon hs in he capeci abine a m (HR: 0.69; 95% CI: 0.33-1.46; P¼0.335). Finally, he median RD in he wild- ype ESR1 popula ion was 9.7 mon hs in he palbociclib plus ET a m and 11.2 mon hs in he capeci abine a m (HR: 0.75; 95% CI: 0.44-1.25; P¼0.269) (Supplemen a y Table S2, a ailable a h ps://doi.o g/10. 1016/j.annonc.2020.12.013). PROs The comple ion a e o he ques ionnai es was simila ac oss he a ms, su passing 82% un il cycle 13. The median ime o de e io a ion in global heal h s a us was 8.6 mon hs in pa ien s ea ed wi h palbociclib plus ET e sus 6.2 mon hs in hose ea ed wi h capeci abine (aHR: 0.67, 95% CI: 0.53-0.85; P¼0.001) (Figu e 4). Table 1. Con inued Va iables Coho 1 Coho 2 Palbociclib plus exemes ane Capeci abine Palbociclib plus ul es an Capeci abine n¼153 n¼143 P alue n¼149 n¼156 P alue S a us a ini ial diagnosis, n(%) M0 127 (83.0) 109 (76.2) 0.1469 115 (77.2) 120 (76.0) 0.9573 M1 (de no o MBC) 26 (17.0) 34 (23.8) 34 (22.8) 36 (23.1) P alue s a is ically significan . ER, es ogen ecep o ; ESR1, es ogen ecep o 1; ET, endoc ine he apy; HER2, human epide mal g ow h ac o ecep o 2; Lum, luminal; MBC, me as a ic b eas cance ; PR, p oges e one ecep o . a No significan di e ences in pa ien s’baseline cha ac e is ics we e iden ified be ween ea men g oups, excep o he numbe o in ol ed si es and b eas /skin/subcu aneous/ lymph node disease si e in coho 2. b Haza d a ios we e no adjus ed by ‘b eas /skin/subcu aneous/lymph node’as disease si e, because his i em is included wi hin s a ifica ion ac o ( isce al e sus non- isce al). c Eas e n Coope a i e Oncology G oup (ECOG) pe o mance s a us sco es ange om 0 o 5, wi h 0 indica ing no symp oms and highe sco es indica ing g ea e disabili y. d Based on local labo a o y de e mina ion, posi i e defined as 1% posi i e cells by immunohis ochemis y o ER and/o PR. Ho mone ecep o s a us was e alua ed on p ima y umou s in 62.1% o pa ien s and on me as a ic lesions in 37.9% o hem. e One pa ien ea ed wi h exemes ane þpalbociclib was iple-nega i e (p o ocol de ia ion). Sensi i i y o p io endoc ine he apy was defined as elapse a e 24 mon hs o adju an ET o esponse (comple e o pa ial) o s abilisa ion a e 24 weeks o he mos ecen ET in he con ex o ad anced disease. g By HTG EdgeSeq Oncology Bioma ke Panel. h Line a s udy en y means he ea men line ecei ed in he s udy, conside ing all p io lines o he apy, ei he chemo he apy and/o endoc ine he apy. Annals o Oncology M. Ma in e al. 6h ps://doi.o g/10.1016/j.annonc.2020.12.013 Volume xxx -Issue xxx -2021 Sa e y Sa e y in o ma ion is shown in Table 2 and Supplemen a y Table S3, a ailable a h ps://doi.o g/10.1016/j.annonc. 2020.12.013. The mos equen g ade 3-4 oxici ies in he palbociclib plus exemes ane, palbociclib plus ul es an , and capeci abine a ms, we e neu openia [(57.4%, 55.7%, 5.5%, espec i ely) wi h eb ile neu openia (1.3%, 0.7%, 1.4%, espec i ely)], hand/ oo synd ome (0%, 0%, 23.5%, espec i ely), dia hoea (1.3%, 1.3%, 7.6%, espec i ely), a igue (1.3%, 0.7%, 5.5%, espec i ely), and anaemia (0.7%, 2.0%, 3.5%, espec i ely). The incidence o non- haema ologic oxici y g ade 3 was highe o pa ien s on capeci abine (38.8%) han o hose on palbociclib plus exemes ane (6.7%) o palbociclib plus ul es an (6.0%). No ably, g ade 1-2 alopecia was epo ed in 11.0% o he 0 6 12 18 24 30 Time (mon hs) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P og ession- ee su i al p obabili y 156 70 39 12 3 0 149 84 35 18 5 1 Capeci abine Palbo + ul e ACoho 2 No. o pa ien s No. o e en s (%) No. o censo ed (%) PFS median no. o mon hs (95% CI) Palbociclib + ul es an 149 108 (72.5) 41 (27.5) Capeci abine 156 94 (60.3) 62 (39.7) No. a isk Palbociclib + ul es an Capeci abine 0 6 12 18 24 30 36 42 48 Time (mon hs) 187 101 58 27 16 12 6 3 1 206 116 67 41 19 12 7 6 5 Capeci abine Palbo + ET B No. a isk Capeci abine Palbociclib + ET Wild- ype ESR1 (Coho 1 + Coho 2) Adjus ed haza d a io (95% CI): 1.13 (0.85-1.50), P = 0.398 7.5 (5.7-10.9) 10.0 (6.3-12.9) No. o pa ien s No. o e en s (%) No. o censo ed (%) PFS median no. o mon hs (95% CI) Palbociclib + ET 206 161 (78.2) 45 (21.8) Capeci abine 187 126 (67.4) 61 (32.6) 8.0 (6.5-10.9) 10.6 (7.4-13.0) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 P og ession- ee su i al p obabili y Adjus ed haza d a io (95% CI): 1.11 (0.87-1.41), P = 0.404 Figu e 2. P og ession- ee su i al. KaplaneMeie cu es o PFS we e ep esen ed o (A) pa ien s in coho 2: palbociclib plus ul es an e sus capeci abine and (B) pa ien s wi h wild- ype ESR1 om coho 1 þcoho 2: palbociclib plus endoc ine he apy e sus capeci abine. Haza d a ios we e adjus ed by disease si e, p io sensi i i y o endoc ine he apy, p io chemo he apy o me as a ic b eas cance , and he numbe o in ol ed si es. CI, confidence in e al; ESR1, es ogen ecep o 1; ET, endoc ine he apy; ul e, ul es an ; No, numbe ; Palbo, palbociclib; PFS, p og ession- ee su i al. M. Ma in e al. Annals o Oncology Volume xxx -Issue xxx -2021 h ps://doi.o g/10.1016/j.annonc.2020.12.013 7 pa ien s on palbociclib plus ET as opposed o 3.8% o he pa ien s on capeci abine. Se ious AEs ela ed o he s udy ea men we e epo ed by 10.4% o he pa ien s on capeci abine, 4.0% o he pa- ien s on palbociclib plus exemes ane, and 3.4% o he pa ien s on palbociclib plus ul es an . A o al o 46 pa ien s on capeci abine (15.9%) d opped ou due o AEs compa ed wi h 9 pa ien s (6%) on palboci- clib plus exemes ane and 10 pa ien s (6.7%) on palbociclib plus ul es an . O he 17 dea hs obse ed du ing he s udy ea men , 11 we e due o p og essi e disease; wo se ious AEs Subg oup 0.996 0.165 0.634 0.335 0.516 0.678 0.302 0.927 0.260 0.514 0.878 0.078 0.423 0.652 0.191 0.425 0.25 0.5 1 1.5 2 3 1.00 (0.75-1.34) 1.33 (0.89-1.99) 1.07 (0.81-1.42) 1.22 (0.81-1.85) 1.16 (0.74-1.83) 1.06 (0.81-1.39) 1.16 (0.87-1.54) 0.98 (0.65-1.48) 1.30 (0.82-2.07) 1.10 (0.83-1.45) 1.02 (0.79-1.33) 1.63 (0.95-2.80) 1.21 (0.76-1.95) 0.92 (0.65-1.31) 1.34 (0.86-2.08) 1.10 (0.87-1.39) (70.4) (63.4) (63.6) (76.4) (71.7) (66.0) (67.2) (67.7) (64.4) (68.8) (68.5) (64.9) (63.2) (74.3) (64.8) (67.4) 81/115 45/71 84/132 42/55 33/46 93/141 84/125 42/62 29/45 97/141 102/149 24/37 36/57 55/74 35/54 126/187 (78.8) (76.8) (75.0) (86.2) (77.2) (78.5) (85.4) (65.8) (73.0) (81.1) (75.7) (89.2) (75.5) (80.2) (78.3) (78.2) 108/137 53/69 111/148 50/58 44/57 117/149 111/130 50/76 54/74 107/132 128/169 33/37 37/49 77/96 47/60 161/206 Visce al Non- isce al P io sensi i i y o ET: yes P io sensi i i y o ET: no P io CT o MBC: yes P io CT o MBC: no Age <65 yea s Age ≥65 yea s One si e o disease Mul iple si es o disease Measu able lesions Non-measu able lesions T ea men line: 1s T ea men line: 2nd T ea men line: ≥3 d ALL Palbociclib + ET be e Capeci abine be e Palbociclib + ET Capeci abine Palbociclib + ul es an Coho 2 (n = 305) A Wild-Type ESR1 (Coho 1 + coho 2) (n = 393) B Capeci abine Haza d a io (95% CI)E en s/N (%)E en s/N (%) Haza d a io (95% CI)E en s/N (%)E en s/N (%) Subg oup 0.811 0.497 0.974 0.057 0.784 0.419 0.566 0.814 0.155 0.786 0.630 0.558 0.503 0.515 0.786 0.880 0.734 0.599 0.25 0.5 11.5 2 3 1.04 (0.75-1.45) 1.19 (0.72-1.98) 0.99 (0.73-1.36) 1.79 (0.98-3.28) 0.93 (0.55-1.56) 1.15 (0.82-1.59) 1.10 (0.79-1.55) 1.06 (0.65-1.72) 1.54 (0.85-2.81) 1.05 (0.76-1.44) 1.08 (0.79-1.47) 1.20 (0.65-2.24) 0.83 (0.47-1.45) 1.14 (0.77-1.67) 1.09 (0.60-1.96) 1.03 (0.73-1.44) 1.10 (0.64-1.87) 1.08 (0.82-1.42) (48.1) (59.0) (64.7) (68.3) (57.4) (61.2) (58.5) (42.9) (65.3) (61.9) (53.3) (59.5) (64.1) (59.4) (61.2) (62.5) (60.3) (66.7)68/102 26/54 72/122 22/34 28/41 66/115 63/103 31/53 15/35 79/121 78/126 16/30 25/42 50/78 19/32 60/98 30/48 94/156 (69.2) (70.6) (80.0) (75.6) (71.3) (78.5) (62.5) (67.9) (75.3) (69.8) (81.8) (68.4) (71.1) (80.0) (74.5) (65.8) (72.5) (74.2) 72/97 36/52 84/119 24/30 31/41 77/108 73/93 35/56 38/56 70/93 81/116 27/33 26/38 54/76 28/35 76/102 25/38 108/149 Visce al Non- isce al P io sensi i i y o ET: yes P io sensi i i y o ET: no P io CT o MBC: yes P io CT o MBC: no Age <65 yea s Age ≥65 yea s One si e o disease Mul iple si es o disease Measu able lesions Non-measu able lesions T ea men line: 1s T ea men line: 2nd T ea men line: ≥3 d Wild- ype ESR1 Mu an ESR1 ALL Palbociclib + ul es an be e Capeci abine be e P aluea P alueb Figu e 3. Fo es plo o p og ession- ee su i al haza d a ios by subg oups. Subg oups o p og ession- ee su i al and hei espec i e haza d a ios we e ep esen ed o (A) pa ien s in coho 2: palbociclib plus ul es an e sus capeci abine and (B) pa ien s wi h wild- ype ESR1 om coho 1 þcoho 2: palbociclib plus endoc ine he apy e sus capeci abine. P alues om ManneWhi ney es (con inuous a iables) and chi-squa e es (ca ego ical a iables). CI, confidence in e al; CT, chemo he apy; ESR1, es ogen ecep o 1; ET, endoc ine he apy; MBC, me as a ic b eas cance ; ALL, all pa ien s o Coho 2 (Figu e A) all pa ien s Wild-Type ESR1 (Coho 1 + coho 2) (Figu e B). a Unadjus ed Cox P alue compa ing palbociclib plus ul es an e sus capeci abine in each subg oup. b Unadjus ed Cox P alue compa ing palbociclib plus endoc ine he apy e sus capeci abine in each subg oup. Annals o Oncology M. Ma in e al. 8h ps://doi.o g/10.1016/j.annonc.2020.12.013 Volume xxx -Issue xxx -2021 occu ed while pa ien s we e on palbociclib plus ET (pneumoni is and sepsis), and ou occu ed while he pa- ien s we e on capeci abine (dia hoea, gene al heal h s a- us wo sening, coli is, and sudden dea h). Dia hoea, gene al heal h s a us wo sening, and coli is we e consid- e ed oxic dea hs acco ding o he in es iga o s’ assessmen s. Explo a o y objec i es P ognos ic/p edic i e alue o in insic BC sub ypes. Sub- ypes we e ob ained o 455 pa ien s (94.4% o he 482 pa ien s assessed) wi h me as a ic (30%) o p ima y umou issue (70%) a ailable (Table 1); 75.7% o coho 2 and 79.6% o he wild- ype ESR1 pa ien popula ion. Mos pa- ien s (93.2%) had luminal umou s. Coho 2 pa ien s wi h luminal umou s showed a median PFS o 7.7 and 10 mon hs wi h palbociclib plus ul es an and capeci abine, espec i ely (HR: 1.07; 95% CI: 0.77-1.49; P¼0.681). Pa- ien s wi h non-luminal umou s (n¼20) had a median PFS o 3.3 and 13.7 mon hs wi h palbociclib plus ul es an and capeci abine, espec i ely (HR: 5.87; 95% CI: 1.60-21.55; P¼0.008). Pa ien s wi h wild- ype ESR1 luminal umou s p esen ed a median PFS o 9.3 and 11.0 mon hs wi h pal- bociclib plus ul es an and capeci abine, espec i ely (HR: 1.01; 95% CI: 0.77-1.33; P¼0.930). Pa ien s wi h non- luminal umou s (n¼25) on palbociclib plus ET and capeci abine had a median PFS o 2.3 and 13.7 mon hs, espec i ely (HR: 7.36; 95% CI: 2.05-26.37; P¼0.002) (Supplemen a y Figu e S4, a ailable a h ps://doi.o g/10. 1016/j.annonc.2020.12.013). DISCUSSION The PEARL ial did no p o ide e idence o PFS supe io i y o palbociclib plus ul es an o o palbociclib plus ET in pa ien s wi hou ESR1 mu a ions o e capeci abine in AI- esis an MBC pa ien s. Howe e , i is wo h no ing ha compa ed wi h capeci abine, palbociclib plus ET was asso- cia ed wi h a significan delay in QoL de e io a ion, less ea men discon inua ions due o AEs, and a lowe p o- po ion o pa ien s wi h ela ed se ious AEs. The ini ial s udy design o he PEARL ial was modified a e some compelling e idence ha ESR1 mu a ions (p e- sen in up o 37% o pa ien s p e ea ed wi h AIs) could p oduce esis ance o addi ional AI he apy, bu no o ul es an . 15-17 Since in he ini ial design he endoc ine a m was exemes ane plus palbociclib, we added a second coho o pa ien s in which he endoc ine a m was ul es an plus palbociclib, o a oid he po en ial nega i e influence o ESR1 mu a ions in pa ien s ea ed wi h AIs. In ac , we iden ified 29% o ESR1 mu a ions in he pa ien s included in his ial. O no e, his modifica ion was made be o e any esul s we e a ailable. The combina ion o palbociclib plus ul es an has been app o ed by se e al egula o y agencies o he ea men Adjus ed haza d a io (95% CI): 0.67 (0.53-0.85), P = 0.001 No. o pa ien s No. o e en s (%) No. o censo ed (%) TTD median no. o mon hs (95% CI) Palbociclib + ET 279 131 (47.0) 140 (53.0) Capeci abine 273 153 (56.0) 120 (44.0) 8.6 (6.4-11.3) 6.2 (4.2-9.6) 0 6 12 18 24 30 Time (mon hs) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 273 95 37 18 8 6 279 108 46 27 11 7 Capeci abine Palbo + ET Capeci abine Palbociclib + ET No. a Risk E en - ee p obabili y Figu e 4. Time o de e io a ion based on EORTC co e quali y-o -li e-C30_global heal h s a us. The figu e shows he median ime o de e io a ion o he global heal h s a us om he Eu opean O ganiza ion o Resea ch and T ea men o Cance co e quali y-o - li e-C30 (EORTC QLQ-C30). The adjus ed haza d a io was ob ained using a s a ified Cox p opo ional haza d model wi h ea men a m, he s a ifica ion ac o s ( isce al, sensi i i y o p io ET, p io CT o MBC), and numbe o in ol ed si es as co a ia es. CI, confidence in e al; CT, chemo he apy; EORTC, Eu opean O ganiza ion o Resea ch and T ea men o Cance ; ET, endoc ine he apy; MBC, me as a ic b eas cance ; No., numbe ; Palbo, palbociclib; TTD, ime o de e io a ion. M. Ma in e al. Annals o Oncology Volume xxx -Issue xxx -2021 h ps://doi.o g/10.1016/j.annonc.2020.12.013 9