Science - USA (2022-01-14)

Fasslet al.,Science 375 , eabc1495 (2022) 14 January 2022 8 of 19

Table 3. Major past clinical trials with CDK4/6 inhibitors.

ER

+, estrogen receptor

• positive; HER2


• , human epidermal growth factor receptor 2


• 
  

  negative; HR

  
  

+, hormone receptor

• positive; PFS,

progression-free survival. FGFR2, fibroblast growth factor receptor 2; ERBB3, receptor tyrosine-protein kinase erbB-3.CDK4/6inhibitor

Trial name

Trial details

Treatment

Patients

Outcome

Ref.

Other outcomes

Palbociclib

PALOMA-1

Randomizedphase 2

Aromatase inhibitorletrozole alone(standard of care)versus letrozoleplus palbociclib

Postmenopausal womenwith advanced ER

+/HER2

• 
  

breast cancer who hadnot received any systemictreatment for theiradvanced disease

Addition of palbociclib markedlyincreased median PFS from10.2 months in theletrozole group to20.2 months in thepalbociclib plusletrozole group

(^78

)

On the basis of this result, palbociclibreceived a

“Breakthrough Therapy

”

designation status from FDA and wasgranted accelerated approval, incombination with letrozole, for thetreatment of ER

+/HER2

• metastatic

breast cancer

...............................................................................................................................................................................................................................................................................................................................................................................................................................................Palbociclib

PALOMA-2

Double-blindphase 3

Palbociclib plusletrozole as first-line therapy

Postmenopausal womenwith ER

+/HER2

• 
  

breast cancer

Addition of palbociclib stronglyincreased median PFS:14.5 months in the placebo-letrozole group versus24.8 months in thepalbociclib-letrozole group

(^123

)

Palbociclib was equally efficacious inpatients with luminal A and B breastcancers, and there was no singlebiomarker associated with the lack ofclinical benefit, except for RB1 loss;CDK4 amplification was associatedwith endocrine resistance, but thiswas mitigated by addition ofpalbociclib; tumors with high levelsof FGFR2 and ERBB3 mRNAdisplayed greater PFS gainafter addition of palbociclib (

79

)

...............................................................................................................................................................................................................................................................................................................................................................................................................................................Palbociclib

PALOMA-3

Randomizedphase 3

Estrogen receptorantagonistfulvestrant plusplacebo versusfulvestrant pluspalbociclib

Women with HR

+/HER2

• 
  

metastatic breast cancerthat had progressed onprevious endocrine therapy

The study demonstrated asubstantial prolongationof median PFS in the palbociclib-treated group: 4.6 months in theplacebo plus fulvestrant groupversus 9.5 months in thepalbociclib plus fulvestrantgroup; addition of palbociclibalso extended median overallsurvival from 28.0 months(placebo-fulvestrant) to34.9 months (palbociclib-fulvestrant); estimated rateof survival at 3 years was41% versus 50%, respectively

(^124

,^125

,^135

)

...............................................................................................................................................................................................................................................................................................................................................................................................................................................Palbociclib

NeoPalAna

Palbociclibin anneoadjuvantsetting (i.e.,prior tosurgery)

Compared the effectsof an aromataseinhibitor anastrozoleversus palbociclibplus anastrozoleon tumor cellproliferation

Women with newlydiagnosed clinicalstage II/III ER

+/HER2

• 
  

breast cancer

Addition of palbociclib enhancedthe antiproliferative effectof anastrozole

(^161

)

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