Breast Trials - LG

Question 1

Destiny04 (Her2low)

Answer 1

P: Phase III metastatic her2 low (1+/2+ISHneg), one or two prior lines of chemo
I: TDxd
C: treatment physicians choice
O: in HR+ cohort (88%) PFS: 10.1 vs 5.4 mo (HR 0.51) OS: 23.9 vs 17.5mo (HR 0.64)
ITT pop: PFS 9.9 vs 5.1mo, OS 23.4 vs 16.8mo (0.64)
AE: gr 3 lower in TDxd arm (52.6% vs 67.4%); pneumonitis 12.1%

Question 2

Keynote 522

Answer 2

P: Ph III, previously untreated stage II or III (T1c N1–2 or T2–4 N0–2) triple negative breast cancer
I: neoadj pembro 200mg +(paclitaxel/carbo) x4, then pembro + (AC or EC)x4 , after surgery pembro q3wk up to 9 cycles
C: TC–>AC/EC
O: pCR: 64.8% vs 51.2%, EFS: at 36 mo 84.5 vs 76.8% (0.63)
AE: gr 3 or higher 78% vs 73%
Other: PDL-1 agnostic. adj cape was not allowed

Question 3

Fast-Forward (hypo fractionation RT)

Answer 3

P: phIII non-inferiority trial, invasive cancer pT1-3 N0-1 after mastectomy or BCS
I: 27Gy/5#, 26Gy/5# to whole breast/chest wall
C: 40Gy/15#
O: 26Gy/5# noninferior to 40Gy/15# in terms of 5 yr incidence ipsilateral relapse; 1.6% non-inferiority margin compared with 2% incidence with 40Gy
AE: 5 day schedule causes milder early skin reaction and similar rates of late adverse effects
Other: exclusion criteria in calgary: T3, macromets, neoadj patients, patients <40, patients not offered SLNB

Question 4

CLEOPATRA (met HER2+)

Answer 4

P:pHIII, met HER2+ 1st line, 46% had prior neoadj or adj tx, no prior HER2-directed therapy or chemo in metastatic setting.
I: trastuzumab + docetaxel + pertuzumab
C: trastuzumab + docetaxel
O: mPFS 18.5 vs 12.4 mo(HR 0.62), mOS 57.1 v 40.8 mo (HR 0.69), 8yr OS rate 37% vs 23%
AE: neutropenia (~49%). LV dysfunction similar in both groups (~6%). more diarrhea in pertuzumab group 28% vs 14% all grade
Other: excluded if CNS mets or LVEF <50.

Question 5

EMELIA (met HER2)

Answer 5

P: PhIII, met HER2 2nd line, previous tx with trastuzumab/taxane
I: T-DM1 (3.6mg/kg iv q3wk)
C: lapatinib (1250mg PO daily d1-21) + cape (1000mg/m2 d1-14)
O: PFS from original trial: 9.6 mo vs 6.4 mo (HR 0.65)
updated OS: 29.9mo vs 25.9 mo (HR0.75)
ORR: 43.6 vs 30.8%
CNS at baseline: PFS 5.9 vs 4.6 (strat HR0.7), OS 26.8 vs 12.9 (HR 0.3)
AE: fewer gr 3 (49% vs 60%), thrombocytopenia 14%, ast 5%, anemia 4%; rare secondary cancer
Other: crossover allowed (27%)

Question 6

NALA (met HER2)

Answer 6

P: ph III, met Her2 (3rd line or greater) prior tx with trastuzumab, pertuzumab, or TDM1
I: neratinib + cape
C: lapatinib + cape
O: mPFS 8.8 vs 6.6 (HR0.76)
mOS: 24 vs 22.2 mo (HR0.88, CI crossed 1)
ORR 32 vs 26%

Question 7

HER2climb (met HER2)

Answer 7

P: ph2, heavily pretreated met HER2, asymptomatic brain mets allowed
I: tucatinib + trastuzumab + cape
C: trastuzumab + cape
O: mPFS 7.8 vs 5.6mo (HR 0.54), mOS 21.9 vs 17.4mo (HR0.66), ORR 40 vs 22%, mPFS w brain mets baseline 7.6mo vs 5.4 mo (HR 0.48) with PFS at 1 yr 24.9% vs 0%
AE: tucatinib group more diarrhea, more LE elevation

Question 8

TROPICS-2 (met HR+)

Answer 8

P: phIII HR+ HER2- met breast ca, 2-4 prior chemos for MBC (1 prior chemo allowed if progressed <12mo after (Neo)adj therapy). must have received >/=1 taxane, CDK4/6, and endo therapy in any setting
I: Sacituzumab govitecan (10mg/kg IV d1/d8 q21d)
C: TPC (cape, eribulin, vinorelbine, gem)
O: mPFS 5.5 v 4.0 mo (HR0.66), 14.4 vs 12mo (HR 0.79)
AE: grade 3 events 74% vs 60%: neutropenia, diarrhea most common

Question 9

Destiny Breast 03 (met HER2+ 2nd line)

Answer 9

P: ph III, met HER2 (3+/2+ISH+), previous trastuzumab and taxane in met setting, could have clinically stable treated brain mets
I: T-DXd 5.4mg/kg q3wk
C:TDM1 3.6mg/kg q3wk
O: updated at 28mo fu; PFS 28.8 vs 6.8 (HR0.33), OS NR (HR 0.64), HR0.76 for HR+ and HR0.55 for HR- , ORR 80%. OS rates at 12 mo 94.1% vs 86% and at 24mo 77.4% vs 69.9%
CR 16% vs 8%
AE: updated fu. gr 3 event rate similar ( ~50%), ILD/pneumonitis any grade 15% vs 3% with no grade 4 or 5 events

Question 10

TH3RESA (met HER2)

Answer 10

P: phIII, met HER2 heavily pretreated; both trastuzumab and lapatinib, taxane (any setting), and progression on 2+ her-2 directed therapies in adv setting
I: TDM-1 (3.6mg/kg q3w)
C: TPC
O: mOS 22.7 vs 15.8 (HR0.68)
other: 47% crossover rate
Supports use of TDM1 in 3rd line

Question 11

MONARCH-E (extended adjuvant therapy high risk HR+)

Answer 11

P: PhIII, extended adjuvant with CDK4/6 in HR+HER2- node positive high risk (4+ axillary LN, 1-3+ ALN with either gr 3 or tumour 5cm or larger; cohort 1) (1-3+ ALN and Ki-67 at least 20%; cohort 2). not all had chemo but most did.
I: abemaciclib 2yr in addition to standard endocrine therapy. dose 150mg PO BID
C: standard endocrine therapy up to 10yr
O: 4 year fu. ITT mIDFS NR, IDFS 85.8% vs 79.4% HR 0.66. Cohort 1: HR0.65 Cohort 2: HR0.76
OS data immature.
AE: 20% neutropenia, 11% leucopenia, 1 pneumonitis death
Other: absolute difference increased with further followup at 4 years (6.8%) compared to 2 (2.8%) and 3 (4.8%) year rates; demonstrates potential carryover effect. abemaciclib benefit regardless of Ki67 status*; prognostic but not predictive of abemaciclib benefit. in pt with high Ki67 (ie 20 or more); 7.1% absolute difference at 3 yr

Question 12

CREATE-X (adjuvant after neoadj tx in HER2-)

Answer 12

P: residual invasive carcinoma after neoadj chemo in HER2- breast cancer. Neoadj regimen containing anthracycline, taxane, or both. 40% stage IIIA or B, 32% triple negative.
I: capecitabine (6-8 cycles)
C: standard post surgical treatment alone
O: DFS at 5 yr 74.1% vs 67.6% HR 0.53, OS at 5 yr 89% vs 83% HR 0.59,
triple negative cohort: DFS 70% vs 56% HR 0.58, OS 78% vs 70% HR0.52
AE: HFS 73.4% all grade; 11% grade 3. gr 3 neutropenia 6%, gr 3 diarrhea 2%
other: age 20-74 years

Question 13

KATHERINE (residual disease HER2+)

Answer 13

P: phIII, HER2+ early breast cancer (T1-4, N0-3 excluding T1aN0 or T1bN0) w residual invasive cancer after neoadjuvant chemo/her2 therapy. chemo must have contained a taxane (+/- anthracycline) and trastuzumab.
I: TDM-1 x 14 cycles 3.6mg/kg IVq3wk
C: trastuzumab x 14 cycles 6mg/kg IVq3wk
O: iDFS at 3 yr 88.3% vs 77% HR 0.50); ie risk of recurrence or death 50% lower with TDM-1
AE: plt 5.7%, HTN 2%, neuropathy 18% vs 6.9%, 2% pneumonitis any grade of which most were radiation related. any gr 3 25% vs 15%
Other: excluded if gross residual disease remaining after mastectomy or + margins.

Question 14

ExteNET (extended adjuvant therapy HER2+)

Answer 14

P: phIII, extended treatment for HER2+/HR+ after neoadj/adjvant trastuzumab-based therapy.
originally stage 1-3c modified to stage 2-3C
I: neratinib 240mg/day for 1 year
C: placebo
O: 5 year iDFS 90% vs 87% HR0.73
8yr fu: ITT OS 90% vs 90% HR crossed 1.
AE: 40% diarrhea in neratinib group
Other: initiate within 1 year of completion of trastuzumab adjuvant.
- better iDFS in HR+ population
- use dose escalation strategy per phase II data and diarrhea prophylaxis

Question 15

APHINITY (adjuvant HER2+)

Answer 15

P: HER2+ early breast cancer adjuvant therapy. Node + (63%) or high risk node negative (this cohort later revoked)
I: pertuzumab + trastuzumab x1yr + standard adj chemo
C: trastuzumab x 1 yr + standard adj chemo
O:node positive cohort: 3 yr iDFS 92 vs 90% (HR0.77)
node negative 3 yr iDFS not significant
AE: slightly more diarrhea with pertuzumab

Question 16

BCIRG 006 (her2+ Chemotherapy regimen)

Answer 16

P: HER2 + (node + or high risk node negative) early breast cancer. 10 year follow up
I: TCH (docetaxel carboplatin Herceptin)
C: anthracycline containing regimens; AC-T, AC-TH
O: trastuzumab regimens superior to AC-T
slight numerical difference between anthracycline and non anthracycline Herceptin containing regimens. risk reduction 28% ACTH and 23% TCH. 10 yr DFS 74% ACTH vs 73% TCH; 10yr OS 85.9% vs 83%
AE: for ACTH there is 5x more CHF, higher secondary cancer rate ,more LV dysfunction
Take home message: docetaxel carboplatin standard chemo backbone in HER2+ patients.

Question 17

APT trial (HER2 adjuvant chemotherapy)

Answer 17

P:phase2 single arm, small (</=3cm) node negative HER2+ (ie chemo deescalation) . 67% were HR+
I: weekly paclitaxel 80mg/m2 + trastuzumab 4mg/kg–>2mg/kg) x12 weeks followed by trastuzumab (2mg/kg weekly or 6mg/kgq3wk) for 40 weeks to complete 1 year of trastuzumab
C: N/A
O: 10 yr fu iDFS 91%, 10yr recurrence free interval 96%, 10 yr OS 94.3%, 10 year br cancer specific survival 98%

Question 18

OlympiAD (met HER2-)

Answer 18

P: Ph3, metastatic breast cancer (HER2-) with gremlin BRCA mutation, no more than 2 prior chemo regimens for metastatic disease, if HR+ at least 1 endocrine therapy any setting, previous taxane tx allowed if at least 12 mo ago or no evidence of progression on taxane in met setting
I: olaparib 300mg BID
C: single agent chemo TPC (cape, eribulin, venorelbine)
O: PFS: 7 v 4.2 mo HR0.58, response rate 60% vs 29%
AE: gr 3 36% olaparib and 50% TPC
not powered to assess OS differences.

Question 19

ASCENT (Met triple neg breast)

Answer 19

P: met triple negative (heavily) pretreated, no known brain mets. 2+ prior chemo including taxanes, at least 1 in metastatic setting.
I: Sacituzumab govitecan
C: single agent chemo TPC (eribulin, vinorelbine, cape, gem)
O: PFS 5.6 vs 1.7 mo (HR0.41), mOS 12 vs 6.7mo (HR0.48). ORR 35% vs 5%
AE: gr 3 neutropenia 51% vs 33%, leukopenia (10%v 5%), diarrhea (10% v <1%), feb neut 6vs2%

Question 20

keynote 355 (met triple negative)

Answer 20

P: ph3, untreated metastatic triple neg. if relapse then last sugery/chemo treatment must have been 6+ months ago (rads okay).
I: pembrolizumab 200mg q3wk + chemo TPC (nabpaclitaxel, paclitaxel, or carbo/gem)
C: placebo + chemo
O:
ITT: mOS 17.2 vs 15.5 mo (CI crossed 1 not significant)
PDL1 1+: mOS 17.6 vs 16 mo (CI crossed 1 not significant)
**PDL1 10+: mOS 23 vs 16mo HR0.73
other: excluded active CNS mets or immunosuppressive therapy or noninfectious pneumonitis history req steroids

Question 21

keynote 119 (met triple neg)

Answer 21

P: ph 3, previously treated (1-2L in met setting) metastatic TNBC. must have have prior anthracycline or taxane.
I: pembro mono therapy (200mg q3wk)
C: single-agent chemo TPC (cape, eribulin, gem, vinorelbine)
O: no OS in ITT for 2L/3L setting
exploratory analysis CPS>/=20: OS 14.9 vs 12 mo HR 0.58
AR: IRAE gr 3 3.2%
* negative trial

Question 22

TAILORx (oncotype)

Answer 22

P: ER+ HER2-, pT1c-pT2 (1-5cm) or T1b(0.5-1cm) w LVI or gr 3, node NEGATIVE breast cancer
I: intermediate RS (11-25) receives chemo+endocrine therapy
C: intermediate RS receives endocrine therapy alone
O: 9 yr fu: NO difference in invasive DFS (85% for both), distant DFS (95% both), OS (95% both)
Other: premenopausal women (<51): 1.6% benefit in 16-20 group (% distant disease recurrence reduction at 9 years), 6.5% difference in distant recurrence free survival in women <51 in the 21-25 group; no OS difference

Question 23

RxPONDER (oncotype)

Answer 23

P: ph III, ER+ breast cancer, adjuvant, 1-3 nodes positive
I: chemo + endocrine therapy in women with score <26
C: endocrine therapy alone in women with score <26
O: invasive DFS in women with RS <26:
premenopausal, Age <51= absolute iDFS of 5%
postmenopausal, Age>51= NO difference
Other: no association between recurrence score and chemo benefit, but association between menopausal status and chemotherapy benefit

Question 24

OLYMPIA (adjuvant PARPi)

Answer 24

P: ph III, BRCA 1/2 gremlin mut, received local therapy + either neoadj or adj chemo
I: 1 year adjuvant olaparib
C: placebo
O: 3 yr iDFS improved from 77.1% to 85.9%. OS benefit at second intermediate analysis w absolute difference of 3.8% at 3 yr (HR 0.68)
Other:

Question 25

PEARL

Answer 25

P: ph III, Postmeno women with HR+/HER2- MBC resistant to previous AIs (recurrence while on or within 12 months after the end of adjuvant treatment, or progression while on or within 1 month after the end of treatment of advanced disease). prior chemo in neoadj or metastatic 1L allowed.
I: palbociclib (125mg 3w on 1wk off) + exemestane (cohort 1); palbo + fulvestrant (cohort 2)
C: capecitabine (1250mg/m2 2 weeks on 1 week off)
O: primary analysis: PFS did not show superiority for palbociclib plus ET compared to capecitabine; however, it was better tolerated and showed a significant delay in the deterioration of QoL
Co-primary endpoints were PFS in cohort 2 and PFS among patients with ESR1 wild-type tumors in both cohorts. Palbociclib did not improve PFS, neither in cohort 2 [mPFS of 7.5 versus 10.0 months, adjusted hazard ratio (HR) 1.13; 95% CI 0.85- 1.50], nor among ESR1 wild-type patients (mPFS of 8.0 versus 10.6 months, adjusted HR 1.11, 95% CI 0.87-1.41).

OS (palbo +fulvestrant): 31 v 32 mo (HR 1.10 not sig)
WT ESR1 mut (palbo + exemestane) 37 v 34 mo (HR 1.06 not sig)
oval pop (palbo + exemestane) 32 v 30 mo (HR 1.0 not sig)
other: Patients with the advanced, symptomatic and visceral spread that were at risk of life-threatening complications in the short term were excluded

Question 26

PARSIFAL (IL met ER+ breast cancer)

Answer 26

P: met HR+HER2- breast cancer, estrogen sensitive disease (relapse > 12 months [mo] after the end of adjuvant endocrine therapy or diagnosed with “de novo” metastatic disease). no prior tx in met setting
I: palbociclib oral 125 mg/day [d]; 3 wks on/1 wk off) plus + fulvestrant 500 mg/d (I.M Days 0, 14, 28, and then every 28 d)
C: palbociclib + letrozole
O: At median follow-up of 32 mo, median PFS was 27.9 mo (95% confidence interval [CI], 24.2-33.1) with PF and 32.8 mo (95% CI, 25.8-35.9) with PL (HR: 1.1; 95% CI, 0.9-1.5; P = 0.321). No differences were observed for pts with or without visceral involvement (HR: 1.3 and HR: 0.97 respectively, interaction P = 0.275), and for “de novo” or recurrent metastatic disease (HR: 1.1 and HR: 1.1 respectively, P = 0.979). The 4-year OS rate was 67.6% in PF and 67.5% in PL arm (HR: 1; 95% CI, 0.7-1.5; P = 0.986). No differences were observed in ORR or CBR between arms.
AE: gr 3 AE similar both arms
Bottom line: no PFS or OS improvement with use of fulvestrant in 1L setting. Use AI.

Question 27

SOLAR-1

Answer 27

P: HR+ HER2- men and postmen female, eligible for/receiving ET in neoadj and adv setting. no prior chemo for adv disease. Cohorts of PIK3CA mut and non-mutated; 86% had endocrine resistant disease
I: alpelisib 300mg PO daily w food + fulvestrant
C: fulvestrant + placebo
O: PFS in PIK3CA mut pts: 11 v 5.7 mo (HR 0.65)
OS in PIK3CA mut 39.3 v 31.4 mo (HR 0.85 not significant). OS and PFS in nonPIK3CA patients not met.

Question 28

BOLERO-2 (exemestane + everolimus)

Answer 28

P: ph III (pre CDK4/6 era), met ER+HER2- recurrence or progression while receiving previous therapy with a nonsteroidal aromatase inhibitor in the adjuvant setting or to treat advanced disease (or both)
I: everolimus + exemestane
C: exemestane + placebo
O: median progression-free survival was 6.9 months with everolimus plus exemestane and 2.8 months with placebo plus exemestane, according to assessments by local investigators (hazard ratio for progression or death, 0.43; 95% confidence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6 months and 4.1 months, respectively, according to central assessment (hazard ratio, 0.36; 95% CI, 0.27 to 0.47; P<0.001).
update: Median OS in patients receiving EVE + EXE was 31.0 months [95% confidence interval (CI) 28.0-34.6 months] compared with 26.6 months (95% CI 22.6-33.1 months) in patients receiving PBO + EXE (hazard ratio = 0.89; 95% CI 0.73-1.10; log-rank P = 0.14).
AE: hyperglycaemia 4%, rash, pneumonitis 3%, stomatitis 8%

Question 29

NeoSphere (neoadj HER2 pertuzumab)

Answer 29

P: Ph II, HER2+
I: cohort 1: trastuzumab/docetaxel; cohort 2: trastuzumab/pertuzumab/docetaxel; cohort 3: pertuzumab/trastuzumab; cohort 4: pertuzumab/docetaxel. then surgery. then 3 cycles FEC (or 4 cycles if cohort 3) + adj trastuzumab
O: increased pCR rate to 50% (HER2+/ER+) and 65-80% (HER2+/ER-)
* not powered for DFS or OS