Advances in Breast Cancer Therapeutics in the Adjuvant and ... › wp-content › uploads › 2015 › 09 › rodler-UC-DAVI… · Jin H et al. J Clin Oncol 2012;30(7):718- 21. 3

Advances in Breast Cancer Therapeutics in the Adjuvant and

Metastatic Settings

Eve Rodler, MDUniversity of California at Davis

October 2016

17th Annual Advances in OncologySeptember 30-October 1, 2016

Sacramento, CA

Anna Orlowski, J.D.End of Life Option Act: Medical Legal

Considerations.

No relevant financial relationships in the past twelve months by presenter or spouse/partner.

The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is

still investigational.

Early Stage Breast Cancer Extended adjuvant endocrine therapy Anthracyclines in HER2- breast cancer Platinum in TNBC Capecitabine for residual disease Dual HER2 blockade

Metastatic Breast Cancer Endocrine monotherapy versus combination

therapy Endocrine resistance and PI3K inhibition Role of T-DM1 in HER2+ disease Checkpoint inhibitors in TNBC

Early Stage Breast Cancer

Long term recurrence risks after use of endocrine therapy for only 5 years

EBCTCG: Data from 91 trials on each individual with ER+ disease allocated only 5 years of endocrine therapy

N= 46,000 women who were alive and disease free at 5 years

Main finding: Even after 5 years of endocrine therapy, recurrences continue steadily, at least to year 20; significant even for T1N0 disease

Pan H et al, 2016 ASCO Annual Meeting, abstract 505

EBCTCG: Long term recurrence risks after 5 years of endocrine therapy

Pan H et al, 2016 ASCO Annual Meeting, abstract 505

Benefits of extended adjuvant endocrine therapy

MA.17: After 5 years of tamoxifen, the addition of 5 years of adjuvant letrozole reduces breast cancer recurrence by 43% compared to placebo (HR 0.57; p < 0.001), and improves survival by 39% at 64 months f/u (HR 0.61; p < 0.001) 1,2

ATLAS/aTTOM: Compared to 5 years of tamoxifen, 10 years of tamoxifen reduces breast cancer mortality by 15% in all years and by 25% starting at year 10. 3,4

1. Goss P et al. NEJM 2003;349(19):1793-8022. Jin H et al. J Clin Oncol 2012;30(7):718-21.3. Davies C et al. Lancet 2013;381:805-164. Gray RG et al. J Clin Oncol 2013;31 (suppl;abstr 5).

MA.17R Trial Study Design

n=1918 randomized phase III

+/- Tamoxifenany duration

AI4.5 to 6 Years R

Letrozole 2.5 mg po daily

Placebo

5 years

Hormone receptor positivePostmenopausal and disease-free

Goss P, et al. ASCO 2016, LBA1

1:1


MA.17R Disease-free survival

Median f/u 6.3 years

MA.17R DFS by pre-specified subgroups


MA.17R

MA.17R is the first study to show benefit of extending AI use beyond 5 years – 34% reduction in disease recurrence.

There were no significant differences between the placebo group and the letrozole group related to most measures of quality of life.

Bone health remains an issue. Biomarkers/multi-gene signatures are needed

to determine which patients are most at risk for late recurrences

Can anthracyclines be omitted in patients with high risk lymph node negative or node positive, HER2-negative breast cancer?

TC x 4 vs AC x 4 demonstrated OS superior for TC (HR =0.69; p=0.032) 2

However, no comparison to combination or sequential anthracycline and taxane regimen.

TC x 6, often used in clinical practice, became the standard to compare with TaxAC regimens

1 Blum JL et al, ASCO 2016, abstract 10002 Jones S et al, J Clin Oncol 2009;27:1173-83

1

ABC Trials Study Design

Arm 1 (TaxAC)

TAC q 3 wk x 6 cyclesorAC q 3 wk x 4 cycles paclitaxel q 1 wk x 12orAC q 2 wk x 4 cycles paclitaxel q 1 wk x 12orAC q 2 wk x 4 cycles paclitaxel q 2 wk x 4

Arm 2 Docetaxel/cyclophosphamide (TC)

TC x 6 cycles

R

* High risk lymph node negative defined as pT2-T3 pN0; or pT1c if pN0 then must be eitherER and PR negative; ER+ or PR+ and either

Grade 3 orOncotype Dx Recurrence Score > 31 for USOR 06-090 and > 25 for B-46I/07132 and B-49

HER2 -Lymph node +High Risk LN-

n = 4,130 phase III

ABC Trials: Invasive Disease Free SurvivalThe primary aim: Determine if invasive disease free survival with TC isnon-inferior compared to TaxAC, defined by HR of less than 1.18

Blum JL et al, ASCO 2016, abstract 1000

Blum JL et al, ASCO 2016, abstract 1000

Triple Negative Breast Cancer has Worse Outcome if Residual Disease Present after Neoadjuvant

ChemotherapyTNBC pts (n=255) compared with non-TNBC pts (n=863) had higher pCR rates (22% vs 11%)

However, TNBC pts hadlower 3-yr PFS and OS rates

If pCR was achieved, TNBC pts and non-TNBC pts had similar outcome

If residual disease present, TNBC pts had worse outcome compared with non-TNBC pts

Liedtke C et al. J Clin Oncol 2008;26:1275-81

GeparSixto Neoadjuvant Study Design TNBC regimen

Paclitaxel 80 mg/m2 q 1 wk x 18 Non-pegylated liposomal doxorubicin

20 mg/m2 q 1wk x 18Bevacizumab 15 mg/kg q 3 wk

Paclitaxel 80 mg/m2 q 1 wk x 18 Non-pegylated liposomal doxorubicin

20 mg/m2 q 1wk x 18Bevacizumab 15 mg/kg q 3 wkCarboplatin AUC 1.5 q wk x 18

R

TNBC

n = 315 phase II

SURGERY

von Minckwitz G et al. SABCS 2015. Abstract S2-04.

pCR, % PMCb PM P Value

TNBC (n = 315) gBRCA wild type (n = 241) gBRCA mutant (n = 50)

53.250.861.5

36.933.150.0

.005†.005.413

GeparSixto: DFS advantage demonstrated with carboplatin in TNBC

von Minckwitz G et al. SABCS 2015. Abstract S2-04.

CALGB 40603: phase II trial neoadjuvant chemo/bev +/- carbo +/- bev – pCR rate in TNBC

Sikov, JCO 2015

CALGB 40603: No DFS advantage with carboplatin in TNBC

Sikov WM, et al. J Clin Oncol. 2015;33:13-21.

Prospective randomized data are conflicting regarding use of pathologic CR as surrogate for DFS on a trial level, though underpowered to show this.

Studies consistently show that achieving a pathologic CR is prognostic on an individual patient level.

The routine addition of a platinum agent to ACT-based neoadjuvant therapy for patients with early stage TNBC should not be considered a standard of care. However, higher pCR rates associated with the

addition of carboplatin may be beneficial for some patients.

Incorporation of robust correlative studies in future trials is needed to identify TNBC patients who will benefit from platinum.

Platinum therapy in early stage TNBC

NRG-BR003 - Randomized Phase III Trial of Adjuvant Therapy Comparing Doxorubicin Plus

Cyclophosphamide Followed by Weekly Paclitaxel with or without Carboplatin for Node-Positive or

High-Risk Node-Negative Triple-Negative Invasive Breast Cancer

N = 990

Resected LN+ or High Risk LN-ER/PR/HER2-Early stage BC

R

AC q 2 wks x 4 followed by paclitaxel q 1 wk x 12

AC q 2 wks x 4 followed by paclitaxel q 1 wk x 12 pluscarboplatin AUC 5 q 3 wk x 4Primary endpoint: IDFS

Residual disease after neoadjuvant chemotherapy and surgery:

CREATE-X n = 910 phase III

HER2- , Stage I-IIIB

NAC SurgeryPathologyNon-pCRor node +

R

ControlStandard Therapy

Standard Therapy+ Capecitabine2500 mg/m2/dd 1-14 q 3 wk x 8

Stratified by ER status, age, neoadjuvant chemotherapy, use of 5-

FU, institution, node status

Standard therapy:HR+: Hormone therapyHR-: No further systemic treatment

1. Toi M, et al. SABCS 2015. Abstract S1-07.2. Ohtani S, et al. SABCS 2013. Abstract P3-12-03.

CREATE-X: 5-Yr Efficacy

Capecitabine achieved significantly higher 5-yr DFS and OS in HER2- BC pts with residual disease

Characteristic, % Capecitabine(n = 440)

No Capecitabine

(n = 445)

HR (95% CI) P Value

5-yr DFS 74.1 67.7 0.70 (0.53-0.93) .00524

5-yr OS 89.2 83.9 0.60 (0.40-0.92) < .01

Toi M, et al. SABCS 2015. Abstract S1-07.

CREATE-X subgroup analysis suggests the benefit was predominantly in the TNBC subgroup (HR 0.58).

Other studies have shown benefits of (neo)adjuvant capecitabine added to standard chemotherapy in TNBC subgroups (ABCSG-24; FinnXX), but did not achieve their primary endpoints, so were negative overall.

Results of CREATE-X should be confirmed in an adjuvant study that would evaluate high risk population of TNBC patients.

Capecitabine may have benefit in high risk populations

EA1131: A randomized phase III post-operative trial of platinum agent chemotherapy vs. capecitabine in patients with

residual triple-negative breast cancer (TNBC) following neoadjuvant chemotherapy

Accrual goal 750

TNBC Stage II/III

NAC SurgeryPathology> 1 cm residual disease

R

Cisplatin 75 mg/m2d1 q 3 wk x 4 cyclesorCarboplatin AUC 6d1 q 3 wk x 4 cycles

Capecitabine1000 mg/m2/dd1-14 q 3 wk x 6 cycles

Tissuesubmission PAM 50analysis

* Choice of platinum agent will be per treating physician discretion

Primary endpoint: IDFS in patients with basal-like TNBCSecondary endpoints: IDFS in patients with non basal-like TNBC, OS, RFS

Metastatic Breast Cancer

Endocrine monotherapy in first line metastatic setting

Postmenopausal patients with HR+ metastatic breast cancer without prior exposure to AIs, or those with late relapses, recommendation is for non-steroidal AI monotherapy (ASCO guidelines).

Phase II FIRST trial results suggest fulvestrant may be superior to non-steroidal AI as front-line therapy. fulvestrant (500mg) (F) vs anastrazole (A) n = 205 postmenopausal, HR+ pts TTP: F 23.4 mo A 13.1 mo HR 0.66 p= 0.01 OS: F 55.1 mo A 48.4 mo HR 0.70 p=0.04

Confirmatory phase III FALCON trial ongoing

Ellis M, et al, J Clin Oncol 2015; Robertson J et al, SABC 2010, abstract S1-3 Robertson J, et al, J Clin Oncol 2009;27:4530-35

Endocrine combination therapy in first line metastatic setting

Preclinical studies identified luminal ER positive subtype as being palbociclib-sensitive with synergy demonstrated between palbociclib and anti-estrogens. 1

PALOMA-I, randomized phase II study of palbociclib plus letrozole vs letrozole alone as first-line therapy for HR+ advanced breast cancer 2

Addition of palbociclib to letrozole demonstrated 10-month improvement in PFS over letrozole alone (HR 0.49; p = 0.0004) and acceptable safety profile

Accelerated FDA approval granted

1. Finn et al, Breast Cancer Research 2009; 2. Finn et al, Lancet Oncol 2015.

PALOMA 2 Study Design

Prospective, randomized, double-blind, placebo-controlled phase III trial

R

Palbociclib 125 mg daily (3/1 schedule) +Letrozole 2.5 mg daily

n = 666 phase

PostmenopausalHR+ HER2- advanced

breast cancer No prior treatment for advanced disease

AI resistant patients excluded

Placebo (3/1 schedule) + Letrozole 2.5 mg daily

Finn R et al, ASCO 2016, Abstract 507

PALOMA 2PFS Investigator-Assessed – (ITT Population)


PALOMA 2


PALOMA-2 Safety

Most common AE was neutropenia: 80% in palbociclib plus letrozole arm vs 6% in placebo plus letrozole.

SAEs occurred in < 1% of pts, except febrile neutropenia in 1.6% in the palbociclib plus letrozole arm vs 0 in placebo arm.

Grade 3/4 non-hematologic AEs uncommon in both arms.

Deliverabilty was > 90% in palbociclib arm and 94% in placebo arm


PALOMA 3: Palbociclib and fulvestrant in endocrine resistant metastatic breast cancer

PALOMA 3 phase III trial (n=512) evaluated palbociclib plus fulvestrant versus fulvestrant alone in patients with HR+ advanced breast cancer that had progressed on prior endocrine therapy Palbociclib plus fulvestrant demonstrated

significant increase in PFS, 9.2 mo vs 3.8 mo(HR 0.42; p < 0.001), similar toxicity profile as observed in PALOMA-1

Basis for FDA approval of palbociclib with fulvestrant

Turner NC, et al. NEJM 2015;373:1672-1683

Sequencing endocrine therapies in the metastatic setting for postmenopausal patients 1st line options:

nonsteroidal AI monotherapy fulvestrant monotherapy (await FALCON) non-steroidal AI plus CDK 4/6 inhibitor (PALOMA-2) non-steroidal AI plus fulvestrant (SWOG 0226)

If use non-steroidal AI plus CDK 4/6 inhibitor upfront, then challenging to determine subsequent lines of therapy after progression

If use non-steroidal AI monotherapy upfront, then can use fulvestrant plus CDK 4/6 inhibitor 2nd line and exemestane +/-everolimus 3rd line

PI3K inhibition in endocrine resistant metastatic breast cancer: BELLE-2 Study

n = 1147 phase III

PostmenopausalHR+ HER2-advancedbreast cancer with progressionon/after AI therapy

R

Buparlisib 100 mg/day +Fulvestrant 500 mg

Placebo + Fulvestrant 500 mg

Baselga J, et al. SABCS 2015. Abstract S6-01.

BELLE-2: PFS results and efficacy by PI3KCA mutation in ctDNA

Median PFS, Mos nBuparlisib + Fulvestrant

(n = 576)

Placebo + Fulvestrant

(n = 571)

HR (95% CI)

PValue

Overall population 1,147 6.9 5.0 0.78 (0.67-0.89) < .001

PI3K-activated pts 372 6.8 4.0 0.76 (0.60-0.97) .014

ctDNA PIK3CA mutant 200 7.0 3.2

0.56 (0.39-0.80)

< .001

ctDNA PIK3CA non-mutant 387 6.8 6.8

1.05 (0.82-1.34)

.642

• PFS significantly longer with use of buparlisib + fulvestrant in the overall population but not significantly extended in pt population with a known PI3K activation status (threshold p = .01 in trial design)

• Buparlisib + fulvestrant extended PFS in pts with PIK3CA mutations in circulating tumor DNA versus fulvestrant alone, but not in pts with non-mutant PIK3CA.

TH3RESA: Study Design

Wildiers H, et al. SABCS 2015. Abstract S5-05.

N = 602Phase 3

Pts with HER2+ advanced

breast cancer, ≥ 2 prior anti-

HER2 therapies

T-DM1 3.6 mg/kg q3w IV

Therapy of Physician’s Choice

PD

PD T-DM1†

†Optional crossover.

R

TH3RESA: Final OS analysis

Median OS significantly improved with use of T-DM1 vs physician-selected therapy in pretreated pts with HER2+ MBC: 22.7 months vs 15.8 months HR 0.68 (95% CI: 0.54-0.85; P = .0007)

44.9% of TPC arm pts received T-DM1 crossover therapy

T-DM1 is preferred treatment for patients whose metastatic disease has progressed after treatment with a combination of a taxane based chemotherapy and trastuzumab, with or without pertuzumab.

Wildiers H, et al. SABCS 2015. Abstract S5-05.

Immunotherapy in TNBC

Cancer cells can use PD1/PDL1 pathway to evade the immune system by expressing PDL1 and down regulating immune responses.

Blocking the interaction of PD1 and PDL1 releases the stop on T cells and allows T cell mediated immune responses against tumor cells.

There is higher expression of PDL1 mRNA in TNBC compared to non-TNBC.

TNBCs have high mutational burden and may produce neoantigens leading to an immune response.

20 to 30% of TNBCs are associated with tumor infiltrating lymphocytes (TILs) which can facilitate an immune response.

Immune checkpoint blockade in metastatic TNBC

Pembrolizumab – ant-PD-1 antibody blocks interaction PD-1 receptor and its ligands PD-L1 and PD-L2

Phase 1B trial in metastatic TNBC KEYNOTE-012 n = 32; 46.9% had > 3 prior line of therapy all tumors positive for PD-L1 expression pembrolizumab 10 mg/kg IV every 2 weeks response rate 18.5% (CR 1 pt; PR 4 pts) median duration of response not reached (range 15 to 40

months) trend toward more clinical benefit with increasing PD-L1

expression

Buisseret L et al, Annals of Onc 2015 ;26 : 6-9.

Immune checkpoint blockade with chemotherapy in metastatic TNBC

Atezolizumab – anti-PDL1 antibody blocks PD-L1/PD-1 and PD-L1/B7.1 interaction.

Phase 1-b evaluated atezolizumab in combination with weekly nab-paclitaxel in metastatic TNBC pts

Up to 3 prior lines of chemotherapy

Responses seen in ptswith (77%) and without (57%) PD-L1 expression

Adams S et al. ASCO 2016, abstract 1007.

ConclusionsEarly Stage Breast Cancer Extended adjuvant AI therapy for 10 years improves DFS in

HR+ postmenopausal BC patients. Adjuvant anthracyclines improve DFS in LN positive and high

risk LN negative HER2- early stage BC patients. The role of platinum in early stage TNBC is not yet defined.

Trials are ongoing to determine who will benefit. Capecitabine for TNBC patients with residual disease after

surgery improved OS in one study and needs confirmation.Advanced breast cancer CDK 4/5 inhibition plus endocrine therapy improves DFS in

advanced HR+ BC, but which line of therapy, which patients? T-DM1 improves OS in HER2+ advanced breast cancer in 2nd

line therapy and beyond. Checkpoint inhibition in TNBC can provide durable responses

and is being tested further. Some PDL-1 expression appears better than none.

Advances in Breast Cancer Therapeutics in the Adjuvant and Metastatic Settings�17th Annual Advances in Oncology�September 30-October 1, 2016�Sacramento, CA��Anna Orlowski, J.D.�End of Life Option Act: Medical Legal Considerations.��No relevant financial relationships in the past twelve months by presenter or spouse/partner.��The speaker will directly disclosure the use of products for which are not labeled (e.g., off label use) or if the product is still investigational. � ��Slide Number 3Early Stage Breast CancerLong term recurrence risks after use of endocrine therapy for only 5 years�Slide 12Benefits of extended adjuvant endocrine therapy MA.17R Trial Study DesignMA.17R Disease-free survivalMA.17R DFS by pre-specified subgroupsMA.17R Slide Number 12ABC Trials Study DesignABC Trials: Invasive Disease Free SurvivalSlide 17Triple Negative Breast Cancer has Worse Outcome if Residual Disease Present after Neoadjuvant ChemotherapyGeparSixto Neoadjuvant Study Design �TNBC regimenGeparSixto: DFS advantage demonstrated with carboplatin in TNBCSlide Number 19Slide Number 20Slide Number 21NRG-BR003 - Randomized Phase III Trial of Adjuvant Therapy Comparing Doxorubicin Plus Cyclophosphamide Followed by Weekly Paclitaxel with or without Carboplatin for Node-Positive or High-Risk Node-Negative Triple-Negative Invasive Breast Cancer�Residual disease after neoadjuvant chemotherapy and surgery: �CREATE-X CREATE-X: 5-Yr EfficacyCapecitabine may have benefit in high risk populationsEA1131: A randomized phase III post-operative trial of platinum agent chemotherapy vs. capecitabine in patients with residual triple-negative breast cancer (TNBC) following neoadjuvant chemotherapy�Metastatic Breast CancerEndocrine monotherapy in first line metastatic setting Endocrine combination therapy in �first line metastatic setting PALOMA 2 Study DesignPALOMA 2�PFS Investigator-Assessed – (ITT Population)PALOMA 2PALOMA-2 �SafetyPALOMA 3: Palbociclib and fulvestrant in endocrine resistant metastatic breast cancerSequencing endocrine therapies in the metastatic setting for postmenopausal patientsPI3K inhibition in endocrine resistant metastatic breast cancer: BELLE-2 StudyBELLE-2: PFS results �and efficacy by PI3KCA mutation in ctDNATH3RESA: Study DesignTH3RESA: Final OS analysisImmunotherapy in TNBCImmune checkpoint blockade in metastatic TNBCImmune checkpoint blockade with chemotherapy in metastatic TNBCConclusions

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Advances in Breast Cancer Therapeutics in the Adjuvant and ... › wp-content › uploads › 2015 › 09 › rodler-UC-DAVI… · Jin H et al. J Clin Oncol 2012;30(7):718- 21. 3