Treatment Sequencing in HR+ ABC:

The New Era of Endocrine-Based Targeted

Combination Therapy
Endocrine therapy is the oldest targeted therapy
in breast cancer

Courtesy of Prof. Dr. Nadia Harbeck

Endocrine therapy for HR+ advanced breast cancer

Arpino G, et al. Endocrine Rev, 2008, 29(2):217–233

Real-world patterns of use of endocrine therapy vs
chemotherapy (n=355, 5 European countries)

Majority (69%) of patients received HT in the first-line setting

Andre F, et al. Curr Med Res Opin. 2014;30:1007-1016

 Physician-reported reasons of choice for
endocrine therapy over chemotherapy
“Absence of life-threatening metastasis” and “slow disease progression”
are the major drivers of choice for first-line endocrine therapy

Andre F, et al. Curr Med Res Opin. 2014;30:1007-1016

 Endocrine therapy (ET) is an established
first-line treatment for advanced BC
The development of ET agents to treat HR+, HER2– advanced BC has
contributed to increased survival rates1
Exemestane
Letrozole (1999)
(1997)

Tamoxifen Toremifene
(1977) (1997)
Anastrozole Fulvestrant
(1995) (2002)

1970 1980 1990 1995 2000 2005 2012 2014

Per guidelines, chemotherapy is no longer recommended for first-line

treatment of HR+, HER2– advanced BC, except in cases of rapidly
progressing visceral disease2-5

BC, breast cancer; ET, endocrine therapy; HR+, hormone receptor-positive, HER2–, human epidermal growth factor receptor-2–negative.

1. Yamamoto-Ibusuki M, et al. BMC Med. 2015;13:137; 2. Hao Y, et al. ASCO 2014. Abstract e11549; 3. NCCN Clinical Practice
Guidelines in Oncology: Breast Cancer. Version 2.2016; 4. Cardoso F, et al. Ann Oncol. 2014;25(10):1871-1888;
5. Rugo HS, et al. J Clin Oncol. 2016;34(25):3069-3103.
 Main challenges in the treatment of hormone
receptor positive breast cancer

• Non-response and side effects

– About 50% of patients with ER+ breast cancer do not respond to the
initial endocrine therapy1,2,5
– The majority of patients who responded initially to an endocrine
therapy develop resistance2,5
– Patients may delevop side effects/intolerance to medical therapies
(chemo- and endocrine therapy)3

• Development of resistance
– Often caused by activation of an alternative signaling pathway3-5

1. Bedard PL, et al. Breast Cancer Res Treat. 2008;108(3):307-317; 2. Normanno N et al. Endocr relat Cancer 2005; 12(4): 721-747;
3. Xu et al. J Cancer Res Clin Oncol 2011; 137:1005-1013; 4. Rimawi & Osborne Nat Rev Clin Oncol 2012; 9:133-134; 5. Pink JJ et al.
Br J Cancer 1996; 74(8): 1227–1236.
 Rationale for Expanding First-Line Treatment
Options for HR+, HER2– Advanced Breast Cancer
Adjuvant therapy (tamoxifen or NSAI) Primary
HR+, HER2– BC

De novo metastatic
BC Disease recurrence
First-line therapy

Recommended First-Line Therapies

• Established endocrine therapies in a first-line setting
– AIs
– Tamoxifen
– Fulvestrant (in patients with prior adjuvant ET)
– Fulvestrant + NSAIa

The majority of patients experience endocrine

Treatment Resistance resistance, leading to tumor recurrence1,2
Disease Progression Only ~30% of patients with advanced disease show objective
tumor regression with first-line endocrine therapy, and an
additional 20% experience prolonged stable disease1

AI, aromatase inhibitor; BC, breast cancer; NSAI, nonsteroidal aromatase inhibitor;
HER2–, human epidermal growth factor receptor-2–negative; HR+, hormone receptor-positive.
a Per ASCO and NCCN guidelines only.

1. Osborne CK, et al. Annu Rev Med. 2011;62:233-247; 2. Fox EM, et al. Front Oncol. 2012;2:145.
Resistance Mechanisms to Endocrine Therapy

1. Jeselsohn et al. Nat Rev Clin Oncol 2015; 2. Ma et al, Nature Rev. Cancer 2015; 3. Arpino G, et al. Endocrine Rev, 2008, 29(2):217–233.
Alterations in target: ESR1 mutation as acquired mutation

ESR1 Mutation Rate 21% (39/187) (Range 14-54%)

For primary lesion, ESR1 mutation rate ≈ 1%
Jeselsohn et al. Nat Rev Clin Oncol 2015
Bypass/compensatory mechanisms

Ma et al, Nature Rev. Cancer 2015

Pathway “Indifference”: Loss or reduced expression of ERα

Arpino G, et al. Endocrine Rev, 2008, 29(2):217–233

Clinical Strategies for Reversing Hormone Resistance:
Focusing on mTOR/PI3K and CDK4/6 Inhibition
 PI3K/AKT/mTOR: The Most Altered Pathway in Breast Cancer
Alterations in up to ~48% of ER+ BC
• mTORC1 activates ER in a
ligand-independent fashion.

• Estradiol suppresses apoptosis

induced by PI3K/mTOR
blockade.

• Hyperactivation of the
PI3K/mTOR pathway
promotes escape from
hormone dependence
– Associated with lower ER and
activity.

Osborne CK, et al. AnnuRev Med. 2011;62:233-247; Creighton et al, Breast Cancer Res 2010; Miller et al, JCI 2010
BOLERO-2: Improved PFS with mTOR Inhibition

Similar Results in combination with tamoxifen (TAMRAD study) and in

combination with fulvestrant (PrECOG0102 study)
CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo.
Yardley et al, AdvTher2013; Baselga et al, NEJM 2012
 BOLERO-4: Phase 2 Study of Everolimus + ET
(Investigational Regimen for First-Line Therapy)

N = 202
Phase 2 Study
 Postmenopausal women with
ER+, HER2– ABC EVE + LETa Disease Progression EVE + EXE
 De novo metastatic or recurring
>1 year after neo(adjuvant) Optional 2nd-
treatment with NSAI
Line Therapy
 No prior therapy for advanced
disease
Safety (most common all-grade AEs)
First-Line Second-Line
• First-line (EVE + LET): stomatitis (69%), weight loss
EVE + LET EVE + EXE
BOLERO-41 (n = 202)
 (n = 50)
(44%), diarrhea (40%), nausea (37%), and anemia (35%)

• Second-line (EVE + EXE): stomatitis (19%) and

Median PFS, weight loss (19%)
22.0 3.7
mo
(18.1-25.1) (1.9-7.4) AEs in both lines of treatment were mostly grade 1 or 2
(95% CI)

ABC, advanced breast cancer; AE, adverse event; CI, confidence interval; ET, endocrine therapy; EVE, everolimus; EXE, exemestane; ER+, estrogen receptor-positive; HER2–, human epidermal growth factor
receptor 2-negative; HR, hazard ratio; LET, letrozole; PFS, progression-free survival.

a Everolimusis not approved for use in the first-line setting.

1. Cardoso F, et al. ASCO 2017. Abstract 1010 [poster].
 BOLERO-6: Phase II EVE + EXE vs EXE vs CAP
Eligibility Criteria R Primary Objective
Oral EVE 10 mg/day
A
• Postmenopausal women with ER+ N + oral EXE 25 mg/day • Estimate the HR of PFS for
HER2– metastatic or recurrent BC, or D (n = 104) EVE + EXE vs EVE alone
locally advanced BC not amenable to O
M
• Primary endpoint: PFS
curative surgery or radiotherapy (investigator-assessed)
I Oral EVE 10 mg/day
• Recurrence or progression on prior Z (n = 103) Key Secondary Objective
LET or ANA A
T • Estimate the HR of PFS for
• Measurable disease per RECIST EVE + EXE vs CAP
I Oral CAP 1250 mg/m2
v1.1 or bone lesions (lytic or mixed),
O Other Secondary Endpoints
and ECOG PS 0–2 twice daily (2 weeks on,
N
1 week off) (n = 102) • OS, ORR, CBR, safety
• N = 309 (1:1:1)
100
• EVE + EXE offers a 90
PFS benefit
vs EVE alone, 80 mPFS, mos
consistent with n/N HR (90% CI)
70 (90% CI)
BOLERO-2 EVE + EXE 80/104 8.4 (6.6–9.7)
60 0.74 (0.57–0.97)
PFS, %

EVE alone 74/103 6.8 (5.5–7.2)

• No new safety signals 50
were observed with
EVE + EXE 40
30
• Supports the
continued use of this 20
therapy in patients 10
whose HR+, HER2–
ABC has progressed 0
on a NSAI 0 3 6 9 12 15 18 21 24 27 30 33 36
Time, months

CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EVE, everolimus; EXE, exemestane; HR, hazard ratio; (m)PFS, (median)
progression-free survival; TTF, time to treatment failure.
Jerusalem G, et al. ASCO 2018
 Benefit from Everolimus Regardless of Mutation Status

• 209/485 (43%) on the everolimus arm and

93/239 (39%) on placebo arm.
• No difference in PFS in the NGS subgroup.
• Most frequently altered genes were:
PIK3CA (47.6%), CCND1 (31.3%), TP53
(23.3%), and FGFR1 (18.1%).
• Greater benefit from everolimus in those
with a lower chromosomal instability score
– Lower CIN: larger PFS benefit (effect seen
only in the everolimus arm)
– CIN score <75th% had a 5.5 months gain in
PFS (8.4 v 2.9 mos)
– CIN >75% had a median PFS gain of 1.5
months (5.6 v 4.1 mos).

Hortobagyi et al, J Clin Oncol. 2016

 Everolimus safety profile: SWISH trial
N = 92
• Females ≥18 years
• Postmenopausal locally advanced or
metastatic HR+, HER2- breast cancer
• Prescribed EVE 10 mg + EXE 25 mg
• ECOG performance status ≤ 2
Open label, phase II, single arm
Endpoints
• Routine good oral care Primary: compare grade ≥2
• EVE 10 mg/day stomatitis incidence at 8 weeks
Baseline • EXE 25 mg/day with BOLERO-2 results
• Oral pain • Alcohol-free steroid-based
assessment Secondary: Mouthwash use by
mouthwasha
• VAS score average times/day, EVE/EXE
− 10 mL (0.5 mg/5 mL dose intensity, all-grade
• NDS score dexamethasone oral solution)
stomatitis incidence and time to
swish for 2 mins and spit QID resolution to grade ≤1, oral pain
scale, normalcy of diet
BOLERO-2, The Breast Cancer Trials of
Oral Everolimus-2
BOLERO-2 stomatitis grading based on
CTCAE v3.0
Rugo HS, et al. Lancet Oncol 2017; 18: 654–62
 Cyclin Dependent Kinase 4/6 Inhibitors
• Growth of HR+ BC is dependent on
cyclin D1, a transcriptional target of ER
• Cyclin D1 activates CDK 4/6 causing
G1-S phase transition and cell cycle
entry
• Endocrine resistant cell lines are
dependent on cyclin D1 and CDK 4/6

Luminal

Asghar et al. Nat Rev Drug Discov. 2015; Finn et al. Breast Can Res 2009
 Selective CDK4/6 Inhibitors:
Three Drugs Have Been Developed

O’Leary et al, Nat Rev Clin Oncol. 2016

Treatment Sequencing in HR+ ABC
 Selecting Treatments in HR+, HER2– ABC
Guidelines for First-Line Treatment

Consistent recommendations per ABC3, NCCN, and ASCO guidelines1-3

Endocrine therapy is the preferred approach for HR+ disease, even in the presence of visceral
disease

Multiple options are available in the first-line setting, including CDK4/6 inhibitors + endocrine
therapy or endocrine monotherapy

Choice of first-line endocrine agent (with or without targeted therapy) depends on patient
and disease characteristics including prior treatments received

23
ABC3, Advanced Breast Cancer Third International Consensus Conference; ASCO, American Society of Clinical Oncology; CDK, cyclin-dependent kinase; HER2–, human epidermal growth factor receptor-2–negative;
HR+, hormone receptor-positive; NCCN, National Comprehensive Cancer Network.
1. Cardoso F, et al. Ann Oncol. 2017;28(1):16-33; 2. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 1.2018; 3. Rugo HS, et al. J Clin Oncol. 2016;34(25):3069-3103.
 Selecting Treatments in HR+, HER2– ABC
Combination Treatment With CDK4/6 Inhibitors in the First-Line Setting

Phase 3 First-Line Therapy Trials (ie, only included patients with no prior ET for advanced disease)1-5

Study N Median PFS, months HR (95% CI) P Value

Ribociclib + letrozole: 25.3 0.57
MONALEESA-21 668 < 0.00001
Letrozole: 16.0 (0.46-0.70)
Ribociclib + tamoxifen/NSAI: 23.8 0.55
MONALEESA-72 672 < 0.00001
Tamoxifen/NSAI: 13.0 (0.44-0.69)
Palbociclib + letrozole: 27.6 0.56
PALOMA-23 666 < 0.00001
Letrozole: 14.5 (0.46-0.69)
Abemaciclib + NSAI: Not reached 0.54
MONARCH-34 493 0.00002
NSAI: 14.7 (0.41-0.72)
Ribociclib + fulvestrant: 20.5 0.59
MONALEESA-35 726 0.00000041
Fulvestrant: 12.8 (0.48-0.73)

1. Hortobagyi GN, et al. ASCO 2017. Abstract 1038 [poster]; 2. Tripathy D, et al. SABCS 2017. Abstract GS2-05 [oral presentation]; 3. Rugo HS, et al. SABCS 2017. Abstract P5-21-03 [poster];
4. Goetz MP, et al. J Clin Oncol. 2017;35(32):3638-3646; 5. Slamon DJ et al, ASCO 2018. Abstract 1000.
 Effect of Targeted Agents on the Backbone Endocrine Therapy
Results of Clinical Trials in HR+, HER2– ABC

Letrozole + CDK 4/6i

Letrozole + CDK 4/6i
Tamoxifen/NSAI + CDK 4/6i

Letrozole + mTORi
Letrozole + CDK 4/6i

Fulvestrant+ CDK 4/6i

Fulvestrant + mTORi
Fulvestrant + CDK 4/6i
Tamoxifen + mTORi
Exemestane + mTORi

months
ABC, advanced breast cancer; CI, confidence interval; ET, endocrine therapy; HER2–, human epidermal growth factor receptor-2–negative; HR, hazard ratio; HR+, hormone receptor-positive.
1. Hortobagyi GN, et al. ASCO 2017. Abstract 1038 [poster]; 2. Rugo HS, et al. SABCS 2017. Abstract P5-21-03 [poster]; 3. Tripathy D, et al. SABCS 2017. Abstract GS2-05 [oral presentation]; 4. Royce M, et al. JAMA
Oncol. 2018; doi:10.1001/jamaoncol.2018.0060 [Epub ahead of print]; 5. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35; 6. Sledge GW, et al. J Clin Oncol. 2017;35(25):2875-2884; 7. Kornblum NS, et al. Cancer Res
2017;77(Suppl 4):S1-02; 8. Turner NC, et al. New Eng J Med. 2015;373(3):209-220; 9. Bachelot T, et al. J Clin Oncol. 2012;30:2718-2724; 10. Yardley DA, et al. Adv Ther. 2013;30:870-885.
 Dual Blockade Therapy for HR+ Advanced Breast Cancer
Summary of Treatment Options for First-Line and Later

First line Second or later line Later lines

Everolimus Superior to
Palbociclib Superior to letrozole
exemestane Other HTs
(PALOMA-21)
Exemestane (BOLERO-25)
Letrozole

Superior to Other HT +
Ribociclib Superior to
Everolimus tamoxifen Targeted agent
letrozole Tamoxifen (TAMRAD6)
Letrozole (MONALEESA-22)

Everolimus Superior to fulvestrant

Abemaciclib Superior to
(PrECOG 1027)
letrozole Fulvestrant
Letrozole (MONARCH-33)

Palbociclib
Superior to fulvestrant
Ribociclib (PALOMA-38)
Superior to letrozole Fulvestrant
Letrozole or tamoxifen
(MONALEESA-74) Abemaciclib
or Superior to fulvestrant
Tamoxifen Fulvestrant (MONARCH-29) HT, hormone therapy; HR, hazard ratio.

26 4.
1. Finn RS, et al. N Engl J Med. 2016;375:1925-1936; 2. Hortobagyi G, et al. N Engl J Med. 2016;375:1738-1748; 3. Goetz MP, et al. J Clin Oncol. 2017;35(32)3638-3646;
Tripathy D, et al. SABCS 2017. Abstract GS2-05 [oral presentation]; 5. Yardley DA, et al. Adv Ther. 2013;30:870-885.; 6. Bachelot T, et al. J Clin Oncol. 2012;30:2718-2724; 7.
Kornblum NS, et al. Cancer Res. 2017;77(suppl 4):S1-02; 8. Turner NC, et al. New Eng J Med. 2015;373(3):209-220; 9. Sledge GW, et al. J Clin Oncol. 2017;35(25):2875-2884.
Optimal sequencing of endocrine therapy in
ER+ MBC

Cumulative Median Progression-Free Survival (PFS) in months Overall Survival (OS)

Jonhston San Antonio Breast Cancer Symposium, 2016

 HR+, HER2─ ABC in premenopausal women
Breast cancer is a leading cause of cancer-related death for women
less than 40 years of age1
Approximately 5%-7% of all breast cancer cases are diagnosed in women <40 years of age2

• Premenopausal women tend to present at more advanced stages2

─ Higher-grade tumors
─ Increased nodal metastasis
─ Larger primary breast tumors

• Young age (≤40 years) is associated with a statistically significant increase in risk of breast-
cancer related death in patients with luminal BC3
• Higher mortality (up to 1.5-fold) is observed for women diagnosed <40 years of age2

• Endocrine therapy with ovarian suppression is the standard first-line treatment for
premenopausal women with ABC4-6; however, therapeutic resistance is common
– The 5-year OS rate for women <40 years of age with ABC is 15% (vs 20% for women aged
40-75 years)7

ABC, advanced breast cancer; HR+, hormone receptor-positive; HER2─, human epidermal growth factor receptor-2–negative; OS, overall survival.

1. Siegel R, et al. CA Cancer J Clin. 2014;64(1):9-29; 2. Reyna C, et al. J Multidiscip Healthc. 2014;7:419-429; 3. Partidge AH, et al. J Clin Oncol. 2016;34(27):3308-3314; 4. NCCN Clinical Practice Guidelines:
Breast Cancer. Version 2.2017; 5. Cardoso F, et al. Ann Oncol. 2016;26(8):1533-1546; 6. Rugo HS, et al. J Clin Oncol. 2016;34(25)3069-3103; 7. Bleyer A et al. Nat Rev Cancer. 2008;8(4):288-298.
 Clinical Trial Data for Premenopausal Patients
With HR+, HER2─ ABC Are Limited
As with postmenopausal women, there
• PALOMA-3 (PAL + FUL in patients with disease
is an unmet need for targeted progression on prior endocrine therapy) included
treatments to improve treatment premenopausal women receiving concomitant goserelin
outcomes for advanced disease in (n = 108)5
premenopausal women • Premenopausal patients experienced
significantly prolonged PFS (9.5 months
 The addition of LHRH agonists to palbociclib arm vs 5.6 months placebo arm; HR =
tamoxifen provides a treatment benefit 0.50; 95% CI, 0.29-0.87)
to premenopausal patients with HR+,
• MONARCH-2 (ABE + FUL in patients with disease
HER2─ ABC1
progression on prior endocrine therapy) included
premenopausal women receiving concomitant GnRH
 Small phase 2 studies show a benefit of agonist (n = 114)6
AIs and ovarian suppression in
• Premenopausal patients experienced a
premenopausal patients with HR+, prolonged PFS with ABE + FUL vs PBO + FUL (HR =
HER2– advanced breast cancer2-4 0.42; 95% CI, 0.25-0.70)
However, fulvestrant is not included in recommendations for
premenopausal patients

ABC, advanced breast cancer; ABE, abemaciclib; AI, aromatase inhibitor; CI, confidence interval; FUL, fulvestrant; HER2-, human epidermal growth factor receptor 2-negative; HR, hazard ratio; HR+, hormone
receptor-positive; LHRH, luteinizing hormone-releasing hormone; PAL, palbociclib; PFS, progression-free survival.

1. Klijn JGM, et al. J Clin Oncol. 2001;19(2):343-353; 2. Nishimura R, et al. Oncol Rep. 2013;29(5):1707-1713; 3. Carlson RW, et al. J Clin Oncol. 2010;28(25):3917-3921; 4. Yao S, et al. Endocr J. 2011;58(6):509-516;
5. Loibl S, et al. ASCO 2016. Abstract 524 [poster]; 6. Sledge GW Jr, et al. J Clin Oncol. 2017;35(25):2875-2884.
 HR+, HER2─ Advanced Breast Cancer:
Where Are We Now?
• Endocrine therapy remains the
EGFR/HER2/HER3 FGFR IGFR
Inhibitors Inhibitors Inhibitors
foundation of treatment for HR+,
Estrogen HER2─ ABC1
EGFR/HER3 FGFR IGFR MET
SRC Inhibitor • Several targeted therapies are
SRC
approved for use as part of endocrine-
RAS PI3K
STAT3 PIP2 PIP3
based regimens:
RAF PI3K Inhibitors
Cyclin D mTORC2
AKT Inhibitors ─ Everolimus, an mTOR inhibitor, is
p21WAF1/CIP1 AKT
MAPK InhibitorsMEK mTOR Inhibitors approved for use in combination with
MDM2
CDK Inhibitors CDK • MEK inhibitors ERK Rheb TSC exemestane after progression on an
p53 NSAI2,3
E2F Rheb
P
mTORC1 ─ Multiple CDK4/6 inhibitors (ribociclib,
ER
palbociclib, and abemaciclib) are
Me/Ac HDAC Inhibitors approved for use in combination with
SRC
an aromatase inhibitor as an initial
therapy, or in combination with
fulvestrant after disease progression
on endocrine therapy4-8,a
 HR+, HER2─ Advanced Breast Cancer:
Where Are We Going?
• Despite the improving efficacy of EGFR/HER2/HER3 FGFR IGFR
new therapies, all patients with Inhibitors Inhibitors Inhibitors
ABC will develop resistance to Estrogen
EGFR/HER3 FGFR IGFR MET
therapy over time1

• A number of novel therapies for SRC Inhibitor SRC

RAS PI3K
ABC are under investigation, STAT3 PIP2 PIP3
including Cyclin D
RAF PI3K Inhibitors
mTORC2
AKT Inhibitors
p21WAF1/CIP1 MEK mTOR Inhibitors AKT
─ PI3K inhibitors such as alpelisib (α- MAPK Inhibitors
MDM2
isoform specific) and taselisib (β- CDK Inhibitors CDK
• MEK inhibitors
TSC
ERK Rheb
isoform sparing)2-4 p53
Rheb
─ Oral SERDs such as LSZ102, GDC- E2F P
0810, mTORC1

and RAD19015-7
ER
─ Novel combination therapies for Me/Ac
HDAC Inhibitors
HR+, HER2─ ABC with immuno- SRC
oncology agents such as
pembrolizumab and atezolizumab8,9
BC, breast cancer; CDK, cyclin-dependent kinase; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; HDAC, histone deacetylase; HER, human epidermal growth factor receptor;
HR+, hormone receptor-positive; IGFR, insulin-like growth factor receptor; MDM2, murine double minute 2; Me, methylation; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol-3 kinase;
STAT3, signal transducer and activator of transcription.

31
Reprinted from Johnston SR. J Natl Cancer Inst. 2015;107(10). pii: djv212. 1. Yamamoto-Ibusuki M, et al. BMC Med. 2015;13:137; 2. Rugo HS, et al. ASCO 2017. Abstract TPS1111 [poster); 3. NCT02340221; 4.
Zumsteg ZS, et al. Clin Cancer Res. 2016;22(8):2009-2019; 5. NCT02734615; 6. NCT01823835; 7. NCT02650817; 8. NCT02648477; 9. NCT02914470.
 Conclusions
• Endocrine therapy is the therapeutic backbone in early and advanced
hormone receptor positive breast cancer

• Current guidelines support continuing endocrine-based therapeutic

approaches after HR+ ABC progresses

• Endocrine plus targeted agent (eg. mTORi and CDK4/6i) is a promising

approach for overcoming endocrine resistance

• Open clinical questions are:

– Premenopausal patients
– Predictive biomarkers
– Duration of therapy
– Optimal combination partners