Everolimus + Exemestane vs Everolimus Alone or ... · László Landherr,9Marianne Ewertz,10Tetiana...

Everolimus + Exemestane vs Everolimus Alone or Capecitabine for Estrogen Receptor-Positive, HER2− Advanced Breast CancerBOLERO-6, a Randomized, Open-label, Phase II Study

1Guy Jerusalem http://jamanetwork.com/journals/jamaoncology/fullarticle/10.1001/jamaoncol.2018.2262

Guy Jerusalem,1 Elena Kovalenko,2 Denise A. Yardley,3 Richard de Boer,4 Sara Hurvitz,5 Bent Ejlertsen,6 Sibel Blau,7 Mustafa Özgüroğlu,8

László Landherr,9 Marianne Ewertz,10 Tetiana Taran,11 Jenna Fan,11 Florence Noel-Baron,12 Anne-Laure Louveau,13 Howard Burris3

1CHU Sart Tilman Liège and Liège University, Liège, Belgium; 2Russian Cancer Research Center, Moscow, Russia; 3Sarah Cannon Research Institute and Tennessee Oncology, PLLC, Nashville, TN; 4Royal Melbourne Hospital, Victoria, Australia; 5UCLA Jonsson Comprehensive Cancer Center, Los Angeles, CA; 6Copenhagen University Hospital, Copenhagen, Denmark; 7Rainier Hematology-Oncology/Northwest Medical Specialties, Tacoma, WA; 8Cerrahpaşa School of Medicine, Istanbul University, Istanbul, Turkey; 9Uzsoki Teaching Hospital, Budapest, Hungary; 10Odense University Hospital, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; 11Novartis Pharmaceuticals Corporation, East Hanover, NJ; 12Novartis Pharma AG, Basel, Switzerland 13Novartis Pharma S.A.S., Paris, France

Background• EVE, an oral rapamycin derivative, inhibits the PI3K–mTOR pathway via

allosteric binding to mTORC11

• In BOLERO-2, EVE + EXE significantly improved median PFS vs EXE alone (7.8 vs 3.2 months; HR 0.45; 95% CI 0.38–0.54) in patients with HR+, HER2− ABC that had progressed on an NSAI2

• CAP, an oral antineoplastic agent with a different safety profile to EVE and EXE has achieved median PFS 4.1–7.9 months in previous studies of HER2– ABC3–7

• EVE has also shown some clinical activity alone (median PFS 3.5 months), although data are limited8

• BOLERO-6 was conducted to fulfill postapproval regulatory commitments to the FDA and EMA to estimate treatment benefit with EVE + EXE vs EVE alone or CAP for ER+, HER2− ABC that had progressed on an NSAI

2Guy Jerusalem

(A)BC, (advanced) breast cancer; AKT, protein kinase B; CAP, capecitabine; CI, confidence interval; EMA, European Medicines Agency; ER(+), estrogen receptor(-positive); EVE, everolimus; EXE, exemestane; FDA, Food and Drug Administration; HER2–, human epidermal growth factor receptor 2-negative; HR, hazard ratio; HR+, hormone receptor-positive; mTOR(C), mammalian target of rapamycin (complex);

NSAI, nonsteroidal aromatase inhibitor; PFS, progression-free survival; PI3K, phosphatidylinositol 3-kinase; PIP2, phosphatidylinositol (3,4)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; S6K, S6 kinase.

1. Baselga J, et al. N Engl J Med. 2012;366:520–529; 2. Yardley DA, et al. Adv Ther. 2013;30:870–884; 3. Robert NJ, et al. J Clin Oncol. 2011;29:1252–1260; 4. O'Shaughnessy JA, et al. Oncologist. 2012;17:476–484; 5. Stockler MR, et al. J Clin Oncol. 2011;29:4498–4504; 6. Kaufmann M, et al. Eur J Cancer. 2010;46:3184–3191; 7. Harbeck N, et al. Breast Cancer Res Treat. 2017;161:63–72; 8. Ellard SL, et al. J Clin Oncol. 2009;27:4536–4541.

.

PI3K

RTK

ER

Estrogen

PIP2

PIP3

PTEN

AKT mTORC2

mTORC1EVE

S6K

EXE

http://jamanetwork.com/journals/jamaoncology/fullarticle/10.1001/jamaoncol.2018.2262

Randomized, Open-Label, Phase II Study

3Guy Jerusalem

*Stratified by presence or absence of visceral disease (lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion, or malignant ascites; †Stratified multivariate Cox regression models were adjusted on treatment and the following prognostic and baseline covariates where imbalances between arms were observed: bone-only lesions (yes vs no); prior

chemotherapy (yes vs no); ECOG PS (0 vs 1–2); organs involved (2 vs 1, and ≥3 vs 1); race (Caucasian vs non-Caucasian); age (<65 vs ≥65 years).ANA, anastrozole; BID, twice daily; CBR, clinical benefit rate; ECOG PS, Eastern Cooperative Oncology Group performance status; LET, letrozole; NSAI, nonsteroidal aromatase inhibitor;

ORR, overall response rate; OS, overall survival; PO, oral administration; QD, once daily; RECIST, Response Evaluation Criteria In Solid Tumors.

• BOLERO-6 was not powered to perform statistical comparisons between arms

Eligibility Criteria

• Postmenopausal women with ER+ HER2–metastatic or recurrent BC, or locally advanced BC not amenable to curative surgery or radiotherapy

• Recurrence or progression on ANA or LET

• Measurable disease per RECIST v1.1 or bone lesions (lytic or mixed), and ECOG PS 0–2

• N = 309

Rand

omiz

atio

n (1

:1:1

)*

EVE 10 mg PO QD+ EXE 25 mg PO QD

(n = 104)

CAP 1250 mg/m2 PO BID (2 weeks on, 1 week off)

(n = 102)

EVE 10 mg PO QD (n = 103)

Primary Objective

• Estimate HR of investigator-assessed PFS for EVE + EXE vs EVE alone†

Key Secondary Objective

• Estimate HR of PFS for EVE + EXE vs CAP†

Other Secondary Endpoints

• OS,† ORR, CBR, and safety

• BOLERO-6 randomized 309 patients to receive EVE + EXE (n = 104), EVE alone (n = 103), or CAP (n = 102)


Baseline Characteristics

4Guy Jerusalem

Characteristic, % EVE + EXE (n = 104) EVE alone (n = 103) CAP (n = 102)Median age (range), years

<65 years, %61.0 (32–86)

6361.0 (38–88)

6259.5 (35–84)

68Race, %

CaucasianOther

7525

8317

8911

ECOG PS, %*01–2

5245

4751

5642

Metastatic site of cancer, %†

Visceral‡ (excluding CNS)BoneBone onlyOther

66851364

64771659

62832459

Metastatic sites, %1–2≥3

5050

5446

5644

*Data missing for 7 patients in the EVE + EXE (n = 3), EVE alone (n = 2), and CAP (n = 2) arms; †CNS in 2 patients in the EVE alone (n = 1) and CAP (n = 1) arms;‡Lung, liver, heart, ovary, spleen, kidney, adrenal gland, malignant pleural or pericardial effusion, or malignant ascites.

CNS, central nervous system.

• More patients in CAP vs EVE-containing arms:• <65 years of age

• Caucasian• Fully active (ECOG PS 0)• Had bone-only metastases

• Fewer patients in CAP vs EVE-containing arms had ≥3 metastatic sites



5Guy Jerusalem


<65 years, %61.0 (32–86)

6361.0 (38–88)

6259.5 (35–84)

68Race, %

CaucasianOther

7525

8317

8911

ECOG PS, %*01–2

5245

4751

5642



66851364

64771659

62832459


5050

5446

5644



• More patients in CAP vs EVE-containing arms:• <65 years of age• Caucasian• Fully active (ECOG PS 0)• Had bone-only metastases




6Guy Jerusalem


<65 years, %61.0 (32–86)

6361.0 (38–88)

6259.5 (35–84)

68Race, %

CaucasianOther

7525

8317

8911

ECOG PS, %*01–2

5245

4751

5642



66851364

64771659

62832459


5050

5446

5644








7Guy Jerusalem


<65 years, %61.0 (32–86)

6361.0 (38–88)

6259.5 (35–84)

68Race, %

CaucasianOther

7525

8317

8911

ECOG PS, %*01–2

5245

4751

5642



66851364

64771659

62832459


5050

5446

5644








8Guy Jerusalem


<65 years, %61.0 (32–86)

6361.0 (38–88)

6259.5 (35–84)

68Race, %

CaucasianOther

7525

8317

8911

ECOG PS, %*01–2

5245

4751

5642



66851364

64771659

62832459


5050

5446

5644








9Guy Jerusalem


<65 years, %61.0 (32–86)

6361.0 (38–88)

6259.5 (35–84)

68Race, %

CaucasianOther

7525

8317

8911

ECOG PS, %*01–2

5245

4751

5642



66851364

64771659

62832459


5050

5446

5644



• More patients in CAP vs EVE-containing arms:• Caucasian

• <65 years of age• Fully active (ECOG PS 0)• Had bone-only metastases



Primary Objective Estimated HR of PFS for EVE + EXE vs EVE aloneEVE + EXE offers a PFS benefit vs EVE alone

10Guy Jerusalem

• Estimated HR of PFS for EVE + EXE vs EVE alone was 0.74 (90% CI 0.57–0.97)

• Censored for initiating new antineoplastic therapies:• EVE + EXE arm, 9%• EVE alone arm, 18%

• A stratified multivariate Cox regression model accounting for baseline imbalances and known prognostic factors gave a consistent HR (0.73; 90% CI 0.56–0.97) for EVE + EXE vs EVE alone

104 73 52 39 26 19 11 10 10 10 9 5 1 0103 66 40 26 14 9 7 4 4 4 2 1 0 0

PFS,

%

Time, months0 3 6 9 12 15 18 21 24 27 30 33 36

1009080706050403020100

Patients still at riskEVE + EXEEVE alone

39

*EVE + EXE vs EVE alone (obtained from a stratified Cox model).mPFS, median progression-free survival.

n/N mPFS,months HR* (90% CI)

CensoringEVE + EXE 80/104 8.4 0.74 (0.57–0.97)EVE alone 74/103 6.8


Key Secondary ObjectiveEstimated HR of PFS for EVE + EXE vs CAPCAP may have been favored by baseline imbalances and potential informative censoring

11Guy Jerusalem

• Estimated HR of PFS for EVE + EXE vs CAP was 1.26 (90% CI 0.96–1.66)

• Censored for initiating new antineoplastic therapies:• EVE + EXE arm, 9%• CAP arm, 20%

• A stratified multivariate Cox regression model accounting for baseline imbalances and known prognostic factors gave a HR of 1.15 (90% CI 0.86–1.52) for EVE + EXE vs CAP

PFS,

%

Time, months0 3 6 9 12 15 18 21 24 27 30 33 36

1009080706050403020100

n/N mPFS, months HR* (90% CI)

CensoringEVE + EXE 80/104 8.4 1.26 (0.96–1.66)CAP 68/102 9.6

39 42

104 73 52 39 26 19 11 10 10 10 9 5 1 0 0102 68 48 38 33 26 19 14 10 9 6 3 2 1 0

Patients still at riskEVE + EXECAP

*EVE + EXE vs CAP (obtained from a stratified Cox model).


Overall SurvivalEVE + EXE vs EVE alone or CAP

12Guy Jerusalem

• New antineoplastic therapies initiated at EOT:• EVE + EXE arm, 78%

• EVE alone arm, 81%• CAP arm, 79%

• A stratified multivariate Cox regression model accounting for baseline imbalances and known prognostic factors gave a HR of 1.27 (90% CI 0.94–1.70) for EVE + EXE vs EVE alone and a HR of 1.19 (90% CI 0.88–1.62) for EVE + EXE vs CAP

*EVE + EXE vs EVE alone or CAP (obtained from a stratified Cox model).EOT, end of treatment; mOS, overall survival.

10410192 81 74 67 63 53 48 43 39 22 13 8 3 1 0 0103 96 86 81 72 69 66 57 55 49 43 27 21 11 4 2 0 0102 94 88 83 78 70 64 61 54 43 38 31 21 16 7 3 1 0

OS,

%

Time, months3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 480 51

1009080706050403020100

Patients still at riskEVE + EXEEVE aloneCAP

n/N mOS, months HR* (90% CI)

CensoringEVE + EXE 71/104 23.1EVE alone 59/103 29.3 1.27 (0.95–1.70)CAP 58/102 25.6 1.33 (0.99–1.79)


Adverse Events

13Guy Jerusalem

*≥5% grade 3–4 events in any arm; †BOLERO-6 was not designed to use the SWISH1 protocol for stomatitis prevention.AE, adverse event; AST, aspartate aminotransferase; GGT, gamma-glutamyl transferase; PPE, palmar-plantar erythrodysesthesia.

1. Rugo HS et al. Lancet Oncol 2017;18:654–662.

AE,* %EVE + EXE (n = 104) EVE alone (n = 103) CAP (n = 102)

All grades Grade 3–4 All grades Grade 3–4 All grades Grade 3–4

Total

Stomatitis†

Fatigue

Diarrhea

Anemia

Elevated GGT

Elevated AST

Hypertension

Hyperglycemia

Pneumonia

Neutropenia

PPE syndrome

100

49

38

35

32

15

15

14

13

11

4

3

70

9

8

5

13

9

7

6

4

7

0

1

98

46

31

33

25

16

14

8

17

9

4

3

59

5

3

3

10

12

8

2

8

3

2

0

100

25

35

54

22

2

9

5

8

3

15

61

74

7

8

8

7

2

1

3

1

2

6

27

• Most frequent all-grade AEs:• Stomatitis in EVE-containing

arms

• PPE syndrome and diarrhea in CAP arm

• Grade 3-4 AEs more frequent in EVE + EXE arm vs EVE alone arm, and comparable between EVE + EXE and CAP arms


Adverse Events

14Guy Jerusalem





Total

Stomatitis†

Fatigue

Diarrhea

Anemia

Elevated GGT

Elevated AST

Hypertension

Hyperglycemia

Pneumonia

Neutropenia

PPE syndrome

100

49

38

35

32

15

15

14

13

11

4

3

70

9

8

5

13

9

7

6

4

7

0

1

98

46

31

33

25

16

14

8

17

9

4

3

59

5

3

3

10

12

8

2

8

3

2

0

100

25

35

54

22

2

9

5

8

3

15

61

74

7

8

8

7

2

1

3

1

2

6

27


arms




Adverse Events

15Guy Jerusalem





Total

Stomatitis†

Fatigue

Diarrhea

Anemia

Elevated GGT

Elevated AST

Hypertension

Hyperglycemia

Pneumonia

Neutropenia

PPE syndrome

100

49

38

35

32

15

15

14

13

11

4

3

70

9

8

5

13

9

7

6

4

7

0

1

98

46

31

33

25

16

14

8

17

9

4

3

59

5

3

3

10

12

8

2

8

3

2

0

100

25

35

54

22

2

9

5

8

3

15

61

74

7

8

8

7

2

1

3

1

2

6

27


arms




Other Safety

16Guy Jerusalem

• Serious AEs more frequent with EVE + EXE vs EVE alone or CAP

• Incidence of AEs leading to discontinuation comparable in each arm

All-grade AEs leading to discontinuationRegardless of causality

All-grade serious AEsRegardless of causality


Deaths

17Guy Jerusalem

*Occurring up to 30 days after treatment discontinuation.

Deaths, n EVE + EXE (n = 104) EVE alone (n = 103) CAP (n = 102)

All study deaths

Disease progression

AE

71

67

4

59

53

6

58

53

5

On-treatment deaths*

Disease progression

AE

9

6

3

5

2

3

2

0

2

• 188 patients died during the study

• Disease progression most frequent reason in each arm

• Few deaths occurred due to AEs

• 16 of 188 deaths occurred on-treatment*

• Disease progression most frequent reason in EVE + EXE arm

• Incidence of death due to AEs comparable in each arm


Deaths

18Guy Jerusalem

*Occurring up to 30 days after treatment discontinuation.

Deaths, n EVE + EXE (n = 104) EVE alone (n = 103) CAP (n = 102)

All study deaths

Disease progression

AE

71

67

4

59

53

6

58

53

5

On-treatment deaths*

Disease progression

AE

9

6

3

5

2

3

2

0

2

• 188 patients died during the study

• Disease progression most frequent reason in each arm

• Few deaths occurred due to AEs

• 16 of 188 deaths occurred on-treatment*

• Disease progression most frequent reason in EVE + EXE arm

• Incidence of death due to AEs comparable in each arm


Conclusions

19Guy Jerusalem

1. Yardley DA, et al. Adv Ther. 2013;30:870–884; 2. Ellard SL, et al. J Clin Oncol. 2009;27:4536–4541 [NCI Canada]; 3. Robert NJ, et al. J Clin Oncol. 2011;29:1252–1260; 4. O'Shaughnessy JA, et al. Oncologist. 2012;17:476–484; 5. Stockler MR, et al. J Clin Oncol. 2011;29:4498–4504; 6. Kaufmann M, et al. Eur J Cancer. 2010;46:3184–3191;

7. Harbeck N, et al. Breast Cancer Res Treat. 2017;161:63–72.

• Median PFS with EVE + EXE (8.4 months) consistent with BOLERO-2 (7.8 months),1 and vs EVE alone here (6.8 months) corresponded to estimated 26% reduction of risk of disease progression or death (HR 0.74)

• Median PFS with EVE alone numerically longer than previously reported in a small phase II study (3.5 months)2

• No new safety signals observed with EVE + EXE

• A numerical median PFS difference was observed for CAP over EVE + EXE (9.6 vs 8.4 months), which may be attributed to various baseline characteristics favoring CAP and potential informative censoring

• Median PFS with CAP also inconsistent with previous studies (4.1–7.9 months)3–7


Conclusions

20Guy Jerusalem

• Interpretation of the results of BOLERO-6 must consider the limited sample size and open-label design

• Nonetheless, the results suggest that EVE + EXE offers a PFS benefit vs EVE alone, supporting the continued use of this combination in this treatment setting

• The benefit–risk profile of EVE + EXE is unchanged from BOLERO-2


Publication in JAMA Oncology

21Guy Jerusalem http://jamanetwork.com/journals/jamaoncology/fullarticle/10.1001/jamaoncol.2018.2262

Acknowledgments

22Guy Jerusalem

• The authors thank the study participants and their families, and the investigators, nurses, and clinical research associates from the participating centers

• The study was sponsored by Novartis Pharmaceuticals Corporation, who also provided financial support for medical editorial assistance from ArticulateScience Ltd

• The authors acknowledge Jeremie Lincy for conducting the primary analysis


Everolimus + Exemestane vs Everolimus Alone or ... · László Landherr,9Marianne Ewertz,10Tetiana...

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