1. Selecting Treatment and Management Approaches in Metastatic Breast Cancer
Kathy D. Miller, MD
Associate Professor
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana
Welcome to “Selecting Treatment and Management Approaches for Metastatic Breast Cancer.” I’m Dr Kathy Miller from the Indiana University Melvin and Bren Simon Cancer Center in Indianapolis. Today, we’re going to talk about several patient scenarios in the setting of metastatic disease and review both treatment options and the data that would support those treatment options.
This program is supported by educational grants from

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3. Disclosure
Kathy D. Miller, MD, has disclosed that she has received consulting fees from Astra Zeneca, Bristol-Myers Squibb, and Genentech and contracted research support from Genentech and Roche.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.
No changes…RSM

4. Case 1
A 70-yr-old woman presents with severe back pain that persists despite NSAID therapy. An x-ray of her spine reveals a compression fracture of T12. MRI confirms fracture but also notes a soft-tissue mass associated with the lesion. Bone scan and chest/abdomen CT scan reveals additional bone metastases in L2, L4, and several ribs but no visceral metastases. A biopsy of the soft-tissue mass at T12 is consistent with metastatic breast cancer that is estrogen receptor (ER > 90%) and progesterone receptor (PgR > 90%) positive and HER2 negative (IHC 1+, FISH ratio 1.26)
So our first case is a 70‑year‑old woman who presented with severe back pain that persisted despite nonsteroidal therapy. A plain x‑ray showed a compression fracture at T12 and that led to an MRI that confirmed the fracture but also noted a suspicious soft tissue mass associated with that lesion. Bone scan and CT scans found additional bony disease at L2, L4, and several ribs, but no visceral metastases were identified. A biopsy of the soft tissue mass at T12 was consistent with metastatic breast cancer that was strongly estrogen and progesterone receptor positive and HER2 receptor negative by both immunohistochemistry and FISH testing.

5. Case 1 The patient’s medical history is notable for
HTN
Osteopenia treated with calcium and vitamin D (T score recorded 18 mos ago)
6-cm infiltrating lobular cancer 10 yrs ago treated with modified radical mastectomy and doxorubicin and cyclophosphamide (AC) x 4 followed by tamoxifen for 5 yrs
Laboratory analyses
CBC, calcium, total bilirubin, AST, ALT, albumin: all normal
Alk phos: 412 mg/dL; CrCl: 55 mL/min
She receives radiation therapy to her involved disease from T12-L4
The patient’s past medical history is most notable for hypertension and osteopenia. And about 10 years ago, she was treated for a 6-cm infiltrating lobular cancer. She had undergone a modified radical mastectomy and then received adjuvant chemotherapy with doxorubicin and cyclophosphamide, and was on tamoxifen for 5 years.
At the time of her current presentation, typical CBC and chemistries were all normal with the exception of an elevation in alkaline phosphatase and minor renal insufficiency with a calculated creatinine clearance of 55. She was treated with palliative radiation to the involved disease from T12 to L4.

6. Case 1: What systemic therapy would you recommend for this patient?
Aromatase inhibitor
Fulvestrant
Fulvestrant + aromatase inhibitor
Tamoxifen
Single-agent chemotherapy
At this point, what systemic therapy would you recommend to her? Your choices would be either: an aromatase inhibitor; fulvestrant; the combination of fulvestrant and an aromatase inhibitor; tamoxifen; or single‑agent chemotherapy. Select your choice and remember to hit “Submit” so that your answers can be tabulated.

7. Expert Insight: 5 Breast Cancer Experts’ Choice of Therapy for This Patient
Expert 1: aromatase inhibitor
Expert 2: aromatase inhibitor
Expert 3: aromatase inhibitor
Expert 4: aromatase inhibitor
Expert 5: aromatase inhibitor
In this activity, we’ve pooled 5 breast cancer experts with various patient scenarios, including this particular patient scenario. And while we often differ in our opinions, in this case, all 5 experts recommended an aromatase inhibitor.
The Expert Insight is from an interactive decision support tool entitled “Expert Guidance in Selecting Therapy for Metastatic Breast Cancer" which is available at:

8. Management of Metastatic Breast Cancer
Diagnosis of metastatic breast cancer
Determination of sites and extent of disease
Assessment of HER2, HR status, disease-free interval, age, and menopausal status
No life-threatening disease,
hormone responsive
Hormone unresponsive or
life-threatening disease
First-line hormonal therapy
First-line chemotherapy
No response
Progression
Response
When we think about the management of metastatic disease, this is how I would think about it in my head. We first have to confirm the diagnosis with a biopsy, evaluate the extent and the sites of disease, and assess the biology of the patient’s disease. This patient has no immediately life‑threatening disease. Her tumor is hormone responsive and this first‑line hormone therapy would be the most appropriate for her.
Progression
Second-line chemotherapy
Second-line hormonal therapy
No response
Progression
Response
Third-line chemotherapy
Progression
Supportive care
Third-line hormonal therapy
No response

9. First-line Metastatic Therapy: Considerations
Goals of treatment
Palliation of symptoms, increase QOL
Prolong survival
Tumor response
Previous therapy
Tumor biology
ER, HER2, disease-free interval
Underlying medical and social issues
Patient considerations
Convenience vs compliance
Toxicities affecting normal functioning
For all of our patients with metastatic disease, our goals include palliation of their symptoms and improvement in their quality of life and, hopefully, prolonging their survival. We need to consider their previous therapy and, in this patient’s case, her only previous therapy had been her adjuvant chemotherapy with an anthracycline-based regimen and 5 years of tamoxifen with a 5-year disease‑free interval. She has no significant underlying medical issues, although she does have mild renal insufficiency, so thinking about the potential renal toxicities of her therapies will be important for us.
We always need to consider patient‑specific factors, including their ability to comply with the therapeutic treatments that we recommend to them, convenience when it comes to number of trips back and forth to the clinic, and toxicities that may impact their ability to continue their daily lives.

10. Chemotherapy vs Endocrine Therapy
Methods
Randomized trials of chemotherapy alone vs endocrine therapy alone
Results
8 trials identified (N = 817)
No significant difference for OS—HR: 0.94 (95% CI: ; P = .5)
Significant difference favoring chemotherapy for ORR—OR: 1.25 (95% CI: ; P = .04)
However the 2 largest trials demonstrated trends in opposite directions
Toxicity: little information available on adverse events and QOL
Increased toxicity with chemotherapy (nausea, vomiting and alopecia)
3 of 7 trials noted QOL aspects, with differing results
Authors’ conclusions
“In women with metastatic breast cancer and where hormone receptors are present, a policy of treating first with endocrine therapy rather than chemotherapy is recommended except in the presence of rapidly progressive disease”
A Cochrane analysis now completed almost a decade ago found 8 clinical trials that compared chemotherapy alone to endocrine therapy alone. There was no difference in overall survival. There was a small but real difference favoring chemotherapy if we focused only on overall response rates, but it’s important to note that the 2 largest trials actually found a trend favoring hormone therapy.. There was relatively less info about toxicity, but more toxicity reported with chemotherapy, and only 3 of the trials evaluated quality of life and they found very different results.
And the authors of that Cochrane analysis concluded that, in patients with metastatic disease, where hormone receptors are present, a policy of first treating with endocrine therapy was recommended unless there was rapidly progressive disease.
Wilcken N, et al. Cochrane Database Syst Rev. 2003:CD

11. What Are the Options Following Tamoxifen?
First treatment
Tamoxifen
Second treatment
Nonsteroidal AI
Fulvestrant
Third treatment
Fulvestrant
Steroidal AI
Nonsteroidal AI
So what endocrine therapy options are available for patients who have had previous tamoxifen therapy? And our choice really boils down to aromatase inhibitors or fulvestrant.
Fourth treatment
Steroidal AI
Nonsteroidal AI
Steroidal AI
Other options for subsequent therapy: progesterone agents, high-dose estrogen, AI + everolimus, clinical trial

12. FIRST: Study Design Randomized, open-label phase II trial
Primary endpoint: CBR, defined as CR, PR, or SD for ≥ 24 wks
Postmenopausal women with previously untreated hormone receptor–positive advanced breast cancer
(N = 205)
Fulvestrant 500 mg by intramuscular injection Days 0, 14, 28, and every 28 days thereafter
(n = 102)
Until disease progression or other event requiring discontinuation
The FIRST study is the most recent trial that directly compared an aromatase inhibitor—in the case of the FIRST trial, that was specifically anastrozole—to fulvestrant using an accelerated loading dose strategy, using fulvestrant at 500 mg, on Day 1, again 2 weeks later, and again 2 weeks later on Day 28, with 500 mg then continuing every 28 days thereafter.
Anastrozole 1 mg/day orally
(n = 103)
Robertson JFR, et al. SABCS Abstract S1-3.

13. FIRST: Fulvestrant Significantly Increased TTP in Secondary Analysis
1.0
Fulvestrant
Anastrozole
0.8
0.6
Proportion of Patients Alive and Progression Free
0.4
HR: 0.66 (95% CI: ; P = .01)
0.2 6 12 18 24 30 36 42 48
Mos
Patients at Risk, n
Fulvestrant
102 74 65 52 45 34 20 6
Now, the primary endpoint of this trial was clinical benefit rate. You will note that over two thirds of patients in both groups had a clinical benefit response, so they either responded or were stable for 6 months or more. There was no significant difference between the 2 treatment arms for that primary endpoint.
Time to progression was a secondary endpoint and that did favor fulvestrant in this relatively small randomized phase II trial.
Anastrozole
103 69 55 39 30 21 8 2
Parameter
Fulvestrant
(n = 102)
Anastrozole
(n = 103)
Patients progressing, n (%)
63 (61.8)
79 (76.7)
Median TTP, mos
23.4
13.1
Clinical benefit rate, %
72.5
67.0
Robertson JFR, et al. SABCS Abstract S1-3.

14. SWOG S0226: Study Design Primary endpoint: PFS
Secondary endpoints: OS, safety
Stratified by previous adjuvant tamoxifen
Treatment until disease progression
Anastrozole 1 mg/day PO +
Fulvestrant 500 mg on Day 1,
250 mg on Days 14 and 28,
250 mg every 28 days thereafter
(n = 355)
Postmenopausal women with hormone receptor–positive MBC
(N = 707)
The SWOG S0226 trial was also recently reported and it evaluated a combination strategy, a combination of fulvestrant plus anastrozole compared to anastrozole. This trial enrolled over 700 patients, all of whom were postmenopausal and had a hormone receptor–positive disease. They could have had previous adjuvant tamoxifen, but previous adjuvant aromatase inhibitor therapy was not allowed.
Anastrozole 1 mg/day PO
(n = 352)
Women with progression encouraged to cross over to receive fulvestrant
Mehta RS, et al. SABCS Abstract S1-1.

15. SWOG S0226: PFS and OS Overall and by Previous Adjuvant Tamoxifen
Endpoint
Anastrozole + Fulvestrant
Anastrozole
HR (95% CI)
P Value
Median PFS (n = 694), mos
No previous adjuvant tamoxifen (n = 414)
Previous adjuvant tamoxifen (n = 280)
15.0
17.0
13.5
12.6
14.1
0.80 ( )
0.74 ( )
0.89 ( )
.007
.0055
.37
Median OS (n = 694), mos
47.7
49.6
41.3
39.7
44.5
0.81 ( )
0.74 ( )
0.91 ( )
.049
.0362
.59
This trial found an improvement in progression‑free survival, its primary endpoint, for the population as a whole from 13.5 months for patients treated with anastrozole to 15 months for patients treated with the combination, but when you look at the subsets based on previous adjuvant tamoxifen therapy, the benefit appeared to be largely if not entirely in the patients who had not had previous tamoxifen therapy. And I suspect that that subset analysis may have been why the experts were less enthusiastic about the combination regimen in this particular patient.
Mehta RS, et al. SABCS Abstract S1-1.

16. First-line Hormonal Agent Phase III Studies in Breast Cancer: OS
Study N
Control Arm (Mos)
Experimental Arm (Mos)
HR for OS
P Value
S [1]
694
Anastrozole
(41.3)
Anastrozole + fulvestrant
(47.7)
0.81
.049
Bergh 2012[2]
514
(38.2)
(37.8)
1.00
Nabholtz 2003[3]
1021
Tamoxifen (40.1)
(39.2)
0.97 NR
Mouridsen 2003[4]
916
Tamoxifen
(30)
Letrozole
(34)
.53
Paridaens 2008[5]
371
Tamoxifen (43.3)
Exemestane
(37.2)
1.04
.82
Howell 2004[6]
587
(38.7)
Fulvestrant
(36.9)
1.29
.04
The results of the S0226 trial also were in stark contrast to a previous trial looking at the identical combination reported by a European group. Jonas Bergh’s phase III trial enrolled just over 500 patients and found absolutely no difference with the combination compared to anastrozole alone.
1. Mehta RS, et al. SABCS Abstract S Bergh J, et al. J Clin Oncol. 2012;[Epub ahead of print]. 3. Nabholtz JM, et al. Eur J Cancer. 2003;39: Mouridsen H, et al. J Clin Oncol. 2003;21: Paridaens RJ, et al. J Clin Oncol. 2008;26: Howell A, et al. J Clin Oncol. 2004;22:

17. Case 1: In addition to systemic therapy, would you recommend skeletal-protective therapy?No
Yes; pamidronate
Yes; denosumab
Yes; dose-adjusted zoledronic acid
Now, also in this case, in addition to systemic therapy, would you recommend skeletal protective therapy? You can either say: no; or yes, I would give this patient pamidronate; yes, I would give her denosumab; or yes, I would give her dose‑adjusted zoledronic acid. After you’ve selected your answer, please remember to hit “Submit” so that your answer can be tabulated with the rest of our participants.

18. Denosumab vs Zoledronic Acid: Study Design
Extended analysis of randomized, double-blind, phase III trial
Primary endpoint: time to first on-study SRE
Stratified by previous SREs, previous oral bisphosphonate, current chemotherapy, geographic region
Zoledronic acid 4 mg IV* + Placebo SC every 4 wks
(n = 1020)
Patients with advanced breast cancer and bone metastases
(N = 2046)
SC, subcutaneously; SRE, skeletal-related event; IU, international units; IV, intravenously.
We now have the results of a very large trial enrolling just over 2000 patients with newly identified bone metastatic disease evaluating zoledronic acid at a standard dose of 4 mg intravenously every 4 weeks with a subcutaneous placebo or denosumab 120 mg subcutaneous with an IV placebo every 4 weeks.
The primary endpoint of this trial was time to first skeletal-related event. And skeletal-related events, I’ll remind you, could have included the need for radiation, for painful bony metastasis, pathologic fracture, including compression fractures in sites of vertebral metastatic disease, or spinal cord compression.
Denosumab 120 mg SC + Placebo IV every 4 wks
(n = 1026)
*Dose adjusted for baseline creatinine clearance and subsequent dose intervals determined by serum creatinine according to product label. All patients encouraged to take supplemental calcium (≥ 500 mg/day) and vitamin D (≥ 400 IU/day).
Stopeck A, et al. SABCS Abstract P

19. Denosumab Reduced Time to First On-Study SRE
HR: 0.82 (95% CI: ; P = .0096, superiority)
1.0
0.8
0.6
Proportion of Subjects Without SRE
0.4
KM Estimate of Median Mos
0.2
Denosumab
32.4
Zoledronic acid
27.4
CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; OS, overall survival; SRE, skeletal-related event.
There was a significant improvement or increase in the time to first skeletal-related event with denosumab, from 27.4 months to 32.4 months. 3 6 9 12 15 18 21 24 27 30 33
Study Mo
Pts at Risk, n
Zoledronic Acid
1020
831
675
584
498
429
356
265
186
111 38 4
Denosumab
1026
834
692
597
510
444
384
280
193
101 38 9
Other endpoints: no difference in OS or time to overall disease progression between denosumab and zoledronic acid arms
Stopeck A, et al. SABCS Abstract P

20. Denosumab Reduced SRE Morbidity Rate
Outcome
Denosumab
(n = 1026)
Zoledronic Acid
(n = 1020)
Relative Reduction, %
P Value
Skeletal morbidity rate*
0.46
0.58
21.0
.0039
Patients with ≥ 1 SRE, %†
Mo 12
25.4
26.6
4.5 --
Mo 18
28.8
32.5
11.4
At extended analysis‡
32.9
38.9
15.4
SREs by type, %
Pathologic fracture
23.5
28.1
.0354
Radiation to bone
13.5
17.2
.0184
SRE, skeletal-related event.
And if we looked further at additional subsets, there were also improvements in the rates of pathologic fracture and the need for radiation to sites of bony metastases as well as improvements in the time to second or subsequent skeletal-related events.
*Number of SREs per patient divided by patient’s time at risk.
†Not all patients completed full study duration.
‡Study duration: 38 mos; median time on study: 18 mos.
Stopeck A, et al. SABCS Abstract P

21. Denosumab vs Zoledronic Acid: Adverse Events
Any
96.2
97.4
Serious events
47.9
50.2
Renal events
5.4
9.4
Osteonecrosis of the jaw*
2.5
1.8
Hypocalcemia
All grades
6.1
3.7
Grade 3/4
1.2
Acute-phase reactions†
10.7
28.2
There are also some differences in toxicity, so while we’ve been concerned about osteonecrosis of the jaw with all of our skeletal-targeted therapies, that is still a concern with denosumab with no significant improvement there, but lower rates of renal toxicity and particularly lower rates of the acute phase reaction, the mild fever, myalgias, achiness, and nausea that can occur in up to a quarter of patients after IV bisphosphonate therapy.
*P = .2861
†Occurring within 3 days of treatment initiation.
Stopeck A, et al. SABCS Abstract P

22. Case 1
She was treated with anastrozole and was well for 22 mos when she complained of increased right hip pain
Imaging confirmed progression of her bone lesions with 3 new small lung lesions (largest: 1.3 cm)
ECOG PS 1; no cough, SOB, or other pulmonary symptoms
Her pain resolved after single fraction RT to the right hip
So this patient was treated with anastrozole and she was well for about 22 months when she had increasing right hip pain. Imaging confirmed that her bony lesions had progressed and she had developed 3 small lung lesions, the largest of which was 1.3 cm. She had an ECOG performance status of 1, primarily driven by her hip pain, but no cough, shortness of breath, or other pulmonary symptoms. She received a single palliative radiation fraction to the right hip with resolution of her pain.

23. At this point, which of the following treatments would recommend for this patient?
Exemestane
Exemestane + everolimus
Fulvestrant
Tamoxifen
Chemotherapy
And, at this point, what would you recommend for this patient, either: changing to the steroidal aromatase inhibitor exemestane; exemestane with the mTOR inhibitor everolimus; fulvestrant; tamoxifen; or at this point you would recommend chemotherapy. Select your answers and remember to hit “Submit.”

24. Expert Insight: 5 Breast Cancer Experts’ Choice of Therapy for This Patient
Expert 1: fulvestrant
Expert 2: exemestane
Expert 3: fulvestrant
Expert 4: fulvestrant
Expert 5: fulvestrant
We start to see some differences in our experts’ choices here with most of the experts choosing fulvestrant, but 1 expert choosing exemestane. And I suspect that if everolimus receives FDA approval for this setting, there might be a difference in the experts’ opinions.
The Expert Insight is from an interactive decision support tool entitled “Expert Guidance in Selecting Therapy for Metastatic Breast Cancer" which is available at:

25. Previous nonsteroidal AI failure (progression or death)
EFECT: Study Design
500 mg Day 1, 250 mg Days 14 & 28, and monthly thereafter
Previous nonsteroidal AI failure
Fulvestrant loading dose + Placebo for
Exemestane (n = 351)
Exemestane 25 mg/day orally
+ Placebo for
Fulvestrant (n = 340)
Some of the data that support these choices include the EFECT study. This was a large trial evaluating either fulvestrant using a loading dose with a placebo for exemestane or exemestane with a placebo for fulvestrant all in patients exactly like this patient who had had previous nonsteroidal AI therapy in the metastatic setting and are now progressing. While the EFECT study did use a loading dose, its loading dose was slightly different and it still only used the 250 milligram dose of fulvestrant going forward, so still a slightly lower dose than in the FIRST trial that we discussed previously.
Progression
Progression
Survival
Survival
Analysis after 580 events
(progression or death)
Chia S, et al. J Clin Oncol. 2008;26:

26. Time to Progression (ITT)
1.0
Fulvestrant
Exemestane
0.8
Fulvestrant
Exemestane
0.6
Proportion of Patients Progression-Free
Median, mos
3.7
3.7
0.4
HR: (95% CI: ; P = .6531)
0.2
Time to progression was absolutely identical in the EFECT trial so either fulvestrant or exemestane would be reasonable choices.
100
200
300
400
500
600
700
800
Days to Progression
Days Fulvestrant at risk Exemestane at risk
Chia S, et al. J Clin Oncol. 2008;26:

27. Objective Response and Clinical Benefit Rate
In population evaluable for response
Response, n (%)
Fulvestrant (n = 270)
Exemestane (n = 270)
OR* (95% CI)
P Value
OR rate
(CR + PR)
20 (7.4)
18 (6.7)
1.12 ( )
.736
CB rate (OR + SD ≥ 24 wks)
87 (32.2)
85 (31.5)
1.03 ( )
.853
Clinical benefit rate: also very similar with about a third of the patients either having an objective response or disease stability for 6 months or more with either of those choices.
*Analyses are not adjusted for baseline covariates.
Chia S, et al. J Clin Oncol. 2008;26:

28. The PI3K/AKT/mTOR Pathway
Growth factors including
IGF-1, VEGF, ErbB
mTOR signaling plays a key role in
Cell growth
Cell proliferation
Regulation of
Apoptosis
Angiogenesis
Lymphocytes
Homeostasis
Metabolism
PI3K
Oxygen, energy, and nutrients
PTEN
Estrogen receptor
AKT
TSC2
TSC1
Ras/Raf pathway kinases
mTOR
The mTOR pathway has been shown to be important in many diseases, including breast cancer, and has particularly been implicated as one of the mechanisms of acquired resistance to previous hormone therapies.
S6K1
4E-BP1
Protein production
elF-4E S6
Cell growth
and proliferation
Nutrient uptake and metabolism
Angiogenesis
Bjornsti MA, et al. Nat Rev Cancer. 2004;34: Crespo JL, et al. Microbiol Mol Biol Rev. 2002;66: Huang S, et al. Cancer Biol Ther. 2003;2: Mita MM, et al. Clin Breast Cancer. 2003;4: Wullschleger S, et al. Cell. 2006;124: Johnston SR. Clin Cancer Res. 2005;11:889S-899S. 28

29. Treatment until disease progression or unacceptable toxicity
BOLERO-2: Study Design
Primary endpoint: PFS (investigator assessment)
Secondary endpoints: OS, ORR, clinical benefit rate, safety
Randomized 2:1; stratified by sensitivity to previous hormonal therapy, presence of visceral metastases
Treatment until disease progression or unacceptable toxicity
Postmenopausal women with ER-positive advanced breast cancer who progressed on previous nonsteroidal AI therapy*
(N = 724)
Exemestane 25 mg/day +
Everolimus 10 mg/day
(n = 485)
And that biologic understanding led to the recently reported BOLERO II trial—so very similar patient population to the patient we’re discussing here. Postmenopausal patients with ER‑positive advanced breast cancer who had progressed on previous nonsteroidal aromatase inhibitor therapy randomized to exemestane and a placebo or exemestane plus everolimus with the everolimus given at a dose of 10 mg daily.
Exemestane 25 mg/day +
Placebo
(n = 239)
*> 50% of patients in each arm with ≥ 3 previous therapies
Hortobagyi GN, et al. SABCS Abstract S3-7.

30. BOLERO-2 (12-Mo Follow-up): PFS
Local
HR: 0.44 (95% CI: ; log-rank P < 1 x 10-16)
EVE + EXE: 7.4 mos PBO + EXE: 3.2 mos
Central
HR: 0.36 (95% CI: ; log-rank P < 1 x 10-16)
EVE + EXE: 11.0 mos PBO + EXE: 4.1 mos
100
100 80 80
EVE + EXE (E/N = 155/485) PBO + EXE (E/N = 127/239) 60
EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239) 60
Patients (%) 40 40 20 20 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96
Wks
Wks
Patients at Risk, n
Everolimus
485
436
365
303
246
188
136 96 64 45 34 21 13 9 2 2
Everolimus
485
422
351
284
224
176
119 86 57 38 32 22 12 7 2 2
Placebo
We now have 12‑month data for this trial and, whether you were most swayed by the local investigators’ assessment or the results of the blinded central review facility assessment, both analyses show significant improvement in progression-free survival with about a 5- to 6-month improvement, with the addition of everolimus to exemestane.
239
190
131 95 63 45 29 19 12 8 6 6 4 2
Placebo
239
179
112 74 56 36 23 18 8 5 4 4 3 1
Significant PFS benefit with everolimus observed in all patient subgroups including: age, hormone sensitivity, visceral metastasis, ECOG PS, previous chemotherapy, number of previous therapies, and PgR status
Hortobagyi GN, et al. SABCS Abstract S3-7.

31. BOLERO-2 (12-Mo Follow-up): Response and Clinical Benefit
100 90 80 70
P < .0001 60
Everolimus + exemestane Placebo + exemestane
50.5
Patients (%) 50 40
There were also improvements in clinical benefit rate with now just over half of the patients with either responses or stability for 6 months or more with the mTOR inhibitor added to hormone therapy. 30
25.5
P < .0001 20
12.0 10
1.3
ORR
Clinical Benefit
Hortobagyi GN, et al. SABCS Abstract S3-7.

32. BOLERO-2 (12-Mo Follow-up): Safety
Adverse Events, %
Exemestane + Everolimus
(n = 482)
Exemestane + Placebo
(n = 238)
All Grades
Grade 3/4
Stomatitis 59 8 11 1
Rash 39 6
Fatigue 36 5 27
Diarrhea 33 3 19
< 1
Appetite decreased 30 12
Nausea 29 2 28
Noninfectious pneumonitis 15
Hyperglycemia 14
There are some increases in toxicity as well with particular increases in stomatitis, rash, and fatigue, as well as some increases in decreased appetite and diarrhea, though, interestingly, no differences in nausea. It’s important to recognize that the mTOR inhibitors do have a small but real incidence of noninfectious pneumonitis, which typically responds to short courses of steroids and discontinuing therapy, but is important to be aware of and to recognize. And a small proportion of patients who will develop hyperglycemia that may need intervention.
Hortobagyi GN, et al. SABCS Abstract S3-7.

33. Case 2 38-yr-old patient presented with inflammatory breast cancer
ER and PgR negative
HER2-positive by FISH (ratio 8.9)
Imaging with PET/CT found regional nodal involvement but was otherwise negative
She was treated with neoadjuvant AC > TH followed by mastectomy (2-cm residual disease, LN negative) and radiation therapy; she completed 1 yr of trastuzumab
We’ll move now to our second patient scenario. This is a much younger woman, a 38‑year‑old patient, who presented with inflammatory breast cancer. Her tumor was estrogen and progesterone receptor negative. HER2 positive by FISH testing with a ratio of 8.9. Imaging at the time of her initial diagnosis found regional nodal involvement, but was otherwise negative.
She was treated in the neoadjuvant setting with doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab, and then underwent a mastectomy. At the time of her surgery, there was about 2 cm of residual disease in the breast but her lymph nodes were negative. She completed radiation to the chest wall and regional nodal basins, and completed her 1 year of trastuzumab therapy.

34. Case 2
3 yrs later, she reports a persistent cough and increased fatigue
Imaging finds several lung lesions with mediastinal and hilar adenopathy; biopsy confirms metastatic disease that remains ER negative/PgR negative/HER2 positive
CBC, total bilirubin, AST, ALT, calcium, albumin: all normal
LVEF 62% by MUGA
Three years later, she developed a persistent cough and increased fatigue. Imaging found several lung lesions, as well as mediastinal and hilar adenopathy. And a biopsy confirmed metastatic disease that remained estrogen and progesterone-receptor negative, and HER2 positive.
Her laboratory studies, including CBC and chemistry panel, were all normal and her ejection fraction was nicely within the normal range, at 62%.

35. Case 2: Which of the following treatment options would you recommend for this patient?
Taxane-based chemotherapy + trastuzumab
Capecitabine + lapatinib
Docetaxel + trastuzumab + pertuzumab
Vinorelbine + trastuzumab
Trastuzumab + lapatinib
At this point would you recommend: taxane‑based chemotherapy with trastuzumab; the combination of capecitabine plus lapatinib; the combination of docetaxel plus trastuzumab plus pertuzumab; vinorelbine plus trastuzumab; or the combination of trastuzumab plus lapatinib? After you select your answer, remember to hit “Submit” so that your answer can be tabulated with the rest of our participants.

36. Expert Insight: 5 Breast Cancer Experts’ Choice of Therapy for This Patient
Expert 1: docetaxel + trastuzumab + pertuzumab
Expert 2: capecitabine + lapatinib
Expert 3: docetaxel + trastuzumab + pertuzumab
Expert 4: capecitabine + lapatinib
Expert 5: capecitabine + lapatinib
This is another case where our experts differed: 2 experts taking the hopeful view that, if pertuzumab were approved and available, that would be their preferred choice, and I suspect 3 experts’ choices driven by the fact that pertuzumab—at the time, they were asked this question—is not yet available, suggesting that capecitabine and lapatinib would be their preferred choice.
The Expert Insight is from an interactive decision support tool entitled “Expert Guidance in Selecting Therapy for Metastatic Breast Cancer" which is available at:

37. HER2 Dimerization Is Key
Ligand-activated HER2:HER3 dimer
Preclinical data has told us that HER2 must dimerize to really effectively drive signaling and that there is the greater strength of downstream signaling with the HER2:HER3 dimer. And thus inhibiting dimerization with HER3 may be a particularly potent strategy. P P P P
Phosphorylation of the tyrosine kinase domain by HER2 initiates intracellular signaling
Ferguson KM, et al. Mol Cell. 2003;11: Olayioye MA, et al. EMBO J. 2000;19: Hynes NE, et al. Nat Rev Cancer. 2005;5: Rowinsky EK. Annu Rev Med. 2004;55:

38. Baselga J, et al. J Clin Oncol. 2010;28:1138-1144.
Pertuzumab
Trastuzumab and pertuzumab have different binding sites on HER2 and may exhibit synergistic activity
N = 66 patients with previous trastuzumab therapy treated with pertuzumab + trastuzumab
ORR: 24%; CBR: 50%
Pertuzumab
Trastuzumab binds to subdomain IV of HER2
Does not prevent HER2 dimerization
Prevents HER2 receptor shedding
Inhibits HER2 signaling
Elicits ADCC
Pertuzumab binds to dimerization domain of HER2
Prevents HER2 from forming dimer pairs
Activates ADCC
Does not prevent HER2 receptor shedding IV I
III II IV I
III II Y X Y
Plasma membrane
HER2
HER3
Trastuzumab recognizes HER2 in domain 4 way down near the cell surface and, while it inhibits signaling through HER2, it does not block dimerization and thus HER2:HER3 dimers could still form and you could still get cross‑phosphorylation of HER3 residues by that dimerization.
Pertuzumab recognizes HER2 in the dimerization domain and thus does prevent dimerization. It may therefore impact signaling through HER3 as well.
We first saw evidence of activity in a relatively small trial of about 66 patients, all of whom had progressed on previous trastuzumab therapy with a response rate of about 25% and nearly 50% of patients with either response or clinical benefit with just the combination of pertuzumab and trastuzumab alone.
Trastuzumab
Baselga J, et al. J Clin Oncol. 2010;28:

39. CLEOPATRA: Study Design
Primary endpoint: PFS (independently assessed)
Secondary endpoints: PFS (investigator assessment), ORR, OS, safety
Stratified by geographic region
and previous (neo)adjuvant chemotherapy
Trastuzumab 6 mg/kg q3w* +
Docetaxel mg/m2 q3w† +
Pertuzumab 420 mg q3w‡
(n = 402)
Women with previously untreated, HER2-positive locally recurrent/metastatic breast cancer
(N = 808)
Treatment until disease progression or unacceptable toxicity
Trastuzumab 6 mg/kg q3w* +
Docetaxel mg/m2 q3w† +
Placebo q3w
(n = 406)
That encouraging phase II data led to the CLEOPATRA trial, evaluating 808 patients with previously untreated HER2-positive metastatic disease, evaluating the standard combination of trastuzumab and docetaxel with a placebo or trastuzumab and docetaxel with pertuzumab, with progression‑free survival as the primary endpoint.
*Trastuzumab 8-mg/kg loading dose given.
†Minimum of 6 docetaxel cycles recommended; < 6 cycles permitted for unacceptable toxicity or PD.
‡Pertuzumab 840-mg loading dose given.
Baselga J, et al. N Engl J Med. 2012;366:

40. CLEOPATRA: Independently Assessed PFS
100
Ptz + T + D: median 18.5 mos
Pbo + T + D: median 12.4 mos 80 60
PFS (%) 40
(HR: 0.62;
95% CI: ;
P < .001) 20
This trial was reported in the New England Journal of Medicine earlier this year and found a significant improvement—about 6 months’ improvement—in progression‑free survival from months with the addition of pertuzumab. 5 10 15 20 25 30 35 40
Mos
Pts at Risk, n
Ptz + T+ D
Pbo + T + D
402
406
345
311
267
209
139 93 83 42 32 17 10 7
Stratified by previous treatment status and region
Baselga J, et al. N Engl J Med. 2012;366:

41. CLEOPATRA: Independently Assessed PFS by Predefined Subgroups
Favors Pertuzumab
Favors Placebo n
808
432
376
306
135
114
253
681
127
789 19
480 30
261 37
630
178
388
408 12
721
767 HR
0.63
0.61
0.72
0.51
0.46
0.68
0.65
0.52
0.64
0.55
0.62
0.39
0.96
0.60
95% CI
All No
Yes
Europe
North America
South America
Asia
< 65 yrs
≥ 65 yrs
< 75 yrs
≥ 75 yrs
White
Black
Asian
Other
Visceral disease
Nonvisceral disease
Positive
Negative
IHC 3+
FISH positive
Previous (Neo)Adjuvant Chemotherapy
Region
Age Group
Race
Disease Type
All of the patient subsets found improvement with the addition of pertuzumab as well. And this trial did allow patients who had had previous adjuvant trastuzumab to enroll, though that counted for only about 10% to 15% of the enrolled patients.
ER/PgR Status
Unknown
HER2 Status
0.2
0.4
0.6
1.0
2.0
Unstratified analyses
Baselga J, et al. N Engl J Med. 2012;366:

42. CLEOPATRA: Response Data
100
5.5
4.2 80
ORR: 69.3%
ORR: 80.2% CR
65.2 60
74.6 PR
Patients (%) SD 40 PD
Not evaluable 20
20.8
With that improvement in progression‑free survival, there were improvements in objective response rate and clinical benefit as well, with only about 5% of patients having progressive disease as their best response with that triplet combination.
14.6
1.5
1.5
8.3
3.8
Trastuzumab + Docetaxel + Pertuzumab
(n = 343)
Trastuzumab +
Docetaxel + Placebo
(n = 336)
Baselga J, et al. N Engl J Med. 2012;366:

43. Trastuzumab + Docetaxel + Pertuzumab Trastuzumab + Docetaxel
CLEOPATRA: Safety
Adverse Events, %
Trastuzumab + Docetaxel + Pertuzumab
(n = 407)
Trastuzumab + Docetaxel
(n = 397)
All Grades
Grade ≥ 3
Diarrhea
66.8
7.9
46.3
5.0
Alopecia
60.9 NR
60.5
Neutropenia
52.8
48.9
49.6
45.8
Nausea
42.3
41.6
Fatigue
37.6
2.2
36.8
3.3
Rash
33.7
24.2
Decreased appetite
29.2
26.4
Mucosal inflammation
27.8
19.9
Asthenia
26.0
2.5
30.2
1.5
Peripheral edema
23.1
30.0
Constipation
15.0
24.9
Febrile neutropenia
13.8
7.6
Dry skin
10.6
4.3
Leukopenia
12.3
14.6
There are some minor increases in toxicity with the addition of the pertuzumab antibody. Specifically, there were increases in diarrhea, rash, and neutropenic fever, though there were no significant differences in the number of patients who discontinued therapy due to toxicity.
Baselga J, et al. N Engl J Med. 2012;366:

44. Case 2
She was treated with docetaxel + trastuzumab + pertuzumab on the CLEOPATRA trial
She had an excellent PR with resolution of symptoms
Docetaxel discontinued after 6 cycles; continued trastuzumab + pertuzumab
10 mos later, she develops headache and diplopia
Imaging finds a large cavernous sinus met with several other small cerebral lesions
This patient was actually treated with the docetaxel, trastuzumab, and pertuzumab combination on the CLEOPATRA trial. She had an excellent partial response with complete resolution of all of her symptoms. Her docetaxel was discontinued after 6 cycles, but she continued the trastuzumab and pertuzumab. About 10 months after the discontinuation of docetaxel, she developed headache and diplopia. And imaging found a large cavernous sinus lesion, with several other smaller cerebral lesions.

45. Case 2
She is started on steroids and completes whole brain radiation therapy
CNS symptoms resolve
Imaging finds asymptomatic progression of her systemic disease with increased lung nodules
She started steroids and completed whole brain radiation therapy with resolution of her CNS symptoms. Additional imaging had found asymptomatic progression of her systemic disease, particularly with increase in the size of several of her lung nodules.

46. Case 2: Which of the following strategies would you recommend for this patient at this point?
Resume docetaxel with continued trastuzumab + pertuzumab
Capecitabine + lapatinib
Trastuzumab + lapatinib
Capecitabine + trastuzumab
Alternate chemotherapy + trastuzumab
At that point, when you think about this patient’s systemic therapy, would you recommend: resuming docetaxel with continuation of trastuzumab and pertuzumab; changing to capecitabine and lapatinib; changing to trastuzumab and lapatinib; changing to capecitabine plus trastuzumab; or some alternate chemotherapy with trastuzumab? And, again, remember to hit “Submit” after you’ve made your selection.

47. Capecitabine 2500 mg/m2/day PO on Days 1-14 q3wk
TKI After Trastuzumab?
HER2+ LABC or MBC with previous exposure to an anthracycline, a taxane and trastuzumab*
(N = 324)
Lapatinib 1250 mg PO QD continuously + Capecitabine 2000 mg/m2/day PO on Days 1-14 q3wk
(n = 163) R A N D O M I Z E
Capecitabine 2500 mg/m2/day PO on Days 1-14 q3wk
(n = 161)
Stratified by
Disease sites
Stage of disease
We first saw data that tyrosine kinase inhibitors could be effective after trastuzumab therapy in a randomized phase III trial, reported over 6 years ago now, in patients who had had previous trastuzumab therapy as well as previous exposure to an anthracycline- and taxane‑based chemotherapy regimen, randomized to capecitabine alone, or capecitabine with lapatinib.
Patients on treatment until progression or unacceptable toxicity, then followed for survival
*Trastuzumab must have been administered for metastatic disease.
Geyer CE, et al. N Engl J Med. 2006;355:

48. Lapatinib Increases TTP After Trastuzumab
100
P < .001 80
Lapatinib + capecitabine (49 events; median TTP: 8.4 mos) 60
Patients Free of Disease Progression (%) 40
This trial found significant improvements in progression‑free survival and time to progression with the combination of capecitabine plus lapatinib compared to capecitabine alone.
Capecitabine alone (72 events; median TTP: 4.4 mos) 20 10 20 30 40 50 60
Wks
Geyer CE, et al. N Engl J Med. 2006;355:

49. Why Not Continue Trastuzumab? GBG 26/BIG 3-05
(Closed Early With Poor Accrual)
Capecitabine 2500 mg/m2/day on Days 1-14 q3w
Women with HER2-positive advanced BC or MBC that progressed on trastuzumab
(N = 156)
Capecitabine 2500 mg/m2/day on Days 1-14 q3w +
Trastuzumab 6 mg/kg q3w
But not long after that we saw the results of a German breast cancer study group trial, evaluating simply continuing trastuzumab with capecitabine compared to capecitabine alone. This trial closed early due to poor accrual, primarily driven by the approval of lapatinib in Europe and in Germany
von Minckwitz G, et al. J Clin Oncol. 2009;27:

50. Trastuzumab Remains Effective After Disease Progression
100
2-Sided P Values
OR: .0115
CB: .0068 90
75.3%
( ) 80 70
54.1 ( ) 60
Patients (%) 50
SD > 24wks 40
But their results still found significant improvement in response rates and clinical benefit rates, with the continuation of trastuzumab and capecitabine compared to capecitabine alone. 30
CR: 7.7%
PR: 40.3% 20
27.0 ( )
48.1 ( )
CR: 2.7%
PR: 24.3%
CR + PR 10
Capecitabine
Capecitabine + Trastuzumab
von Minckwitz G, et al. J Clin Oncol. 2009;27:

51. Longer PFS With Lapatinib + Tmab vs Lapatinib Alone in Tmab-Refractory MBC
100
PFS Outcome
Lapatinib
(n = 145)
Lapatinib + Trastuzumab
(n = 146)
Progressed or died, n
128
127
Median, wks
8.1
12.0
HR (95% CI)
0.73 ( )
P value
.008 80 60
Cumulative % Alive Without Progression 40
28% 20 L
L + T
13%
Perhaps most striking are the results of a randomized trial evaluating the combination of trastuzumab and lapatinib compared to lapatinib alone in patients with trastuzumab refractory disease. To be eligible for this trial, patients had to have had previous therapy with an anthracycline, taxane, and capecitabine, and had to be actively progressing on their most recent regimen.
The trial found significant improvements in progression‑free survival and clinical benefit rates with the dual inhibition with lapatinib and trastuzumab compared to lapatinib alone . . . 10 20 30 40 50 60
Wks From Randomization
Response, %
Lapatinib
Lapatinib + Trastuzumab OR
P Value
ORR
6.9
10.3
1.5
.46
CBR
12.4
24.7
2.2
.01
Blackwell KL, et al. J Clin Oncol. 2010;28:

52. Updated Overall Survival in ITT
100 L
(n = 145)
L+ T
(n = 146)
Died, n (%)
113 (78)
105 (72)
Median, mos
9.5 14
HR (95% CI)
0.74 ( )
Log-rank P value
.026
80% 80
56% 60
70%
Survival (%)
6-mo OS 40
41% L
L + T
12-mo OS 20
. . . and, somewhat surprisingly, found a significant improvement in overall survival with dual inhibition in these highly refractory patients as well. 5 10 15 20 25 30 35
Mos From Randomization
Patients at Risk, n L + T L
88 65
64 47
43 28
25 13 1
Blackwell K, et al, SABCS Abstract 61.

53. High Risk of Brain Metastases in Patients With HER2-Positive MBC
Study
Incidence, %
Bendell et al, 2003[1] 34
Clayton et al, 2004[2] 25
Stemmler et al, 2006[3] 31
Kennecke et al, 2010[4]
29 (ER negative)
15 (ER positive)
Now, this patient also had presented with brain metastasis, which had been treated successfully with steroids and whole brain radiation. And several trials have now found a particular risk of brain metastasis in patients with HER2-positive metastatic disease. That’s suggesting brain metastasis will be a component of our patients’ natural history with the HER2-positive disease. It’s somewhere between a quarter and a third of our patients.
1. Bendell JC, et al. Cancer. 2003;97: Clayton AJ, et al. Br J Cancer. 2004;91: Stemmler HJ, et al. Breast. 2006;15: Kennecke H, et al. J Clin Oncol. 2010;28:

54. CNS-Specific Goals for Patients With HER2-Positive Breast Cancer
Improve/maintain quality of life
Relieve symptoms
Prevent symptomatic progression
Minimize impact of treatment-related toxicity
Prolong survival
Prevention
As in all of our patients with metastatic disease, our goals for patients with CNS metastatic disease are to relieve their symptoms and to prevent symptomatic progression, as well as to minimize toxicity. And particularly in the case of CNS disease, one of our goals is to prevent further CNS progression, which could bring with it fairly devastating neurologic progression.

55. Studies of Lapatinib for HER2-Positive Breast Cancer Brain Metastases
Study
Regimen N
Previous Chemo
Previous RT, %
Response Criteria
CNS ORR, %
TTP/PFS OS
Lin et al, 2009*[1]
L + cape 50
81% with ≥ 2 T + chemo; PD on lapatinib alone
100
≥ 50% vol. reduction + no NSS, steroid incr, non-CNS PD 20
3.6 mos NR
Boccardo et al, 2008 (LEAP)[2]
138
Previous T required
Investigator-assessed on survey 18
Median time on study 2.9 mos
Sutherland et al, 2010 (LEAP)[3] 34
Mean 2.4 previous tx; previous T required 94
RECIST 21
5.1 mos
Metro et al, 2011[4] 22
Median of 2 previous T-based tx for MBC 87
WHO 32
5.6 mos
27.9 mos
Lin et al, 2011*[5]
L+ cape 13
≥ 50% vol. reduction + no steroid incr, new CNS or non-CNS lesions 38
Bachelot et al, 2011*[6] 45
22% with
≥ 2 T + chemo
(31%: no previous T for MBC)
≥ 50% vol. reduction + absence of NSS, steroid incr, non-CNS PD 67
5.5 mos
91% alive at 6 mos
Several trials have evaluated lapatinib particularly as treatment for patients with HER2-positive CNS disease. Their response rates have ranged quite dramatically from only about 15% to 20% in trials that largely included patients who’d had previous radiation to up to two thirds of patients responding in the landmark trial evaluating the combination of capecitabine plus lapatinib in patients, none of whom had had previous radiation therapy.
*Prospective trial.
1. Lin NU, et al. Clin Cancer Res. 2009;15: Boccardo F, et al. ASCO Abstract Sutherland S, et al. Br J Cancer. 2010;102: Metro G, et al. Ann Oncol. 2011;22: Lin NU, et al. J Neurooncol. 2011;105: Bachelot TD, et al. ASCO Abstract 509.

56. Case 3
53-yr-old black woman diagnosed with stage I (11-mm; ER-, PgR-, and HER2-negative) breast cancer
Initial therapy: lumpectomy, AC x 4, RT
Persistent cough developed 18 mos later
Imaging found a pleural effusion and multiple lung nodules
Cytology confirms original diagnosis
Treated with docetaxel + capecitabine but disease progresses after 2 cycles
Currently PS = 1
We’ll switch now to our third patient case scenario. This is a 53‑year‑old woman diagnosed with a stage I ER‑, PR‑, and HER2‑negative tumor, initially treated with lumpectomy, adjuvant doxorubicin, and cyclophosphamide therapy and radiation.
Eighteen months later, she also develops a persistent cough and was found to have a pleural effusion and multiple lung lesions. Cytology on her pleural effusion confirms her original diagnosis. Receptors were repeated and again she had triple-negative disease.
She was treated with a combination of docetaxel and capecitabine, but her disease progressed after only 2 cycles of therapy. She currently has a performance status of 1.

57. Case 3: Which of the following treatment options would you recommend for this patient?
Ixabepilone
Cisplatin + gemcitabine
Eribulin
Liposomal doxorubicin
Vinorelbine
Which of these treatment options would you recommend for this patient, either ixabepilone monotherapy, the combination of cisplatin plus gemcitabine, single‑agent eribulin, single‑agent liposomal doxorubicin, or single‑agent vinorelbine? Make your choice now and remember to hit “Submit.”

58. Expert Insight: 5 Breast Cancer Experts’ Choice of Therapy for This Patient
Expert 1: eribulin
Expert 2: eribulin
Expert 3: eribulin
Expert 4: cisplatin + gemcitabine
Expert 5: cisplatin + gemcitabine
In this case, our experts differed with 3 experts suggesting that they would choose eribulin, 2 experts, I suspect, hoping that there might be a DNA repair pathway defect that could be exploited and preferring a cisplatin/gemcitabine combination.

59. Single-Agent vs Combination Chemotherapy for MBC
Response rate  favors combination
TTP  favors combination
Survival  ?
Toxicity  favors single agent
Quality of life  ?
We spend a lot of time thinking about the relative virtues of either single‑agent or combination therapy. If we focus only on response rates, most trials would favor combinations with higher response rates and slight improvement in time to progression, but most trials have not found improvements in survival. There are increases in toxicity with combination therapy, so the toxicity side of the equation typically favors single‑agent therapy. And, unfortunately, most of our trials have not included robust quality-of-life assessments.
Importantly, few of the combination trials using investigational drugs really tested the hypothesis of combination therapy vs sequential single‑agent therapy as a strategy. They really were designed to evaluate whether the drug itself was active, rather than testing that particular strategy question.
Few combination trials using investigational drugs truly tested the hypothesis of combination vs sequential single-agent therapy

60. Eribulin Mesylate (E7389): A Novel Tubulin-Targeted Agent
Synthetic analogue of halichondrin B; natural product from marine sponge Halichondria okadai
Novel chemical structure
Unique effect on microtubule dynamics
Blocks microtubule polymerization
No effect on depolymerization
Sequesters tubulin into nonfunctional aggregates
MeO H O HO O O O H H O
H2N O O O O Me H O
I mentioned eribulin having perhaps the greatest strength of evidence in this particular setting. Eribulin is a synthetic analogue of the natural product halichondrin B, which is extracted from a marine sea sponge. It has a novel chemical structure that gives it a unique effect on microtubule dynamics. It blocks polymerization and sequesters the microtubules into nonfunctional aggregates. Me S OH O
Jordan MA, et al. Mol Cancer Ther. 2005;4: 60

61. (cytotoxic, hormonal, biologic, radiotherapy, or supportive care only)
EMBRACE: Study Design
Trial Design
Open-label, multicenter study (N = 762)
Locally recurrent or MBC
2-5 previous chemotherapies (≥ 2 for advanced disease)
Previous anthracycline and taxane
Refractory to most recent chemotherapy
Treatment
Eribulin mesylate
1.4 mg/m2, 2-5 min IV bolus
Days 1 and 8 of 21-day cycle
Primary Endpoints OS
Secondary Endpoints
PFS
ORR
DoR
Safety
RND 2:1
It had phase II data supporting activity in heavily pretreated patients and that led to the EMBRACE trial, enrolling over 750 patients, all of whom had had previous anthracycline- and taxane‑based therapy. They could have had up to 5 previous chemotherapies including at least 2 previous therapies for advanced or metastatic disease. And they all had to be actively progressing on their most recent therapy.
They were randomized in a 2-to-1 fashion to either eribulin monotherapy or monotherapy of the physician’s choice, and the choices could have included a wide range of cytotoxic, hormonal, or biologic therapies. The primary endpoint was overall survival with progression‑free survival and response rate as secondary efficacy endpoints.
Physician’s choice
Any monotherapy
(cytotoxic, hormonal, biologic, radiotherapy, or supportive care only)
Cortes J, et al. Lancet. 2011;377: 61

62. EMBRACE: Survival and Response
Eribulin
TPC
ORR*
12.2
4.7 CR
0.6 PR
11.5 20
*P = .002 18
P = .04 16
13.1 14 12
10.6
P = .159
Mos 10
Eribulin
Overall survival was significantly improved in patients randomized to eribulin monotherapy. There were improvements in progression‑free survival and overall response rates as well. 8
P = .137
6.7
TPC = tx of
Physicians’
choice 6
3.7
4.2 4
2.2 2
Median OS
Median PFS
Median DoR
Cortes J, et al. Lancet. 2011;377:

63. EMBRACE: Adverse Events
25% of patients receiving eribulin monotherapy experienced serious adverse events
Adverse Events With Eribulin Monotherapy, %
Grade 3
Grade 4
Asthenia/fatigue 8 1
Peripheral neuropathy
< 1
Neutropenia 21 24
Leukopenia 12 2
There certainly are toxicities with eribulin, most notably difficulty with myelosuppression with about a quarter of patients having grade 4 neutropenia, grade 3 peripheral neuropathy, and fatigue or asthenia occurring in just under 10% of patients.
Cortes J, et al. Lancet. 2011;377: 63

64. Go Online for More CCO Oncology Programming!
Interactive Decision Support Tool: Expert Guidance in Selecting Therapy for Metastatic Breast Cancers This tool provides recommendations from 5 breast cancer experts on choice of therapy in a variety of clinical scenarios
And I’ll thank you for joining us in this Clinical Care Options activity, and I hope you join us again in a future activity soon.
clinicaloptions.com/oncology