cco her2 negative mbc clinfocus tu15 slides

HER2-Negative Metastatic Breast Cancer: Chemotherapy After Anthracyclines and Taxane TreatmentThis activity is supported by an educational grant from Eisai. Joyce OShaughnessy, MD Director, Breast Cancer Research Program Baylor Charles A. Sammons Cancer Center Texas Oncology US Oncology Dallas, Texas Jointly provided by Postgraduate Institute for Medicine and Clinical Care Options, LLC

clinicaloptions.com/oncologyChemotherapy After Anthracyclines and Taxane Treatment

No compelling evidence that combination regimens are superior to sequential single-agent regimens or that cytotoxic agents are subtype specific1. NCCN. Clinical practice guidelines in oncology: breast cancer. v.1.2015.Single vs Combination RegimensSingle AgentAnthracyclinesDoxorubicin, pegylated liposomal doxorubicinTaxanesPaclitaxelAntimetabolitesCapecitabine, gemcitabineNontaxane microtubule agentsVinorelbine, eribulin, ixibepiloneCombinationCAF/FAC (cyclophosphamide/ doxorubicin/fluorouracil)FEC (fluorouracil/epirubicin/cyclophosphamide)AC (doxorubicin/cyclophosphamide)EC (epirubicin/cyclophosphamide)CMF (cyclophosphamide/methotrexate/fluorouracil)GT (gemcitabine/paclitaxel)Docetaxel/capecitabineGemcitabine/carboplatinPaclitaxel/bevacizumab


TNBC vs Other Phenotypes in the California Cancer Registry StudyPopulation-based study6370 (12%) with triple-negative disease compared with 44,704 other casesTNBC more likely to be associated withYounger age (< 40 yrs) (OR: 1.53)Non-Hispanic black (OR: 1.77) or Hispanic (OR: 1.23)Higher grade (72% grade 3)More advanced stage (66% stage II vs 50% ER positive/HER2 negative)Poorer 5-yr RFI regardless of stageTNBC: 76% (similar to 76% for HER2+)Hormone receptor positive, HER2 negative: 94%Greater propensity for lung and brain metastases 2. Bauer KR, et al. Cancer. 2007;109:1721-1728. 3. Parise CA, et al. Breast J. 2009;15:593-602.


TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BCPrimary endpoint: ORR in ITT populationSecondary endpoints: PFS, OS, ORR (crossover), toxicitySubgroup analyses: BRCA1/2 mutation, basal-like subgroups, HRD biomarkers4. Tutt A, et al. SABCS 2014. Abstract S3-01.Patients with ER-, PgR-/unknown, and HER2- or BRCA1/2+ metastatic or recurrent LA BC(N = 376)Carboplatin AUC6 q3w x 6 cycles (n = 188)Docetaxel 100 mg/m2 q3w x 6 cycles ( n = 188)For both arms, crossover upon progression allowed


TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC: ORR4. Tutt A, et al. SABCS 2014. Abstract S3-01.0102030405060708090Response at Cycle 3 or 6 (%)All Pts (N = 376)C D C Crossover* (All pts; n = 182)BRCA1/2 Mutation (n = 43)No BRCA1/2 Mutation (n = 273)31.4%35.6%22.8%25.6%P = .44P = .7368.0%33.3%P = .0328.1%36.6%P = .16Carboplatin Docetaxel Crossover*Excludes those with no first progression or not starting crossover treatment.


TNT: Carboplatin vs Docetaxel in Advanced TNBC or BRCA1/2+ BC: PFSMedian OS was similar with carboplatin and docetaxel (12.4 vs 12.3 mos)4. Tutt A, et al. SABCS 2014. Abstract S3-01.PFS (%)0369121518Mos From RandomizationMedian PFS, Mos (95% CI)Carboplatin: 3.1 (2.5-4.2) Docetaxel: 4.5 (4.1-5.2)


TNT: Carboplatin vs Docetaxel in Adv TNBC or BRCA1/2+ BC: PFS by BRCA1/24. Tutt A, et al. SABCS 2014. Abstract S3-01.Carboplatin + BRCA1/2 mutatedCarboplatin + BRCA1/2 not mutatedDocetaxel + BRCA1/2 mutatedDocetaxel + BRCA1/2 not mutatedMos From RandomizationPFS (%)1803691215

Median PFS, MosCarboDocBRCA1/2 mutated6.84.8BRCA1/2 not mutated3.14.6


Case Study: Novel Therapy for Metastatic TNBC28-yr-old Hispanic woman, 4 yrs postpartum, with left breast T3N0 grade 3 TNBC (ER, PgR, HER2 negative), ki67 80%, high grade carcinoma with sarcomatoid featuresBRCA1/2 wild typePreop DD AC with PgR, then preop weekly paclitaxel plus 4 cycles carboplatin AUC 6 with minor responseBilateral mastectomy: 3.6-cm residual disease with metaplastic features, N0, no LVI, ki67 75-100%, ER, PgR HER2 0 Received PMRTMenses resumed


Case Study (contd)5 mos after radiation, developed RUQ pain with a 7 x 6 cm solitary liver metastasisLiver biopsy: highly mitotic, ER, PgR, HER2-negative carcinoma NGS of residual disease post-AC/TCb: amplification of AKT3, RICTOR, IGF1R, c-MYC, and p53 mutationWhat are her therapeutic options now?


Capecitabine Monotherapy in Pretreated Advanced Breast CancerEligibilityProgressive locally advanced MBC pretreated with 2 chemotherapy regimens including previous paclitaxel or docetaxelInterventionCapecitabine 1250 mg/m2 PO BID on Days 1-14 every 3 wks5. Venturini M, et al. Oncology. 2007;72:51-57.


Capecitabine Monotherapy: Efficacy and Safety OutcomesEfficacy (N = 349)ORR: 34.7%CR: 2.9%PR: 31.8%Median TTP: 6.6 mosMedian OS: 10.0 mosSafetyAdverse events grade 3:Handfoot syndrome (7.6%)Diarrhea (9.0%)Nausea (1.7%)Vomiting (2.7%)Mucositis (1.9%)

5. Venturini M, et al. Oncology. 2007;72:51-57.


Eribulin Strongly Disrupts Interphase Microtubule Dynamics6. Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095.


Phase III EMBRACE Trial of Eribulin vs TPC for Heavily Pretreated MBCEligibility criteria:Locally recurrent or metastatic breast cancer2-5 prior chemotherapies: 2 for advanced diseasePrior anthracycline and taxaneProgression 6 mos since last chemotherapyNeuropathy grade 2RANDOMIZEPrimary endpoint: OSSecondary endpoints: PFS, ORR, safety 2 : 1TPCAny monotherapy approved for treatment of cancer, radiotherapy, or supportive care onlyEribulin mesylate 1.4 mg/m2 on Days 1, 8 every 3 wks7. Cortes J, et al. Lancet. 2011;377:914-923.


Phase III EMBRACE Trial: Overall SurvivalOS: 13.1 vs 10.6 mosPFS: 3.7 vs 2.2 mosHR: 0.81 (95% CI: 0.66-0.99; P = .041) Eribulin (n = 508) TPC (n = 254) Deaths: 274 (54%), eribulin; 148 (58%), TPC OS (%)7. Cortes J, et al. Lancet. 2011;377:914-923.


Study 305: EMBRACE Subset Analysis of OS by Disease Characteristics**Intent-to-treat population; based on a stratified Cox analysis including geographic region, HER2/neu status, and prior capecitabine therapy as strata. Original analysis based on 55% events in the intent to treat population[2]8. Twelves C, et al. SABCS 2010. Abstract P6-14-18. 9. Menis J. Breast Cancer. 2011;3:103-111. Overall results[8] (n = 762)

Receptor status

No. of organs involved

Sites of diseaseER/PgR+ (n = 528)ER/PgR- (n = 187)HER2+ (n = 123)HER2- (n = 565)ER/PgR/HER2- (n = 144)

2 (n = 537)> 2 (n = 217)

Visceral (n = 624)Nonvisceral (n = 130)

HR (95% CI)Favors EribulinFavors TPC0.20.51.02.05.0


Phase III EMBRACE Trial: Grade 3/4 Adverse EventsThe incidence of fatal adverse events related to treatment was 1% in both arms10. Twelves C, et al. ASCO 2010. Abstract CRA1004.*Grade 3 only.

AE, %Eribulin(n = 503)TPC(n = 247)Neutropenia4521Leukopenia146Anemia24Febrile neutropenia41Asthenia/fatigue910*Peripheral neuropathy82*Nausea1*2*Dyspnea4*3Handfoot syndrome< 1*4*


Study 301: TNBC Treatment With Eribulin vs CapecitabineOpen-label, randomized, multicenter phase III study of eribulin mesylate vs capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes11. Kaufman PA, et al. SABCS 2012. Abstract S6-6. 12. Kaufman PA, et al. J Clin Oncol. 2015;33:594-601. Capecitabine 1250 mg/m2 BID orally on Days 1-14 every 21 daysEribulin mesylate 1.4 mg/m2 2- to 5-min IVon Days 1, 8 every 21 daysCoprimary endpointOS and PFS

Secondary endpointsQuality of lifeORRDuration of response1-, 2-, and 3-yr survivalTumor-related symptom assessments Safety parameters Population PK/PDPatients (N = 1102)Locally advanced or MBC 3 prior chemotherapy regimens ( 2 for advanced disease)Prior anthracycline and taxane in (neo)adjuvant setting or for locally advanced or MBC


Study 301 Eribulin vs Capecitabine: OSEribulin vs capecitabine OS rates: 1 yr, 64.4% vs 58.0% (P = .04); 2 yr, 32.8% vs 29.8% (P = .32); 3 yr, 17.8% vs 14.5% (P = .18)12. Kaufman PA, et al. J Clin Oncol. 2015;33:594-601. HR: 0.88 (95% CI: 0.77-1.00; P = .056)Probability of OSMos

Events/nMedian, Mos95% CIEribulin446/55415.915.2-17.6Capecitabine459/54814.513.1-16.0


Study 301: OS by Receptor Status in a Prespecified Subgroup Analysis11. Kaufmann P, et al. SABCS 2012. Abstract S6-6. 0.20.51.02.0Favors EribulinFavors Capecitabine

SubgroupHR (95% CI)Median OS, MosEribulinCapeOverall0.879 (0.770-1.003)15.914.5HER2 Status Positive0.965 (0.688-1.355)14.317.1 Negative0.838 (0.715-0.983)15.913.5ER Status Positive0.897 (0.737-1.093)18.216.8 Negative0.779 (0.635-0.955)14.410.5Triple Negative Yes0.702 (0.545-0.906)14.49.4 No0.927 (0.795-1.081)17.516.6


Phase II Eribulin Plus Capecitabine in MBC13. Twelves C, et al. SABCS 2014. Abstract P3-13-04.Advanced/ metastatic breast cancer(n = 42)Key inclusion criteria:Up to 3 prior regimens (any setting)Prior anthracycline (unless CI)Prior taxane No prior capecitabineMeasurable tumor diseasePS 0-1Eribulin 1.4 mg/m2 on Days 1, 8 + Capecitabine 1000 mg/m2 BID on Days 1-14 for21-day cyclesEnd of study visit within 30 days of last treatment doseEndpoints:ORRSafety, tolerabilityDOR, CBRExploratory: PK/PD

EnrollmentPD/toxicity/deathTumor assessments performed once every 6 wks


Phase II Eribulin Plus CapecitabinePrior anthracycline and taxane requiredUp to 3 prior chemotherapy regimensMeasurable diseaseN = 42 ptsORR: 43%; CBR (ORR + SD 6 mos): 57%Median PFS: 7.2 mos (all pts), 7.1 mos (HER2- pts)Toxicities: 21% grade 1 handfoot syndrome; 5%/8% grade 2/3 handfoot syndrome13. Twelves C, et al. SABCS 2014. Abstract P3-13-04. 14. Smith J, et al. SABCS 2014. Abstract P3-09-09.


Case Study (contd)5 mos after radiation and 8 mos s/p AC, then TCb developed RUQ pain with 7 x 6 cm solitary liver metastasisLiver biopsy: highly mitotic; triple-negative carcinoma and NGS: amplification of AKT3, RICTOR, IGF1R, c-MYC and p53 mutationReceived eribulin plus capecitabine 1500 mg BID 7 on/ 7 off with slowly evolving nCR over 10 mosUnderwent resection residual liver metastasis: 1 mm residual disease with ki67 40%Continuing eribulin plus capecitabine 2+ yrs with no toxicity


Phase II Study: Ixabepilone Monotherapy in Resistant MBC[16]Epothilone B analoguePromotes polymerization of microtublesApproved as monotherapy for MBC refractory to an anthracycline, taxane, and capecitabine[15]Pt eligibility (N = 126)Tumor progression while receiving prior anthracycline, taxane, and capecitabineInterventionIxabepilone 40 mg/m2 monotherapy administered as a 3-hr IV infusion on Day 1 of an every-3-wk cycle16. Perez EA, et al. J Clin Oncol. 2007;25:3407-3414. 15. Ixabepilone [package insert].


Ixabepilone: Efficacy and Safety OutcomesEfficacy (N = 113)OR: 11.5%SD 6 mos: 13.3%DOR: 5.7 mosPFS: 3.1 mosOS: 8.6 mosSafety (grade 3/4)Peripheral sensory neuropathy (14%)Fatigue/asthenia (14%)Myalgia (8%)Stomatitis/mucositis (7%)Leukopenia (49%)Neutropenia (54%)16. Perez EA, et al. J Clin Oncol. 2007;25:3407-3414.


Capecitabine Ixabepilone in Pts With MBC Previously Treated With A/T: OS17. Sparano JA, et al. J Clin Oncol. 2010;28:3256-3263.Proportion Not ProgressedPhase III trial N = 1221Ixabepilone + capecitabine

Capecitabine

Median OS mos (95% CI)6.2 (5.6-6.8)

4.4 (4.1-5.4)

17. Sparano JA, et al. J Clin Oncol. 2010;28:3256-3263.


Capecitabine Ixabepilone in Pts With MBC Previously Treated With A/T: PFS17. Sparano JA, et al. J Clin Oncol. 2010;28:3256-3263.

Go Online for More CCO Coverage of Breast Cancer!Interactive programs in communicating and individualizing treatment plans with your patients with breast cancerCME-certified slidesets on breast cancer with expert faculty commentaryConference coverage of key studies from recent breast cancer symposiaclinicaloptions.com/oncology

Im Joyce OShaughnessy, MD, Director of Breast Cancer Research at Baylor Charles A. Sammons Cancer Center, Texas Oncology and US Oncology. In this activity, I discuss emerging data regarding the optimal management of HER2-negative metastatic breast cancer (MBC), with a particular focus on patients who are refractory to endocrine therapy. Many of these studies are in the setting of triple-negative breast cancer (TNBC), but I also review data that include both triple-negative and estrogen receptor (ER)positive breast cancer. Anthracyclines and taxanes are commonly used to treat breast cancer, particularly in the neoadjuvant or adjuvant settings. Taxanes are often used as first-line therapy for MBC, as well. A current clinical challenge is selecting optimal therapy after anthracyclines and taxanes. I discuss which treatment options are best supported by available data and may benefit patients who are in need of effective antitumor therapy to improve their survival and palliate tumor-related symptoms. *The NCCN clinical practice guidelines for breast cancer are based on a careful review of the evidence and suggest preferred single agents as well as combination therapy regimens.[1] The NCCN has stated that there is no compelling evidence that combination regimens are superior to sequential single-agent regimens in the treatment of breast cancer and also that there is no compelling evidence that cytotoxic agents are subtype specific. To date, few studies have focused on comparing different regimens in breast cancer subtypes, for example, ER-positive breast cancer vs TNBC. This is increasingly of interest because, in general, TNBCs have limited chemotherapy sensitivity after pretreatment with chemotherapy, and the duration of response is not as robust as typically seen in patients with ERpositive breast cancer. So, although the NCCN guideline states that there is no compelling evidence that cytotoxic agents benefit particular subtypes, as clinicians, we have a strong interest in knowing the data in TNBC because it is so challenging to achieve durable tumor control once the disease has metastasized.

Reference:1. NCCN. Clinical practice guidelines in oncology: breast cancer. v.1.2015. **ER, estrogen receptor; OR, odds ratio; RFI, relapse-free interval; TNBC, triple-negative breast cancer.Treating TNBC is a particular challenge in the metastatic setting. This very large dataset from the California Cancer Registry was used to conduct a population-based study comparing breast cancer patients with TNBC (n = 6370) vs without TNBC (n = 44,704).[2,3] In this study TNBC represented 12% of all cases (mostly early stage); in other studies, patients with TNBC ranged from 12% to 18%. TNBC was more likely to be associated with younger age (younger than 40 years) and nonHispanic black or Hispanic patients and was more likely to be a higher-grade tumor; 71% of patients with TNBC presented with grade 3 tumor, and 66% were stage II or higher at diagnosis vs only 50% of patients with ERpositive, HER2negative disease. Results showed that patients with TNBC had a relatively poor rate of 5-year relapse-free survival, regardless of stage (76% vs 94% in the ER-positive, HER2negative group). Of note, TNBCs have a propensity for metastasis to the lungs and brain. They also metastasize to the liver, bone, and lymph nodes. TNBC is clearly a distinct clinical entity, and we are very interested in the emerging data focusing on this difficult-to-treat patient population.

References:2. Bauer KR, et al. Cancer. 2007:109;1721-1728.3. Parise CA, et al. Breast J. 2009:15:593-602.

AUC, area under the curve; BC, breast cancer; ER, estrogen receptor; HRD, homologous recombination deficiency; ITT, intent to treat; LA, locally advanced; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PgR, progesterone receptor; q3w, every 3 weeks; TNBC, triple-negative breast cancer.At the 2014 SanAntonio Breast Cancer Symposium, Tutt and colleagues[4] presented results from the TNT trial comparing first-line chemotherapy regimens in patients with advanced TNBC or BRCA1/2-positive breast cancer. In this randomized phase III trial, patients (N = 376) received either carboplatin (area under the curve [AUC] 6), or docetaxel 100 mg/m2, both given every 3 weeks for 6 cycles.Of note, nearly all cancers with BRCA1 germline mutations are triple negative, whereas tumors with BRCA2 mutations can be either ER positive or triple negative. So, in the BRCA2 population of this study, there were also some ERpositive patients. TNT was based on the hypothesis that because BRCA1/2 germline mutations produce breast cancers that have defects in homologous recombination DNA repair, carboplatin would be lethal to cells with germline and somatic mutations in BRCA1/2. In other words, carboplatin might be especially good therapy in terms of exploiting the defect in homologous recombination DNA repair, and that is why patients with BRCA1/2 mutations were included with TNBC patients. The primary endpoint was the objective response rate in the intenttotreat population.

Reference:4. Tutt A, et al. SABCS 2014. Abstract S3-01.

*BC, breast cancer; C D, carboplatin followed by docetaxel; D C, docetaxel followed by carboplatin; ORR, overall response rate; TNBC, triple-negative breast cancer.Results showed no significant difference in response rates between carboplatin and docetaxel in the overall patient group or in patients who received either agent as firstline therapy then crossed over to the other agent as secondline treatment.[4] The only significant difference was in patients with BRCA1/2 germline mutations; the response rate with carboplatin was 68% compared with 33% with docetaxel (P = .03). Although more of the overall population responded to docetaxel, the most striking result was the more than doubling of the response rate with carboplatin in those patients with BRCA1/2 germline mutations. This is compelling evidence that platinum-based agents can be particularly useful in patients with BRCA1/2 germline mutations. In patients with wildtype BRCA1/2, there was a trend toward improved response rate with docetaxel, but this was not statistically significant.


*PFS, progression-free survival; OS, overall survival; TNBC, triple-negative breast cancer.

There was no significant difference in median progression-free survival (PFS) between carboplatin and docetaxel in all patients. There was also no significant difference in median overall survival (OS), which was disappointingly lowapproximately 1 year in both arms of the study.[4] These are quite sobering data for the setting of firstline therapy for metastatic TNBC.


*Adv, advanced; BC, breast cancer; Carbo, carboplatin; Doc, docetaxel; PFS, progression-free survival; TNBC, triple-negative breast cancer.

However, despite the lack of benefit in the overall population, there were differences by BRCA1/2 mutation status. Although docetaxel did not have a differential effect in patients with or without BRCA1/2 mutations (eg, similar median PFS), carboplatin was substantially more effective in those patients with BRCA1/2 germline mutations. In patients with wild-type BRCA1/2 who received carboplatin, the median PFS was only 3.1 months, whereas those with BRCA1/2 mutations had a median PFS of 6.8 months. Median PFS with docetaxel was 4.6-4.8 months regardless of mutation status.[4]The median PFS was disappointingly short with both drugs in the overall population, particularly given that docetaxel 100 mg/m2 has demonstrated efficacy. Overall, the results showed that carboplatin is not particularly effective in TNBC, except in those with BRCA1/2 mutations.Of note, other heritable mutations can lead to homologous recombination defects. If a patient has a strong family history of breast cancer, their oncologist may be more likely to choose a carboplatinbased regimen. Conversely, if the patient has TNBC, but no family history of breast cancer, then it would be reasonable to use a taxane based on these data.The take-home message is that carboplatin appears to be effective in patients with breast cancer and a homologous recombination deficit but does not appear to be particularly effective in tumors with no such DNA repair deficit. This means that treatment with taxanes remains a first-line standard of care.


*AC, doxorubicin/cyclophosphamide; AUC, area under the curve; DD, dose-dense; ER, estrogen receptor; N0, node negative; PgR, progesterone receptor; PMRT, post-mastectomy radiation therapy; TNBC, triple-negative breast cancer.This case study is typical of patients with TNBC and refractory disease. I met the patient, a Hispanic woman, when she was 28 years of age and 4 years postpartum. She presented with a T3N0 grade 3 TNBC in her left breast. The Ki67 percentage was quite high at 80%, and the pathologist noted a high-grade carcinoma with sarcomatoid features. She was tested and found to have wild-type BRCA1/2 and had no family history of breast cancer that was concerning for homologous recombination deficit. She was treated with preoperative dosedense doxorubicin and cyclophosphamide (AC), and achieved a partial response (PR). She then received neoadjuvant weekly paclitaxel. I added carboplatin (AUC 6) to the weekly paclitaxel because she had not had a clinical complete response (CR) with AC but also was not refractory to AC. I wanted to optimize her response, but she achieved only a minor response to the paclitaxel and carboplatin; overall, she had a PR. The patient underwent bilateral mastectomy, after which her left breast retained a 3.6-cm residual tumor with metaplastic features. It was pathologically node negative with no lymphovascular invasion. However, her Ki67 level on the remaining cancer remained high (75% to 100%), and the tumor was triple negative. She received postmastectomy radiation therapy, and her menstrual cycles resumed. *AC, doxorubicin/cyclophosphamide; ER, estrogen receptor; NGS, next-generation sequencing; PgR, progesterone receptor; RUQ, right upper quadrant; TCb, docetaxel and carboplatin; TNBC, triple-negative breast cancer.

Five months after she completed radiation therapy she developed right upper quadrant abdominal pain. A computed tomography (CT) scan found a 7 x 6cm solitary liver metastasis. Biopsy showed a highly mitotic triple-negative carcinoma. Next-generation sequencing of this highly refractory and recurrent disease showed amplification of several genes in the PI3K pathway: AKT3, RICTOR, IGF1R, and c-MYC and p53 mutations. She had a very fast recurrence after first-line therapy, and treatment with a taxane and carboplatin did not provide durable disease control. What are her therapeutic options now? What is supported by level 1 evidence? How should she be treated now that she is experiencing pain in her liver?

*BID, twice a day; MBC, metastatic breast cancer; PO, orally.One option is capecitabine. The US Food and Drug Administration (FDA) approved capecitabine specifically for patients like this one whose disease was refractory to an anthracycline and a taxane. Venturini and colleagues[5] conduced the largest phaseII study to date of capecitabine monotherapy in pretreated patients with metastatic breast cancer (N = 349). Patients had to have received at least 2 previous chemotherapy regimens, including a previous taxane. They received full-dose capecitabine per the FDA label.

Reference:5. Venturini M, et al. Oncology. 2007;72:51-57.

*CR, complete response; ORR, overall response rate; OS, overall survival; PR, partial response; TTP, time to progression.

The response rate to capecitabine was quite reasonable at approximately 35% in these refractory patients. Median time to progression was 6.6 months and median OS was 10 months. The adverse events were acceptablethe incidence for each was below 10%. For example, only 7.6% experienced grade 3 handfoot syndrome, and only 9% had diarrhea.[5] Although these results are not specific to triple-negative patients, capecitabine clearly has level 1 evidence to support its use in patients with anthracycline/ taxane-refractory breast cancer.

Reference:5. Venturini M, et al. Oncology. 2007;72:51-57.

*Another option supported by level 1 evidence is eribulin. A very strong microtubule inhibitor, it actually stops the assembly of interphase, S phase, and mitosis microtubules.[6] As seen here, the lower row of images shows the effect of eribulina real disruption in the mitotic spindle because of the interruption in the assembly of microtubules. Panels G and H show the microtubules that extend in the cytoplasm to help cells with anchorage dependence, as well as mobility and metastasis. These interphase microtubules are important in the dynamics of metastatic cell invasion, and they are very strongly disrupted by eribulin. In short, eribulin not only interrupts the mitotic spindle, but also the interphase microtubules, limiting the ability of these cells to invade and metastasize.

Reference:6. Jordan MA, et al. Mol Cancer Ther. 2005;4:1086-1095.

**MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; TPC, treatment of physicians choice.

The phase III EMBRACE trial[7] led to the FDAs approval of eribulin for the treatment of patients with MBC who have received at least 2 chemotherapy regimens for late-stage disease. In this trial, patients (N = 762) were heavily pretreated including 2 or more chemotherapy regimens for metastatic disease, previous anthracycline and a taxane, and progression within 6 months of their last chemotherapy. Patients were randomized 2:1 to intravenous (IV) eribulin 1.4 mg/m2 on Days 1 and 8 every 3 weeks vs treatment of physicians choice, which was any monotherapy approved for MBC, or radiotherapy, or supportive care only. Almost all of the patients in the control arm received single-agent chemotherapy: either gemcitabine, vinorelbine, capecitabine, a taxane, or an anthracycline. The primary endpoint was OS.

Reference:7. Cortes J, et al. Lancet. 2011;377:914-923.

*HR, hazard ratio; Mos, months; OS, overall survival; PFS, progression-free survival; TPC, treatment of physicians choice.

Median OS was significantly longer with eribulin vs physicians choice of treatment: 13.1 months vs 10.7 months, respectively (HR: 0.81; P = .041), an improvement of 2.4 months. Although no significant difference was seen in PFS, this was a positive study.[7]

Reference:7. Cortes J, et al. Lancet. 2011;377:914-923.

*ER, estrogen receptor; HER2, human epidermal growth factor receptor type 2; PR, progesterone receptor; TPC, treatment of physicians choice.

This subset analysis of EMBRACE showed a trend in favor of eribulin over physicians choice in virtually all breast cancer subsets, including ER positive and ER negative.[8,9] The benefit of eribulin was particularly impressive in patients with visceral disease, who had a very strong improvement in OS. Patients with nonvisceral disease did not appear to benefit from eribulin, but these were small numbers. In the triple-negative subset (n = 144), there was also a strong trend toward improvement in OS with eribulin compared to capecitabine.

References:8. Twelves C, et al. SABCS 2010. Abstract P6-14-18.9. Menis J, Twelves C. Breast Cancer. 2011;3:101-111.17*AE, adverse events; TPC, treatment of physicians choice.

Some grade 3/4 adverse events were more common with eribulin than physicians choice of treatment; for example, neutropenia (45% vs 21%). Febrile neutropenia was uncommon: only 4% with eribulin vs 1% with physicians choice. Grade 3/4 peripheral neuropathy was seen in 8% vs 2% (grade 3 only), respectively. Neutropenia and peripheral neuropathy are the main adverse events of eribulin.[8,10]

References:8. Twelves C, et al. SABCS 2010. Abstract P6-14-18.10. Twelves C, et al. ASCO 2010. Abstract CRA 1004.

*BID, twice daily; IV, intravenous; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; PD, pharmacodynamics; PFS, progression-free survival; PK, pharmacokinetics; TPC, treatment of physicians choice.

Study 301 was a very large phase III trial (N = 1102) of eribulin vs full-dose capecitabine in patients with locally advanced or MBC who had received a previous anthracycline and a taxane in the neo/adjuvant or metastatic setting.[11,12] This essentially second-line study used a 1:1 randomization to eribulin or capecitabine. Patients could have received up to 2 regimens for metastatic disease; most received only 1 regimen. The primary endpoints were OS and PFS.

References:11. Kaufman PA, et al. SABCS 2012. Abstract S6-6.12. Kaufman PA, et al. J Clin Oncol. 2015;33:594-601.HR, hazard ratio; Mos, months; OS, overall survival.

Results from Study 301 showed no statistically significant improvement in OS for eribulin vs capecitabine, although it came close: the HR was 0.88, with a P value of .056 in favor of eribulin.[12] However, the widespread interpretation of these data was that the efficacy of eribulin was equivalent to capecitabine as secondline therapy for MBC. I support that interpretation. So, although these results did not show that eribulin was significantly superior to capecitabine in this setting, this very large study supports the use of either eribulin or capecitabine as second-line therapy for MBC after an anthracycline and a taxane.

Reference:12. Kaufman PA, et al. J Clin Oncol. 2015;33:594-601.

*Cape, capecitabine; HR, hazard ratio; Mos, months; OS, overall survival.

In a prespecified subgroup analysis, patients with TNBC treated with eribulin had an HR for survival of 0.7 vs those treated with capecitabine. The median OS with capecitabine was low at 9.4 months compared with 14.4 months for eribulin.[11] This is a very large improvement in the triple-negative population, where eribulin is clearly of greater clinical benefit than capecitabine. In patients who were not triple negative, the HR was 0.9, which is only an approximately 1-month improvement in OS.

Reference:11. Kaufman PA, et al. SABCS 2012. Abstract S6-6.

21CBR, clinical benefit rate; DOR, duration of response; MBC, metastatic breast cancer; ORR, overall response rate; PD, pharmacodynamics; PK, pharmacokinetics; PS, performance status.

As discussed, eribulin and capecitabine are proven noncross-resistant therapy for patients whose breast cancer is refractory to an anthracycline and a taxane. Therefore, Twelves and colleagues[13] conducted a phase II study combining these agents together in patients with breast cancer who have received anthracycline and taxane treatment. This study enrolled 42 patients who had received pretreatment with up to 3 chemotherapy regimens in any setting, including anthracycline and taxane but no capecitabine, and had measurable disease. They received full-dose eribulin 1.4 mg/m2 with capecitabine 1000 mg/m2 on Days 1-14 of a 21-day cycle. The primary endpoint was the overall response rate.

Reference:13. Twelves C, et al. SABCS 2014. Abstract P3-13-04.

*CBR, clinical benefit rate; ORR, overall response rate; PFS, progression-free survival; SD, stable disease.

The response rate was quite reasonable, at 43%, and the clinical benefit rate, including patients who had had at least 6 months of stable disease, was 57%. These are very good rates in this difficult-to-treat group of patients. Median PFS was 7.2 months. Toxicities include handfoot syndrome (grade 1: 21%; grade 2: 5%; grade 3: 8%), which was the major toxicity. Neutropenia, of course, was also seen with this combination.[13,14] Eribulin and capecitabine is a very active combination that could be considered in certain patients with MBC previously treated with an anthracycline and a taxane, where the tumor burden and the patients mortality risk are clinically significant enough to consider combination therapy.

References:13. Twelves C, et al. SABCS 2014. Abstract P3-13-04.14. Smith JW II, et al. SABCS 2014. Abstract P3-09-09.

*AC, doxorubicin/cyclophosphamide; nCR, near complete response; NGS, next-generation sequencing; PgR, progesterone receptor; RUQ, right upper quadrant; TCb, docetaxel and carboplatin; TNBC, triple-negative breast cancer.Returning to the young case patient, who was 29 years of age at the time, 5 months after radiation therapy and 8 months after neoadjuvant AC followed by weekly paclitaxel and carboplatin, she developed a 7.6-cm solitary liver metastasis. A liver biopsy revealed triple-negative disease with multiple amplicons in the PI3K pathway, a very seriously resistant disease.I decided not to resect her liver metastasis, due to concern that she would simply proceed to develop multiple other metastases and I would not have helped her with the resection. I chose to treat her first with chemotherapy to see if the liver metastasis responded, with the goal of proceeding to resection of any residual disease. In addition, a PET/CT scan revealed a questionable lesion in the lung, which was another reason I did not proceed immediately to resection; I wanted to follow the PET/CT scan and make sure she responded to subsequent systemic therapies and also make sure that she did not have a small lung metastasis.I treated her with eribulin plus capecitabine using a 7-days-on, 7-days-off flat-dose schedule because she was getting considerable handfoot syndrome with the 14-days-on, 7-days-off schedule. I utilize the 14/7 schedule for capecitabine as a single agent, but I find that in combination with either eribulin or a taxane, for example, that the 7 days on/7 days off schedule is well tolerated and highly effective. The case patient was able to tolerate full-dose eribulin with capecitabine on this schedule.She had a slowly evolving near CR over 10 months. Each CT scan showed further improvement in her liver metastasis. Repeat PET scans made it clear that she did not have a metastasis to her lung, although she retained a very small positive area on her liver. She did not have a CR by her liver CT scan, so she therefore underwent resection of the residual liver metastasis. She had 1-mm residual disease, TNBC, and 40% Ki67 staining. We do not know why she still had residual refractory cells. She is now almost 31 years of age, recently was married, and is continuing full-dose eribulin with capecitabine on the 7-days-on, 7-days-off schedule. She has been on this regimen for more than 2 years, is menstruating normally, and has an excellent quality of life. I think I will continue therapy for as long as she tolerates it well because I am concerned that she will recur if I stop treatment. She has had a remarkable response, particularly given that the first 4 standard agents were not particularly helpful. This is a potentially effective and noncross-resistant regimen for patients with TNBC who need combination therapy.

*IV, intravenous; MBC, metastatic breast cancer.

In addition to eribulin, the microtubule inhibitor ixabepilone also is recommended in the NCCN guidelines[1] for the treatment of triple-negative or heavily pretreated ER-positive breast cancer. Ixabepilone is an epothilone B analogue, which promotes permanent polymerization of the microtubule, essentially freezing them in place. Supported with level 1 evidence, it is approved as monotherapy for MBC that is refractory to an anthracycline, a taxane, and capecitabine[2]; in other words, truly refractory disease. In this phase II study conducted by Perez and colleagues,[3] 126 patients with resistant MBC received single-agent ixabepilone 40 mg/m2 IV over 3 hours (because it contains polyethoxylated castor oil) every 21 days until disease progression.

References:NCCN. Clinical practice guidelines in oncology: breast cancer. v.1.2015. 15. Ixabepilone [package insert].16. Perez EA, et al. J Clin Oncol. 2007;25:3407-3414.

*DOR, duration of response; OR, overall response; OS, overall survival; PFS, progression-free survival; SD, stable disease.

The response rate was 11.5%, with stable disease lasting 6 months or longer in 13.3% of patients; the clinical benefit rate was approximately 25%. The duration of response was 5.7 months, median PFS was 3.1 months, and median OS was 8.6 months. The response rate was 12% in the triple-negative population. Grade 3/4 adverse events included leukopenia and neutropenia in approximately half of patients, as well as sensory neuropathy, fatigue, myalgia, and stomatitis/mucositis.[16]

Reference:16. Perez EA, et al. J Clin Oncol. 2007;25:3407-3414.

*A/T, anthracyclines and taxanes; MBC, metastatic breast cancer; OS, overall survival.The combination of ixabepilone and capecitabine has level 1 evidence supporting its use in patients with MBC. In this large phase III trial (N = 1221), Sparano and colleagues[17] evaluated the combination in patients who were refractory to an anthracycline and a taxane, including triple-negative, ERpositive, and HER2positive patients. Patients were randomized to single-agent capecitabine vs capecitabine plus full-dose ixabepilone 40 mg/m2. Median PFS was significantly extended from 4.4 months with capecitabine alone to 6.2 months with the combination, and this led to the FDA approval of ixabepilone plus capecitabine in anthracycline-refractory and taxane-refractory patients with metastatic or locally advanced breast cancer.

Reference:17. Sparano JA, et al. J Clin Oncol. 2010;28:3256-3263.

*A/T, anthracyclines and taxanes; MBC, metastatic breast cancer; PFS, progression-free survival.

This forest plot of the subset analysis shows that in the triple-negative population, the addition of ixabepilone to capecitabine led to an HR of 0.64 in favor of the combination vs capecitabine alone. In fact, most of the benefit from the combination was seen in the triple-negative population. In the nontriple-negative population, the HR was 0.86, a relatively small trend toward benefit.[17]

Reference:17. Sparano JA, et al. J Clin Oncol. 2010;28:3256-3263.

*29Cape, capecitabine; CR, complete response; HR, hazard ratio; Ixa, ixabepilone; MBC, metastatic breast cancer; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response.This pooled analysis by Rugo and colleagues[18] encompasses 2 very large phase III trials of capecitabine with or without ixabepilone in a mixed population of patients with breast cancer, including 443 patients with TNBC. Results showed that the use of single-agent capecitabine produced a 15% response rate in patients with metastatic TNBC that is refractory to an anthracycline and a taxane. Median PFS with capecitabine alone was very short at 1.7 months. So, there is a small population of TNBC patients who will respond to capecitabine alone, but we do not know how to identify them at this time. The response rate in TNBC more than doubled to 31% with the addition of ixabepilone to capecitabine and the median PFS increased to 4.2 months. But, overall, there was no significant improvement in OS from adding ixabepilone to capecitabine in this population. By contrast, in the previously discussed study, the addition of eribulin to capecitabine did improve survival.

Reference:18. Rugo HS, et al. SABCS 2008. Abstract 3057.

A/T, anthracyclines and taxanes; GC, gemcitabine/carboplatin; GCI, gemcitabine/carboplatin/iniparib; ITT, intent to treat; OS, overall survival; PFS, progression-free survival; TNBC, triple-negative breast cancer.

Gemcitabine plus carboplatin is another important level 1 therapy option for TNBC. My colleagues and I conducted a phase III study of this combination with or without iniparib, a chemotherapeutic agent originally thought to be a PARP inhibitor, as first-line and second-line therapy for patients who had previously received an anthracycline and a taxane.[19] Results showed that iniparib was largely ineffective in this hard-to-treat patient population. The response rate to gemcitabine/carboplatin alone was 30% vs 34% with the addition of iniparib. Median PFS was 4-5 months with or without iniparib. Median OS was approximately 12 months for both arms. This was a challenging patient population: Of the first-line patients, approximately one third had a disease-free interval of less than 1 year after anthracycline and taxane pretreatment.

Reference:19. OShaughnessy J, et al. J Clin Oncol. 2014;32:3840-3847.

*ADCC, antibody-dependent cell-mediated cytotoxicity; BC, breast cancer; CDC, complement-dependent cytotoxicity; CR, complete response; ER, estrogen receptor; PD, progressive disease; PgR, progesterone receptor; PR, partial response; q2w, every 2 weeks; SD, stable disease; TNBC, triple-negative breast cancer.Nanda and colleagues[20] conducted a phase II study of single-agent pembrolizumab, an antiPD-1 monoclonal antibody, in heavily pretreated patients with metastatic TNBC (N = 32) who were positive by immunohistochemistry for PD-L1 expression. The primary endpoint was overall response rate.Patients received pembrolizumab 10 mg/kg every 2 weeks. Those who had a PR continued treatment for 2 years or until disease progression; patients with a CR could discontinue or keep going. The PD-1 ligands PDL1 and PDL2 are frequently expressed on tumor cells, including PD-L1 expression on a high percentage of TNBCs, which leads to tolerance of the immune system to the breast cancer. Binding of PD-L1 to PD-1 inhibits T-cell proliferation, suppresses the cytolytic Tcells, and turns off the antigen-presenting capabilities of the dendritic cells; in short, PD-L1 and PD-L2 expression basically dampens down the entire immune system against the cancer. Pembrolizumab binds the PD1 receptor, which stops this tolerance and, hopefully, unleashes cytolytic Tcell activity against the cancers. Pembrolizumab has proven clinical activity in multiple tumor types, including non-small-cell lung cancer, and is approved for the treatment of melanoma.

Reference:20. Nanda R, et al. SABCS 2014. Abstract S1-09.

*CR, complete response; DOR, duration of response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease; TNBC, triple-negative breast cancer.

The overall response rate was 18.5%. At the time these data were presented, the median duration of response was not reached, ranging between 15 weeks and more than 40 weeks; 3 patients had responses lasting 11 months or longer.[20] These are encouragingly durable responses in this heavily pretreated patient population.


*AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; TNBC, triple-negative breast cancer.

In this study, few grade 3 toxicities were reported, including headache in 1 patient, and no grade 4/5 events were reported. Other adverse events included arthralgias, fatigue, myalgia, nausea, transaminase increase, diarrhea, headaches, and erythema. Of note, some adverse events may be immune related, such as grade 1/2 pruritus, grade 3 hepatitis, and grade 2 hypothyroidism. Overall, pembrolizumab appears to be safe and, in this study, showed a definite signal of antitumor activity.[20] A large phase II study of pembrolizumab is being planned to obtain additional data in the population of pretreated patients with metastatic TNBC. That trial should be opening soon and I expect it will enroll very rapidly. Pembrolizumab is a very exciting new agent.


*Lastly, I will discuss etirinotecan pegol (NKTR-102), which is a polymer conjugate of irinotecan, a topoisomerase I inhibitor. Etirinotecan uses a biodegradable spacer.[21] It is more active than irinotecan in animal models and better tolerated.[22,23] It is designed to cross the leaky vasculature that is associated with MBC, and once in the tumor interstitium, the biodegradable spacer disappears and releases the irinotecan from the scaffold. This provides a way to concentrate irinotecan in the tumor interstitium via the leaky vasculature.

References: 21. Awada A, et al. Lancet Oncol. 2013;14:1216-1225.22. Hoch U, et al. Cancer Chemother Pharmacol. 2014;74:1125-1137.23. Jameson GS, et al. Clin Cancer Res. 2013;19:268-278.

*ORR, overall response rate; TNBC, triple-negative breast cancer.

Awada and colleagues[21,24] conducted a randomized phase II study of etirinotecan pegol in pretreated patients with MBC (N = 70). In the 21 patients with TNBC, the response rate was 33%. This waterfall plot shows that more patients benefited than not in this heavily pretreated population. This level of antitumor activity is exciting. Diarrhea was the main toxicity. These promising phase II results led to the phase III BEACON trial.

References:24. Awada A, et al. IMPAKT 2012. Abstract 101P.21. Awada A, et al. Lancet Oncol. 2013;14:1216-1225.35IV, intravenous; MBC, metastatic breast cancer; R, randomization.In the ongoing phase III BEACON trial, etirinotecan pegol is being compared with physicians choice of single-agent treatment in patients with locally recurrent breast cancer or MBC (planned N = 840).[25] This study is enrolling patients with pretreated MBC who had been treated with at least 2 previous cytotoxic regimens for metastatic disease, including an anthracycline, a taxane, and capecitabine, and were either ER positive or triple negative. Patients are being randomized to receive etirinotecan once every 21 days vs a single-agent chemotherapy treatment of physicians choice, such as eribulin, gemcitabine, vinorelbine, and taxanes.Top-line data from BEACON were recently made available in a press release[26] and the results appear to be positive; we have not seen the official data yet but they will be presented at a major medical meeting this year. SummaryThe NCCN guidelines provide level 1 evidence for several treatment options for patients with MBC who are refractory to endocrine therapy and have already been treated with an anthracycline and taxane. Special consideration must be given to patients with TNBC, who are particularly challenging to treat.Clinical trial results suggested that capecitabine and eribulin are equally efficacious in MBC, except in the triple-negative population where eribulin appears to be of greater clinical benefit. There are intriguing early data from a phase II study of a combination of eribulin and capecitabine. We have seen that gemcitabine/carboplatin is active in triple-negative patients who have been treated with an anthracycline and a taxane. Ixabepilone is active as a single agent in either triple-negative or ERpositive disease. There is evidence of benefit for the ixabepilone/capecitabine combination in the ER-positive population, particularly in triple-negative patients. Two promising new agents were discussed. Etirinotecan pegol is a topoisomerase I inhibitor with apparent activity, including in patients with brain and liver metastases, where it has been very difficult to achieve durable benefit. Pembrolizumab is an exciting PD-1 inhibitor that will be entering a large phase II study in the very near future. These agents likely represent progress for patients, and it is hoped that they may specifically be of use as adjuvant and neoadjuvant therapy for triple-negative patients with metastatic disease.

References:25. ClinicalTrials.gov. NCT01492101.26. Nektar. Press release. Mar. 17, 2015.

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cco her2 negative mbc clinfocus tu15 slides

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