Walter Alexander

In the first-line setting, recently updated findings from EMBRACE, the phase III trial that led to the 2010 FDA approval of eribulin as monotherapy in patients with relapsed locally advanced or metastatic breast cancer, demonstrated improved survival compared with physician&rsquo;s choice of controls at 13.2 months versus 10.5 months (HR, 0.81; 95% CI, 0.67-0.96;

= .014) in patients who had received 2 to 5 previous treatment regimens. Eribulin is a fully synthetic macrocyclic analogue of a naturally occurring mitotic inhibitor.

The current study (ONCOSUR 2012-02), which was presented at ESMO, was conducted, as researchers needed data that were specific to third-line treatment for breast cancer, said Sanchez, of University Hospital, Madrid, Spain, in an interview with

. &ldquo;We wanted real-world data on these patients,&rdquo; he added.

ONCOSUR 2012-02 had safety as its primary endpoint, and overall survival (OS), progression-free survival (PFS), clinical benefit rate (CBR), and overall response rate (ORR) as secondary endpoints.

Patients had received 2 prior lines of chemotherapy in the advanced disease setting. Patients received eribulin at 1.23 mg/m

on days 1 and 8 of every 21-day cycle until disease progression, unacceptable toxicity, or withdrawal.

Among 59 patients (mean age 57.7 years), 98.3% had received previous taxanes and/or anthracyclines. Regarding subtypes, 71.2% were estrogen receptor-positive, 66.1% were progesterone receptor-positive, and 20.3% had triple-negative breast cancer. The majority of patients had HER2-negative status (96.6%), and nearly all had metastatic disease (98.3%).

Ductal disease was present in 91.5% of patients. Metastases in the liver were present in 64.4% of patients, 57.6% were in the bone, and 50.9% were in the lung. Nearly half of patients had lymph node metastases (49.2%), and 84.8% had visceral disease. Prior cardiovascular disease was noted in 35.6% of patients. Mean treatment duration was 4.5 months and the mean number of cycles was 6.9.

The most common grade 3/4 adverse event (AE) considered to be associated with eribulin was neutropenia at 16.95%. Other grade 3/4 AEs included febrile neutropenia rate (5.08%), alopecia (5.08%), and leukopenia (5.08%). Grade 1/2 events included asthenia, gamma-glutamyltransferase increase, respiratory tract infection, mucosal inflammation, peripheral neuropathy, and polyneuropathy, all at 1.69%. Dose reductions were required in 52.5% of patients.

The median PFS was 4.03 months (95% CI, 3.07-5.93), while the median OS was 13.6 months (95% CI, 11.8-not reached). &ldquo;Importantly, this OS rate was very similar to the rate in the phase III trials.&rdquo; Partial responses were observed in 17.0%, and stable disease in 39.0%, leading to a CBR of 56%. Progression was reported in 35.6% of patients.

At a 20-month follow-up, 44 patients (74.6%) were still alive, Sanchez said. Eleven patients left the study for reasons other than disease progression. Ay the end of the end of the follow-up period (median 2.67 months), 10 (90.9%) had not progressed. Further treatment was administered in 35 (77.8%) of the 45 patients (76.3%) who ultimately had progressive disease.

&ldquo;Treatment with eribulin as third-line chemotherapy for locally advanced or metastatic breast cancer resulted in minimally toxic, manageable adverse events, similar to the previously described events in the pivotal trials,&rdquo; Sanchez said. &ldquo;Treatment was effective with a clinical benefit in more than half of the women treated.&rdquo;

Additionally, he added that other available regimens for third-line treatment typically have more neuropathy, more hematologic toxicity, and higher rates of alopecia.

&ldquo;Eribulin is better tolerated. It&rsquo;s an option for patients with metastatic breast cancer,&rdquo; he said.

Sanchez LMM, Anton FM, Peron IA, et al. Single arm, multicentre, non-randomized open-label trial to evaluate the safety of eribulin in third line chemotherapy in patients with HER2-negative metastatic or locally advanced breast cancer previously treated with anthracyclines and taxanes: Onsite study (ONCOSUR 2012-02). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 246P.

Articles

Among patients with HER2-negative stage IIIb/IV breast cancer who have progressed after a taxane or anthracycline therapy, a multicenter single-arm study of third-line eribulin demonstrated both safety and efficacy.

Third-Line Eribulin Effective, Safe in Metastatic Breast Cancer

In the &ldquo;real world&rdquo; NABUCCO trial, results with nab-paclitaxel were consistent with those reported in the pivotal trial among patients with metastatic breast cancer who are ineligible to receive anthracycline therapy.

The benefits associated with the treatment extend also to patients who are 65 years or older, said Karin Potthoff, MD, of IOMEDICO AG in Freiburg, Germany, during a poster session at the 2016 ESMO Congress.

In a pivotal phase III trial by Gradishar et al,

nab-paclitaxel was compared with paclitaxel in a similar patient population. Results showed that the overall response rate (ORR) with nab-paclitaxel was 33%. The time to tumor progression was 23.0 weeks with nab-paclitaxel and 16.9 weeks with paclitaxel, and an overall survival (OS) of 60 weeks.

Nab-paclitaxel was associated with an acceptable toxicity profile in this trial. Grade 3 peripheral sensory polyneuropathy occurred in 10% of patients and was the most critical safety issue.

While several clinical trials of nab-paclitaxel have been conducted, prospective data on real-world practice consistent with increased use of prior taxane-containing regimens in the neoadjuvant setting were lacking, explained Potthoff in an interview with

. &ldquo;We wondered if patients, in fact, were able to receive the recommended 260 mg/m

dose or if it was too toxic,&rdquo; she added.

Therefore, in the real-world German NABUCCO study,

investigators collected data on routine treatment from 2012 to 2015 of 697 patients with metastatic breast cancer and contraindications for anthracycline therapy in approximately 100 oncology outpatient centers across Germany. Data on treatment for a maximum of 6 months were captured, with follow-up for a median of 17.7 months including details on disease progression, OS, and safety with focus on neurotoxicity.

A total of 419 patients (60.1%) received prior taxane therapy. The median age in the overall trial was 62.3 years, with 58.2% being less than 65 years of age. Median time from primary diagnosis was 65.2 months.

Dosing schedules, which were at the discretion of the physician, ranged from 78 to 260 mg/m

and with cycles from q3w to q4w. Nab-paclitaxel was administered as a first-, second-, third- and fourth- or later-line therapy in 40%, 24%, 20%, and 15% of patients, respectively.

Receptor status varied in the NABUCCO population: hormone receptor (HR)-positive/HER2-negative (58.4%), HR-positive/HER2-positive (9.9%), HR-negative/HER2-positive (3.9%), triple-negative breast cancer (TNBC; 13.8%) and unknown (14.1%).

The ORR across the study population was 37.2%. In the first-line setting, nab-paclitaxel was associated with a 46.1% ORR; in second-line, the ORR was 32%. Third-line paclitaxel was associated with a 31.9% ORR, while treatment in fourth-line and beyond led to a 29.0% ORR.

Stable disease percentages ranged from 30.5% in third-line therapy to 37.3% in second-line therapy. Response rates were highest among patients who were HR-negative/HER2-positive (55.6%) and lowest in TNBC (32.7%).

&ldquo;That rate for triple-negative disease is still quite good,&rdquo; Potthoff commented. Progressive disease was highest in TNBC (27.1%) and lowest in HR-negative/HER2-positive (11.1%).

Although responses were lower in patients 65 years and older than those were younger (31.6% vs 41.1%), progressive disease was not higher in older patients (17.2% vs 20.0%). Also, ORRs were not reduced in patients who received doses lower than 260 mg/m

The median time to tumor progression was 5.9 months for the overall population and similar for those less than 65 years (5.7 months) and 65 years or older (6.5 months). It was shortest for those with TNBC (4.9 months) and longest for patients who were HR-positive/HER2-positive (8.6 months).

Grade 3/4 neurotoxic adverse events (AEs) were observed in 5.2% of patients, particularly peripheral sensory neuropathy (4.3%), peripheral motor neuropathy (1.1%) and paresthesia (0.1%).

Grade 1/2 AEs were reported in 47.3% of patients, peripheral sensory neuropathy being the most common (35.0%). Rates for peripheral motor neuropathy and paresthesia were 11.6% and 8.6%, respectively.

Potthoff said that despite the common phenomenon of underreporting in non-interventional studies, the explicit focus on capturing neurotoxic adverse events during NABUCCO resulted in an overrepresentation of neurotoxic events compared with other adverse events.

Additionally, she underscored that response rates were high in populations typically difficult to treat: patients who had received multiple lines of prior therapy, in elderly patients, and those with TNBC.

&ldquo;Our real-world data from NABUCCO confirm the earlier clinical trial findings,&rdquo; Potthoff concluded. &ldquo;They confirm also that nab-paclitaxel is an effective and safe treatment option with a favorable benefit-risk profile in metastatic breast cancer patients not eligible for anthracycline therapy.&rdquo;

Potthoff K, Nusch A, S&ouml;ling U, et al. Efficacy and safety of nab-paclitaxel in patients with metastatic breast cancer: final results of the non-interventional study NABUCCO. Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract 236P.

Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.

Recent Results of Nab-Paclitaxel in Breast Cancer Consistent With Phase III Data

Toxicities associated with capecitabine may be better managed by dose reductions and/or a week-on/week-off (WOWO) dosing schedule among patients aged 70 years or older with metastatic breast cancer, according to David O. Okonji, MD, clinical research fellow at The Royal Marsden Hospital NHS Foundation Trust in London.

Capecitabine monotherapy is prescribed for patients who have progressed after all available endocrine therapies no longer offer benefit, Okonji said in an interview with

during the 2016 ESMO Congress. It may be administered as a last oral agent option before resorting to intravenous chemotherapy with its attendant potential side effects of alopecia, nausea, vomiting, and fatigue.

&ldquo;Chemotherapy with capecitabine has been around for about 25 years. Its registration dose of 1250 mg/m

twice daily is very hefty for the elderly, however,&rdquo; Okonji said.

Its clinical benefit rate (CBR) as a monotherapy is 60% and median time to progression in patients &ge;65 years is 4 months. Of those receiving that dose, 27% to 50% require a dose reduction due to toxicity.

The starting dose and schedule for capecitabine at The Royal Marsden Hospital and NHS Foundation Trust is 2000 mg/m

on days 1 to 14, every 3 weeks (2 weeks on/1 week off). However, older patients, and those with a poor performance status, comorbidities, and/or moderate to severe renal impairment may need a further dose reduction.

Because capecitabine is metabolized by the liver and cleared renally, a switch to a WOWO schedule is being substituted in order to improve tolerance in the elderly. The strategy was devised at Memorial Sloan Kettering Cancer Center, but is infrequently used in Europe, Okonji noted.

In a single-center retrospective observational cohort study, led by Okonji, researchers sought to assess the safety and efficacy of low-dose capecitabine monotherapy in elderly patients with metastatic breast cancer, with toxicity as the primary endpoint.

Eligible patients were 70 years of age or older and had relapsed

metastatic breast cancer. Those receiving the standard 2 weeks on/1 week off regimen (2000 mg/m

) were compared to those receiving a dose reduction or the WOWO (2000 mg/m

Among a total of 77 patients, those receiving the dose reduction or the WOWO schedule were older (median age 79 versus 73;

The complete response rates were 7% and 0% for the 2000 mg/m

(n = 34) groups, respectively, with corresponding partial response rates at 37% and 16%. Progressive disease was reported in 30% of those receiving higher doses of capecitabine and in 50% of those receiving below 2000 mg/m

The clinical benefit rate was 67% for those receiving 2000 mg/m

and 43% for those receiving less than 2000 mg/m

= .05). Okonji commented that this difference might be accounted for by longer treatment duration in the 2000 mg/m

At a median follow-up of 28.1 months, the combined time-to-progression was 8.2 months and an overall survival OS of 18.6 months. Time-to-progression was 11.7 months and 6.2 months in the 2000 mg/m

cohort experienced less grade 3/4 toxicities (3% vs 19%) with fewer subsequent dose reductions.

&ldquo;Patients on the WOWO schedule tolerated capecitabine better because of less diarrhea, less hand inflammation, and little to no reduced white cell counts with their infection risk,&rdquo; Okonji said. &ldquo;This enabled them to stay on their dose for a longer time, despite their poor performance status and impaired kidney function, which is usually a contraindication for this drug.

&ldquo;Capecitabine toxicity can be managed by dose reduction and/or a switch to a WOWO schedule; both strategies enabled continued treatment in those deriving clinical benefit,&rdquo; he concluded.

Additionally, he added that the study&rsquo;s findings revive the use of capecitabine for these patients with metastatic breast cancer.

&ldquo;In many respects, the major conferences are all about getting new drugwhich get us very excited for a while&mdash;and then we forget about them sooner or later after a few years. With this modification of the capecitabine regimen, we have given this old drug a new lease on life and allowed it to be used in patients who would not otherwise be able to tolerate it. And, it&rsquo;s off-patent and cheap.&rdquo;

Okonji D, Mohammed K, Redana S, et al. Capecitabine monotherapy in patients aged 70 years and older with metastatic breast cancer (MBC).

Toxicities associated with capecitabine may be better managed by dose reductions and/or a week-on/week-off (WOWO) dosing schedule among patients aged 70 years or older with metastatic breast cancer.

Walter Alexander | Authors

Articles

Third-Line Eribulin Effective, Safe in Metastatic Breast Cancer

Recent Results of Nab-Paclitaxel in Breast Cancer Consistent With Phase III Data

Management of Capecitabine Toxicities in Breast Cancer May Be Better With Dose Reduction