Quick Takes on Promising New Approaches to Treating Breast Cancer

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At the 2016 ASCO Annual Meeting, researchers reported encouraging results for several new drugs and treatment strategies for breast cancer. The ASCO Post brings you brief summaries of a select few.

Abemaciclib Trial

The cyclin-dependent kinase 4/6 (CDK4/6) inhibitor abemaciclib produced responses in almost 20% of heavily pretreated hormone receptor–positive, HER2-negative advanced breast cancer, according to the single-arm phase II MONARCH 1 trial.1 Median progression-free survival was 6 months, and median overall survival was 17.7 months, with the upper boundary of the confidence interval not yet reached.

Maura N. Dickler, MD

Maura N. Dickler, MD

“MONARCH 1 confirms single-agent activity with abemaciclib,” said Maura N. Dickler, MD, of Memorial Sloan Kettering Cancer Center, New York.

In October 2015, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to the CDK4/6 inhibitor for patients with refractory hormone receptor–positive advanced or metastatic breast cancer.

MONARCH 1 included 132 patients progressing on endocrine therapy and chemotherapy, of whom 90% had visceral disease and 86% had at least two metastatic sites. Patients had received a median of three prior lines of therapy for metastatic disease, including fulvestrant (Faslodex) in 51%.

Patients received abemaciclib at 200 mg orally every 12 hours on a continuous schedule. At the 8-month interim analysis, 35.6% of patients had received at least 8 cycles of the drug.

Response and Toxicity

The investigator-assessed objective response rate was 19.7%, all partial responses. Another 22.7% of patients achieved stable disease (≥ 6 months), producing a clinical benefit rate of 42.4%. The median duration of response was 8.6 months.

The most common adverse events of all grades included diarrhea (90.2%), fatigue (65.2%), nausea (64.4%), decreased appetite (45.5%), and abdominal pain (38.6%). Grade 3 diarrhea occurred in 19.7% and grade 3 fatigue, in 12.9%. The only grade 4 adverse event was neutropenia, seen in 4.6% of ­patients.

Dr. Dickler commented on diarrhea as a side effect, explaining that it was generally experienced during the first cycle, with an onset around 7 days, and “resolved quickly.” The median duration of grade 2 and 3 diarrhea was 7.5 and 4.5 days, respectively. No patient had grade 4 diarrhea, and only one patient discontinued treatment because of diarrhea. Most cases were managed with standard antidiarrheal regimens and dose reductions, she revealed.

Jose Baselga, MD, PhD

Jose Baselga, MD, PhD

The study’s senior author, Jose Baselga, MD, PhD, Physician-in-Chief and Chief Medical Office at Memorial Sloan Kettering Cancer Center, pointed out that after endocrine therapies stop working in these patients and the disease is refractory or aggressive, chemotherapy, with its accompanying toxicity, “is the only option.” He continued: “To see this level of antitumor activity, combined with the toxicity profile observed in MONARCH 1, is promising.”

The combination of abemaciclib and fulvestrant, vs fulvestrant alone, is being studied in the phase III MONARCH 2 study for postmenopausal patients with hormone receptor–positive, HER2-negative locally advanced or metastatic breast cancer who have received no more than one prior therapy (and no chemotherapy). MONARCH 3 is evaluating the drug with a nonsteroidal aromatase inhibitor.

Vaccine Encouraging in Immune Responders

Hope Rugo, MD

Hope Rugo, MD

Chiun-Sheng Huang, MD

Chiun-Sheng Huang, MD

Vaccination with OPT-822/OPT-821 as maintenance therapy for metastatic breast cancer did not meet the primary endpoint of progression-free survival, but patients generating a robust immune response did show improvement over placebo, in a study reported by Hope Rugo, MD, of the University of California San Francisco.2 The study’s first author was Chiun-Sheng Huang, MD, of the National Taiwan University in Taipei.

“In patients receiving the vaccine who generated an IgG titer ≥ 160 at any time during treatment, progression-free survival was superior to placebo….” she reported. “Lack of immune response to the vaccine correlated with very poor outcomes.”

OPT-822/OPT-821 is a “novel active immunotherapy for breast cancer” that induces IgG and IgM by targeting Globo H. Globo H is a cancer-associated carbohydrate antigen expressed by a number of epithelial cancers, including 60% to 80% of breast cancers. The vaccine reportedly depletes Globo H, and this effectively blocks immunosuppression by increasing Notch1 degradation, thus achieving tumor regression, explained Dr. Rugo.

This phase II/III double-blind, randomized, international study enrolled 349 patients with metastatic breast cancer with response or stable disease following no more than 2 lines of chemotherapy or hormonal therapy. Patients were randomized 2:1 to receive subcutaneous OPT-822/OPT-821 or control on weeks 1, 2, 3, 5, 9, 13, 17, 25, and 37 or until disease progression, in combination with low-dose cyclophosphamide (300 mg/m2). Hormone therapy was allowed. Of the 349 patients enrolled, 48% received all 9 injections. The primary endpoint was progression-free survival.

Survival and Immune Response

No difference was observed in median progression-free survival (hazard ratio [HR] = 0.96; P = .77) or interim overall survival (HR = 0.79; P = .29); however, both endpoints were significantly improved in the 50% of patients who developed a Globo H–specific IgG response to OPT-822/OPT-821 (ie, titer ≥ 1:160 at any time during treatment).

Study results for median progression-free survival, by treatment group and immune response, follow:

  • In the intention-to-treat population: 32.9 weeks for the vaccine group vs 40.0 weeks for the control group (HR = 0.96; P = .7728)
  • Among patients who received all 9 injections: 90.1 weeks for the vaccine group vs 72.6 weeks for the control group (HR = 0.66; P = .0566)
  • Among vaccinated patients achieving IgG response (titer ratio ≥ 1:160) vs no response: 48.4 weeks vs 23.9 weeks for nonresponders (HR = 0.51; P < .0001)
  • For vaccinated patients with an IgG response vs placebo: 48.4 weeks vs 40.0 weeks (HR = 0.71; P = .0295)
  • For vaccinated nonresponders vs placebo: 23.9 weeks vs 40.0 weeks (HR = 1.38; P = .0366)

The treatment response appeared to be independent of the tumor biologic subtype and Globo H expression levels; 72% of patients had some expression of Globo H. Median overall survival at 4 years was 69.3%, vs 60.5% for vaccinated vs placebo in the intent-to-treat population (HR = 0.79; P = .289), Dr. Rugo reported.

OPT-822/OPT-821 was well tolerated; the most common drug-related adverse event was grade 1/2 injection reaction.

“Additional studies are planned to further explore the efficacy of OPT-822/OPT-821 in patients who generate an immune response,” added Dr. Rugo.

Steven J. Isakoff, MD, PhD

Steven J. Isakoff, MD, PhD

Discussing the study was Steven J. Isakoff, MD, PhD, of Massachusetts General Hospital, Boston, who noted: “The primary endpoint was not met, but we saw a very provocative result in IgG/IgM responders…. Further development is clearly warranted.”

Tailored Dose-Dense Schedule Improves Efficacy

A tailored approach to a dose-dense schedule for epirubicin/cyclophosphamide followed by docetaxel ­(EC-D) improved all efficacy endpoints, compared with more traditional dosing, in the PANTHER trial presented by Jonas Bergh, MD, of the Karolinska Institute in Stockholm, Sweden.3 The PANTHER study was a joint project of the Swedish Breast Cancer Group, the Austrian Breast-Colorectal Cancer Study Group, and the German Breast Group.

Jonas Bergh, MD

Jonas Bergh, MD

“The superiority of tailored-dose-dense EC-D was consistent in all studied subgroups, including estrogen receptor–positive disease and HER2-positive disease treated with trastuzumab [Herceptin],” Dr. Bergh said, noting that relative risk reductions ranged from 17% to 23% for the various outcomes.

Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxicities, and efficacy, he explained. This study aimed to determine whether leukocyte nadir–based tailored and dose-dense adjuvant EC-D improves outcomes in early breast cancer compared with a conventional three-weekly chemotherapy schedule of fluorouracil/epirubicin/cyclophosphamide (FEC) 100/docetaxel 100.

“The PANTHER study is not a conventional dose-escalation study. Only patients with less toxicity receive dose escalations, on an individual patient basis at each course,” revealed Dr. Bergh. “This is a different strategy than ‘across the board dose escalation,’ which was not shown to be beneficial in studies from the [Cancer and Leukemia Group B] and [National Surgical Adjuvant Breast and Bowel Project].”

The study included 2,017 patients with node-positive or high-risk node-negative breast cancer recruited from 86 centers in Sweden, Austria, and Germany. Patients received either four cycles of leukocyte nadir–based tailored and dose-dense adjuvant epirubicin (38–120 mg/m2, starting at 90 mg/m2) and cyclophosphamide (450–1,200 mg/m2, starting at 600 mg/m2) every 2 weeks, followed by 4 cycles of docetaxel (75–100 mg/m2, starting at 75 mg/m2) every 2 weeks (3 weeks pause between EC and D) or 3 cycles of standard FEC every 3 weeks followed by 3 cycles of docetaxel at 100 mg/m2 every 3 weeks (the control arm). If appropriate, patients received endocrine therapy for at least 5 years and trastuzumab for 1 year, and this therapy was balanced between the arms.

Total treatment duration was the same in the two arms. The primary endpoint was breast cancer relapse–free survival assessed in the intention-to-treat population. Tailoring based on leukocyte count resulted in higher cumulative doses of epirubicin and cyclophosphamide, with the same treatment duration as in the control arm, reported Dr. Bergh.

Results and Toxicity

After a median follow-up of 5.3 years, 269 breast cancer relapse–free survival events were reported, 118 in the tailored dose-dense arm and 151 in the control arm. The 5-year breast cancer relapse–free survival was 88.7% and 85.0%, respectively, yielding an absolute gain of 3.7% with tailored-dose–dense treatment (HR = 0.79; P = .062).

Update on Novel Treatments in Breast Cancer

  • The phase II MONARCH 1 trial evaluated the CDK4/6 inhibitor abemaciclib in heavily pretreated patients with hormone receptor–positive metastatic breast cancer and found median progression-free survival of 6 months and median overall survival of 17.7 months.
  • In an international open-label trial of active immunotherapy with the OPT-822/OPT-821 vaccine (as maintenance therapy) in metastatic breast cancer, the primary endpoint of progression-free survival was not met, but in the 50% of patients mounting a robust immune response to the antigen, the vaccine reduced the risk of disease progression by 29%, vs placebo, and by 49%, vs patients receiving the vaccine but not mounting a response.
  • The PANTHER trial, which evaluated a dosing strategy that tailored dose-dense chemotherapy based on leukocyte count, found a trend for improvement in breast cancer relapse–free survival. Patients in the tailored-dose-dense arm also had better 5-year event-free survival than those receiving conventional chemotherapy, and this absolute gain of 4.6% was statistically significant.

Patients in the tailored-dose–dense arm also had better 5-year event-free survival, defined as breast cancer relapse, any death or malignancy, and contralateral breast cancer, and this 4.6% gain (86.7% vs 82.1%) was statistically significant (HR = 0.79; P = .042). A trend was observed for better overall survival, which was 92.1% vs 90.2%, respectively (HR = 0.77; P = .093), Dr. Bergh reported.

Grade 3/4 nonhematologic toxicity was increased with tailored dosing, but hematologic toxicity was greater in the control arm. Five cases of myelodysplastic syndrome/acute myeloid leukemia were reported: three in the tailored-dosing arm and two in the control arm.

“Based on our results, chemotherapy template orders, including electronic order systems, should be adaptable for dose escalation/de-escalation at each course. Chemotherapy remains a cornerstone for breast cancer management, likely for many years to come,” concluded Dr. Bergh. “Why not use the drugs slightly better, as described in the PANTHER study?” ■

Disclosure: For full disclosures for Drs. Dickler and Baselga, visit; for Drs. Rugo and Hwang, visit; and for Dr. Bergh, visit Dr. Isakoff reported no potential conflicts of interest.


1. Dickler MN, Tolaney SM, Rugo HS, et al: MONARCH 1: Results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2– breast cancer, after chemotherapy for advanced disease. 2016 ASCO Annual Meeting. Abstract 510. Presented June 3, 2016.

2. Huang CS, Yu AL, Tseng LM, et al: Randomized phase II/III trial of active immunotherapy with OPT-822/OPT-821 in patients with metastatic breast cancer. 2016 ASCO Annual Meeting. Abstract 1003. Presented June 4, 2016.

3. Bergh JCS, Foukakis T, von Minckwitz G, et al: PANTHER: Prospective randomized phase III trial of tailored and dose-dense versus standard tri-weekly adjuvant chemotherapy for high-risk breast cancer in the modern era of endocrine and anti-HER2 therapy. 2016 ASCO Annual Meeting. Abstract 1002. Presented June 4, 2016.