Linda Brookes, MSc


June 22, 2016

Therapeutic options have recently expanded and are set to increase further for patients with refractory hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC), according to clinical research presented at this year's annual meeting of the American Society of Clinical Oncology (ASCO).

Palbociclib, Another Option for Metastatic HR-Positive Patients

The first-in-class CDK4/6 inhibitor palbociclib (Ibrance®, Pfizer) was recently approved for use in HR-positive/HER2-negative advanced breast cancer or MBC in combination with fulvestrant in women with disease progression following endocrine therapy.[1,2] This expanded indication was given on the basis of results from the phase 3 PALOMA-3 trial,[3] which showed significant and consistent improvement in progression-free survival (PFS) with fulvestrant plus palbociclib compared with fulvestrant plus placebo, irrespective of the degree of endocrine resistance, HR expression level, and PIK3CA mutational status.[4]

Palbociclib plus fulvestrant...may offer another treatment option to premenopausal women for overcoming resistance in HR-positive breast cancer.

Of note, PALOMA-3 was the first large registrational study to include pre- and perimenopausal women with HR-positive/HER2-negative MBC, a group with limited endocrine therapy options and unfavorable prognosis, noted trial investigator Sibylle Loibl, MD, PhD (German Breast Group, Neu-Isenburg, Germany). Premenopausal MBC presents a particular challenge regarding ovarian suppression and optimal use of hormonal therapy. But in PALOMA-3, the combination of palbociclib plus fulvestrant with goserelin was effective and well tolerated, and may offer another treatment option to premenopausal women for overcoming resistance in HR-positive breast cancer, Dr Loibl suggested.[5]

Among the 521 patients randomly assigned in PALOMA-3, 108 (21%) were pre- or perimenopausal. All patients received fulvestrant 500 mg on days 1 and 15 of cycle 1 and then on day 1 of each subsequent cycle (28 days)—either palbociclib 125 mg or placebo orally for 3 weeks followed by 1 week off. All pre-/perimenopausal women started treatment with a luteinizing hormone-releasing hormone agonist starting ≥ 4 weeks before randomization and received goserelin at the time of fulvestrant administration. Subgroup analysis of data from this group showed a median PFS of 9.5 months with palbociclib versus 5.6 months for placebo (HR, 0.50; 95% CI, 0.29-0.87; P = .006).

This combination treatment was "very efficacious" in premenopausal women and "very comparable" with postmenopausal women, noted ASCO-designated discussant Cornelia Liedtke, MD, PhD (University Hospital Schleswig-Holstein/Campus Lübeck, Germany). "Most interesting" were the endocrine effects of treatment, she added. Estradiol and follicle-stimulating hormone were "well suppressed," ovarian function suppression was not altered by palbociclib, and plasma estradiol levels were not significantly associated with the PFS results. Although data are limited in premenopausal women, CDK4/6 inhibition is being studied using ribociclib in premenopausal patients with advanced breast cancer in two trials: MONALEESA-7 and TEEL.

Early Results Show Abemaciclib Active, Well Tolerated

Another CDK4/6 inhibitor currently in clinical development, abemaciclib (Eli Lilly), has greater selectivity for CDK4 compared with palbociclib, which may have clinical implications. Abemaciclib is the only drug in its class that can be taken on a continuous schedule. The US Food and Drug Administration (FDA) granted Breakthrough Therapy Designation to abemaciclib for patients with refractory HR-positive advanced breast cancer or MBC in October 2015.[6] Phase 1 studies showed durable clinical activity against a number of tumors, including breast cancers.[7]

Phase 2 data from MONARCH1[8] presented at ASCO 2016 by Maura Dickler, MD (Memorial Sloan Kettering Cancer Center, New York), showed its single-agent activity in MBC patients whose disease had progressed on or after endocrine therapy and chemotherapy. Treatment was well tolerated, allowing prolonged exposure to therapy.

MONARCH1 was a single-arm study that enrolled 132 patients who received 200 mg of abemaciclib orally on a continuous schedule every 12 hours until disease progression. Patients had a median of three lines of prior therapy for advanced disease, including a median of two lines of chemotherapy for advanced disease. After a minimum of 12 months of follow-up, patients treated with abemaciclib showed an overall response rate of 19.7% (95% CI, 13.3%-27.5%). This is similar to response rates with chemotherapy in a taxane-pretreated population, Dr Dickler noted. All responses were partial, and 22.7% of patients had stable disease at ≥ 6 months. Median PFS was 6.0 months and median overall survival 17.7 months, consistent with phase 1 experience.

Overall, abemaciclib was well tolerated, with a low rate of adverse events, Dr Dickler reported, with the most common being diarrhea, fatigue, nausea, and decreased appetite. Grade 3 diarrhea (median, 4.5 days) developed in 19.7% and grade 3 fatigue in 12.9%. "Generally, the diarrhea was experienced within the first cycle of treatment and resolved quickly," Dr Dickler observed. "High-grade neutropenia was an uncommon event" (22.3% grade 3, 4.6% grade 4). Discontinuation of abemaciclib was low (7.6%), but 49.2% of patients required dose reduction, mostly because of diarrhea (20.5%) or neutropenia (10.6%).

In phase 3 clinical trials, a lower dose of abemaciclib, 150 mg twice daily, is being used in combination with endocrine therapies. MONARCH2 is evaluating the combination of abemaciclib and fulvestrant for treatment of HR-positive/HER2-negative advanced breast cancer or MBC in postmenopausal women.

PI3K Inhibitor Taselisib Deterred by Toxicity

In phase 1 studies, the PI3K inhibitor taselisib (Roche) appeared to be clinically active in PIK3CA-mutant solid tumors[9] and showed manageable tolerability and preliminary efficacy, and no pharmacokinetic interaction in combination with fulvestrant in HR-positive breast cancer.[10]

A phase 2 study of taselisib plus fulvestrant, which was presented by Dr Dickler, confirmed the safety profile and clinical activity in postmenopausal patients with HR-positive/HER2-negative advanced breast cancer or MBC.[11] The open-label, single-arm study enrolled 60 patients, who exhibited disease progression or failure to respond to at least one prior endocrine therapy. All patients received taselisib (6-mg capsule orally daily) plus fulvestrant (500 mg intramuscularly on cycle 1, days 1 and 15, then every 4 weeks on day 1 of each 28-day cycle) until progressive disease or unacceptable toxicity.

Response rates were numerically higher in the 20 patients with PIK3CA mutations compared with the 25 patients with wild-type tumors. Among patients with baseline measurable disease, ORR was 22.7%, consisting of 38.5% confirmed partial responses in PIK3CA mutated tumors, 10.5% in wild-type, and 25.0% in tumors of unknown mutation status.

The most common grade ≥ 3 adverse events were colitis (13.3%), diarrhea (11.7%), hyperglycemia (6.7%), and pneumonia (5%). Taselisib treatment was discontinued in 20.0% of patients because of an adverse event. Overall, 50% of patients discontinued the study (about 50% in each mutation status group) for reasons still being determined.

Maintaining dose intensity is important for efficacy, so we will wait to see whether the potency of taselisib will overcome the rates of dose reductions and adverse events.

ASCO-designated discussant Sherene Loi, MD (Peter MacCallum Cancer Centre, Melbourne, Australia), noted that in clinical trials in advanced or advanced breast cancer, pan-PI3K inhibitors such as buparlisib[12] and pictilisib[13] "were not well tolerated and likely reduced dose intensity compromised efficacy." More potent inhibitors of the target are more likely to be efficacious, she suggested, but "maintaining dose intensity is important for the efficacy, so we will wait to see whether the potency of taselisib will overcome the rates of dose reductions and adverse events seen in the phase 2 data," she said.

Dr Loi also cautioned about the possibility of patients becoming resistant to PIK3 inhibitors, as has been reported with alpelisib.[14] "Maybe we should be considering intermittent therapy with these agents in some patients with high disease burden," she suggested. Taselisib is currently being investigated in HR-positive MBC in combination with fulvestrant in a phase 3 trial, SANDPIPER.

TKIs Appear Promising in Patients With Brain Metastases

Two new tyrosine kinase inhibitors (TKIs) may have potential efficacy in patients with HR-positive/HER2-positive MBC with brain metastases, which affects up to 50% of these patients and is associated with a poor prognosis.[15] Most systemic treatments for MBC have limited brain penetration, and clinical trials often exclude patients with CNS metastases, leading to a lack of prospective data on outcomes. ONT-380 (Cascadian Therapeutics) is a small-molecule TKI that is highly selective for HER2 over epidermal growth factor receptor (EGFR), so it has less potential for gastrointestinal toxicities than HER2 inhibitors such as lapatinib or neratinib. In a phase 1b study, ONT-380 in combination with ado-trastuzumab emtansine (T-DM1) showed "encouraging activity and tolerability" in patients with HER2-positive MBC with and without brain metastases, reported Virginia F. Borges, MD (University of Colorado Cancer Center, Aurora).[16]

Fifty patients (60% with brain metastases) received the ONT-380 recommended phase 2 dose, 300 mg twice daily, and T-DM1 3.6 mg/kg intravenously (IV) every 21 days. ORR was 47%, and median PFS was 8.2 months. Benefit was similar in patients regardless of the number of prior anti-HER2 agents, and outcomes were similar in patients with and without brain metastases (PFS 6.7 vs 8.2 months, respectively). CNS response rate was 36% in patients with measurable brain metastases and 63% in those with nonmeasurable brain metastases.

Of 30 patients with brain metastases at baseline, five remain active on study without progressive disease (7-12 months), Dr Borges added. No patients with brain metastases at baseline developed new clinically apparent brain metastases while on the study. Twenty patients without brain metastases at baseline developed brain metastases.

The findings warrant further study, especially in patients with brain metastases.

The overall safety was unchanged from results previously reported in 2015.[17] The majority of adverse events were grade 1. Dose reductions were needed with ONT-380 (28% of patients) most commonly because of reversible elevations in liver enzymes) and with T-DM1 (38% of patients) most commonly because of thrombocytopenia. Most patients who required an ONT-380 dose reduction maintained disease control at the lower dose. Patient discontinuations were 10% on ONT-380 and 16% on T-DM1. "The patient population in this study was heterogeneous. The study included patients previously treated with pertuzumab and patients with brain metastases, which mirrors HER2-positive patients seen in clinical practice," Dr Borges pointed out. The findings warrant further study in these populations, especially in patients with brain metastases, she believes. In the HER2CLIMB study, ONT-380 is being evaluated in combination with capecitabine and trastuzumab in patients with HER2-positive MBC who have had prior treatment with trastuzumab and T-DM1.

The oral TKI tesevatinib (Kadmon) also targets EGFR, HER2, VEGFR2/3, and SRC while crossing the blood-brain barrier in whole animal models, explained Nancy Lin, MD (Dana-Farber Cancer Institute, Boston). In a phase 1 dose-escalation study, tesevatinib was combined with trastuzumab 6 mg/kg IV every 3 weeks in HER2-positive MBC patients, with or without brain metastases. Patients were heavily pretreated with trastuzumab, pertuzumab, or T-DM1. Following demonstration of the tolerability of 150 mg and 250 mg daily dosing,[18] the maximum tolerated dose was identified as 300 mg daily of oral tesevatinib with standard-dose intravenous trastuzumab.[19]

The adverse-event profile appeared manageable at this dose level; the major toxicity was all-grade diarrhea (75% at the 300-mg daily dose; grade 3, 12.5%). The most common toxicities (> 30%) were rash, diarrhea, decreased appetite, and nausea.

Of two patients with brain metastases, one on tesevatinib 300 mg daily (reduced to 250 mg daily) had stable disease for 7 months, and the other, on 350 mg (reduced to 300 mg daily), had stable disease for 6 months. The most common reason for treatment discontinuation was objective disease progression. ASCO-designated discussant Shannon Puhalla, MD (University of Pittsburgh School of Medicine) called the results "a promising positive signal for activity in patients with CNS metastases, suggesting a role for combination of HER2 antibody therapy with a TKI."

Trastuzumab Biosimilar Comparable to Trastuzumab

In the future, the option may exist to treat HR-positive/HER2-positive MBC with Myl-1401O (Bicon/Mylan), a "proposed trastuzumab biosimilar," explained Hope S. Rugo, MD (University of California San Francisco Comprehensive Cancer Center). The US government defines biosimilars as "highly similar to the reference product notwithstanding minor differences in clinically inactive components" and having "no clinically meaningful differences between the biosimilar product and the reference biological product in terms of the safety, purity, and potency of the product."[20] Biosimilars are developed to be marketed when patent protection for approved biologics expire, which for trastuzumab (Herceptin®, Roche) in the United States is in 2019.

HERITAGE,[21] a double-blind, randomized clinical trial, is one of the first trials of a biosimilar in oncology to demonstrate similar efficacy, safety, and immunogenicity against the reference product. A total of 500 patients with measurable HER2-positive MBC who had not been given prior chemotherapy or trastuzumab for metastatic disease received either Myl-1401O or trastuzumab with docetaxel or paclitaxel for a minimum of eight cycles (24 weeks), until documented response to therapy, disease progression, or discontinuation.

These results, we believe, will change the treatment of HER2-positive breast cancer worldwide.

At 24 weeks, ORR was 69.6% for Myl-14010 compared with 64.0% for trastuzumab. Efficacy equivalence was confirmed on the basis of the ratio of ORR. Median PFS has not yet been reached, but there was no significant difference in PFS at 24 weeks. Safety was comparable with both treatments; adverse events (primarily neutropenia related) occurred in 38% of patients on Myl-1401O versus 36% on trastuzumab, with four fatal events on each arm, not related to the HER2-targeted agents. There were no cardiac deaths and no significant change in left ventricular ejection fraction from baseline to week 24 in patients on either arm.

"These results, we believe, will change the treatment of HER2-positive breast cancer worldwide," Dr Rugo declared. "Trastuzumab has markedly improved survival of women with HER2-positive breast cancer, but many women around the world can't benefit from trastuzumab due to its high cost. We hope that the introduction of biosimilars will expand patient access to this effective drug," she added.

ASCO-designated discussant Sunil Verma, MD (Tom Baker Cancer Centre, University of Calgary, Canada) noted the following study limitations of HERITAGE: no duration-of-response results available yet, no median PFS results, and limited follow-up. "We need PFS data at 48 weeks and mature OS data," he declared. "We have to look at what it takes to be a biosimilar. Myl-1401O is still a "proposed biosimilar" because critical quality attributes (eg, amino acid sequence, glycosylation) still need to be established as similar, he said.

Dr Rugo pointed out that many oncologists use pertuzumab in the neoadjuvant setting, despite a lack of survival data. "We use response data as an indicator of outcome. If we wait for survival data we will never get any biosimilars," she remarked.

Although biosimilars have been available outside the United States for almost a decade, to date, biosimilars of trastuzumab have been launched in only two countries: India (Biocon/Mylan's candidate, approved as a "biologic similar" rather than a biosimilar, in 2014[22]) and South Korea (Celltrion's Herzuma [CT-P6] in 2014[23]). At least 11 other trastuzumab biosimilar candidates are currently in clinical development by different companies, possibly heralding what Dr Verma predicted will be "a tsunami of biologics."


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