At ASCO 2019, New Studies Provide Hope for Patients With Metastatic Breast Cancer

Kate M. O'Rourke


July 12, 2019

Results from several key studies on breast cancer presented at the 2019 annual meeting of the American Society of Clinical Oncology (ASCO) provide new hope for patients with metastatic breast cancer (MBC). Among them, results were presented for the first and only phase 3 trial to show the clinically meaningful benefit of first-line immunotherapy in metastatic triple-negative breast cancer.

Moreover, several new agents, including a monoclonal antibody that targets HER-expressing tumors, tyrosine kinase inhibitors, and a CKD4/6 inhibitor used with or without chemotherapy, provided improvements in progression-free survival (PFS). However, more follow-up is necessary to determine whether these results translate into overall survival benefit. 


Zefei Jiang, MD, director of the Department of Breast Cancer, 307th Hospital of PLA (AMMS China) in Beijing, China, presented results from the phase 3 Phenix trial testing pyrotinib (Puma Biotechnologies), an irreversible pan-HER receptor tyrosine kinase inhibitor. In this 279-patient trial, capecitabine plus pyrotinib significantly improved median PFS compared with capecitabine and placebo, in women with HER2-positive MBC after treatment with trastuzumab and taxanes (median PFS, 11.1 vs 4.1 months; hazard ratio [HR], 0.18; P < .001).[1] "Pyrotinib plus capecitabine was well-tolerated," said Jiang. The most common treatment-related adverse events with the combination were diarrhea (all-grade, 98.4% vs 68.1% with capecitabine) and hand-foot syndrome (all-grade, 59.5% vs 29.8% with capecitabine), most of which were controllable and resolved by dose modification or symptomatic treatment.

The current standard of care for HER2-positive MBC is first-line treatment with trastuzumab (Herceptin) and pertuzumab (Perjeta) with chemotherapy and second-line treatment with T-DM1. Subsequent therapies after this standard of care include sequential chemotherapy with trastuzumab and/or lapatinib (Tykerb); continued anti-HER therapy after progression in combination with chemotherapy is generally preferred.

Carlos Barrios, MD, an oncologist from Hospital São Lucas in Brazil, who served as the discussant for several studies at the meeting, said Phenix's strengths included the large PFS benefit and suggestion of central nervous system (CNS) activity, but the comparator was not a standard second-line regimen and the rate of grade 3 diarrhea with the combination was 30%. He is anxiously awaiting overall survival results from the study.


Hope Rugo, MD, professor of medicine and director of Breast Oncology and Clinical Trials Education at the University of California San Francisco's Comprehensive Cancer Center Primary, presented results from the phase 3 SOPHIA trial that studied patients with HER2-positive MBC who had received at least two prior anti-HER2 therapies, including pertuzumab, one to three prior treatment lines in the metastatic setting, and an investigator's choice of chemotherapy.[2] Patients were randomly assigned to receive margetuximab plus chemotherapy (n = 266) or trastuzumab plus chemotherapy (n = 270), both in 3-week cycles. Similar to trastuzumab, margetuximab binds HER2 with high specificity and affinity and disrupts signaling that drives cell proliferation and survival, but margetuximab binds with elevated affinity to both the lower- and higher-affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated cytotoxicity against tumor cells.

Margetuximab improved PFS (median, 5.8 months vs 4.9 months; P = .033) as well as overall response rate and clinical benefit rate, but was associated with increased infusion-related reactions (13% vs 4%), primarily of low grade and manageable with premedication. SOPHIA is the first prospective analysis of CD16A genotype as a predictor of efficacy of anti-HER2 therapy. Rugo said controversy exists about the role of CD16A polymorphisms on the efficacy of trastuzumab. In SOPHIA, where 86% of participants had the CD16A-F allele, the researchers identified an enhanced benefit with margetuximab in low-affinity CD16A-158F carriers (median PFS, 6.9 months vs 5.1 months; HR, 0.68; P = .005).

In discussing the study, Barrios pointed out that SOPHIA was open-label and the jury was still out on whether the 1-month PFS benefit would turn out to be clinically relevant.


NALA pitted neratinib (Nerlynx) plus capecitabine against lapatinib plus capecitabine, in patients with HER2-positive MBC previously treated with at least two HER2-directed regimens.[3] The phase 3 trial, which included 621 patients, met its primary objective with the combination of neratinib plus capecitabine showing a benefit in a PFS-prespecified restricted means analysis (mean, 8.8 vs 6.6 months; P < .001), a numerical improvement in mean overall survival of 1.8 months (HR, 0.88; P = .2086), and increased duration of response (HR, 0.50; P < .001). Fewer patients required intervention for symptomatic CNS metastases with the neratinib combination (22.8% vs 29.2%; P = .043). Discontinuation due to diarrhea was 2.3% with neratinib plus capecitabine, with a median cumulative duration of grade 3 diarrhea of 4 days. "No new safety signals were seen," said NALA investigator Adam Brufsky, MD, PhD, professor of medicine at the University of Pittsburgh School of Medicine.

In discussing the study, Barrios emphasized that the trial was open-label, 40% of patients had received only trastuzumab as anti-HER2 therapy, and follow-up was needed to determine survival benefit. "Diarrhea was still a concern for 25% of patients despite loperamide," said Barrios.


The phase 3, placebo-controlled MONALEESA-7 trial, which included 672 patients, is the only study to evaluate CDK4/6 inhibitors exclusively in premenopausal women with HR-positive, HER2-negative advanced breast cancer.[4] In this study, ribociclib (Kisqali) added to endocrine therapy resulted in a longer overall survival compared with endocrine therapy alone, with an approximate 29% reduction in the risk for death (P = .00973). "At 42 months, 46% of the patients in the placebo arm were still alive compared with 70.2% of patients in the ribociclib arm," said Sarah Hurvitz, MD, director of the Breast Cancer Research Program at University of California, Los Angeles, who presented the study.

In discussing the study, Angelo Di Leo, MD, head of the Sandro Pitigliani Medical Unit and chair of the Oncology Department, Hospital of Prato, Istituto Toscano Tumori, in Prato, Italy, noted that 60% of the trial population was endocrine therapy-naive. "Most of the benefit, if not all of the survival benefit, was observed in patients who were endocrine therapy-naive," said Di Leo. The survival benefit, he said, was similar to that seen in the SWOG S0226 trial of anastrozole versus anastrozole and fulvestrant (Faslodex) as first-line therapy for postmenopausal women with MBC, which had a hazard ratio of 0.82 favoring combination therapy.

"I think the MONALEESA-7 results set a new standard of care for patients who are endocrine therapy-naive," said Di Leo. "I think this is now a population where we should consider the combination of a CDK4/6 inhibitor plus endocrine therapy as our new standard of care, and my personal opinion is that this result should be extended also to the menopausal population."


In the FAKTION trial, the addition of capivasertib to fulvestrant more than doubled the PFS seen with fulvestrant alone in women with ER-positive, HER2-negative MBC (median PFS, 10.3 vs 4.8 months; HR, 0.58; P = .004).[5] Benefit was seen irrespective of PI3K pathway activation status.

In a discussion of the study, Cesar Santa-Maria, MD, assistant professor of oncology at Johns Hopkins Medicine in Baltimore, noted that capivasertib was associated with significant toxicities, in particular diarrhea, rash, and hypoglycemia. These toxicities lead to significant dose reduction rates (39%), but only 12% of participants discontinued because of toxicity. "We now have two approved agents against this pathway in metastatic ER-positive breast cancer refractory [to] endocrine-based therapy," said Santa-Maria. Everolimus (Afinitor) has shown benefit irrespective of PI3K mutation status, he said, and alpelisib (Piqray) has shown benefit for patients with PI3KCA-mutated mutation status. "The FAKTION study demonstrates significant activity of capivasertib irrespective of PI3K mutation status, and we now await phase 3 results to confirm benefit," said Santa-Maria. "We don't know how these agents will compare against each other."


Results from the phase 2 Young-PEARL trial, which included 184 patients, demonstrated that palbociclib (Ibrance) plus exemestane with ovarian suppression prolonged PFS compared with capecitabine (20.1 vs 14.4 months; HR, 0.659; P = .0469) in premenopausal women with ER-positive, HER2-negative MBC.[6] Hematologic toxicities of all grades were more frequent in the palbociclib arm, the majority being neutropenia (all grade, 62% vs 26.7%).

"Endocrine treatment is the preferred standard recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone-positive, HER2-negative, metastatic breast cancer. However, in the real world, 30%-65% of patients with HER2-positive MBC are still treated with chemotherapy in all areas across the United States, in European countries, and Korea," said Yeon Hee Park, who presented the study findings.

In discussing the study, Di Leo said that confirmation of the study results was needed from ongoing randomized trials. He also questioned whether the results were applicable to patients with multiple visceral metastases.


Peter Schmid, MD, PhD, chair in cancer medicine at Barts Cancer Institute, Queen Mary University of London, United Kingdom, delivered updated results from the phase 3 IMpassion130 trial that included 902 patients with previously untreated or locally advanced metastatic triple-negative breast cancer.[7] Compared with placebo plus nab-paclitaxel, PD-L1–positive patients treated with the immunotherapy atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) had an improved median overall survival from 18 months to 25 months (HR, 0.71), although not statistically significant. The combination was well-tolerated, with no cumulative toxicities and no new- or late-onset safety signals. "IMpassion130 is the first and only phase 3 study to show the clinically meaningful benefit of first-line immunotherapy in metastatic triple-negative breast cancer," said Schmid.

During a discussion session at ASCO, Santa-Maria pointed out that atezolizumab received accelerated approval in PD-L1–positive patients along with a PD-L1 status companion diagnostic in March 2019, and no line of therapy was indicated in the approval. He is awaiting further overall survival results.

Dr Rugo disclosed relevant relationships with Amgen, Daiichi Sankyo, Eisai, Genentech, Immunomedics, Lilly, Macrogenics, Merck, Mylan, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, Puma Biotechnology, Roche/Genentech, Sanofi, and Seattle Genetics. Dr Hurvitz disclosed relevant relationships with Ambryx, Amgen, Bayer, Biomarin, Boehringer Ingelheim, Cascadian Therapeutics, Daiichi Sankyo, Genentech/Roche, GlaxoSmithKline, Lilly, Macrogenics, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, Sanofi, and Seattle Genetics. Dr Brufsky disclosed relevant relationships with Agendia, Bayer, Bioarray Therapeutics, BioTheranostics, Celgene, Eisai, Genentech/Roche, Genomic Health, Lilly, Myriad, Merck, NanoString Technologies, Novartis, Pfizer, Puma Biotechnology. Dr Park disclosed relevant relationships with AstraZeneca, Eisai Merck, Novartis, and Pfizer. Dr Schmid disclosed relevant relationships with AstraZeneca, Astellas, Bayer, Boehringer Ingelheim, Eisai, Merck, Novartis, Oncogenex, Pfizer, Puma, and Roche/Genentech. Dr Santa-Maria disclosed relevant relationships with Genomic Health, Halozyme, Polyphor, Medimmune, and Pfizer. Dr Di Leo disclosed relevant relationships with Amgen, AstraZeneca, Bayer, Celgene, Daiichi Sankyo, Eisai, Genomic Health, Ipsen, Lilly, Novartis, Pfizer, Pierre Fabre, Puma Biotechnology, and Roche. Dr Barrios disclosed relationships with AbbVie, Abraxis Biosciences, AstraZeneca, Amgen, Asana Biosciences, Astellas Pharma, Biomarker, Biomarin, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Covance, Daiichi Sankyo, Exelixis, Eisai, GlaxoSmithKline, Halozyme, ImClone Systems, INC Research, inVentiv Health, Janssen, Libbs, Leo Pharma, Lilly, Medivation, MedSIR, Merck, Merrimack, Millennium, MSD Oncology, Mylan, Novartis, Pfizer, Roche/Genentech, Sanofi, Taiho Pharmaceutical, Tummi. Dr Jiang has no relevant disclosures.

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