Potent Anti-HER2 Agents on the Horizon


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THANKS TO the efficacy of five approved anti-HER2 agents, patients with HER2-positive breast cancer have overall survival numbers that are as good as, or better than, their HER2-negative counterparts. With the next generation of anti-HER2 therapies in clinical trials, these outcomes may become even better. 

Sara A. Hurvitz, MD

Sara A. Hurvitz, MD

“These treatments are altering the way patients can now live with this disease,” said Sara A. Hurvitz, MD, of the University of California, Los Angeles, who described the exciting new agents at the 2018 Miami Breast Cancer Conference.1 A few of these drugs have already been granted accelerated approval or Orphan Drug status by the U.S. Food and Drug Administration (FDA). 

Margetuximab: An Fc-Optimized Chimeric Monoclonal Antibody 

MARGETUXIMAB (MGAH22) is an Fc-optimized chimeric monoclonal antibody whose target is the same as that of trastuzumab (Herceptin) but whose tail-end Fc portion—which activates immune effectors—is optimized. This allows it to bind more tightly to effector cells and to increase antibody-dependent cell-mediated cytotoxicity/adaptive immunity, specifically through increased binding to activating CD16a and decreased binding to inhibitory CD32B. 

“The thought is that margetuximab will be like a ‘super trastuzumab.’ It will not only be good at inducing apoptosis and diminishing the intracellular signaling pathway that’s set off by HER2, but also good at inciting the immune system against the cancer cells,” Dr. Hurvitz explained. 

In a phase I first-in-human study of 24 patients with metastatic breast cancer who were unresponsive to standard therapy, margetuximab was adequately tolerated, and its adverse event profile was similar to that seen with trastuzumab.2 Some infusion reactions occurred, but no antidrug antibodies were observed. It proved to be clinically active, producing a response rate of 17%; 3 of the 4 responders remained on treatment for 39 to 54 months. 

“The thought is that margetuximab will be like a ‘super trastuzumab.’”
— Sara A. Hurvitz, MD

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Margetuximab is moving forward into larger studies. The phase III SOPHIA trial aims to confirm the superiority of margetuximab over trastuzumab in the metastatic setting. It will randomize 530 patients whose disease has progressed after two or more anti-HER agents (including pertuzumab [Perjeta]) to receive one of the two agents, plus physician’s choice of chemotherapy. 

“The FDA recently granted Fast Track designation to margetuximab. There’s a lot of excitement about enrolling patients on this [confirmatory] study,” she said. 

Trastuzumab Deruxtecan: HER2-Targeting Antibody-Drug Conjugate 

TRASTUZUMAB DERUXTECAN (DS-8201) is an antibody-drug conjugate comprising a HER2 antibody, a drug linker, and a relatively unique “payload”—a topoisomerase inhibitor—as opposed to a tubulin inhibitor used in ado-trastuzumab emtansine (formerly T-DM1; Kadcyla), which is also an antibody-drug conjugate. 

The drug-to-antibody ratio is also higher than that of ado-trastuzumab emtansine, 7.8 vs 3.5, and trastuzumab deruxtecan has a potent bystander effect due to its highly membrane-permeable payload, according to Dr. Hurvitz. 

In a 24-patient phase I trial of advanced breast and gastric cancers conducted in Japan, the drug was found to be generally safe, with no dose-limiting toxicities or deaths.3 The response rate in patients with breast cancer was 43%, and 91% achieved disease control. Antitumor activity was observed in patients previously treated with ado-trastuzumab emtansine or trastuzumab, and in patients with low HER2 expression, as well as clearly HER2-positive patients. 

An updated analysis was presented at the 2017 San Antonio Breast Cancer Symposium of 96 patients who were HER2-positive (2+ or 3+ by immunohistochemistry [IHC] or positive by fluorescence in situ hybridization [FISH]) and 34 patients who were HER2-low or FISH-negative.4 At least five prior lines of therapy had been administered to 73% of the HER2-positive group and 82% of the HER2-low group. 

“The objective response rate in these heavily pretreated HER2-positive patients was 61%, the disease control rate was 95%, and the median progression-free survival was 10.4 months,” Dr. Hurvitz reported. A high response rate was seen in both hormone receptor–positive and –negative subsets and in patients with prior pertuzumab exposure. 

“In the HER2-low group, the results were even more interesting, with responses seen in 31% of patients with IHC 1+ to 2+ expression and a disease control rate of 84%.” Dr. Hurvitz deemed these early-phase findings “intriguing and very exciting.” 

Trastuzumab deruxtecan was relatively well tolerated, with the main concern being cytopenias, although they were mostly grade 1/2. 

A number of ongoing or upcoming trials will further study trastuzumab deruxtecan, including the pivotal phase II DESTINY study. A phase I trial will evaluate the drug in combination with immunotherapy, and several phase III trials are being planned. The FDA granted the drug Breakthrough Therapy designation in August 2017. 

Pyrotinib: Irreversible Pan-HER Receptor Tyrosine Kinase Inhibitor 

PYROTINIB, A NEW irreversible pan-HER receptor tyrosine kinase inhibitor, was evaluated in a 38-patient phase I trial, which determined the dose-limiting toxicity to be grade 3 diarrhea.5 “With such a highly potent tyrosine kinase inhibitor, you can imagine the kind of toxicity you see due to epidermal growth factor receptor inhibition,” she commented. 

At the maximum tolerated dose of 400 mg/d, the objective response rate was 50%. Responses were seen in one-third of patients with prior trastuzumab exposure. 

A phase II trial presented at the 2017 San Antonio Breast Cancer Symposium included patients who had received up to two lines of therapy, including taxanes and anthracyclines with or without trastuzumab.6 Patients were randomized to receive pyrotinib plus capecitabine or lapatinib (Tykerb) plus capecitabine. 

Responses were observed in 78.5% of the pyrotinib/capecitabine arm and in 57.1% of the capecitabine/lapatinib arm, with a median progression-free survival of 18 months and 7 months, respectively (hazard ratio [HR] = 0.36; P < .001). Responses, and the superiority of pyrotinib/capecitabine, were observed irrespective of prior trastuzumab exposure. 

“Hopefully, the study [with tucatinib and trastuzumab or capecitabine] will be positive, because we all have patients who could benefit from a drug with activity in the central nervous system.”
— Sara A. Hurvitz, MD

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“The cautionary note is that pyrotinib was associated with higher rates of adverse events,” she acknowledged. They included hand-foot syndrome (25% vs 21%), diarrhea (15% vs 5%), neutropenia (9% vs 3%), and vomiting (5% vs 2%), and there were more serious adverse events (8% vs 6%). 

“We hope an ongoing phase III trial will give more information about the activity of this drug, which appears quite promising, and will also be informative about the management of side effects,” she said. 

Tucatinib: Oral HER2-Selective Tyrosine Kinase Inhibitor 

TUCATINIB (ONT-380) is the first HER2-selective tyrosine kinase inhibitor to advance this far in clinical trials, according to Dr. Hurvitz, who commented, “If you can select for HER2 inhibition and avoid HER1 inhibition, hopefully you can avoid toxicities.” 

In a phase Ib study, tucatinib was combined with capecitabine and/or trastuzumab in 23 patients with HER2-positive metastatic breast cancer.7 The triplet especially demonstrated encouraging antitumor activity in this heavily pretreated population, including patients with brain metastases. The objective response rate was 61% (including a 42% response rate in the brain), the median progression-free survival was 7.8 months, and the median duration of response was 10 months. 

At the 2017 San Antonio Breast Cancer Symposium, the results of two phase Ib studies were presented.8 The analysis combined the populations of ONT-380-004 (tucatinib plus ado-trastuzumab emtansine) and ONT-380-005 (tucatinib plus capecitabine and trastuzumab), resulting in 127 patients for the analysis. The aim was to better characterize patients with prolonged progression-free survival (ie, with remissions lasting twice as long as the median progression-free survival). 

The analysis was based on 77 patients with a median of two prior therapies. The median progression-free survival in patients given the maximum tolerated dose in Study 004 was 8.2 months, and for the triplet cohort in Study 005, it was 7.8 months. Altogether, 17 patients (22%) achieved progression-free survival of at least 17 months, including 20% from Study 004 and 26% from Study 005. 

NOVEL TREATMENTS FOR HER2-POSITIVE BREAST CANCER

Monoclonal Antibodies
  • Margetuximab
  • PRS343
Antibody-Drug Conjugates
  • Trastuzumab deruxtecan
  • ARX788
Tyrosine Kinase Inhibitors
  • Pyrotinib
  • Tucatinib

The standard disease characteristics that usually predict for limited survival were not predictive here, including hormone receptor status, metastatic sites, burden of disease, and age. Baseline brain metastases also did not differentiate patients with prolonged progression-free survival. 

In June 2017, tucatinib was granted Orphan Drug status for HER2-positive patients with brain metastases. The phase II registrational HER2CLIMB study will randomize 480 metastatic patients to receive tucatinib plus either trastuzumab or capecitabine. 

“Hopefully, the study will be positive, because we all have patients who could benefit from a drug with activity in the central nervous system,” she commented. 

Other Agents in Development 

DR. HURVITZ also mentioned two other agents that are in early-phase testing: 

  • ARX788: HER2 antibody-drug conjugate comprising an anti-HER2 humanized antibody linked to a microtubule-disrupting agent.
  • PRS343: Monoclonal antibody–bispecific protein targeting HER2 and the immune receptor CD137. ■ 

DISCLOSURE: Dr. Hurvitz has received grants/support paid to her institution from Amgen, Bayer, BI Pharma, Genentech, GSK, Lilly, Novartis, Pfizer, Roche, PUMA, Merrimack, Medivation, Dignitana, OBI Pharma, Biomarin, and Cascadian and has been compensated for her travel from Lilly, Novartis, OBI Pharma, and Bayer. 

REFERENCES 

1. Hurvitz SA: Newer HER2-targeted approaches. 2018 Miami Breast Cancer Conference. Invited Lecture. Presented March 9, 2018. 

2. Bang YJ, Giaccone G, Im SA, et al: First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol 28:855-861, 2017. 

3. Doi T, Shitara K, Naito Y, et al: Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: A phase 1 dose-escalation study. Lancet Oncol 18:1512-1522, 2017. 

4. Modi S, Tsurutani J, Takahashi S, et al: Safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. 2017 San Antonio Breast Cancer Symposium. Abstract PD3-07. Presented December 7, 2017. 

5. Ma F, Li Q, Chen S, et al: Phase I study and biomarker analysis of pyrotinib, a novel irreversible pan-ErbB receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol 35:3105-3112, 2017. 

6. Xu B, Ma F, Ouyang Q, et al: A randomized phase II trial of pyrotinib plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines and/or trastuzumab. 2017 San Antonio Breast Cancer Symposium. Abstract PD3-08. Presented December 7, 2017. 

7. Hamilton E, Borges V, Conlin A, et al: Efficacy results of a phase 1b study of ONT-380, an oral HER2-specific inhibitor, in combination with capecitabine and trastuzumab in HER2+ metastatic breast cancer, including patients with brain metastases. 2016 San Antonio Breast Cancer Symposium. Abstract P4- 21-01. Presented December 9, 2016. 

8. Hamilton E, Murthy R, Ferrario C, et al: Prolonged progression-free survival in advanced HER2+ metastatic breast cancer with or without brain metastases: A pooled analysis of tucatinib phase 1b studies. 2017 San Antonio Breast Cancer Symposium. Abstract P5-20-01. Presented December 8, 2017.


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