In December 2017, the trastuzumab (Herceptin) biosimilar MYL-1401O (trastuzumab-dkst; Ogivri) was approved for patients with HER2-positive breast cancer and metastatic gastric or gastroesophageal junction adenocarcinoma, the same indications as trastuzumab. The biologics license application for MYL-1401O included results from the 2-part phase III HERiTAge trial, which was a randomized multicenter double-blind parallel-group study. Among women who received the biosimilar in combination with a taxane, MYL-1401O demonstrated an overall response rate (ORR) of 69.6% after 24 weeks. This was in comparison to a 64% ORR for patients who took trastuzumab plus a taxane.
The uptake on biosimilars has been slow, with some in industry, the community, and even physicians not fully understanding the utility or benefit of embracing biosimilars. The approval of the trastuzumab biosimilar may mark the beginning of a new era though, with experts such as Kimberly L. Blackwell, MD, predicting that they are here to stay.
There are a few novel agents coming down the pipeline, as well. The HER2CLIMB trial is currently investigating tucatinib (ONT-380), a novel small molecule HER2 inhibitor, in a triplet regimen (NCT02614794). The regimen is a dual targeted approach of tucatinib and trastuzumab with capecitabine in patients with unresectable locally advanced or metastatic HER2-positive disease with or without brain metastases.
Tucatinib may have the ability to penetrate the blood-brain barrier, says Blackwell. If so, this could be a promising agent and, considering its low toxicity profile, it provides the opportunity to be combined with chemotherapy.
Another novel agent in the pipeline is DS-8201, a HER2-targeting antibody-drug conjugate. It was found to be well tolerated in a phase I trial, and showed signs of activity in patients with HER2-positive breast cancer who were previously treated with ado-trastuzumab emtansine (T-DM1; Kadcyla). The ORR was 61.4%, including 1 complete response.2 DS-8201 was granted a breakthrough designation by the FDA in August 2017.
In an interview with OncLive, a sister publication to Oncology Nursing News, Blackwell, a medical oncologist at Duke Cancer Institute, discussed these novel agents and other recent advancements in the treatment of HER2-positive breast cancer.
What are your thoughts on the data reported with tucatinib in patients with brain metastases?
Tucatinib is one of the most exciting agents out there in the investigative space that is trying to improve on current therapies for HER2-positive breast cancer. The data out of the 2017 San Antonio Breast Cancer Symposium evaluated giving tucatinib, a small molecule inhibitor very specific against HER2, prior to a patient receiving whole-brain radiotherapy in patients who are facing brain metastases.
In these HER2-positive patients who had tumors in the brain, there was an ORR prior to radiotherapy and, to me, that is very exciting and tells me that maybe we can kick the “radiation can” down the road. Particularly, we could move whole-brain radiation therapy further down the patient's treatment course and use these very tiny small-molecule inhibitors to treat HER2-positive breast cancer with brain metastases.
The other thing that most of us are excited about with tucatinib is that it differentiates itself from the other inhibitors, such as neratinib (Nerlynx) and lapatinib (Tykerb), and even some of the ones that we use outside of the breast cancer space.
[Tucatinib] is such a pure small molecule inhibitor that doesn’t have some of the side effects that are problematic for patients, including the most problematic one, which is diarrhea. To my knowledge, the rash that patients receive while they are taking tucatinib is of much less intensity than what we see with some of the other HER2 inhibitors.
It is a very exciting drug because it appears to work and get into the blood-brain barrier space, and it looks like its toxicity profile is quite nice, with very low incidence of diarrhea and rash. The low side effect profile is going to make this a very exciting drug to combine with standard chemotherapy, as well.
Tucatinib is currently being looked at in the HER2CLIMB study. Can you share some insight on that trial?
HER2CLIMB is actively accruing patients and it is a great study design. It is taking patients who have metastatic HER2-positive breast cancer and comparing a regimen that many of us use—capecitabine plus trastuzumab—to capecitabine, trastuzumab and tucatinib. Hopefully, the addition of this 1 tucatinib pill will make the combination of capecitabine and trastuzumab work longer and not add a lot to the toxicity profile.
The other thing that is unique about HER2CLIMB is that it is allowing patients with brain metastases on the study. Although that isn't the primary endpoint of the study, we will hopefully get some efficacy information on whether or not tucatinib as a small molecule inhibitor might prevent progression of brain metastases when added to the regimen of capecitabine and trastuzumab. It is interesting, not just because it is a novel combination and a new drug, but it will also give us some information about HER2-positive breast cancer with brain metastases.
There was a breakthrough designation for DS-8201 in August 2017. What are your thoughts about this agent and how it may fit into the treatment landscape?
There has been great clinical success with DS-8201 and T-DM1. [T-DM1] is an antibody of our old friend trastuzumab with chemotherapy attached and offers a very specific delivery system—"Trojan horse" or "carrier pigeon"—for the older form of chemotherapy that it carries. Now, there are a number of antibody-drug conjugates utilizing HER2 as the target, and then a toxin. In the case of this antibody-drug conjugate (DS-8201), not only is the toxic payload different than what we see with T-DM1, but it has demonstrated to have very high levels of response rates in patients, even those who had received T-DM1.
There is something unique about that compound; it deserves the breakthrough status that it got. I am very excited about seeing it moved along into clinical trial development.
With the approval of the first trastuzumab biosimilar, do you anticipate greater acceptance of biosimilars?
Trastuzumab is one of the first [oncology drugs to have a] biosimilar in the therapeutic arena, and the thing about the trastuzumab biosimilar space is that all of them have demonstrated equivalent consistent efficacy with the originator drug. What is going to happen is that insurers are going to embrace the concept, and physicians who take 30 to 60 minutes and understand the amount of resources and time that have been spent developing these biosimilars are ultimately going to embrace the concept.
Between the insurers and the physicians understanding the concept, and the FDA saying that this is the way drug development should be happening in a competitive environment, the uptake is going to be significant. It is going to take some time, but whether it is the physicians or the insurers driving the decision making, [biosimilars] are here to stay.
- Rugo HS, Barve A, Waller CF, et al. Heritage: A phase III safety and efficacy trial of the proposed trastuzumab biosimilar Myl-1401O versus Herceptin [published online ahead of print]. J Clin Oncol. doi: 10.1200/JCO.2016.34.18_suppl.LBA503.
- 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. In: Proceedings from the 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, Texas. Abstract PD3-07.