Mittendorf Explains Growing Role of Checkpoint Inhibitors in Breast Cancer

Laura Panjwani
Published Online: Monday, Mar 21, 2016

Much of the checkpoint inhibitor research in breast cancer has been focused on TNBC. Do you see potential for other subtypes as well? TNBC is an area with no targeted agents, so much of the focus has been based on need. However, if you think about checkpoint blockade, it is a drug that works by taking the breaks off of T cells, so in order for it to have an effect there needs to be T cells present. If you look at the published data, it has shown that the presence of tumor-infiltrating lymphocytes (TILs) is greatest in the TNBC subtype when compared to the other subtypes. Based on that, the thought is that TNBC will be more susceptible to checkpoint blockade. However, there is an opportunity to turn these other breast cancer subtypes, like HR-positive breast cancer, more immunogenic and then come in with checkpoint blockade after that.

How could that potentially be achieved?

There are studies that have looked at strategies like cryoablation and radiation. There are data that suggest that chemotherapy in some cases can be immune stimulating. Vaccines are also a possibility. There are strategies investigating these novel intratumoral injection agents like talimogene laherparepvec (T-VEC). There are also strategies using other drugs that modify the innate immune system. There are a lot of possibilities.

What role does PD L1 status play in the use of checkpoint inhibitors in breast cancer?

When this class of drugs initially started showing benefit in breast cancer, people suggested that the expression of PD-L1 was required—that it was a biomarker needed to predict response to treatment. I think most of the experts now feel that is not the case. The reason for that is that it is very dynamic how PD-1 expression can go up and down in a tumor depending on aspects of the microenvironment. The JAVELIN trial did have some interesting data that suggested that the expression of PD-L1 by the tumor was not predictive of response, but the expression of PD-L1 by other immune cells in the microenvironment did appear, at least in TNBC, to potentially be predictive. They refer to these as ‘immune hotspots.’ I do not think the trials should be designed to require PD-L1 positivity in order for patients to enroll, but that needs to be further evaluated in biospecimens collected from patients who are on the studies.

What’s on the horizon for immunotherapy in breast cancer?

I think we are going to move to an era where it is not limited to anti-CTLA-4 or anti-PD-1/anti- PD-L1 agents. There will be an opportunity to move agents that are currently being evaluated in other tumors to be evaluated in broad, phase I basket trials where many tumor types are included and to look at different agonist antibodies against co-stimulatory molecules. An example of that is OX40 or 4-1BB. I think we will also look at antagonist antibodies against inhibitory molecules other than just CTLA-4 or PD-1.

In breast cancer, the really interesting work is going to be focused on better characterizing the immune aspects of the tumor microenvironment with our current standard of care therapies, so that we can rationally add them in.

There will likely be a role for immunotherapies in most if not all of our breast cancer patients. But we need to—as a group—approach this in a very thoughtful manner. We have therapies that work in breast cancer; we cure a lot of patients. We need to figure out what those therapies are doing to the immune response so that we can better design trials that will incorporate these immune agents to be a benefit to our patients. We have a different challenge than colleagues in fields like melanoma had, where they really had few effective systemic therapies.


References

  1. Dirix LY, Takacs I, Nikolinakos P, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. Presented at: San Antonio Breast Cancer Symposium; December 8-12, 2015; San Antonio, TX. Abstract: S1-07.
  2. Rugo HS, Delord J-P, Im S-A, et al. Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PD-L1–positive, estrogen receptor– positive (ER+)/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. Presented at the 2015 San Antonio Breast Cancer Symposium; San Antonio, TX; December 8-12, 2015. Abstract S5-07



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Community Practice Connections: 15th Annual International Congress on the Future of Breast Cancer®Oct 06, 20172.0
Medical Crossfire®: Leveraging New Evidence in the Context of Evolving Early-Stage Treatment Standards in HER2-Positive Breast CancerJan 30, 20181.5
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