Nivolumab/Ipilimumab Combo Shows Promise in Metaplastic Breast Cancer

Sylvia Adams, MD

The combination of nivolumab (Opdivo) and ipilimumab (Yervoy) showed early promising activity in patients with metaplastic breast cancer, according to cohort findings of the phase 2 DART study (SWOG S1609), explained Sylvia Adams, MD.

In the small study, 17 patients with metaplastic breast were enrolled and treated with 240 mg of intravenous (IV) nivolumab on days 1, 15, and 29 plus 1 mg/kg of IV ipilimumab on day 1 of continuous 6-week cycles. Results, which were from cohort 36 of the trial, showed that the overall response rate was 12% by RECIST 1.1 criteria and was 18% via iRECIST criteria. Stable disease was identified in 24% of patients, and the median overall survival was 12 months.

“It's an exciting testament of the power of immunotherapy, which I certainly believed in for over 20 years, and I've worked in this field for that time, and finally, it is now [becoming] more applicable to breast cancer,” said Adams. “We were pushing for the utilization of these drugs in breast cancer, but it's also a testament to the strength of clinical research of translational research.”

In an interview with OncLive, Adams, director of the Breast Cancer Center, professor of medicine, NYU Langone Health’s Perlmutter Cancer Center, discussed the cohort 36 findings of the DART trial in metaplastic breast cancer and the evolution of immunotherapy, specifically in this rare breast cancer subtype.

OncLive: How have anti–CTLA-4 and anti–PD-1 directed approaches improved outcomes overall in oncology?

Adams: It's a powerful duo of therapy; the CTLA-4 antibodies actually unleash the immune response and really invigorates it. The PD-1/PD-L1 therapies then further stimulate the T-cell response against the tumor. They're very powerful immune therapeutics. In breast cancer in particular, there is already an approval of a PD-L1 [inhibitor in combination] with chemotherapy in triple-negative breast cancer (TNBC).

But, CTLA-4 antibodies have not been approved over routinely use in breast cancer. There's always the knowledge that they carry some toxicity; therefore, for breast cancer specifically, we try to only give it to patients on trials where they have a very poor prognosis and other treatments have not worked. However, it has been shown in melanoma and lung cancer, for example, that the combination is certainly more effective than either drug alone. I'm very excited that we were able to test this combination in a very rare breast cancer subtype, called metaplastic breast cancer.

What was the rationale that this approach might be effective in this breast cancer subtype?

The reason why we planned this study was an observation that we had at NYU Langone Health’s Perlmutter Cancer Center in one of my immunotherapy trials for TNBC where we enrolled a woman who had been refractory to all therapies. She received a chemoimmunotherapy combination of nab-paclitaxel (Abraxane) and pembrolizumab (Keytruda), a PD-1 inhibitor. She had this amazing tumor shrinkage. This has been published as a case report; a large chest wall mass that was exposed for months with resistance to prior therapies has actually healed up completely. This was a very interesting observation. 

At the same time, there were more data being generated in breast cancer regarding PD-L1 expression in breast cancer. We have worked on tumor-infiltrating lymphocytes (TILs) in breast cancer for a while now, and we showed that the presence of an immune response toward the cancer in TNBC, in particular, is very important for patient’s outcomes in early-stage disease. There was also a publication, which showed that PD-L1 is frequently overexpressed in these tumors. In breast cancer, we see PD-L1 in tumors and typically in immune cells. However, in metaplastic breast cancer, it was actually the opposite. It was mostly in tumor cells, but there were TILs too, which tells us that there is an underlying immune response that started.

These findings suggest that, for the first time, patients with metaplastic breast cancer could be treated potentially with immune-based therapies. Since it's such an aggressive tumor that rarely responds to chemotherapy, we wanted to embark on this novel approach with these tumors.

To give some background on metaplastic breast cancer, the life expectancy is very short with an expected survival of less than 8 months—definitely shorter than 1 year with standard approaches, including chemotherapy. The hope is that we would be able to induce durable responses so these patients could live longer lives. This woman that I described to you, in whom we utilized chemotherapy and immunotherapy together, had a dramatic response, but it wasn't extremely durable. That durability was about 6 to 8 months, unfortunately. However, what we actually have seen in this study is that the responses we saw are durable in several of the patients, which is very exciting. That gives some evidence that the CTLA-4 inhibition as part of the treatment is very important. We did not even use chemotherapy in this combination.

The DART trial is a very large, National Cancer Institute (NCI)–led initiative that is run by SWOG investigators. This is a basket study in which patients with very rare tumors can be enrolled to test the combination of anti-PD-1 and anti-CTLA-4 together. They had about 35 cohorts in the study, so 35 rare cancer types were included.

When we had our observation, we went to the NCI and talked about finding a niche for metaplastic breast cancer and how to enroll patients on it quickly. The benefit of the DART trial was that it was already open at the time at more than 700 sites in the United States. In talking to the study chairs of DART, the NCI leadership, and the ECOG group, which I'm an investigator in, we agreed to incorporate metaplastic breast cancer into the DART study.

We were cohort 36 and the study was designed to start with 8 to 10 patients initially. If you had 1 of those patients at least show shrinkage of the tumor on subsequent scans, then the study would expand to a total of 16 patients. It's a relatively small sample size, but it is designed in this overall larger trial to look for signals. Once you have a signal, then you can move onto a different study or further analysis. Luckily, the first stage of this design showed that we had a woman who had an impressive response to the dual immunotherapy. The study continued with enrollment of all 16 patients and it [expanded] quickly across the country.

Most importantly, we have a durability of more than 2 years in all 3 women. One woman is 23 months into this response, another is up to 27 months, and the third is in between at 25 months. This is very impressive and not seen with chemotherapy; there is usually no shrinkage with chemotherapy.

The other 14 patients had either stable disease, but it was not very long. Or, they had disease progression and tumor growth relatively quickly, which is what we see typically in these subtypes. Again, it is just a relatively smaller percentage of patients—18% had this shrinkage— but it is dramatic, and it's certainly long-lasting. Women with this very rare cancer have limited treatment options and relatively poor outcomes.

Patients with treated brain metastases were also permitted to enroll. What were the outcomes for those patients?

Only 1 woman had brain metastasis, which was actually stable, well-controlled, and also had treatment with radiotherapy. We can't make any claims of activity in the brain. In other cancer types, certainly, this regimen showed activity in brain metastasis, mainly from lung cancer and melanoma. Metaplastic breast cancer does not frequently spread to the brain. The main areas of tumor expansion are the chest wall with very large nodules and masses that grow outside but also into the chest. A lot of these women have very deep wounds that don't heal and we call them fungating masses, which affects their quality of life.

What was the safety profile of this combination?

As I mentioned early on CTLA-4 antibodies do have toxicity that is known. CTLA-4 antibodies have the potential to cause heart failure or inflammation of the heart, inflammation of the bowel, and inflammation of the liver, because it's a strong immune stimulant. It doesn't just work against the cancer, but it also reignites the own immune attack against certain organs. It's a known profile and there are guidelines that were proposed, not only by ASCO but also by the National Comprehensive Cancer Network and other groups, on how to manage those patients. It's important that you are on top of the patients and that you discuss the safety profile with them upfront.

Of course, they have to sign consent to get the treatment and report all of the symptoms. Any minor diarrhea or abdominal bloating, new cough, shortness of breath, rashes, any liver function abnormality or thyroid function abnormalities need to be taken seriously. If it's very serious, then you have to stop the medication and use steroids to dampen the immune response. In our study, we had 1 patient who died likely from toxicity with the combination; that was a patient who had early cardiac arrest. Looking through the records of the patient, it could have been inflammation of the heart muscle. There are guidelines where you're actually encouraged to work up a patient in a certain way and then start them on immune suppression.

What are the next steps with this research?

It is my mission to make an impact on patients who have metaplastic breast cancer. I've seen many women from across the nation, especially for second opinions with this type of tumor. The next step will be to look at the differences of the tumors of the 3 women who had this durable response versus those who did not show any response, to figure out if there are any predictive markers of response. The numbers are relatively small, so we will have to have a second study that follows [these data] before it could be an FDA-approved regimen. I can tell you that the durability seen in 3 patients, not just 1 patient, makes me strongly believe that this is an active treatment for a subset of metaplastic breast cancers.

Reference

1. Adams S, Othus M, Patel SP, et al. Dual anti-CTLA-4 and anti-PD-1 blockade in metaplastic carcinoma of the breast: Dart (SWOG S1609, Cohort 36). J Clin Oncol. 2020;38(suppl 15; abstr 1073). doi:10.1200/JCO.2020.38.15_suppl.1073