Immunotherapy, PARP Inhibitors Picking Up Steam in TNBC Pipeline

Howard A. “Skip” Burris, MD

Ongoing clinical trials are exploring novel approaches in triple-negative breast cancer (TNBC), such as PARP inhibition and immunotherapy.

Early promise has already been observed, as phase Ib/II findings found that a combination of eribulin (Halaven) and pembrolizumab (Keytruda) was associated with an objective response rate (ORR) of 41.2% for untreated patients with metastatic TNBC.¹

Additionally, the ORR from cohort A of the phase II KEYNOTE-086 trial, which was presented at the 2017 ASCO Annual Meeting, was 4.7% (95% CI, 2.3-9.2) with single-agent pembrolizumab for patients with metastatic TNBC.2 The complete response rate was 0.6%, the partial response rate of 4.1%, and the median duration of response was 6.3 months (range, 1.2+ to 10.3+).

“When we think about hormone-positive breast cancer, we think about the hormone therapies and how we approach that disease, [and there is] HER2-positive breast cancer and the great advances there, but triple-negative [disease] is a bit confusing for many oncologists, including myself,” said Howard “Skip” A. Burris, MD.

OncLive^®: Can you give an overview of the presentation you gave on TNBC?

In an interview with OncLive^® during the 2017 State of the Science Summit^TM on Breast Cancer, Burris, who is chief medical officer at Sarah Cannon Research Institute, and a 2014 Giant of Cancer Care^® in Drug Development, discussed the ongoing research with PARP inhibitors and the advances in immunotherapy for patients with TNBC.Burris: Our presentation focused on the advances in the treatment of TNBC. One of the things to think about is, really, what is TNBC? It’s what it’s not, as opposed to what it is.

Every patient is clearly even more unique than we see among other patients with cancer. I spoke a bit about what we're seeing with DNA damage—response modifiers or the idea of using drugs like PARP inhibitors in the treatment of TNBC. There are molecular subtypes of patients with TNBC who might benefit from these very exciting potent oral compounds.

I also spoke a bit about the role of immunotherapy. This has been an area where we think that this type of cancer with unique molecular aberrations did not have great results with targeted therapies. Is this the place that immunotherapy agents might play a role? We discussed about some strategies even to improve the effectiveness of the early results of immunotherapy.

There are some strategies around induction with chemotherapy or radiation therapy that would be particularly attractive. There are several antibody-drug conjugates—very potent chemotherapy linked to antibodies—that target specific receptors on the TNBC cell. We've got several of those in clinical development.

How would you recommend oncologists discuss the complex diagnosis of TNBC with their patients?

Then, lastly, [I made] a few comments…about the recent publication [in The New England Journal of Medicine] of using adjuvant capecitabine…after patients had received neoadjuvant therapy for TNBC. Many of these patients, in fact, don't have complete responses to their induction treatments. This was an interesting result, which showed that subsets of patients really seemed to benefit from a few courses of adjuvant capecitabine among those patients with TNBC.The key to talking to a patient with TNBC is to emphasize the fact that, while we know they're not going to benefit from hormonal therapy or HER2-directed therapy, that there is great research ongoing [for] other targets. Instead of focusing on the “what it’s not,” [we should] focus on the “what is possible” for treatments.

Can you discuss the excitement with PARP inhibitors and what we're seeing there?

We know there are chemotherapy drugs that seem to work well on these patients—among those are the platinum agents and the taxanes. We also know that this is a type of cancer where molecular profiling and an earlier look at what the molecular subset of patients are out there for potential treatment and even matching those patients to trials or matching those to immunotherapy might be the best approach. There is a great deal of excitement about the PARP inhibitors in the treatment of [patients with] breast cancer and, in particular, the treatment of these [BRCA-mutated] patients. People talk about the BRCA genes; we know there are germline mutations, which are inherited. We know there are somatic mutations and what was thought to be very rare might be a subtype of patients that represents closer to 15 % to 20% of patients with breast cancer, which would be a substantial difference. These PARP inhibitors are oral compounds. Many of them are given once a day.

We've had some early results that have been positive in the treatment [of patients with] ovarian cancer. We've got several new PARP inhibitors approved in the maintenance [setting] or in the later-line therapies of ovarian cancer. The clinical trial results of breast cancer are very exciting. We know that there are groups of patients and the greatest benefit seems to be in the TNBC group—they have a molecular genotype that makes them sensitive to these PARP inhibitors.

What are some of the immunotherapy strategies you mentioned?

More research needs to be done [on] how to give these in a later-line setting; perhaps even rolling them forward into some of the neoadjuvant programs are particularly an area of great excitement for a substantial number of [patients with] breast cancer.The immunotherapy today focuses heavily on the single antibodies targeting PD-1 and PD-L1. These checkpoint inhibitors release the breaks on the immune system, allowing the patient's immune system to attack the cancer; they’re very attractive.

We have some combination therapies that are moving forward in that direction with a variety of compounds that have been out there, including OX40, LAG-3, and TIGIT. All of these ideas are combining immunologics.

However, it looks like there’s a strategy in several diseases—breast cancer being one—where induction therapy with a little bit of chemotherapy or some radiation therapy might be sufficient to trigger the immune response in combination with one of these PD-1 or PD-L1 agents.

We’ve got several clinical trials that are ongoing and evaluating ways to take this small group of patients who seems to be uniquely sensitive to immunotherapy—probably 10% to 12% of the group, and bring that number much higher—20%, 30%, or even 40%, depending on the subtypes of benefit.

Can you expand on the research with antibody-drug conjugates in this landscape?

The idea of immunotherapy for breast cancer is going to be unique when we talk about how to bring it into the different subtypes of breast cancer. In TNBC, for starters, it is likely to be one where this idea of sequencing with chemotherapy or radiation might be very attractive.The antibody-drug conjugates continue to be of great interest to me. We've been disappointed with a lack of seeing this move into a number of approved therapies, but it’s turned out to be a little bit tricky. We're talking about an antibody that’s going to target a receptor or a target specifically on cancer cells, so maybe it is not easy to have specific cancer cells versus normal tissue.

Secondly, we are talking about very potent chemotherapy being linked to this antibody and being released only at the site of the cancer, so this is avoiding collateral damage and systemic toxicity. The idea of this smart bomb approach—attacking only the cancer cells—is attractive.

It's turned out, though, finding targets that are unique to cancer cells and then giving chemotherapy that can be tolerable has been a little bit of a challenge. We're excited to see a boost of new targets that have come forward, targets like LIV-1 and [EPH/ephrin. There is] also the idea of taking some classic chemotherapies, such as the camptothecins and linking those to an antibody.

Can you provide some background on the adjuvant capecitabine trial?

There are some great clinical trials that are ongoing and are looking at this next round of approaches. Hopefully this style of giving chemotherapy will be the way forward for many of our regimens.The adjuvant capecitabine trial was a study of nearly 1000 patients that looked at a population that causes us some concern, which [are patients who have undergone] an aggressive neoadjuvant approach—this includes receiving anthracycline, a taxane-based treatment, prior to the surgery.

We often see a very good clinical response. Then, at the time the tumor is removed, we find that there's still some substantial residual and potentially resistant cancer that remains in the breast specimen. This was a trial that randomized these nearly 1000 patients to receive 6 cycles of capecitabine, an oral and approved chemotherapeutic agent, or to receive no further therapy. The early results from this trial show a statistically significant, progression-free survival (PFS) [benefit] for this group of patients.

What is important to note about the evolution of TNBC treatment?

It’ll take many years to reach any overall survival [data], but PFS is very interesting in this group. [For the TNBC group], this is a group of great interest and it looks like that group received the greatest benefit from adjuvant capecitabine. Overall, the doses and schedules used were very well tolerated.It’s important to learn about TNBC that results in the subtypes that we all need to continue to molecularly profile these patients. They're not as simple as thinking about primary hormonal pathways driving their cancer or the unique gene expression of HER2.

There are a variety of targets that are a theme; there are a variety of aberrations in these patients, from the PI3K/AKT pathway to the RAS/BRAF pathway to p53 and the like. These molecular profiles with next-generation sequencing are going to be important to obtain and important to pull into the data analyses and the clinical trial information in order to sort out which patients are benefiting from what type of therapy.

References

1. Tolaney S, Savulsky C, Aktan G, et al. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. In: Proceedings from the 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P5-15-02.
2. Adams S, Schmid P, Rugo HS, et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A. J Clin Oncol. 2017;35(suppl; abstr 1008).