Updated: Oct 19, 2018
There are many ongoing clinical trials for Stage IV TNBC. In fact, the incremental improvements in quality of life and longevity that are seen each day make enrolling in a clinical trial more appealing.
Immunotherapy for metastatic TNBC
One of the most exciting change in cancer care is immunotherapy, which makes it possible for patients to take a pill as opposed to chemotherapy. In addition, side-effects are often less severe, allowing patients to enjoy a better quality of life.
A good summary of emerging treatments were presented at the Penn Med 23rd LIfe After Breast Cancer Conference. If you are interested in viewing the conference, please click here.
Immunotherapy may be an option for patients with metastatic TNBC. Currently, the population gaining the most benefit from this are those who have tumors expressing the programmed cell death protein/ligand (PD-L1). PD-1 acts as a checkpoint on T cells to turn them "off" and keep them from attacking cells. It does this when it attaches to PD-L1 on normal cells and some turmor cells. The immune system, therefore, has a better chance of reacting to a tumor cell that does not express PD-L1. However, with new agents targeting PD-L1 and PD-1, the "off" signal can be interrupted, allowing T cells to attack tumor cells. Some agents that target PD-1/PD-L1 include pembrolizumab, durvalumab, and nivilumab.
Several trials are ongoing, some of which are summarized below:
According to an international clinical trial led by Sylvia Adams, MD, at NYU Langone’s Perlmutter Cancer Center, Pembrolizumab (Keytruda) shrinks tumors in patients with metastatic TNBC, regardless of whether they had prior treatment.
There were 2 separate cohorts, A and B.
Cohort A included 170 patients with "heavily" pretreated metastatic TNBC (mTNBC), regardless of programmed death receptor ligand 1 (PD-L1) tumor expression.
Cohort B included 52 patients with PD-L1 positive tumors that received Pembrolizumab as first line therapy.
In cohort A, tumors shrank more than 30% in 8 of the 170 patients (5%) and stabilized the disease in 35 patients (21%). In the patients who experienced tumor shrinkage, all lived for an additional year.
In cohort B, 12 of the 52 patients (52%) experienced more than 30% of tumor shrinkage. Disease was stabilized in another 9 patients (17%).
This was a phase 2 study to evaluate the tolerability of Pembrolizumab at a dose of 200 mg every 3 weeks.
Only 12% in cohort A (7 who had to discontinue therapy) and 8% in cohort B experienced severe side-effects (no discontinuation of therapy in cohort B).
More recently, researchers have been looking into new ways to "prime" the tumor for immunotherapy to achieve better results. By increasing immune cell response to the tumor bed either by radiotherapy or chemotherapy, the tumor turns from "cold" or nonimmunogenic to "hot" or immunogenic. A phase II trial by Marleen Kok, MD, PhD, of the Netherlands Cancer Institute in Amsterdam, was presented at the European Society for Medical Oncology (ESMO) Congress. Please see the TONIC trial link on the ASCO Post website. In the study, 50 women with metastatic TNBC received a 2 week induction of radiotherapy to one metastatic lesion or low dose doxorubicin, cyclophosphamide, or cisplatin prior to treatment with Opdivo (nivolumab). The control arm received no induction therapy.
The combined objective response rate to therapy was 24% with 26% having a clinical benefit. The median duration of response was 9 months and 83% of those who responded were alive at 1 year. 13% of non-responders were alive at one year.
Trop-2 is a potential new target for metastatic TNBC.
Dr. Bardia at the ADC University performed a phase I/II study using Sacituzumab govitecan (IMMU-132), which links the active metabolite of a chemotherapeutic agent called irinotecan to an antibody that binds to Trop-2 (which is of TNBC). Sixty-nine patients (1 male) with stage IV TNBC expressed in more than 80% and ECOG status of 0 (fully active) who had a median number of 5 prior treatments (including taxanes, cyclophosphamide, anthracyclines, and platinum agents) received a 10 mg/kg dose of sacituzumab govitecan on days 1 and 8 of repeated 21-day cycles. 62 patients discontinued treatment while 7 remained. 21 patients objectively responded, 19 partially responded, and there was a complete response in 2 patients. The median time to observe a response was 1.9 months and the median duration of response was 8.9 months (95% CI=6.1-11.3 months). Stable disease was observed in 31 patients (45%) and clinical benefit (objective response plus stable disease for 6 months or more) was 46%. Median progression-free survival was 6 months and overall survival was 16.6 months (95% CI=11.1-20.6 months).
The observed impact is impressive since median progression-free survival of "heavily pretreated" patients with metastatic TNBC is 3-4 months (importantly, the patients chosen for this study had a good baseline functional status and probably a slightly better expected survival). Nonetheless, it is exciting that 2 patients had a complete response. Please see the link to the website for the ADC university as well as Vol. 8, issue 16 of The ASCO Post. Dr. Aditya Bardia, MBBS,MPH can be found at Massachusetts General Hospital or by calling 617-724-4000.
About 15% of patients with TNBC carry BRCA mutations, which respond better to platinum salts and poly (ADP-ribose) polymerase inhibitors (PARP inhibitors). Most TNBC have a p53 mutations that, unfortunately, have no targetable therapy.
October 19, 2018: A recent trial started by Dr. Yuan Yuan at the City of Hope has expanded to the University of California Davis, University of Utah, University of Kansas, and Ohio State University. Trial subjects are receiving pembrolizumab, which boosts the immune system, along with enobosarm, which targets androgen receptors. For some patients, this has been very successful! Please see https://www.cityofhope.org/physician-news/new-hormone-immunotherapy-trial-for-breast-cancer-patients for more information!!