Update on Strategies to Improve Treatment for Triple Negative Breast Cancer

Neoadjuvant Keytruda, Tecentriq, and Sacituzumab Govitecan (IMMU-132) are promising TNBC treatment advances.

Medically reviewed by Dr. C.H. Weaver M.D. updated 7/2019

Approximately 12% of all breast cancers are TNBC, meaning that they are estrogen-receptor negative (ER-), progesterone-receptor negative (PR-), and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones estrogen or progesterone, nor through an overactive HER2 pathway.

Unfortunately, many available and effective treatment options for the majority of breast cancers block the growth stimulating effects of ER, PR and/or HER2; therefore, TNBC has had limited therapeutic options.

In addition, TNBC tends to be an aggressive type of cancer, is often diagnosed at a more advanced stage, and proportionately affects younger women more often than other breast cancers. Novel treatment options for TNBC have lagged behind that of other types of breast cancers.

The development of more effective treatment for triple negative breast cancer (TNBC) requires that new and innovative therapies be evaluated in TNBC patients. Areas of active investigation aimed at improving the treatment of TNBC include some of the following:

PD-1 Checkpoint Inhibitors

The cancer immunotherapy strategy known as programmed cell death 1 (PD-1) has generated great excitement for its ability to help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 are called checkpoint inhibitors and may enhance the ability of the immune system to fight cancer.

Keytruda Promising in Neoadjuvant Setting for TNBC

Keytruda is a fully humanized monoclonal antibody checkpoint inhibitor that binds with high-affinity to the PD-1 receptor. Results in advanced breast cancer have been mixed. In heavily pretreated patients with recurrent or metastatic TNBC positive for PD-1 Keytruda has been reported to produce a response rate of 18.5% (1) however a trial directly comparing single agent Keytruda to chemotherapy in recurrent TNBC found that Keytruda was no better.(2)

Chemotherapy administered before surgery with the goal of reducing the size of the cancer for surgical removal is called neoadjuvant chemotherapy. Use of Keytruda earlier in the adjuvant and neoadjuvant setting may hold more promise. In June 2019 neoadjuvant Keytruda was reported to be significantly more effective than chemotherapy at eradicating cancer confined to the breast prior to surgery. (3) These results are consistent with the ​I-SPY 2 clinical trial.

I-SPY 2 investigated Keytruda in combination with standard therapy as neoadjuvant treatment for patients with locally advanced TNBC. The estimated pathologic complete response (pCR) rate increased nearly threefold in patients with TNBC.

The I-SPY 2 clinical trial, sponsored by Quantum Leap Healthcare Collaborative, is a standing Phase 2 clinical trial for women with newly diagnosed, locally advanced breast cancer (Stage II/III), and is designed to screen promising new treatments and identify which therapies are most effective in specific patient subgroups based on molecular characteristics (biomarker signatures).

In the trial patients were treated with standard weekly Taxol (paclitaxel) chemotherapy for 12 weeks with or without Keytruda, followed by doxorubicin and cyclophosphamide (AC) every 3 weeks for four cycles. Preliminary results revealed that patients with TNBC had an estimated pCR of 60%. Individuals with TNBC achieved an absolute increase in the estimated response of 40% with the addition of Keytruda over the historical experience of 20% with standard therapy alone.(5)

Tecentriq Improves Survival in Advanced TNBC

Tecentriq (atezolizumb) is another checkpoint inhibitor and when
combined with Abraxane in women with advanced TNBC produced an anti-cancer response in 70.8% of patients.(5) The combination of Tecentriq and Abraxane improved average survival duration from 15.5 months among patients with PD-L1–positive tumors compared to 25 months compared to Abraxane alone, leading to accelerated FDA approval. (8,9)

Treatment combinations consisting of checkpoint inhibitors plus Abraxane and other known active drugs in TNBC like Gemzar (gemcitabine) and Carboplatin are ongoing to determine the optimal way to incorporate this new class of drugs into the overall management of TNBC.(6)

Sacituzumab Govitecan (IMMU-132) is referred to as an antibody-conjugate, and is still in investigative stages. It is comprised of an antibody that attaches to specific receptors called Trop-2 receptors. The antibody is attached to a drug that kills cancer cells, called SN-38.

Trop-2 receptors are often found in large numbers on the surface of cancer cells, but not healthy cells. Once IMMU-132 binds to the Trop-2 receptors, it delivers SN-38 into the cancer cell. This kills the cancer cell, while only affecting a small portion of healthy cells. By targeting Trop-2 receptors, larger amounts of chemotherapy can be delivered to the cancer cells because healthy cells are largely spared from the cancer-killing effects of the treatment.

A recent clinical trial was conducted to further evaluate the effectiveness of IMMU-132 in patients with TNBC. The trial included patients with TNBC that had spread to distant sites in their body, and had received a median of 5 prior therapies. Final results from the trial are awaited to fully determine patient outcomes. Meanwhile, patient enrollment for continuing larger comparative trials with IMMU-132 in TNBC is ongoing.(6)

Strategies To Improve The Treatment of Early Stage TNBC

Adding neoadjuvant carboplatin to pre-surgery chemotherapy improved disease-free survival for patients with TNBC

Previously reported clinical study results have suggested that adding carboplatin to anthracycline/taxane-based neoadjuvant chemotherapy can increase the proportion of patients with TNBC who had attained a pathologic complete response [pCR], from 36.9 percent to 53.2 percent.

In the currently reported study researchers enrolled 315 patients with TNBC to receive 18 weeks of neoadjuvant chemotherapy consisting of paclitaxel, non-pegylated-liposomal doxorubicin, and bevacizumab and were randomly assigned to concurrently receive weekly carboplatin or nothing extra and then directly compared.

After a median follow-up of three years, 85.5 percent of TNBC patients treated with the additional carboplatin survived without evidence of cancer recurrence compared to only 76.1 percent of patients treated with paclitaxel, non-pegylated-liposomal doxorubicin, bevacizumab, and no carboplatin.(7)

References:

  1. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. Presented at the 2014 San Antonio Breast Cancer Symposium, December 9-13, 2014. San Antonio, Texas. Abstract S1-09.
  2. https://www.pmlive.com/pharma_news/keytruda_monotherapy_fails_in_triple_negative_breast_cancer_1288830
  3. https://investors.merck.com/news/press-release-details/2019/Mercks-KEYTRUDA-pembrolizumab-in-Combination-with-Chemotherapy-Met-Primary-Endpoint-of-Pathological-Complete-Response-pCR-in-Pivotal-Phase-3-KEYNOTE-522-Trial-in-Patients-with-Triple-Negative-Breast-Cancer-TNBC/default.aspx
  4. Adams S, et al. Safety and clinical activity of atezolizumab (anti-PD-L1) in combination with nab-paclitaxel in patients with triple-negative breast cancer. Proceedings from the 2015 annual San Antonio Breast Cancer Symposium. Presented December 10, 2015. Abstract number: 850477.
  5. Adams S, et al. Phase Ib trial of atezolizumab (anti-PD-L1) in combination with nab-paclitaxel in patients with triple-negative breast cancer. J Clin Oncol. 2016:34 (suppl: abst 1009)
  6. Immunomedics, Inc. Press Release. U.S. Food and Drug Adminstration (FDA) Grants Breakthrough Therapy Designation to Immunomedics for Sacituzumab Govitecan for the Treatment of Patients with Triple-Negative Breast Cancer. . Available at: http://www.immunomedics.com/news-2016.shtml.
  7. von Minckwitz G, Loibl S, Schneeweiss A, et al. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Abstract: S2-04. Presented at the 2015 San Antonio Breast Cancer Symposium, San Antonio, TX. December 9, 2015.
  8. N Engl J Med. Published on October 20, 2018. Abstract
  9. Schmid P, Adams S, Rugo HS, et al. IMpassion130: updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo) + nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). Presented at: the 2019 ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. Abstract 1003.
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