Update on Strategies to Improve Treatment for Triple Negative Breast Cancer

Cancer Connect

by Dr. C.H. Weaver M.D. updated 6/2020

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 Effective as Neoadjuvant Treatment 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. 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 which demonstrated that Keytruda in combination with standard therapy as neoadjuvant treatment for patients with locally advanced TNBC increased the pathologic complete response (pCR) nearly threefold in patients with TNBC.(5)

This was confirmed in the KEYNOTE 522 clinical trial which enrolled 1,174 patients with locally advanced TNBC to receive treatment with standard chemotherapy with or without the addition of Keytruda followed by definitive surgery and radiation therapy. After completion of local therapy patients were treated with additional Keytruda.

Analyses revealed that Keytruda treated patents were less likely to have evidence of cancer in their surgically removed breast tissue and more likely to survive without evidence of cancer recurrence. Overall 65% off Keytruda treated patients had a pathologic complete remission compared to only 51 % of women not treated with Keytruda and 91% survived without evidence of cancer compared to 85% at the time of this analyses. PDL-1-positive patients had a higher response to chemotherapy and combination treatment with Keytruda without unexpected side effects. (10)

First-Line Keytruda Plus Chemotherapy Improved PFS in PD-L1–Positive mTNBC

Initial results from the KEYNOTE-355 clinical trial in previously untreated advanced triple negative breast cancer and some level of PD-L1 expression were released at the 2020 American Society of Clinical Oncology Annual Meeting. Overall 847 patients were treated with Keytruda plus chemotherapy or chemotherapy alone and directly compared. Patients were evaluated based on their CPS which measures the amount of PD-L1 expression on cancer cells.

In patients with the highest CPS of 10 or greater the addition of Keytruda to chemotherapy significantly prolonged survival without cancer progression to 9.7 months compared with 5.6 months for chemotherapy alone. At one year 39.1% of patients treated with Keytruda survived progression free compared with 23% for those treated with chemotherapy. Among patients with CPS of 1 or greater the median progression-free survival was 7.6 months for Keytruda plus chemotherapy compared with 5.6 months for chemotherapy alone. (12)

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)

Trodelvy (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)

What About HDC and ASCT?

​One of the largest and best controlled clinical trials evaluating the use of high-dose chemotherapy (HDC) and autologous stem cell transplant (ASCT) to treat patients with early stage breast cancer and more than 9 involved axillary lymph nodes continues to show survival benefit 20 years from receiving treatment. (10) In fact HDC was associated with improved overall survival in the subgroup of women with triple-negative breast cancers: 52.9% of these patients were alive at 20 years compared with 37.5% of those in the conventional-dose chemotherapy. (11)

In the 1990’s HDC and ASCT was increasingly used to treat breast cancer and other solid tumors based on its success in curing certain individuals with lymphoma, leukemia, and multiple myeloma. HDC continue to be the standard of care for many cancers but became out of favor as a treatment option for breast cancer due to conflicting study results and concerns about side effects.

The use of HDC for the treatment of breast cancer was based on the idea that breast cancer treatment could be improved if higher doses of chemotherapy could be administered and this has been borne out to be true. A standard treatment for high risk early stage breast cancer today is “dose-dense” chemotherapy which is widely used instead of HDC and ASCT and requires the use of “blood cell growth boosters” to ensure the chemotherapy can be safely administered in a timely manner.

The current reported trial results are from a “pivotal” study conducted between 1993 and 1999 where 885 women younger than 56 with early stage breast cancer and at least 4 involved axillary lymph nodes were treated with either conventional dose fluorouracil, epirubicin, and cyclophosphamide chemotherapy or HDC and ASCT. The HDC regimen was similar to the conventional regimen but replaced the last cycle with high-dose cyclophosphamide, thiotepa, and carboplatin.

The study authors have reported that among patients with more than 9 involved axillary lymph nodes HDC significantly improves outcomes 20 years from the initiation of treatment. HDC significantly improved overall survival; 44% of HDC treated patients survive today compared to only 30% of women treated with conventional chemotherapy. The relapse-free survival rate was also improved; 39% of patients who received HDC survive without cancer recurrence compared with 27% after conventional chemotherapy.

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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. pmlive.com/pharma_news/keytruda_monotherapy_fails_in_triple_negative_breast_cancer_1288830
  3. Merck’s 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)
  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: 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.
  10. Schmid P, Cortés J, Dent R, et al: KEYNOTE-522: Phase III study of pembrolizumab + chemotherapy vs placebo + chemo as neoadjuvant treatment, followed by pembrolizumab vs placebo as adjuvant treatment for early triple-negative breast cancer. ESMO Congress 2019. Abstract LBA8_PR. Presented September 29, 2019.
  11. Steenbruggen TG, et al "High-dose chemotherapy with hematopoietic stem cell transplant in patients with high-risk breast cancer and 4 or more involved axillary lymph nodes -- 20-year follow-up of a phase 3 randomized clinical trial" JAMA Oncol 2020; DOI: 10.1001/jamaoncol.2019.6276.
  12. Cortes J, Cescon DW, Rugo HS, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. Presented at: ASCO20 Virtual Scientific Program. J Clin Oncol. 2020;38(suppl):abstr 1000.
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