Keytruda Shows Promise for Patients With Herceptin-resistant Breast Cancer
by C.H. Weaver M.D. (04/2018)
A combination of Keytruda (pembrolizumab) and Herceptin (trastuzumab), tested in patients with Herceptin-resistant advanced HER2-positive breast cancer, was well tolerated and had clinical benefit in patients whose tumors were positive for a biomarker for Keytruda, according to data presented at the 2017 San Antonio Breast Cancer Symposium.
About HER2-Positive Breast Cancer
About one in five patients with breast cancer overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.2 Many tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease. Furthermore, there is no standard of care for HER2-positive tumors following treatment with Herceptin.3 Herceptin targets and blocks the HER2-protein, and is used for the treatment of both early-stage and more advanced HER2-positive breast cancer. Some patients however develop resistance to Herceptin.
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.
Keytruda is a fully humanized monoclonal antibody that binds with high-affinity to the PD-1 receptor that helps to restore the body’s immune system in fighting cancer. It creates its anti-cancer effects by blocking a specific protein used by cancer cells called PD-L1, to escape an attack by the immune system. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 are called checkpoint inhibitors and enhance the ability of the immune system to fight cancer. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat, and initiate an attack to destroy the cancer.
Understanding DNA Damage Response or DDR and Cancer Treatment
What is DNA Damage Response or DDR?
The current clinical trial enrolled patients with advanced breast cancer that had progressed on prior Herceptin based therapies; 40 and 12 patients respectively to the PDL1-positive and PDL1-negative groups. Patients received Keytruda every three weeks in combination with the standard dose of Herceptin for 24 months or until disease progression.
Patients in the PD-L1 positive group had an objective response rate of 15% and a disease control rate of 25% was observed. In a subgroup of PD-L1-positive patients with 5 percent or more (tumor infiltrating lymphocytes) TILs present the overall response rate was 39% and the disease control rate was 47%.
Tumor-infiltrating lymphocytes are mononuclear immune white blood cells that have left the bloodstream and can often be found and measured in the cancer. The presence of TILS is often associated with better clinical outcomes after surgery or immunotherapy.4 Measurement of TILs may help identify patients who will most benefit from this treatment. No responses were observed in PD-L1 negative patients.
The study authors concluded that this proof-of-principle study suggests that immune evasion may be a method of Herceptin resistance and that PD1 inhibition is likely to become part of the treatment armamentarium of HER2-positive disease in the future.
- Loi S, Giobbie-Hurder A, Gombos A, et al. Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: results from the PANACEA study (IBCSG 45-13/BIG 4-13/KEYNOTE-014). Presented at: 2017 San Antonio Breast Cancer Symposium; December 5-9, 2017; San Antonio, TX. Abstract GS2-06.
- American Cancer Society. Breast Cancer Overview. 2016.
- NCCN Guidelines. Breast Cancer. Version 2.2017.
- Zhang L, Conejo-Garcia JR, Katsaros D, et al. (January 2003). “Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer”. The New England Journal of Medicine. 348 (3): 203–13. doi:1056/NEJMoa020177. PMID12529460.
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