By Karuna Jaggar, Former Executive Director and SABCS Guest Writer
As explained in the prior blog post, immunotherapy seeks to harness the immune system to recognize and target cancer cells. The immunotherapy drug pembrolizumab (brand name Keytruda) is a checkpoint inhibitor that blocks the activity of PD-1 (programmed cell death protein 1), a protein on immune system’s T cells that normally keeps these cells from attacking other cells in the body.
The PD-1 on a T-cell interacts with PD-L1 (programmed death-ligand 1) on a tumor cell to prevent the immune system from attacking the tumor cells. By blocking the interaction of PD-L1 with the PD-1 receptor, checkpoint inhibitors like pembrolizumab aim to boost the immune response against breast cancer cells. PD-L1 enrichment is not unique to breast cancer, and in 2017, the FDA approved pembrolizumab for use based on the genetic mutations of a cancer, rather than the originating organ of the tumor, marking the first time the FDA granted such an approval based on tumor genomics.
Thursday morning’s General Session of SABCS opened with Dr. Hope Rugo presenting additional data from the KEYNOTE 355 trial, which was the basis for the FDA’s breakthrough approval just last month of the immunotherapy pembrolizumab for advanced triple negative breast cancer (TNBC) that express PD-L1. It should be noted that the researchers have not shown overall survival benefit, and the basis for the accelerated approval is progression-free survival (PFS), which is the time from the start of treatment until the cancer grows or progresses.
Dr. Rugo presented subgroup analysis looking at specific “partner chemos” and found that pembrolizumab (or Pembro, as it’s often called) improves progression free survival for triple negative breast cancer with PD-L1 positive tumors no matter which approved chemo regimen it’s paired with. The benefit of Pembro seems to increase with PD-L1 enrichment, shown as a combined positive score (CPS) of at least 10.
The KEYNOTE 355 trial included 847 patients with locally recurrent inoperable or metastatic triple-negative breast cancer who were enrolled between January 2017 and June 2018 in the international, randomized, placebo-controlled, double-blind, phase 3 trial. Patients could not previously have received chemotherapy for metastasis. Participants were randomly assigned two-to-one to receive pembrolizumab plus chemotherapy or chemotherapy alone. The researchers did imaging every eight weeks for the first few months to evaluate possible cancer growth or spread.
The pembrolizumab treatment effect was greatest with PD-L1 enrichment. With median follow up just over a year, progression-free survival was better on the pembrolizumab arm, at 9.7 months compared to 5.6 months on chemotherapy alone for those patients with PD-L1 enrichment. The benefit was not statistically significant for those patients whose tumors did not overexpress PD-L1, and any perceived benefit for the overall group (all those with a CPS of 1) was driven by the responses of the CPS 10-plus group. Subgroup analysis showed that progression free survival was improved regardless of which chemotherapy (nab-paclitaxel, paclitaxel, or gemcitabine plus carboplatin) was used in combination with Pembro.
Treatment for metastatic triple negative breast cancer is notoriously harsh and grade 3–5 treatment-related adverse event rates were experience by 68% of patients in the pembrolizumab plus chemotherapy group compared to 67% in the chemotherapy alone group. The most common side effects on the Pembro arm were fatigue, nausea, diarrhea, constipation, vomiting, alopecia, rash, cough, decreased appetite, headache. Additional side effects include anemia, low white blood cell counts, and other laboratory abnormalities. Keytruda can cause your immune system to attack normal organs and tissues in any area of your body and can affect the way they work. These problems can sometimes become severe or life-threatening and can lead to death. These problems may happen anytime during treatment or even after your treatment has ended.
Despite the growing popularity of the phrase “financial toxicity” to refer to the financial toll of treatment, the researchers did not discuss the price of treatment with pembrolizumab, which is estimated to be approximately $150,000 per patient for each year of treatment, despite not having shown overall survival benefit.
Merck, the company that makes pembrolizumab, is currently waiting for an FDA decision, anticipated on March 29, 2021, for the use of Pembro, in combination with platinum-based chemotherapy, for early stage, high risk triple negative breast cancer. Breast Cancer Action believes that approval should be based on demonstrated overall survival benefit, given the documented toxicity and high cost of treatment with Pembro.