Dr. Sandra Dunn co-authored this blog with Dr. Mary Rose Pambid, Clinical Research Manager at Phoenix Molecular Designs.
A lot of excitement has been generated around the potential for immunotherapy (I/O) for the treatment of breast cancer. The idea behind I/O is to harness immune cells to seek and destroy tumor cells that disguise themselves by displaying PD-L1 (programmed death ligand). PD-L1 signals T cells that the tumor cells are normal. The other part of I/O that makes it so interesting is that tumors can be stained for PD-L1, thus organizing patients into groups that will benefit from I/O. The cutoff is extremely low at 1% or more. The I/O agents that have been in the spotlight in the past year, and rightfully so, are atezolizumab (Tecentriq) and pembrolizumab (Keytruda), which we will discuss further below.
Pembro was originally designed for melanoma and has since ventured into other solid tumors. In the KEYNOTE-012 Phase 1b trial, 32 patients with triple negative breast cancer (TNBC) were treated with pembro. 25% percent of these patients had received several lines of chemotherapy prior to enrolling. The objective response rate (ORR), or percentage of patients who saw positive results, was 18.5%.
The subsequent Phase 2 study, KEYNOTE-086, enrolled 170 TNBC patients who had no previous treatment prior to starting the trial. The ORR was 4.7%, but when stratified to PD-L1+ patients, the ORR was 22.6%. With over 75% of patients not seeing tumor shrinkage, this leaves a lot of room for improvement.
Six hundred and twenty-two patients who had been heavily pretreated joined the KEYNOTE-119 Phase 3 trial. The study failed because they did not show improved overall survival on pembro compared to existing chemotherapy.
Roy Barnes, senior vice president, chief medical officer, and head of global clinical development at Merck Research Laboratories, acknowledges the shortfalls but looks to the future: “While we are disappointed by the outcome of this monotherapy trial, we are continuing to study Keytruda in earlier stages of the disease and in combination with chemotherapy to address the unmet medical need of patients with triple negative breast cancer.”
Atezolizumab was first developed for urothelial cancer, or bladder cancer, and has extended into non-small cell lung carcinoma. The Phase 1 trial had 116 patients participate, but the ORR was 12.7% even with enrichment for PD-L1.
What we are learning is that immunotherapy alone is not enough. Patients deserve a response rate that is better than 22.6%. Looking at combination therapy with existing chemotherapy is the next logical step.
Dr. Aditya Bardia of Massachusetts General Hospital recently discussed breast cancer and immunotherapy: “We know from prior studies that response to immunotherapy goes down in pretreated patients; that may be because some of the T cells get affected by chemotherapy. Even if the T cells had been activated, the chemotherapy could take that away, leaving no T cells to attack the tumor. Even if you take the breaks away, we wouldn’t have the ammunition or the T cells to attack the tumor. In general, the response to immunotherapy is lower in later lines of therapy; it’s highest in the first-line setting. The real excitement is in early breast cancer. Specifically, in the neoadjuvant and adjuvant setting where the response to immunotherapy is likely going to be higher than what we’ve seen in the metastatic setting…However, immunotherapy is also associated with several adverse events.”
Because this therapy bypasses the typical immune checkpoint, patients can become susceptible to certain side effects immediately or even up to 2 years post-treatment. These side effects are referred to as immune-related adverse events (irAEs). In irAEs, the T cells begin to attack normal cells leading to organ-specific inflammation ie pneumonitis (lung inflammation), colitis (intestinal inflammation), brain inflammation, and more. Even with the success of I/O in early breast cancer, patients are left with a less-than-ideal quality of life. Since irAEs are a new type of side effect, they are not as manageable compared to standard chemotherapy side effects.
Dr. Sandra Dunn, CEO of Phoenix Molecular Designs, believes that a combination of therapies is the key to treating TNBC: “I fully agree that combination therapies will ultimately be the way to go for managing TNBC. We have seen this to be true in hormone positive breast cancer as a test of time. For example, the combination of anti-estrogens plus targeted therapies to kinases such as CDK4/6 demonstrated impressive improvements in the survival of breast cancer patients. More recently, studies show that inhibiting the kinase PI3K in combination with hormone targeted therapies is also showing improvements.”
With combination therapies, patients only have to take lower doses of each drug. Due to these reduced dosages, patients experience lower exposures to these drugs, and thus have the potential to experience fewer side effects and less chance of resistance.
PhoenixMD’s preclinical studies support single-agent activity PMD-026, a purpose built kinase inhibitor targeting RSK most effectively in TNBC. The synergies in marketed cancer therapies offer the potential to make a big impact in breast cancer therapeutics. PMD-026 is therefore seen as a combinatorial platform. PMD-026 is synergistic with paclitaxel as well as doxorubicin, two mainstay chemotherapies used for the treatment of TNBC as well as many other cancers. The inhibitor also suppresses PD-L1 expression and stimulates the production of neutrophils in mice, suggesting there is a much bigger role for RSK inhibitors in the treatment of cancer than originally expected.