This post is written by FPA intern Lindsey Milisits
While there have been several advances in the treatment of breast cancer over the past decade, one subset has seen little improvement in the development of effective and tolerable therapeutic options. Triple-negative breast cancer (TNBC) is an aggressive histological subtype of breast cancer that has limited treatment options, a high recurrence rate, and is associated with a poor prognosis. 10-20% of breast cancers are triple-negative and often occur more frequently in young women, African Americans, Hispanics, and those who exhibit a BRCA1 gene mutation. Currently, chemotherapeutic regimens remain the lead candidates in the standard of care (SOC) treatment for TNBC. This subtype is particularly difficult to treat due to its lack of estrogen, progesterone, and HER2 receptors, causing targeted therapies to be ineffective. Of all breast cancer subtypes, TNBC has the lowest survival rates making the development of effective and non-toxic treatments a priority. To understand how the future standard of care may change over time, therapeutic options in development that utilize alternative mechanisms of action were analyzed. A review of the development pipeline produced several classes of drugs that are more likely to improve survival outcomes.
The handful of toxic chemotherapy options that exhibit modest benefit in TNBC demonstrate a clinical need for alternative treatment mechanisms. One of the most intriguing areas in oncology research is the development of immunotherapy regimens. Immunotherapies aim to enhance the ability of the body’s own immune system to help detect and fight tumor cells. Within the TNBC space, there has been one recent immunotherapy approval and several additional immunotherapies in development. Combinations of immunotherapy and chemotherapy appear to be trending in TNBC clinical research and have the potential to influence future SOC.
In March of 2019, Genentech’s atezolizumab (TECENTRIQ), an anti-PD-L1 antibody, was approved for use in PD-L1 positive, metastatic triple-negative breast cancer (mTNBC) patients in combination with paclitaxel, a chemotherapeutic drug. This approval was based on IMpassion130: a multicenter, international, double-blinded, placebo-controlled, randomized phase III clinical trial. 902 patients that had not received prior treatment in the metastatic setting participated in the protocol, leading to the approval of the regimen in the first-line treatment for mTNBC. IMpassion130 was a game-changing trial that excited medical oncologists about the impact immunotherapy could have on breast cancer. Given the success of this trial, atezolizumab is currently being studied in a variety of other settings in combination with chemotherapy, including the neoadjuvant (IMpassion031), adjuvant (IMpassion030), and recurrent TNBC (IMpassion132), among others. It is possible we will see a label expansion of atezolizumab in the coming years, providing access to patients in various stages of the disease.
Another promising anti-PD-1 immunotherapy in development for the treatment of TNBC is Merck’s pembrolizumab (KEYTRUDA), a humanized monoclonal antibody. This immunotherapy is currently approved for use in a variety of other oncology indications and is seeking approval for TNBC through phase III clinical testing. The pivotal phase III clinical study, Keynote355, of pembrolizumab in combination with chemotherapy as a first-line treatment in the metastatic setting met one of its primary endpoints at an interim analysis in February 2020. The addition of pembrolizumab to chemotherapy significantly improved progression-free survival compared to chemotherapy alone in patients with mTNBC whose tumors expressed PD-L1. Pembrolizumab in combination with chemotherapy is also being studied as a neoadjuvant treatment for patients with early-stage TNBC in Keynote522. An interim analysis in October 2019 showed evidence of increased pathological complete response rates in the combination arm compared to chemotherapy alone. It is possible that pembrolizumab will become an immunotherapy option for the standard of care treatment in the neoadjuvant and metastatic settings.
Also on the horizon is Immunomedics’s sacituzumab govitecan (IMMU-132), an antibody-drug conjugate that is in phase III confirmatory study, ASCENT. This international, multi-center, open-label, randomized, clinical trial is designed to validate the safety and efficacy of sacituzumab govitecan in heavily pretreated patients with metastatic TNBC. The eligible patient population includes patients that have relapsed after at least two prior chemotherapies in the metastatic setting. Participants were randomized 1:1 to receive either sacituzumab govitecan or treatment of physician’s choice. In April 2020, Immunomedics announced that the ASCENT study would be halted due to compelling evidence of efficacy and was supported by the study’s Data Safety Monitoring Committee. The study reported remarkable results across multiple endpoints which warranted early discontinuation. Currently, sacituzumab govitecan has received Fast Track designation and Breakthrough Therapy designation from the FDA in the treatment of mTNBC for patients who relapsed on at least two prior therapies. The FDA is currently reviewing a resubmission of a biologics license application for accelerated approval of sacituzumab govitecan in this setting. Given the promising results from the ASCENT study, it is likely that patients who had limited options after progressing on prior therapies in the metastatic setting will soon have an additional therapeutic option.
In order to determine which other drug candidates have the potential to impact the future standard of care for TNBC, all of the active phase III clinical trials for triple-negative breast cancer with a primary completion date within the next five years were analyzed. From this data, it was evident that there are only a handful of therapeutic approaches likely to impact the SOC in the near future outside of chemotherapy regimens. The drug classes with the highest chance of success include anti-PD1 immunotherapies, AKT inhibitors, and PARP inhibitors. These mechanistic pathways are quickly evolving as lead targets for the treatment of TNBC.
Aside from atezolizumab and pembrolizumab, there are several other anti -PD1 drugs in the pipeline. Current phase III studies include Pfizer’s avelumab (BAVENCIO) as an adjuvant treatment for high-risk TNBC and Shanghai Jushi Biosicence Co’s toripalimab (JS001) for treatment of patients in the metastatic setting. Bristol Myers Squibb’s nivolumab (OPDIVO), AstraZeneca’s durvalumab (IMFINZI), and Novartis’s spartalizumab (PDR 001) are additional anti-PD1 candidates that are in various phase II clinical studies.
Though there is a lot of focus on immunotherapeutic options, AKT inhibitors appear to be another potentially promising mechanism of action. By inhibiting the PI3K/AKT pathway, these drugs may contribute to the reversal of T-cell mediated immunotherapy resistance. Roche’s ipatasertib (RG7440) and AstraZeneca’s capivasertib (AZD5363) are both being studied in combination with paclitaxel vs placebo in phase III trials for locally advanced and metastatic TNBC patients. The trials are anticipated to complete in December 2021 and July 2022 respectively. Though AKT inhibitors have the potential to impact SOC, confirmatory data supporting their use is still a few years away.
One final class that may impact future SOC are PARP inhibitory therapeutics, which hold promise for treating BRCA-related cancers. PARP enzymes are responsible for repairing damaged DNA, which is essential for tumor cells to thrive. Therefore, PARP inhibitors are utilized as a targeted therapy to inhibit PARP enzymes and prevent tumor cell proliferation. AstraZeneca’s olaparib (LYNPARZA) and Pfizer’s talazoparib (TALZENNA) are currently approved for use in metastatic TNBC or HER2-, HR+ cancers. Hormone receptor-positive patients are eligible for these PARP inhibitors if they failed past endocrine therapy. Research is ongoing to determine if this mechanism is efficacious in earlier disease settings. Olaparib is currently in clinical studies as a neoadjuvant treatment in combination with chemotherapy. Tesaro’s niraparib (ZEJULA) is a PARP inhibitor currently approved for use in ovarian cancer and is in phase II clinical studies to determine its effect in TNBC.
Though the current standard of care options for TNBC are very narrow, the future landscape holds promise if the trials discussed result in positive data. Now that atezolizumab is approved as a first-line treatment in the metastatic setting, PD-L1 positive patients have an alternative. However, patients that are PD-L1 negative still only have the choice of chemotherapy regimens or potentially clinical trial options. While immunotherapy is a current area of focus, it is not the only future direction of SOC treatment. AKT and PARP inhibitors could fill a gap and provide alternative options for the PD-L1 negative patient population.
There are many therapeutics in development that hold promise, but uncertainty regarding outcomes of clinical trials is even greater today than it has ever been in the past due to the global pandemic. COVID-19 has undoubtedly created significant shifts in the way that clinical research is conducted, forcing pharmaceutical companies, clinical research organizations, universities, and medical centers to rethink their clinical trial operations to prioritize patient safety. Research visits and biological sample collection have often been halted, causing us to wonder if the integrity of clinical trial data will stand over this period of time. Additionally, many clinical trials have announced suspensions and delays in enrollment. It is unclear when clinical research will be able to safely resume and strategically operate at full capacity. Therefore, it is evident that without data being collected from pivotal trials, new drug filings will be delayed. While there is ongoing research to improve the SOC for TNBC, this pandemic has added greater uncertainty as to when there will be sufficient data and evidence to bring new therapeutic medications to the market.