Special Edition: Update on Approval for Immune Therapy in Early-Stage Triple Negative Breast Cancer

Research remains an essential part of cancer care. In this monthly blog, we will provide information about recent updates or new approvals as it applies to breast cancer written by Dr. Sharon Wilks.

Though enormously practice changing, we still have unmet needs and research at NEXT Oncology is looking at better ways to improve immune recognition for better tumor response in all cancers.

It was one year ago (July, 2021) that the FDA approved the use of Pembrolizumab, a checkpoint inhibitor – a form of immune therapy to be used in women with an aggressive form of breast cancer known as Triple Negative Breast Cancer. This approval was based upon the results of several studies including an important study referred to as KEYNOTE 522.

The study design of Keynote 522 included 1,174 patients (international study) and randomized those with stage II and stage III (tumors at least 2 cm in size and/or had nodes involved with cancer at the time of diagnosis of breast cancer) between chemotherapy alone – combination of four cycles of Carboplatin + Paclitaxel then followed by four courses of Adriamcyin/Epirubicin + Cytoxan versus the same chemotherapy schema with combination of Pemrolizumab every three weeks during each phase of the same chemotherapy. This treatment was given prior to surgery (Neoadjuvant chemotherapy) and then once completed, surgery with lumpectomy or mastectomy with lymph node removal was carried out. Those assigned to Immune therapy with Pembrolizumab in the Neoadjuvant phase, resumed Pembrolizumab every three weeks for nine cycles.

Clinically and statistically significant outcomes were seen in the immune therapy treated patients including Event Free Survival (EFS) rate at the interim analysis four of this study with 84.5% EFS with the Pembrolizumab + Chemotherapy group compared to 76.8% in the standard chemotherapy alone arm. Patients with a complete disappearance of tumor at time of surgery (referred to as PCR, or pathologic complete remission) enjoyed a PCR of 94.4% with immune therapy and even amongst those who did not achieve a PCR, the EFS was better in the group who received Pembrolizumab at 67.4% versus 56.8% in the standard no immune therapy arm. Interestingly, patients whose tumors had or did not have a PDL-1 + tumor seemed to respond to the addition of Pembrolizumab though clearly the PDL+ group did better overall even if they did not receive Pembrolizumab with a PCR of 68.9% in the Pembrolizumab group compared to 54.9% in the no Pembrolizumab group. Patients that had tumors that were PDL- at time of study entry experienced a 45.3% PCR rate in the Pembrolizumab compared to 30.3% in the cohort who did not receive Pembrolizumab. A trend towards improvement in Overall Survival (OS) has been reported but no statistical improvement in OS has been reported to date.

These findings led to a practice changing approach to fight an aggressive form of breast cancer more effectively. But overall survival rates have not yet been proven to be enhanced with this approach and there are short- and long-term side effects with these new agents including rash, gastrointestinal, respiratory, hepatic and a host of short and long term immune related events including thyroid dysfunction.
Though this new approach and success is so enheartening, we still have numerous questions:

  • Can you augment the immune response in non-TNBC patients and by doing this allow for an opportunity to use immune therapy in other breast cancer survivors who do not have TNBC?
  • Do we need all this chemotherapy in all patients with TNBC-baseline chemotherapy was intense with four agents given?
  • Since some patients who did not receive Pembrolizumab achieved a PCR anyway, how can we identify patients who do not need Pembrolizumab?
  • Is it necessary to give Pembroliuzmab after surgery?

Other Neoadjuvant studies showed favorable survival rates even in those who only received Pembrolizumab in the Neoadjuvant setting. Some patients who did not achieve a PCR enjoyed a better EFS (67.4%) compared to 56.8% EFS amongst those who did not receive Pembrolizumab as Neoadjuvant treatment. As a result of these data, additional questions that have been raised include:

  • Are these the patients that may benefit from additional Pembrolizumab postoperatively?
  • What is a good biomarker that predicts for treatment response?
  • an we find improved ways to use immune therapy but reduce short- and long-term adverse effects?

Clearly, the addition of Pembrolizumab to the armamentarium to standard chemotherapy has been practice changing, not only in the early-stage patient with TNBC but also those with advanced stages of disease. However, we need to understand ways to improve upon this success and ultimately show better outcomes with overall survival. New strategies that are looking at different ways to enhance immunogenicity and T-cell recognition and avoidance of T cell exhaustion and methods to overcome tumor immune suppressive effects in the tumor microenvironment are ongoing. These are just some of the reasons that research is essential to lead to better outcomes and survival in cancer survivors.