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Deciphering the Role of CDK4/6 and PDL-1 in Breast Cancer Immunotherapy Strategies
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Key Takeaways
- Immunotherapy and CDK4/6 inhibitors are being investigated for HR+ and TNBC, addressing limitations of current treatments and improving outcomes.
- Pembrolizumab shows potential in specific BC subtypes, but its efficacy is inconsistent, highlighting the need for better patient selection.
Combining CDK4/6 and PDL-1 inhibitors enhances treatment responses in patients with hormone receptor positive and triple-negative breast cancer.
At the 2024 San Antonio Breast Cancer Symposium (SABCS) in Texas, experts addressed the role of immunotherapy, its limitations, and the potential of CDK4/6 inhibitors in combination therapies in the treatment of hormone receptor positive (HR+) breast cancer (BC) and triple-negative BC (TNBC).1
Depiction of cancer cell signaling pathways | Image Credit: © Ummeya - stock.adobe.com
HR+ BC is the most common subtype of cancer, accounting for approximately 70% of all BC diagnoses. Historically, endocrine therapy (ET) has been the standard of care (SOC); however, there is still a significant risk of recurrence in early-stage disease. About 90% of all recurrent BC after 5 years is metastatic, and when the disease becomes metastatic patients will often become resistant to ET. Additionally, ET is associated with toxicities that can have an impact on patients’ quality of life. This underscores the need for therapies to prevent disease progression and recurrence.2
“While [ET] certainly is generally more tolerable [than] immunotherapy, it can have its own toxicities, which can affect quality of life over outcomes,” explained Cesar Santa-Maria, MD, MS, oncologist at John Hopkins Hospital, during the SABCS session. “A lot of research to improve treatments for patients with [HR+ BC] have focused on targeted therapies against common resistant pathways, but still, novel approaches are needed, and the case is that immunotherapy may have a role.”
Early-Stage HR+ BC
The development of immunotherapies has helped overcome the limitations of ET, as well as advanced the treatment landscape for HR+ BC. However, initial experiences with single-agent immune checkpoint inhibitors (ICIs) such as pembrolizumab (Keytruda; Merck) in metastatic disease demonstrate lower response rates. Investigators attribute this to differences in the tumor microenvironment (TME). Compared to other subtypes of BC, HR+ BC has lower PDL-1 expression, tumor mutational burden, and tumor-infiltrating lymphocytes, contributing to the challenges seen with immunotherapy.
Pembrolizumab is the first and only FDA approved ICI PD-1–blocking treatment, and is indicated for high-risk, early-stage TNBC in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery. This decision was based on data from the KEYNOTE-522 trial (NCT03036488) which showed pembrolizumab improved pathologic complete response (pCR) rate (63%) in early-stage HR+/human epidermal growth factor receptor 2-negative (HER2–) BC.3,4
Pembrolizumab has demonstrated efficacy in select BC subtypes, namely HR low/ER-low BC, but has failed to demonstrate favorable or notable progression-free survival (PFS) and overall survival (OS). This was observed in the KEYNOTE-765 trial (NCT03725059), a randomized phase 3 trial that evaluated the addition of pembrolizumab to standard neoadjuvant and adjuvant chemotherapy in patients with stage 2 to 4 HR+/HER2– BC. The data showed that the addition pembrolizumab resulted in an increase in pCR rates from 15.6% in the control arm to 24.3%, providing evidence that the agent can improve pathologic response. Additionally, the researchers found that increased PDL-1 expression was associated with higher pCR rates. This suggests the potential benefit of PDL-1 status as a biomarker for determining which patients would benefit most from treatment with pembrolizumab.5
Immune checkpoint inhibitors | Image Credit: © Papisut - stock.adobe.com
According to preclinical studies, combining CDK4/6 inhibitors with PD-1 or PDL-1 inhibitors can have synergistic anti-tumor effects by enhancing T-cell recruitment and activation, as well as increasing cytokine production, type 1 interferon signaling, and major histocompatibility complex class 1 and 2 expressions.
“CDK4/6 inhibitors have been shown to increase the expression of class 1 and 2 molecules, as well as type 3 interferons, which in turn elevate cytokine levels. This process enhances T-cell recruitment and memory while increasing T-cell activation,” said Santa-Maria. “Notably, several in vivo models have consistently demonstrated across various studies that combining CDK4/6 inhibitors with PD-1 or PDL-1 inhibitors can create a synergistic effect, resulting in tumor-suppressive outcomes. Furthermore, clinical data suggests that CDK4/6 inhibitors may also have [TME]-modulating effects."
In the neoMONARCH trial (NCT02441946), combining the CDK4/6 inhibitor abemaciclib (Verzenio; Eli Lilly) with ET resulted in a 43% overall response rate (ORR) and was well tolerated, with only 10% of patients experiencing grade 3 immune-related toxicities. The researchers found, through translational analyses of patient biopsies, that the addition of abemaciclib increased the expression of genes responsible for immune activation and antigen presentation, as well as T-cell activity, recruitment, and memory T-cell formation. These data provide evidence of the tumor modulating capabilities of CDK4/6 inhibitors in early-stage HR+ BC.6
TNBC
TNBC is an aggressive, high-risk BC subtype that disproportionately affects younger women and has a higher likelihood of recurrence, emphasizing the importance of optimizing treatment approaches that consider the long-term impacts of more aggressive therapies, reduce toxicity, and preserve quality of life.
Due to the lack of estrogen receptor, progesterone receptor, and HER2 expression in TNBC, it is more challenging to treat with targeted therapies, leaving chemotherapy and immunotherapies as the primary treatment approaches. However, toxicity risks with chemo-immunotherapy regimens remain, such as adrenal insufficiency, which can have lifelong consequences. As more patients with TNBC are treated with immunotherapies, it is crucial to investigate which patients would benefit from less intensive treatment without compromising survival.
Chemotherapy drug molecules interacting with cancer cells | Image Credit: © Ummeya - stock.adobe.com
According to data from the Genome 521 study and NeoPACT trial (NCT03639948), adjuvant immunotherapy may not be necessary for all patients, particularly those who achieved a pCR with neoadjuvant treatment. Both trials demonstrated similar survival outcomes for patients who received chemotherapy alone and those who received adjuvant pembrolizumab after chemotherapy.7
"If you review the curves, and this is most recent [OS] data for the pCR patients,” said Marleen Kok, MD, PhD, oncologist and immunologist, group leader for the Breast Cancer Immunotherapy Group at the Netherlands Cancer Institute in Amsterdam, Netherlands. “You see that the pCR with chemotherapy, the survival, is almost as good as survival with chemo-immunotherapy. So, is there a pembrolizumab benefit in patients with a pCR? If there is one, it will be very minimal."
These results underscore the need for continued study on the relative contributions of adjuvant vs neoadjuvant immunotherapy to treatment outcomes in patients with TNBC, who may benefit from less intensive treatment approaches.
The Future of Immunotherapy in BC
The continued development and study of ICIs, such as pembrolizumab and abemaciclib, and novel therapies is crucial to address the needs of patients with early-stage HR+ BC and TNBC. Development of treatment combinations capable of modulating the TME to overcome immune evasion mechanisms is essential for improving outcomes in these challenging subtypes of BC.
Another potential approach is the combination of the anti-PD-1 ICI nivolumab (Opvido; Bristol Myers Squibb) and ipilimumab (Yervoy; Bristol Myers Squibb), an anti-CTLA-4, with the histone deacetylase (HDAC) inhibitor entinostat (SNDX-275, MS-275; EOC Pharma/Syndax Pharmaceuticals). Evanthia Roussos Torres, MD, PhD, assistant professor of Medicine and Biochemistry & Molecular Medicine at the Kerk School of Medicine USC in Los Angeles, discussed the results of a phase 1 clinical trial conducted by her team. Her rationale behind combining an ICI with HDAC was that the HDAC inhibitor could help modulate the TME while the ICI activates an adaptive immune response, potentially overcoming immune evasion mechanisms in cancer treatment.
The results of Torres’s investigation showed that patients with TNBC who received nivolumab and ipilimumab with entinostat achieved an ORR of 40% compared with 10% in the HR+ BC group. The investigators also reported a PFS of 9.6 months in the TNBC population. However, Torres found that the treatment responses did not correlate with traditional biomarkers such as PDL-1 expression, prompting her to revert to mouse models before continuing studies in clinical trials.
"So, this is an overview of the translational research approach from mice to men, with some math and back. This is just to highlight that a lot of these studies being done in my lab, as well as many, many other labs all around the world really kind of embody this,” said Torres. “We have to start pre-clinically, then move into clinical trials, and then go back to learn more about the immunology and basic science driving the mechanisms of response. After that we can go back to our clinical trials to do better."
The future of immunotherapy for patients with early-stage HR+ BC or TNBC is dependent on the continued study of innovative combination therapies that modulate the TME to become more responsive to anti-tumor immunity. Additionally, there is a need for standardization and improvement of predictive biomarkers to identify which patients would benefit from immunotherapy. The continued development and study of ICIs and novel therapies is crucial to address the evolving needs of patients with early-stage HR+ BC and TNBC.
