By Joan Mancuso
In her presentation at the San Antonio Breast Cancer Symposium in December, Dr. Leisha Emens noted that scientists want to turn on our immune system, to convert non-responders to responders in order to treat metastatic breast cancer patients with immunotherapy.
Several clinical trials have shown that immunotherapy for MBC is currently most effective for metastatic triple negative breast cancer (mTNBC). However, response rates and durable responses can be improved for all the subtypes, according to Dr. Emens. She proposed that drug combinations are most likely the answer.
Dr. Emens is professor of oncology in the Immunology and Breast Cancer Research Program at Johns Hopkins University School of Medicine.
PD-L1 positive breast cancer
A clinical trial with 168 unselected enrollees found that the overall response rate (ORR) for mTNBC who were PD-L1 positive was roughly 44% with the PD-L1 inhibitor, avelumab. The ORR of all breast cancer subtypes in the trial regardless of PD-L1 status was just under 5%. In an unselected population, enrollees are positive and negative for the biomarker. PD-L1 is an immunotherapy marker. However, according to Dr. Emens, it is not perfect because some patients who are not positive may still respond to a PD-L1 blocker.
In a different trial using the anti-PD-L1 drug pembroluzumab, mTNBC/PD-L1 positive patients had an ORR of 18.5%, and patients with metastatic ER positive/HER2 negative/PD-L1 positive breast cancer had an ORR of 12%. Pembroluzumab is an FDA-approved drug for patients with metastatic melanoma and metastatic non-small cell lung cancer (NSCLC), as well as other advanced cancer. However, recently, the FDA also approved the drug for any metastatic tumors with specific genetic features. That the FDA’s approval is based on molecular changes and not organ type is novel. Their decision will help MBC patients access the drug even though it is not approved specifically for MBC. The brand name of pembroluzumab is Keytruda.
The PD-L1 blocker atezulizomab showed an ORR of 19% in mTNBC patients in another study. Atezulizomab was FDA approved as Tecentriq for an advanced type of bladder cancer and metastatic NSCLC. If an already approved drug could be repurposed for MBC, patients would benefit. In particular, effective targeted drugs for TNBC is clearly a medical need.
Drug combinations for durable response
Dr. Emens proposed that based on evidence, combination therapies should improve the response rate for mTNBC patients, kick-start the immune system for patients with other subtypes of breast cancer and prolong the duration of response. The question, however, is which combinations will work well together.
A Phase Ib clinical trial of atezulizumab and nab-paclitaxel (Abraxane) in unselected mTNBC patients showed a roughly 42% ORR. Stratification by chemotherapy line showed that first-line patients, or otherwise enrollees who had never been treated for MBC, had an ORR of 67%, while enrollees who were on their second or later line of treatment showed an ORR of 25%–28%. This suggests that introducing a combination protocol earlier would be beneficial, and it speaks to the potential benefit of entering a clinical trial prior to any treatment.
The data from that trial is the basis of a Phase III randomized, placebo-controlled clinical trial of atezulizumab and Abraxane for treatment-naïve mTNBC patients, where enrollees in one arm of the trial will receive the combination therapy and patients in the other arm will get Abraxane, or the standard of care. https://clinicaltrials.gov/ct2/show/NCT02425891
The trial’s primary endpoints are determining whether the combination is significant in improving progression free survival and overall survival (OS) over the standard of care of Abraxane alone. A secondary endpoint will look at the duration of response. The particulars of the ImPassion130 clinical trial protocol can be viewed online at clinicaltrials.gov
This study is double-blinded, and patients in the Abraxane-only arm receive a placebo so oncologists will not know who received the experimental drug.
Finding Achilles Heel
Scientists are understanding better than before, the tumor/immune system cycle, which will help determine at which stage or stages to intervene with therapeutic drugs during that cycle. They have now identified a protein along the adenosine pathway that may be a potential effective target of the oral compound CPI-444.
That identification has lead to a dose-selection study of CPI-444, with or without atezulizumab, for several PD-L1 positive metastatic cancers https://clinicaltrials.gov/ct2/show/NCT02655822?term=CPI-444&recrs=a&rank=1 Of the 40 patients enrolled in the trial, nine had mTNBC. The study found that in the CPI-444–only arm an mTNBC patient had a 15% immune response at baseline that increased to 23%. Response was measured by an increase in T cells, among other factors. The idea is to determine the impact on a tumor’s size when those cells are increased. T cells are a type of white blood cell. They play a role in the immune system and fighting cancer. The ongoing results of this study have lead to a dose expansion trial.