FEATURED , Chemotherapy , Neoadjuvant Treatment , Research

Alan Stolier, MD/

Checkpoint Inhibitor Plus Chemotherapy Dramatically Improves Complete Response Rates Over Chemotherapy Alone in Neoadjuvant Setting

checkpoint inhibitor

Evading the immune system is mandatory for a tumor to progress. To mount an attack on invading tumor cells, T-cells use a cell surface protein called PD-1 (PD, an acronym for programmed cell death protein). 

If it probes the cell and finds it to be an invading cell, an attack commences. Tumor cells, however, have developed a mechanism to fool the T-cell, and that is using a protein called PD-L1 (programmed cell death ligand). This topic was covered in a prior post in May 2018, complete with a video link.

Drugs that block this PD-1, PD-L1 connection are called checkpoint inhibitors. We noted at that time that it was primarily triple-negative cancers (TNBC) that were immunogenic and would likely respond to immunotherapy. The use of single-agent pembrolizumab (checkpoint inhibitor) in both TNBCs and ER+ cancers has not been impressive. I-SPY2 is a phase 2 study designed to rapidly screen agents that are likely to succeed in phase 3 trials. A trial using chemotherapy with pembrolizumab was undertaken with the hypothesis that “immune-targeted agents would be more effective in the early-stage setting when the immune system is less likely to be compromised. 

The current trial was a multicenter randomized phase II trial for high-risk stage II/III breast cancer. Patients were randomized between neoadjuvant weekly paclitaxel followed by doxorubicin/cyclophosphamide plus or minus 4 cycles of the checkpoint inhibitor, pembrolizumab. One hundred eighty-one women were randomized to neoadjuvant chemotherapy alone, whereas 69 were randomized to also receive pembrolizumab. In the pembrolizumab group, 40 patients had hormone receptor-positive (HR+) disease and 29 had triple-negative disease (TN).

 

Complete Response Rates

Estimated complete pathologic response rates (pCR) for Her2 negative, HR-positive/Her2 negative, and TNBC signatures in the pembrolizumab arm were 44%, 30%, and 60%, compared with 17%, 13%, and 22% in the control chemotherapy populations, respectively.

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Conclusions

The addition of 4 cycles of the checkpoint inhibitor, pembrolizumab, to the standard of care chemotherapy more than doubled the pCR rates in all biometric signatures studied. Of importance, it should be noted that pembrolizumab was the first of 10 checkpoint inhibitors to qualify for use in hormone receptor-positive signatures since I-SPY2 opened in 2010.

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