Background for Neoadjuvant Immunotherapy Improving TNBC Prognosis

Lajos Pusztai, MD, DPhil, professor of medicine and coleader of Genetics, Genomics, and Epigenetics at Yale Cancer Center, discusses the promise of neoadjuvant immunotherapy trials including the KEYNOTE-522 trial (NCT03036488) evaluating pembrolizumab (Keytruda) plus chemotherapy in patients with triple-negative breast cancer (TNBC).

Pusztai says that the introduction of immune checkpoint inhibitors (ICIs) enabled investigators to study whether a greater immune response with more immune cells present in the tumor microenvironment improves the overall prognosis of patients with TNBC.

There have been several trials that have explored preoperative ICI therapy in TNBC, showing an increase in pathologic complete response (pCR) rate, with the exception of the NeoTRIPaPDL1 study (NCT002620280) of atezolizumab (Tecentriq). While the pCR increase in these trials is not numerically high, it has shown statistical significance in larger trials. Event-free survival (EFS) benefit may be seen even in patients without a pCR.

According to Pusztai, the GeparNuevo trial (NCT02685059) results reported in August 2022 showed an absolute increase of 9 percentage points in pCR rate in 88 patients who were randomly assigned to receive durvalumab (Imfinzi) with neoadjuvant chemotherapy versus 86 who received chemotherapy alone. In KEYNOTE-522, in which over 1000 patients were enrolled, pembrolizumab had a 13.6 percentage point absolute increase in pCR versus chemotherapy and a strong EFS advantage, supporting the use of neoadjuvant ICI therapy for TNBC.

TRANSCRIPTION:

0:08 | The advent of immunotherapy drugs being highly effective ICIs enabled us to ask this question. If the immune response contributes to the good prognosis, then boosting the immune system will improve the prognosis of patients who have a moderate amount or even large amount of immune cells, you can make that progress better. This was the theoretical background to testing immune checkpoint inhibitors in breast cancer, and lo and behold, it's worked.

0:41 | There are at least 4 randomized neoadjuvant chemotherapy trials that tested various different types of ICIs combined with chemotherapy in the preoperative setting. Essentially, all of them showed an improvement in pCR rate, except 1 study in Italy, the NeoTRIP [study] of ​​atezolizumab. We also learned that the pCR rate improvements are relatively modest and often in single digits. In large studies, these reached significance. In smaller phase 2 studies, they did not have significance, just the numerical improvement.

1:24 | Even in a relatively small phase 2 trial, GeparNuevo, which tested durvalumab [Imfinzi] under a similar sort of schema of neoadjuvant weekly nab-paclitaxel followed by EC [epirubicin plus cyclophosphamide] with or without durvalumab, showed a slight improvement in pCR rate and a significant improvement in EFS. I think the data are very consistent that ICIs improve the outcome of patients with triple-negative disease. KEYNOTE-522 is the largest and most definitive study.