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Team Science

Breast

Breast Parallel Session 1

8: A high pre-existing TCR repertoire diversity may predict response to preoperative radiotherapy and pembrolizumab in early-stage breast cancer – NCT04454528 preliminary results

Friday, March 22, 2024
10:52am – 11:02am ET
Location: Georgia Ballroom
Disclosure(s):
Julia Tchou, MD PhD: BD/Bard: Consultant (Ongoing)
Introduction:

Pembrolizumab, an immune checkpoint inhibitor (ICI), in combination with neoadjuvant chemotherapy (NAC) is standard of care for early stage triple negative breast cancer (TNBC) with high-risk features but is considered an over treatment for TNBC without high-risk features. To evaluate if radiotherapy (RT) may synergize with ICI as a chemotherapy-free neoadjuvant strategy, we initiated a clinical trial (NCT04454528) (Fig. a) in January 2021.  We hypothesize that preoperative RT + ICI may elicit tumor response and that pre-existing immune markers in peripheral blood mononuclear cells (PBMCs) may correlate with treatment response.


Methods:

Participants were assigned to receive preoperative RT (7 Gy, single fraction) + ICI (single pembrolizumab dose), ICI + RT, or ICI alone in Arms 1, 2, or 3 respectively (Fig. a). Pre- and post-treatment PBMCs were collected for correlative analyses. A clinically significant treatment response, defined as tumor size reduction of >30% (TΔ30), was compared across Arms using Fisher-Irwin tests. Analyses of pre- and post-treatment PBMCs to include bulk TCR sequencing were performed using Adaptive Biotechnologies© platform.


Results:

Nineteen participants (21 evaluable tumors) completed the study with no adverse events > grade 2 CTCAE v.5. The race/ethnicity composition of our cohort was 12 White, 5 Black, and 2 Hispanic Black with a median age of 57 (range 20-80). Tumor subtype distribution was TNBC (n=14), Hormone receptor (+) HER2- (n=6), and HER2+ (n=1). TΔ30 was noted in 9 of 21 (43%) tumors (Fig. b). RT + ICI (Arm 1 or 2) resulted in a significantly higher TΔ30 rate (9 of 15, 60%) than ICI alone (0 of 6), p=0.0143. Treatment sequence, i.e., RT before ICI (Arm 1) vs. RT after ICI (Arm 2) resulted in a similar TΔ30 rate in 5 of 9 (55%) vs. 3 of 5 (60%) respectively, p=0.862. Correlative analyses in PBMCs demonstrated that a higher pre-existing TCR repertoire diversity was significantly associated with TΔ30, p=0.035 (Fig. c).


Conclusions:

In this study, TΔ30 was seen in 43% of tumors after preoperative RT + ICI but the impact of this preoperative treatment on long-term outcomes remains undefined. Pre-existing TCR repertoire diversity in PBMC may help identify treatment responders. Future work to unravel the local and systemic immunologic consequences in this and other window of opportunity study may provide a rational approach and framework to de-escalate immunotherapy in select patients.

Learning Objectives:

  • • Upon completion, participant will be able to understand that preoperative radiotherapy may synergize with pembrolizumab to elicit a clinically significant tumor response.
  • • Upon completion, participant will be able to understand that preoperative treatment sequence, i.e. RT before ICI or RT after ICI is similarly effective in eliciting a treatment response.
  • • Upon completion, participant will understand that pre-existing TCR repertoire diversity may predict treatment response in patients receiving a de-escalated combination immunotherapy in the neoadjuvant setting.