Background: Pembrolizumab (pembro)-mediated checkpoint blockade has shown only modest efficacy in triple negative breast cancer (TNBC). Pathologic complete response (pCR) rates in TNBC are 34-55% with neoadjuvant chemotherapy and 26% with neoadjuvant stereotactic radiation therapy (RT) alone. However, because RT induces immune-mediated cell death that can generate a rich supply of tumor antigens and trigger anti-tumor immunity, the addition of pembro to RT can generate robust anti-tumor immune responses as demonstrated in metastatic TNBC. If administered in the pre-operative setting, immune therapy plus RT could induce long-term tumor-specific memory, and ultimately, improve cure rates. This study aimed to establish the safety of pre-operative pembro plus RT in 20 TNBC patients for whom lumpectomy and adjuvant RT were planned and to explore predictive biomarkers (NCT03366844).

Methods: Women planning breast conserving surgery for operable, stage II/III, TNBC were enrolled in this single-institution pilot study. Study treatment consisted of pre-operative pembro (200mg IV) followed 3 weeks later by pembro (200mg IV) plus RT (24 Gy/3 fractions) to the primary breast tumor followed 3-5 weeks later by standard-of-care (SOC) neoadjuvant chemotherapy. Adjuvant RT was administered per SOC after surgery, but without a boost dose. Research blood and tumor biopsies were obtained at baseline, at week 4 prior to pembro/RT, and at week 6-8 prior to chemotherapy initiation. Co-primary endpoints were: safety/tolerability (defined by the number of patients who do not necessitate a delay in SOC chemotherapy or surgery) and change in tumor infiltrating lymphocyte (TIL) score. Secondary endpoints include safety/toxicity up to 19 weeks after study enrollment and pathologic complete response (pCR) rate.

Results: 20 patients were enrolled and completed all treatment (pembro, RT, chemotherapy and surgery) as of July 2020. The median age is 55y (range 33-70y). The stage distribution is IIA (11), IIB (6), IIIA (2) and IIIC (1) with biopsy proven nodal involvement in 55%. All patients received a taxane containing regimen, 12/20 (60%) received carboplatin and 15/20 (75%) received an anthracycline. Three patients did not complete the planned course of chemotherapy, two of whom had residual disease. None of the patients experienced significant delay (>2 weeks) in receiving SOC treatment. There were no observed grade 3 or 4 toxicities observed during the pembro +/- RT treatment. Grade 4 colitis in 2/20 was reported during SOC chemotherapy and was attributed to pembro. The most frequent grade 1/2 toxicities were nausea (4/20), arthralgia (15/20), fatigue (16/20), maculopapular rash (1/20), diarrhea (1/20) and mucositis (1/20). At the time of surgery, 12/20 (60%) were ypT0N0 and 13/20 (65%) were ypT0/Tis. 15/20 (75%) achieved an RCB 0/1, 4/20 (20%) were RCB 2 and 1/20 (5%) was RCB 3. Of the 11 patients with node-positive disease at diagnosis, 9/11 (82%) became ypN0, 1/11 (9%) became ypN1mic and 1/11 (9%) became ypN1a. No patients progressed during treatment. Change in TILs after pembro or pembro-RT did not correlate with treatment response, however baseline TIL count ≥10% in the initial biopsy was associated with pCR (p = 0.005). Further profiling of the immune cells in the biopsies revealed that RCB 0/1 patients were strongly associated with increased numbers of CD8+ T cells and lower numbers of CD11b+ myeloid cells following the combination of pembro and RT.

Conclusions: Neoadjuvant pembro plus RT prior to SOC chemotherapy is safe/feasible and may increase pCR rates and clearance of nodal metastases beyond chemotherapy alone. A phase 2 study of checkpoint blockade + RT expansion of this trial (n=50) is currently accruing.

Citation Format: Heather McArthur, Stephen Shiao, Scott Karlan, Reva Basho, Farin Amersi, Brittany Arnold, Michele Burnison, Alice Chung, Cathie Chung, Catherine Dang, Armando Giuliano, Nimmi Kapoor, Negin Habibi Khameneh, Simon Knott, Cynthia Martin, Philomena McAndrew, Monica Mita, Dorothy Park, Christina DiLauro Abaya, Alice Ho. Pre-operative pembrolizumab (Pembro) with radiation therapy (RT) in patients with operable triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-09.