The PEARL trial: Pre-operative pembrolizumab with radiation therapy in early stage triple negative breast cancer

Abstract Background: Anti-PD(L)1 in addition to neoadjuvant chemotherapy (NAC) can achieve pathologic complete response (pCR) rates of up to 65% in patients with early stage triple negative breast cancer (TNBC). However, patients with non-pCR can have dismal prognosis. Innovative strategies that render the tumor microenvironment more sensitive to anti-PD(L)1 may confer benefit. Preclinical studies have shown that hypofractionated radiation therapy (RT) delivered to an in-situ breast tumor, when combined with immune checkpoint blockade, stimulates anti-tumor immune responses and induces long-term, tumor-specific memory. Here, we report the first results of a phase II study that established the feasibility and efficacy of this approach in the pre-operative treatment setting for TNBC. Methods: Fifty patients with stage I-III TNBC, defined as ER<10%,PR<10%, HER2-negative, were enrolled between 12/17-4/21. Study treatment consisted of one cycle (C1) of pembro (200 mg iv q 3wks), followed by cycle 2 (C2) of pembro + RT (24Gy) delivered to a breast primary, followed by NAC regimen per MD choice, surgery and adjuvant therapy. Paired tumor biopsies and blood were collected at 3 serial time points: 1) baseline (pre-treatment); 2) after pembro C1; 3) after pembro C2 + RT (prior to initiation of NAC). All patients received breast and axillary surgery and postoperative RT to the chest wall and regional lymph nodes. Dual primary endpoints were: 1) feasibility, defined by the number of patients who did not necessitate a >4-week delay in initiating NAC after pembro C2 + RT; 2) change in tumor infiltrating lymphocyte (TIL) score. Secondary endpoints included pCR, defined as ypT0/TisypN0, in addition to toxicity and cosmesis evaluations. Results: To date, 50 patients are evaluable with a median follow up of 12 months (range 6-12). Median age of cohort is 55y (range 26-76). The majority (92%) were clinical stage II; 2% stage I and 6% stage III. 34% of the cohort had biopsy-proven, node positive disease. All patients received a taxane, 52% carboplatin and 74% anthracycline. 12% did not complete the planned course of NAC due to toxicities. No patients experienced a delay in initiating NAC. 50% received breast-conserving surgery and 50% mastectomy. Grade 1 or 2 toxicities consisted of fatigue (76%), nausea (66%), maculopapular rash (32%), diarrhea (38%), colitis (2%), hypothyroidism (8%) and peripheral neuropathy (40%). Four patients had grade 3 toxicities that were attributable to pembro: hyponatremia(1), colitis (1), adrenal insufficiency(1) and pneumonitis (1). Three patients had grade 4 neutropenia which were not attributable to pembro. The overall rate of pCR was 74% (37/50). Among the 13 patients with non-pCR, 0% were RCB 1, 16% RCB 2 and 10% RCB 3. Among the 17 N+ patients, 13 converted to ypN0, 1 ypN1mic and 3 ypN1a. No patients progressed during treatment. Changes in TIL count, PD-L1 and other biomarkers after pembro +/- RT and their association with treatment response, will be presented at the meeting. Conclusions: The novel combination of pre-operative pembro followed by the addition of RT to pembro prior to NAC is not only feasible, but also achieves pCR rates that are higher-than-expected compared to the pembro arm of KEYNOTE-522. AEs were consistent with known safety profiles of each agent. If confirmed by larger, randomized studies, this combination will be paradigm-changing for the treatment of TNBC. Citation Format: Heather L McArthur, Stephen Shiao, Scott Karlan, Reva Basho, Farin Amersi, Michele Burnison, Amin Mirhadi, Alice Chung, Cathie T Chung, Catherine Dang, Heather Richardson, Armando E Giuliano, Nimmi Kapoor, Brigid Larkin, Hector Godinez, Samantha A Dunn, Negin Habibi Khameneh, Simon Knott, Philomena McAndrew, Monica Mita, Dorothy J Park, Christina Abaya, Jonathan H Chen, Amy Ly, Veerle Bossuyt, Alice Ho. The PEARL trial: Pre-operative pembrolizumab with radiation therapy in early stage triple negative breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-01.