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.

Background Loss of HER2 “positivity” can occur in patients with residual disease after neoadjuvant treatment, but the incidence of HER2‐positivity loss after neoadjuvant dual HER2‐targeted treatment plus chemotherapy, the current standard‐of‐care for most early stage HER2‐positive breast cancers, is not well described. Previous studies that report the HER2 discordance rate after neoadjuvant treatment also do not include the novel HER2‐low category. In this retrospective study, we determine the incidence and prognostic impact of HER2‐positivity loss, including the evolution to HER2‐low disease, after neoadjuvant dual HER2‐targeted therapy with chemotherapy. Methods Clinicopathologic data for patients with stage I‐III HER2+ breast cancer diagnosed between 2015 and 2019 were reviewed in this single institution retrospective study. Patients who received dual HER2‐targeted treatment with chemotherapy were included, and HER2 status before and after neoadjuvant therapy was interrogated. Results A total of 163 female patients were included in the analysis with a median age of 50 years. A pathologic complete response (pCR as defined by ypT0/is) was achieved in 102 (62.5%) of 163 evaluable patients. Among the 61 patients with residual disease after neoadjuvant therapy, 36 (59.0%) had HER2‐positive and 25 (41.0%) had HER2‐negative residual disease. Of the 25 patients with HER2‐negative residual disease, 22 (88%) of patients were classified as HER2‐low. After a median follow‐up of 3.3 years, patients who retained HER2‐positivity after neoadjuvant treatment had a 3‐year IDFS rate of 91% (95% CI, 91%–100%), while patients who lost HER2‐positivity had a 3‐year IDFS rate of 82% (95% CI, 67%–100%). Conclusion Almost half of patients with residual disease following neoadjuvant dual HER2‐targeted therapy plus chemotherapy lost HER2‐positivity. The loss of HER2‐positivity may not confer negative prognostic impact, although the results were limited by short follow‐up time. Further research on the HER2 status after neoadjuvant treatment may help guide treatment decisions in the adjuvant setting.

TPS617 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with checkpoint inhibition augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ipi/nivo/cryo in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER < 10%, PR < 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 80 pts will be enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686.

Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with immune checkpoint inhibition (ICI)-augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ipilimumab (ipi) +/- nivolumab (nivo) was not only safe in patients (pts) with operable, early stage breast cancer (ESBC) but also generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ICI in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible pts are ≥18y, with ER &lt; 10%, PR &lt; 10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. Approximately 80 pts will be enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo across multiple institutions. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and will receive ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts will receive 3 additional doses of nivo at 240mg IV Q2 weeks. Adjuvant capecitabine is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Funding sources: Susan G. Komen, ASCO Conquer Cancer Foundation, Breast Cancer Research Foundation, Bristol-Myers Squibb, BTG International Ltd. NCT03546686 Citation Format: Heather McArthur, Elizabeth Comen, Yolanda Bryce, Stephen Solomon, Jorge Henrique Santos Leal, Christina DiLauro Abaya, Cristal Martinez, Reva Basho, Dorothy Park, Philomena McAndrew, Brigid Larkin, William Mills, David B. Page, Staci Mellinger, Nicole Fredrich, Nicole Moxon, Sangeetha Reddy, Meredith Carter, Sujata Patil, Larry Norton. A Single Arm Phase 2 Study of Peri-Operative Checkpoint-Mediated Immune Therapy and Cryoablation in Women with Hormone Receptor-Negative, HER2-Negative Early Stage/Resectable Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-19-01.

TPS635 Background: Local tumor destruction with cryoablation (cryo) induces inflammation and releases antigens that can activate tumor-specific immune responses. Pre-clinically, cryo with immune checkpoint inhibition (ICI) augmented tumor-specific immune responses and prevented recurrence. Clinically, we established that peri-operative (peri-op) cryo with ICI [ipilimumab (ipi) +/- nivolumab (nivo)] was safe in patients (pts) with operable, early stage breast cancer (ESBC) and generated robust intra-tumoral and systemic immune responses. In this phase 2 study, we evaluate the disease specific impact of peri-op ICI in women with residual triple negative breast cancer (TNBC) after neoadjuvant chemotherapy (NAC), a subset at high risk of early relapse. Methods: Eligible women are ≥18y, with ER <10%, PR <10%, HER2 negative (per ASCO/CAP definition), ≥ 1.0 cm, residual operable disease after taxane-based NAC. As of 2/14/21, 16/80 pts have been enrolled and treated with ipi/nivo/cryo followed by breast surgery and adjuvant nivo. Pts undergo percutaneous, image-guided cryo with concurrent research core biopsy 7-10 days prior to surgery and received ipi (1mg/kg IV) with nivo (240mg IV) 1 to 5 days prior to cryo. After surgery, pts received 3 additional doses of nivo at 240mg IV Q2 weeks. To reflect the US FDA approval of curative-intent pembrolizumab (pembro) in 2021, the protocol was recently amended to allow standard-of-care pembro as an alternative ICI option. Adjuvant capecitabine or olaparib is recommended for all patients per local standard-of-care. Patients will be stratified by NAC platinum administration, NAC anthracycline administration, and clinical nodal status (positive versus negative). The primary endpoint is 3-year Event Free Survival (EFS). Secondary endpoints include Invasive Disease-Free Survival (IDFS), Distant Disease-Free Survival (DDFS), overall survival (OS) and safety. Exploratory correlative studies will be performed on tumor and serum to characterize the immunologic impact of the intervention and to explore predictors of efficacy and toxicity. Clinical trial information: NCT03546686 .