Search

Background: Neoadjuvant association of immune checkpoints inhibitors (ICI) and dose dense chemotherapy is promising for triple negative breast cancers (TNBC). However, response rates vary from one study to another. Timing, best chemotherapy partner and efficacy in less immunogenic breast cancer (BC), like luminal B tumors, should be further investigated. This study evaluates for TNBC and luminal B HER2(-) BC the neoadjuvant treatment with paclitaxel followed by a short combination of an anti-PD-L1 antibody with anthracyclines. Method B-IMMUNE (NCT03356860), a multicentric phase Ib/II prospective trial, included patients with stage I to III luminal B HER2(-) or TNBC treated with paclitaxel 80mg/m2 weekly from week 1 to 12 followed by 4 cycles of epirubicine 90mg/m2 and cyclophosphamide 600 mg/m2 (EC) Q2W in a neoadjuvant setting. Phase Ib evaluated a single infusion of durvalumab (anti-PD-L1) combined with the 3rd cycle of EC. Phase II evaluated infusions of durvalumab with the 1st and 3rd EC cycles. Surgery was planned 3 weeks after the last EC cycle. Primary objectives were safety and pathological complete response (pCR) rate compared to a historical control. Secondary endpoint was the overall response rate (ORR) based on breast MRI. Eleven patients were enrolled in a control arm without durvalumab, exclusively for translational research purposes. Based on a 2-stage Simon design with an α = 0.1 and β = 0.1, 22 TNBC patients were needed in the phase II to test a null hypothesis of 30% pCR rate against a one-side alternative of 60%, and 24 luminal B BC patients to test a null hypothesis of 15% pCR rate against a one-side alternative of 40% (including an additional accrual margin of 10% for eventual dropouts). At least 9 pCRs had to be observed among the first 20 evaluable TNBC patients and 6 among the first 22 evaluable luminal B patients to rule out the null hypothesis. Results This analysis concerns the 50 patients treated with the experimental treatment, 3 from the phase Ib and 47 from the phase II part. Median age was 51 y-old (31 to 72y), tumor subtypes were 24 TNBC, 25 Luminal B and one sarcoma excluded from the efficacy analysis. Seven (14%) patients had a stage I tumor, 17 (34%) a stage IIA, 13 (26%) a stage IIB, 8 (16%) a stage IIIA, 4 (8%) a stage IIIB and 1 (2%) a stage IIIC. Concerning safety, 232 AEs were reported on 39/50 patients and 34 (14,6%) were graded ≥ 3. The 5 most frequent all-grade AEs were fatigue (8,2%), diarrhea (5,6%), neutropenia (5,2%), anemia and nausea (4,3%). Most frequent grade 3 AEs were anemia and neutropenia (14,7%). Among 4 immune-related adverse events, all were thyroid disorders. One patient died 10 months after the end of treatment due to progressive disease in the liver. Forty-six of the 47 phase II patients were evaluable for efficacy. pCR was reported in 12/22 TNBC patients (55%) and 8/24 luminal B HER2(-) patients (33%). Subgroup analyses based on PD-L1 expression and TILs score are planned. Conclusions The B-IMMUNE study met its primary objective showing a significant improvement in pCR versus the historical control in both TNBC and in Luminal B HER2(-) BC cohorts with the addition of only 2 doses of durvalumab to the anthracyclines. The safety profile is comparable to those previously described with reported immune related adverse events limited to thyroid endocrine disorders. Citation Format: Alix Devaux, Gabriela Beniuga, Claire Quaghebeur, Stéphanie Henry, Mieke Van Bockstal, Christine Galant, Paul Delrée, Jean-Luc Canon, Brigitte Honhon, Dominique Korman, Vincent Verschaeve, Christophe Lonchay, Sarah Lefevre, Lionel D’Hondt, Martine Berlière, Sophie Delmarcelle, Jean-Michel Mine, Timour Willems, Gebhard Müller, Nathalie Myant, Isabelle Bar, Sandy Haussy, Pierre G. Coulie, François P. Duhoux, Javier Carrasco. B-IMMUNE final analysis: a phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers. [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 P4-07-16.

Background: The association of immune checkpoints inhibitors (ICI) and dose dense chemotherapy is a promising combination in a neoadjuvant setting for triple negative breast cancers (TNBC). However, response rates vary from one study to another and timing, best chemotherapy partner and efficacy in breast cancer subtypes considered as less immunogenic, like luminal B tumors, should be further investigated. The B-immune study evaluates a neoadjuvant treatment with paclitaxel followed by a short combination of an anti-PD-L1 antibody with anthracyclines for TNBC and luminal B breast cancers (BC). Method: B-immune (NCT03356860), a multicentric phase Ib/II prospective trial, includes patients with stage I to III luminal B or TNBC treated with paclitaxel 80mg/m2 weekly from week 1 to 12 followed by 4 cycles of epirubicine 90mg/m2 and cyclophosphamide 600 mg/m2 (EC) Q2W in a neoadjuvant setting. The phase Ib evaluated a single infusion of durvalumab (anti-PD-L1) combined with the 3rd cycle of EC. The phase II, in progress, evaluates 2 infusions of durvalumab with the 1st and 3rd cycle of EC respectively. Surgery is planned 3 weeks after the last preoperative treatment. Primary objectives are safety and efficacy based on pathological complete response (pCR) rate. Considering a 2-stage Simon design, 22 TNBC patients are needed in the phase II to detect a pCR rate increase from 30% to 60% and 24 luminal B BC patients are needed to detect a pCR rate increase from 15% to 40% (α = 0.1 and β = 0.1). At least 3 pCRs must be observed among 8 TNBC patients and 2 among 10 Luminal B patients treated in the 1st stage to move to the 2nd stage. Results: This analysis concerns 3 treated patients from phase Ib and 18 from phase II who received the experimental treatment (median age 55 y-old, 10 TNBC, 11 Luminal B, 14% stage I, 67% stage II, 19% stage III). Overall, 169 AEs were reported and 22 (13%) were graded > 2 on 10/21 patients, including 27% of neutropenia (6/22), 22% of anemia (5/22), 13% of severe asthenia (3/22) and 9% of diarrhea (2/22). Four patients (19%) developed thyroid immune endocrine disorders. Efficacy was evaluated on 18 patients included in the 1st stage of phase II (8 TNBC and 10 luminal B). Five among 8 TNBC patients (62%) and 2 among 10 luminal B patients (20%) had a pCR. Conclusions: The B-immune interim analysis reveals an acceptable global safety profile. Reported immune related adverse events were limited to thyroid endocrine disorders. Observed pCR rate after neoadjuvant paclitaxel followed by 2 durvalumab infusions combined to EC chemotherapy warrants pursuing the trial for the TNBC and luminal B cohorts. Citation Format: Javier Carrasco, Claire Quaghebeur, Stephanie Henry, Christine Galant, Mieke Van Bockstal, Paul Delrée, Brigitte Honhon, Dominique Korman, Vincent Verschaeve, Christophe Lonchay, Sarah Levefre, Lionel D'hondt, Martine Berliere, Sophie Delmarcelle, Jean-Michel Mine, Timour Willems, Gebhard Müller, Nathalie Myant, Isabelle Bar, Manuel Constant, Sandy Haussy, Alix Devaux, Pierre Coulie, Jean-Luc Canon, François Duhoux. B-immune interim analysis: A phase Ib/II study of durvalumab combined with dose-dense EC in a neoadjuvant setting for patients with locally advanced luminal B HER2(-) or triple negative breast cancers [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 P2-14-12.

Background: The majority of human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) present upregulation of the epidermal growth factor receptor (EGFR) and frequent alterations in the cyclin D1-cyclin dependent kinase (CDK) 4/6 (CDK 4/6)-retinoblastoma protein (pRb) pathway, resulting in cell cycle progression and tumor proliferation. This study investigated the combination of ribociclib, an orally highly selective inhibitor of CDK 4/6, and cetuximab in recurrent and/or metastatic (R/M) SCCHN. Methods: A phase I trial using a 3 + 3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of ribociclib with standard dose of weekly cetuximab in HPV-negative patients with R/M SCCHN. Ribociclib was administered orally (3 weeks on/1 week off) at dose level 1 of 400 mg daily and dose level 2 of 600 mg daily. The MTD of ribocilib was then further evaluated in an expansion cohort. Results: 10 patients were enrolled in the escalation trial. No DLTs were observed at dose level 1 (n = 3); at dose level 2, one patient was replaced due to rapid disease progression, and one patient out of six evaluable patients experienced a DLT (grade 4 thrombocytopenia >7 days). Ribociclib 600 mg daily was thus determined to be the MTD. Eleven additional patients were enrolled in the expansion cohort. Diarrhea (52%), rash (52%), fatigue (43%), nausea (33%), and mucositis (28%) were the most frequent grade 1–2 adverse events (AE). Neutropenia was the most frequent grade 3–4 AE (20%). Median progression-free survival (PFS) was 3.5 months (range 0.4–17.3 months) and median overall survival (OS) was 8.3 months (range 0.4–24.1 months). Among the 19 radiologically evaluable patients, two (10.5%) achieved a partial response and 11 (58%) had stable disease. Conclusions: The MTD of ribociclib is 600 mg daily when administered in combination with standard dose cetuximab for 3 weeks on and 1 week off. This combination was safe and showed efficacy. Further clinical trials should be conducted to evaluate the antitumor effects of this combination. Trial Information: ClinicalTrials.gov: NCT02429089; Eudract number 2014-005371-83.

Lessons Learned Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate. This phase II study did not meet its primary endpoint. Cabazitaxel has low activity in SCCHN. The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). Background. Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. Methods. Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. Results. Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41–80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%–25%) for cabazitaxel and 8.3% (95% CI, 2%–20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3–4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). Conclusion. This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.

Tumor infiltrating lymphocytes (TIL) display activation markers and their presence is often associated with a favorable outcome. The role of tumor antigens in T cell recruitment into tumors is unclear. In an attempt to address this issue, we purified lymphocytes from breast tumor or nontumor, mammary tissue from patients, and normal mammary tissue from healthy individuals. In all groups, including healthy individuals, the majority of cells displayed an effector/memory (CD45RA lo /CD27 1/2 ) phenotype and quite surprisingly the early and transient activation marker CD69, thus, questioning the tumor antigen specificity of TIL. Because the human repertoire is diverse, the T cells found in the tumors could recognize both self/tumor and environmental antigens through cross-reactivity. To test this hypothesis, we used two anti-male HY monospecific TCR transgenic mouse models. We found an infiltration of HY negative tumors by the CD4 1 and CD8 1 monoclonal T cells after priming with HY positive cells in the periphery. Thus, the presence of activated effector/memory T lymphocytes in tumors can be independent of reactivity against tumor antigens. These results suggest that to find activated effector T cells in a tissue does not always mean that a specific immune response is taking place. ' 2005 Wiley-Liss, Inc.