Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Schmid, Peter; Chui, Stephen Y.; Emens, Leisha A.

doi:10.1056/nejmoa1809615

Cited by 3,331 publications

(3,189 citation statements)

References 28 publications

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“…Only 18.5% of TNBC patients responded to pembrolizumab monotherapy in the Keynote 012 trial . Similarly, 8.6% of locally advanced or metastatic TNBC patients responded to avelumab, and 26% of metastatic TNBC patients responded to atezolizumab . It has been proposed that a combination of PD‐L1‐targeting therapies with other targeted agents may work more effectively compared to anti‐PD‐L1 monotherapy in TNBCs .…”

Section: Discussionmentioning

confidence: 99%

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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Triple‐negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25–30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non‐TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA‐approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA‐MB‐231 xenograft and patient‐derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T‐cell tumor infiltration in vivo and upregulated immune checkpoint PD‐L1 expression in an ERK1/2‐MYC‐dependent manner. Moreover, combination of AF with anti‐PD‐L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti‐PD‐L1 antibody that warrants further clinical investigation for TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Raninga

Lee

Sinha

et al. 2019

Intl Journal of Cancer

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“…For various reasons, the results herein were not directly comparable to those of other trials investigating checkpoint inhibitors in patients with mTNBC. 34 In contrast, all patients in the current study had significantly more advanced disease, as denoted by the high median number of prior chemotherapies and the sizeable percentage of patients (6 of 17 patients) who required reirradiation for local PD despite the receipt of prior RT. 7,[30][31][32][33] In the KEYNOTE-012 trial of pembrolizumab alone in patients with mTNBC, the ORR was 18.5%; however, all patients had >1% PD-L1 positivity according to immunohistochemistry.…”

Section: Discussionmentioning

confidence: 53%

“…7,[30][31][32][33] In the KEYNOTE-012 trial of pembrolizumab alone in patients with mTNBC, the ORR was 18.5%; however, all patients had >1% PD-L1 positivity according to immunohistochemistry. For various reasons, the results herein were not directly comparable to those of other trials investigating checkpoint inhibitors in patients with mTNBC.…”

Section: Discussionmentioning

confidence: 99%

“…7,[30][31][32][33] In the KEYNOTE-012 trial of pembrolizumab alone in patients with mTNBC, the ORR was 18.5%; however, all patients had >1% PD-L1 positivity according to immunohistochemistry. 34 Conversely, in the KEYNOTE-086 study, there was no difference in the ORR noted between the PD-L1-positive patients compared with the PD-L1-negative patients (5% [95% CI, 2%-11%] vs 5% [95% CI, 1%-13%]; P = 1) after the administration of pembrolizumab. 34 In contrast, all patients in the current study had significantly more advanced disease, as denoted by the high median number of prior chemotherapies and the sizeable percentage of patients (6 of 17 patients) who required reirradiation for local PD despite the receipt of prior RT.…”

Section: Discussionmentioning

confidence: 99%

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A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple‐negative breast cancer

Barker

Arnold

et al. 2019

Cancer

131

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BACKGROUND:The current study was conducted to evaluate the efficacy and safety of pembrolizumab-mediated programmed cell death protein 1 inhibition plus radiotherapy (RT) in patients with metastatic triple-negative breast cancer who were unselected for programmed death-ligand 1 expression. METHODS: The current study was a single-arm, Simon 2-stage, phase 2 clinical trial that enrolled a total of 17 patients with a median age of 52 years (range, 37-73 years). An RT dose of 3000 centigrays (cGy) was delivered in 5 daily fractions. Pembrolizumab was administered intravenously at a dose of 200 mg within 3 days of the first RT fraction, and then every 3 weeks ± 3 days until disease progression. The median follow-up was 34.5 weeks (range, 2.1-108.3 weeks). The primary endpoint of the current study was the overall response rate (ORR) at week 13 in patients with unirradiated lesions measured using Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1). Secondary endpoints included safety and progression-free survival. Exploratory objectives were to identify biomarkers predictive of ORR and progression-free survival. RESULTS: The ORR for the entire cohort was 17.6% (3 of 17 patients; 95% CI, 4.7%-44.2%), with 3 complete responses (CRs), 1 case of stable disease, and 13 cases of progressive disease. Eight patients died prior to week 13 due to disease progression. Among the 9 women assessed using RECIST version 1.1 at week 13, 3 (33%) achieved a CR, with a 100% reduction in tumor volume outside of the irradiated portal. The CRs were durable for 18 weeks, 20 weeks, and 108 weeks, respectively. The most common grade 1 to 2 toxicity (assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0) was dermatitis (29%). Four grade 3 adverse events were attributed to pembrolizumab: fatigue, lymphopenia, and infection. No were no grade 4 adverse events or treatment-related deaths reported. CONCLUSIONS: The combination of pembrolizumab and RT was found to be safe and demonstrated encouraging activity in patients with poor-prognosis, metastatic, triplenegative breast cancer who were unselected for programmed death-ligand 1 expression. Larger clinical trials of checkpoint blockade plus RT with predictive biomarkers of response are needed. Cancer 2020;126:850-860.

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“…In addition, maximum benefit might be restricted to patients with certain characteristics and detection of biomarkers including but not limited to T cell infiltration, mutational load and PD‐L1 expression . Very recently, a prospective, randomized phase 3 trial in advanced untreated triple‐negative breast cancer (TNBC) showed increased PFS in patients receiving the PD‐L1 blocking antibody atezolizumab plus nab‐paclitaxel in comparison to nab‐paclitaxel plus placebo . Increased OS by adding atezolizumab to nab‐paclitaxel was only reported for PD‐L1 positive tumors.…”

Section: Introductionmentioning

confidence: 99%

Localization of PD‐L1 on single cancer cells by iSERS microscopy with Au/Au core/satellite nanoparticles

Stepula

König

Wang

et al. 2020

Journal of Biophotonics

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Programmed cell death‐ligand 1 (PD‐L1) is an important predictive biomarker. The detection of PD‐L1 can be crucial for patients with advanced cancer where the use of immunotherapy is considered. Here, we demonstrate the use of immuno‐SERS microscopy (iSERS) for localizing PD‐L1 on single cancer SkBr‐3 cells. A central advantage of iSERS is that the disturbing autofluorescence from cells and tissues can be efficiently minimized by red to near‐infrared laser excitation. In this study we employed Au/Au core/satellite nanoparticles as SERS nanotags because of their remarkable signal brightness and colloidal stability upon red laser excitation. False‐color iSERS images of the positive and negative controls clearly reveal the specific localization of PD‐L1 with SERS nanotag‐labeled antibodies.

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Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Cited by 3,331 publications

References 28 publications

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple‐negative breast cancer

Localization of PD‐L1 on single cancer cells by iSERS microscopy with Au/Au core/satellite nanoparticles

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Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer

Cited by 3,331 publications

References 28 publications

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple‐negative breast cancer

Localization of PD‐L1 on single cancer cells by iSERS microscopy with Au/Au core/satellite nanoparticles

Contact Info

Product

Resources

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A phase 2 clinical trial assessing the efficacy and safety of pembrolizumab and radiotherapy in patients with metastatic triple‐negative breast cancer