Dataset Information

A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer.

ABSTRACT: Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200 mg IV every 3 weeks) with either weekly paclitaxel (80 mg/m² weekly) or flat-dose capecitabine (2000 mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n = 4/13, 95% CI: 10-61%) and 43% for pembrolizumab/capecitabine (n = 6/14, 95% CI: 18-71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor-infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted. The clinical trial registration is NCT02734290.

SUBMITTER: Page DB

PROVIDER: S-EPMC10284878 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer.

Page David B DB Pucilowska Joanna J Chun Brie B Kim Isaac I Sanchez Katherine K Moxon Nicole N Mellinger Staci S Wu Yaping Y Koguchi Yoshinobu Y Conrad Valerie V Redmond William L WL Martel Maritza M Sun Zhaoyu Z Campbell Mary B MB Conlin Alison A Acheson Anupama A Basho Reva R McAndrew Philomena P El-Masry Mary M Park Dorothy D Bennetts Laura L Seitz Robert S RS Nielsen Tyler J TJ McGregor Kimberly K Rajamanickam Venkatesh V Bernard Brady B Urba Walter J WJ McArthur Heather L HL

NPJ breast cancer 20230621 1

Chemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200 mg IV every 3 weeks) with either weekly paclitaxel (80 mg/m<sup>2</sup> weekly) or flat-dose capecitabine (2000 mg orally twice daily for 7 days of every ...[more]

PMID: 37344474

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Project description:Chemoimmunotherapy is a standard treatment for triple-negative breast cancer (TNBC), however, the impacts of different chemotherapies on T-cell populations, which could correlate with clinical activity, are not known. Quantifying T-cell populations with flow cytometry and T-cell receptor (TCR) immunosequencing may improve our understanding of how chemoimmunotherapy affects T-cell subsets, and to what extent clonal shifts occur during treatment. TCR immunosequencing of intratumoral T cells may facilitate the identification and monitoring of putatively tumor-reactive T-cell clones within the blood. Blood and tumor biopsies were collected from patients with metastatic TNBC enrolled in a phase Ib clinical trial of first or second-line pembrolizumab with paclitaxel or capecitabine. Using identical biospecimen processing protocols, blood samples from a cohort of patients treated for early-stage breast cancer were obtained for comparison. Treatment-related immunological changes in peripheral blood and intratumoral T cells were characterized using flow cytometry and TCR immunosequencing. Clonal proliferation rates of T cells were compared based on intratumoral enrichment. When combined with pembrolizumab, paclitaxel and capecitabine resulted in similar time-dependent lymphodepletions across measured peripheral T-cell subsets. Their effects were more modest than that observed following curative-intent dose-dense anthracycline and cyclophosphamide (ddAC) (average fold-change in CD3+ cells, capecitabine: -0.42, paclitaxel: -0.56, ddAC: -1.21). No differences in T-cell clonality or richness were observed following capecitabine or paclitaxel-based treatments. Regression modeling identified differences in the emergence of novel T-cell clones that were not detected at baseline (odds compared with ddAC, capecitabine: 0.292, paclitaxel: 0.652). Pembrolizumab with paclitaxel or capecitabine expanded T-cell clones within tumors; however, these clones did not always expand within the blood. Proliferation rates within the blood were similar between clones that were enriched and those that were not enriched within tumors. Chemoimmunotherapy for metastatic TNBC with pembrolizumab and capecitabine or paclitaxel resulted in similar peripheral T-cell subset lymphodepletion without altering T-cell clonal diversity. Regression modeling methods are applicable in immune monitoring studies, such as this to identify the odds of novel T-cell clones emerging during treatment, and proliferation rates of tumor-enriched T-cell clones.

Project description:BackgroundLenvatinib plus pembrolizumab has demonstrated improved survival compared with doxorubicin or paclitaxel monotherapy in patients with advanced or recurrent endometrial cancers (ECs). However, response rates to monotherapy are poor in recurrent settings. Herein, we performed a retrospective analysis using real-world data to compare the outcomes of lenvatinib plus pembrolizumab, carboplatin plus paclitaxel (PT), and doxorubicin for patients with PT-pretreated, advanced, or recurrent ECs.MethodsWe performed a multi-institutional retrospective analysis using de-identified electronic health record database (TriNetX) to compare lenvatinib plus pembrolizumab, carboplatin plus paclitaxel (PT), and doxorubicin outcomes in patients with PT-pretreated, advanced, or recurrent ECs. A 1:1 propensity score matching (PSM) was conducted. The primary outcome was the overall survival (OS) among treatment groups. The secondary outcome was the adverse event profile.ResultsBetween January 2012 and September 2023, we identified 397 patients with PT-treated, advanced, or recurrent ECs who received lenvatinib plus pembrolizumab, and 469 patients receiving PT at a platinum-free interval of over 6 months. Following PSM, no significant difference in median OS was observed between the lenvatinib plus pembrolizumab and re-challenge PT groups (19.1 vs. 18.5 months, p = 0.60; hazard ratio: 1.08, 95% confidence interval 0.81-1.46). However, lenvatinib plus pembrolizumab provided better survival benefits than doxorubicin. Adverse event analysis showed more hypothyroidism, hypertension, and proteinuria with lenvatinib plus pembrolizumab, and more hematologic toxicities in both chemotherapy groups.ConclusionsLenvatinib plus pembrolizumab was not associated with improved survival when compared with re-challenge PT in patients with a platinum-free interval of over 6 months. Re-challenge PT remains a valid option for PT-treated, recurrent, or advanced ECs, especially in patients with a substantially long platinum-free interval.

Dataset Information

A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer.

Publications

A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer.

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