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Paclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial.

ABSTRACT: Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD73 antibody oleclumab in combination with the anti-PD-L1 durvalumab and 12 cycles of weekly carboplatin and paclitaxel. In the phase II part, 127 women were randomized 1:1 to receive chemo-immunotherapy, with (arm A) or without (arm B) oleclumab. The primary endpoint was the clinical benefit rate at week 24, defined as stable disease, partial or complete response per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, survival outcomes (progression-free survival and overall survival), and safety. The trial did not meet its primary endpoint, as the 24-week clinical benefit rate was not significantly improved by adding oleclumab (43% vs. 44%, p = 0.61). Exploratory median progression-free survival was 5.9 months in arm A as compared to 7.0 months in arm B (p = 0.90). The safety profile was manageable in both arms.

SUBMITTER: Buisseret L

PROVIDER: S-EPMC10622534 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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Paclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial.

Buisseret Laurence L Loirat Delphine D Aftimos Philippe P Maurer Christian C Punie Kevin K Debien Véronique V Kristanto Paulus P Eiger Daniel D Goncalves Anthony A Ghiringhelli François F Taylor Donatienne D Clatot Florent F Van den Mooter Tom T Ferrero Jean-Marc JM Bonnefoi Hervé H Canon Jean-Luc JL Duhoux Francois P FP Mansi Laura L Poncin Renaud R Barthélémy Philippe P Isambert Nicolas N Denis Zoë Z Catteau Xavier X Salgado Roberto R Agostinetto Elisa E de Azambuja Evandro E Rothé Françoise F Craciun Ligia L Venet David D Romano Emanuela E Stagg John J Paesmans Marianne M Larsimont Denis D Sotiriou Christos C Ignatiadis Michail M Piccart-Gebhart Martine M

Nature communications 20231102 1

Chemo-immunotherapy is the first-line standard of care for patients with PD-L1 positive metastatic triple-negative breast cancer (mTNBC). SYNERGY (NCT03616886) is a dose-finding phase I and a randomized phase II, open-label trial evaluating if targeting the immunosuppressive adenosine pathway can enhance the antitumor activity of chemo-immunotherapy. The phase I part included 6 patients with untreated locally-advanced or mTNBC to determine the safety and recommended phase II dose of the anti-CD7 ...[more]

PMID: 37919269

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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.

Project description:PurposeImmunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease.MethodsThis phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control.ResultsSeven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents.ConclusionCarboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer.

Dataset Information

Paclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial.

Publications

Paclitaxel plus carboplatin and durvalumab with or without oleclumab for women with previously untreated locally advanced or metastatic triple-negative breast cancer: the randomized SYNERGY phase I/II trial.

Similar Datasets

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