Chemotherapy and immune checkpoint inhibitors have a role in the post-neoadjuvant setting in patients with triple-negative breast cancer (TNBC). However, the effects of nivolumab, a checkpoint inhibitor, capecitabine, or the combination in changing peripheral immunoscore (PIS) remains unclear. This open-label randomized phase II OXEL study (NCT03487666) aimed to assess the immunologic effects of nivolumab, capecitabine, or the combination in terms of the change in PIS (primary endpoint). Secondary endpoints include the presence of ctDNA, toxicity, clinical outcomes at 2-years and association of ctDNA and PIS with clinical outcomes. Forty-five women with TNBC and residual invasive disease after standard neoadjuvant chemotherapy were randomized to nivolumab, capecitabine, or the combination. Here we show that a combination of nivolumab plus capecitabine leads to a greater increase in PIS from baseline to week 6 (91%) compared with nivolumab (47%) or capecitabine (53%) alone (log-rank p = 0.08), meeting the pre-specified primary endpoint. In addition, the presence of circulating tumor DNA (ctDNA) was associated with disease recurrence, with no new safety signals in the combination arm. Our results provide efficacy and safety data on this combination in TNBC and support further development of PIS and ctDNA analyses to identify patients at high risk of recurrence.

FL reports consulting/advisory role for AstraZeneca, Pfizer, Merck and Daiichi Sankyo; and institutional research funding from Eisai, AstraZeneca, CytomX and Gilead Sciences. MGM reports consulting/advisory roles for GE and Seagen. GJ reports being a shareholder and employee of NeoGenomics. CG reports serving on advisory boards for AstraZeneca, Daiichi Sankyo and Lilly Oncology. R.Na reports serving on advisory boards for AstraZeneca, BeyondSpring, Fujifilm, GE, Gilead, Infinity, iTeos, Merck, OBI, Oncosec, Sanofi and Seagen; and reports research funding from Arvinas, AstraZeneca, Celgene, Corcept Therapeutics, Genentech/Roche, Gilead/Immunomedics, Merck, OBI Pharma, OncoSec, Pfizer, Relay, Seattle Genetics, Sun Pharma and Taiho. ES-R reports serving as a consultant for Lilly, Mylan, Novartis, Immunomedics, AstraZeneca, Seagen, and Merck; and institutional research funding from Susan G. Komen, V Foundation, Breast Cancer Research Foundation of Alabama and the National Institutes of Health. ND, JC and R.Nu report current employment with AstraZeneca. PT reports advisory/consultancy roles for AstraZeneca, Daiichi Sankyo and Lilly. SMT reports a consulting or advisory role for Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, Seattle Genetics, CytomX Therapeutics, Daiichi-Sankyo, Gilead, Ellipses Pharma, 4D Pharma, OncoSec Medical Inc., BeyondSpring Pharmaceuticals, OncXerna, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Myovant, Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Biopharma, Bayer, Incyte Corp, and Jazz Pharmaceuticals. SMT receives research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, Gilead, NanoString Technologies, Seattle Genetics, and OncoPep. SMS reports serving on advisory boards with honorarium at AstraZeneca, Daiichi-Sankyo, Aventis, Silverback Therapeutics, Genentech/Roche, Merck, Biotheranostics, Natera, Lilly, Molecular Templates and Exact Sciences; institutional research funding from Kailos Genetics and Genentech/Roche; third party in-kind writing from Genentech/Roche and AstraZeneca; and stock and stock options from Seagen. PP reports consulting for BOLT Therapeutics, AbbVie and Perthera; and serving as an unpaid steering committee member of a clinical trial for Seagen.

NCT03487666

This study was supported by research grant P30CA051008-25 from the National Cancer Institute (NCI), the Schulbe Family/Nina Hyde Center for Breast Cancer Research, a Partners in Research grant from Georgetown University, the Intramural Research Program Center for Cancer Research, NCI, the Benderson Family Funds (FL), the Forget Me Not Fund (HAP), and Inivata. Bristol-Myers Squibb provided nivolumab. The funders did not play a role in the study design, data collection and analysis, or manuscript writing. The sponsor investigator is Dr. Filipa Lynce.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The MedStar Georgetown University Hospital Institutional Review Board gave ethical approval for this work.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Summarized clinical data, peripheral immune subset data and the original clinical trial protocol are provided as Supplementary Information. According to Georgetown IRB authorization based on patients consent to share genomic data, the WES data of 26/35 patients will be deposited to dbGaP. Source data are provided with this paper. Data will be located indefinitely in controlled access data storage at Dana-Farber Cancer Institute.