The S2212 De-Escalation Trial: Only in Public-Powered Research

A classic example to come out of the cooperative group system is the myeloma trial that lowered the dosage of dexamethasone patients newly diagnosed were typically getting. Trial ECOG E4A03 found that cutting this by more than half actually resulted in better short-term overall survival and spared many patients serious adverse events, including life-threatening toxicities. This de-escalation trial was a game changer for myeloma patients (a trial initially proposed and championed by a patient advocate, by the way).

SWOG S2212 – Shorter Anthracycline-Free Chemo Immunotherapy Adapted to Pathological Response in Early Triple-Negative Breast Cancer, also known as SCARLET – is a de-escalation trial in a similar mold. 

Neoadjuvant chemo-immunotherapy that pairs taxane, platinum, and anthracycline drugs with an immune checkpoint inhibitor is widely used in treating patients with early-stage triple-negative breast cancer (TNBC). But anthracyclines such as doxorubicin come with long-term risks, including cardiotoxicity (qv SWOG S1501) and an increased risk of secondary leukemias long after therapy is completed. 

Evidence from smaller studies has suggested that chemo-immunotherapy without an anthracycline may be as efficacious for treating early-stage TNBC. 

S2212 asks whether a shorter, anthracycline-free neoadjuvant chemo-immunotherapy regimen can be used in patients with early-stage TNBC without compromising survival. And whether we can document the quality-of-life benefits of such a regimen via patient-reported outcomes (PROs). This non-inferiority trial uses breast cancer event-free survival as a primary endpoint.

Patients are randomized to one of two neoadjuvant regimens. Those on the control arm are treated with a combination of four chemotherapy drugs – paclitaxel, carboplatin, doxorubicin, and cyclophosphamide – plus pembrolizumab, for eight cycles (24 weeks). Patients on the investigational arm get a two-drug chemotherapy combination (docetaxel and carboplatin), plus pembrolizumab, for six cycles (18 weeks).

If these two regimens are shown to have similar efficacy, insight from PROs collected on the trial will be important in helping future patients and their doctors select between them. S2212’s PRO sub-study tests the hypothesis that patients on the shorter, anthracycline-free regimen will experience less fatigue and better physical functioning than their counterparts on the standard regimen.

Also, prior research has shown that in patients with early-stage TNBC, higher levels of stromal tumor-infiltrating lymphocyte (sTILs) are associated with better outcomes. So, S2212 will also compare response rates and survival between treatment arms by sTIL enrichment status, using centrally assessed sTILs. 

Once their neoadjuvant therapy is complete and patients on S2212 have undergone surgery, adjuvant therapy is at the treating physician’s discretion, although for both arms the protocol recommends a full year of adjuvant pembrolizumab, the current standard of care.

For patients whose disease exhibits pathologic complete remission after neoadjuvant therapy, the protocol recommends pembrolizumab alone. For those with residual disease, pembrolizumab plus adjuvant chemotherapy at the physician’s discretion is recommended.

Who can be enrolled to S2212? Most patients with histologically confirmed early-stage TNBC who are eligible to receive chemo-immunotherapy would be eligible for the trial (the few exceptions include patients with N3 or T4 disease, inflammatory breast cancer, or metastatic disease).

The study opened in July of 2023, and as of early this week 541 patients have been enrolled toward an accrual goal of 2,400 participants (S2212 is one of the largest trials we have underway). Almost 900 sites are approved to conduct the study, and about 200 of those sites have already registered at least one patient.

Dr. Priyanka Sharma is S2212 study chair, with Dr. Zahi Mitri as international co-chair and Dr. David Rimm as translational medicine chair. Allison Meisner, PhD, is the study’s lead biostatistician, and the S2212 PRO sub-study is chaired by Drs. Michelle Loch and Lynn Henry.

Importantly, the study is supported widely across the National Clinical Trials Network – NRG Oncology, Alliance, and ECOG-ACRIN all have study champions on this trial.

An S2212 revision is now under review that will expand remote consenting, telehealth options, local laboratory testing, and administration of treatment by local oncologists. These changes should make it easier for more patients in the U.S. to consider joining the study and for some of our Latin American member sites to also open the trial. 

As with all of our trials, when you present S2212 to a potential participant, please make use of our patient-friendly trial summary (also available in Spanish).

S2212 asks important questions. The answers could improve the lives of many who develop TNBC, which accounts for about 15 percent of all breast cancer diagnoses. These are questions the National Cancer Institute’s cooperative group system – public-powered research devoted to improving patients’ lives – is uniquely qualified to answer. SWOG is proud to be a part of that patient-centric system, and is proud to lead S2212.

Register now to attend our Best of SWOG one-hour research showcase on March 26th, 2-3 ET / 11-12 PT. Learn more.