DART Rare Cancers Trial Publishes Comprehensive Results

The SWOG S1609 DART trial has broken considerable new ground in the study of rare cancers since its launch almost a decade ago. Now, the comprehensive final results of the trial have been published, in the August issue of Annals of Oncology. 

Some of the principal takeaways: 

• 24 of DART’s 53 rare cancer cohorts reported clinical activity, defined as having at least two patients with a confirmed response to the study’s dual immune checkpoint inhibitor (ICI) treatment
• 31 of the 53 cohorts recorded at least one objective response
• patients in a number of cohorts had durable responses to treatment, and across all cohorts 3-year overall survival was 24 percent

Collectively, rare malignancies account for more than one in five of all cancer diagnoses. But given the small number of patients diagnosed with any individual malignancy and the large number of rare cancer histologies, these patients are substantially underrepresented in clinical trials overall.

DART (Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors) is one model for addressing this unmet need. The S1609 basket trial was designed to evaluate the efficacy of dual ICIs (ipilimumab and nivolumab) against a range of refractory rare cancers.

The primary endpoint for each cohort was objective response rate (ORR). Secondary endpoints included toxicity, progression-free survival, overall survival, and clinical benefit rate (ORR plus stable diseaese for at least six months). 

Activated in early 2017, the study initially featured 32 rare cancer cohorts, along with a not otherwise categorized group. Trial accrual was unexpectedly brisk, and new cohorts representing additional rare cancers were soon added, with DART eventually encompassing 53 patient cohorts. 

Putting all of these cohorts under a single trial protocol meant trial sites faced a much lower regulatory burden than they would have in opening multiple rare cancer studies. It also meant sites could open a rare cancer trial without as much concern about their ability to accrue to it. 

More than 1,000 clinical sites did open DART, and 218 sites enrolled patients. When accrual closed in 2023, a total of 798 patients with rare cancers had been registered, with 727 eligible and going on to receive treatment on the trial.

Malignancies in which DART’s dual ICI regimen demonstrated some efficacy, often with durable responses, have included (among others): 

• metaplastic breast cancer, 
• neuroendocrine tumors,
• angiosarcoma,
• thyroid carcinomas,
• rare gynecologic cancers,
• high-grade neuroendocrine neoplasms, 
• adrenocortical carcinoma, 
• gestational trophoblastic neoplasms,
• sarcomatoid carcinoma of the lung, and
• desmoid tumors.

For a number of these rare cancers, DART results have changed the standard-of-care and have been incorporated into National Comprehensive Cancer Network (NCCN) guidelines. 

Many hands have contributed to the trial’s success. Study co-chairs are Drs. Sandip Patel, Young Kwang Chae, and Razelle Kurzrock, and the trial’s innovative statistical framework was crafted (and recrafted as additional cohorts were added) by Megan Othus, PhD; Melissa Plets, MS; and Edward Mayerson, MS. 

SWOG group chair Dr. Charles Blanke and executive officer Dr. Christopher Ryan provided key leadership in getting the trial up and running, and essential patient perspective was provided all along the way by, among others, patient advocate Marcia Horn, JD. 

This SWOG team worked in close collaboration with researchers at the National Cancer Institute as well, including Drs. Howard Streicher, Helen X. Chen, and Elad Sharon.

To date, more than 60 publications and presentations have come from DART, and analysis of trial results continues, including correlative work to better understand the factors associated with response – and resistance – to immunotherapy across many of these rare cancers.

A full bibliography is available via the S1609 trial page on swog.org. Scroll halfway down that page and click on “Publication Information” to expand the list. 

In the history of progress in developing treatments for rare cancers, the S1609 DART trial warrants its own chapter.