Adrenocortical carcinomas are quite rare (1-2 cases per million person-years annually), but they are typically aggressive, and patient prognosis is poor. For those with advanced disease, median survival time is only about one year, and few patients achieve five-year survival.

Enrollment to SWOG’s S1609 DART (Dual Anti-CTLA-4 and Anti-PD-1 blockade in Rare Tumors) trial included 21 eligible patients with advanced/metastatic adrenocortical carcinoma, all of whom had had at least one prior line of therapy. All were treated on trial with the standard DART combination of ipilimumab and nivolumab. Results from this cohort of patients were recently reported in the Journal for Immunotherapy of Cancer.

In seven of these 21 patients, the treatment prompted a partial response or stable disease for at least six months as measured by either RECIST (Response Evaluation Criteria in Solid Tumors) or immune-related RECIST criteria. Five patients achieved progression-free survival times greater than 12 months (considered durable remissions), with the longest being 57 months.

Given the rarity of this disease, prior treatment standards were derived largely from retrospective studies, and there has also been little progress in identifying new therapies. Our authors concluded appropriately that immune checkpoint blockade is a reasonable consideration for these patients, and that DART results are encouraging.

The list of other rare cancers the DART combination has shown some success in include metaplastic breast cancerneuroendocrine tumors, angiosarcomathyroid carcinomas, gynecologic cancers, and sarcomatoid carcinoma of the lung. 

The DART trial closed to accrual last year, but I’m pleased to be able to report that development of DART II is well underway.

Its overall design closely reflects the approach used by the original DART, with about 50 rare tumor cohorts identified. But whereas DART used a combination of anti-PD-1 and anti-CTLA-4 immunotherapies, DART II (S2432) will combine an anti-PD-1 drug with an anti-LAG-3 agent.

Our principal investigator for DART II is Young Kwang Chae, MD, MPH, with co-PIs Sandip Patel, MD, PI of the original DART, and Razelle Kurzrock, MD, chair of SWOG’s early therapeutics and rare cancers committee, home to both DARTs.

Dr. Chae presented the concept to a group of SWOG patient advocates last week in a Pitch the PAC session. Advocates were enthusiastic about the design, in part because a number of them work with or have other connections to patients diagnosed with one of the included rare tumor types. 

They also noted that DART II will offer many patients with rare cancers a treatment option that would not otherwise be available to them, and the trial opens the door to learning much more about a wide array of understudied cancers.

The committee response was so positive that co-chairs Barbara Segarra-Vazquez, DHSc, and Anne Marie Mercurio agreed to provide a letter of support for DART II when the concept is submitted to the NCI’s CTEP.

The original DART is one of the studies NCI leadership points to most frequently when presenting on NCTN accomplishments, and a couple of years back it was honored with an NCI Director’s Award of Merit. There’s no question it’s one of the crown jewels of SWOG’s portfolio (patient advocate Marcia Horn, JD, described DART that way, and it’s too perfect not to use those words).

NCCN treatment guidelines have already incorporated the trial’s immunotherapy regimen for two tumor types, and there are at least 12 other cohorts with results that are also potentially practice changing.

I expect DART II will build upon the legacy of the original, and along with the study team and the entire early therapeutics and rare cancers committee, I’m hopeful it will be similarly practice-changing for many rare and ultra-rare tumors. These represent a large unmet need in a group of underserved patients who in general have few effective therapy options and little to no access to clinical trials, just the population a public-powered cancer research network (ours!) should be aiming to serve.

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