A phase II basket trial evaluating the efficacy of dual immune checkpoint inhibition in patients with rare tumors has shown promising results for those with desmoid tumors. The study, published in the Journal for ImmunoTherapy of Cancer in 2024, was conducted by researchers from multiple institutions across the United States as part of the SWOG Cancer Research Network.
The SWOG S1609 Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors (DART) trial was a prospective, open-label, multicenter study that enrolled patients at 1,016 US sites. Funded by the National Cancer Institute and Bristol Myers Squibb, this trial aimed to assess the efficacy of combining ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1) in various rare tumor types, with this particular analysis focusing on the desmoid tumor cohort.
Desmoid tumors, also known as aggressive fibromatosis, are rare soft tissue tumors that, while not metastatic, can cause significant morbidity due to their locally invasive nature. Traditional treatments have included surgery, radiation, and systemic therapies, but there is a need for more effective and less toxic options.
The study included 16 evaluable patients with desmoid tumors who had a median of 1.5 prior therapies and no previous exposure to immunotherapy. Eligibility criteria included histologically confirmed desmoid tumors, age 18 or older, and adequate organ function. The median age of participants was 37 years, with 75% being female.
Patients received a combination of nivolumab (240 mg intravenously every 2 weeks) and ipilimumab (1 mg/kg intravenously every 6 weeks) on an ongoing schedule. The primary endpoint was overall response rate (ORR) according to RECIST v1.1 criteria, with secondary endpoints including progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), and toxicity assessment.
The results were encouraging, with an ORR of 18.8% (3/16 patients achieving partial responses) and a CBR of 62.5% (10/16 patients). Three patients demonstrated partial responses with tumor regressions of 40%, 83%, and 71%, with durations of response ranging from 8.4 to over 30 months. Additionally, seven patients (43.8%) achieved stable disease lasting over 6 months, with PFS ranging from 16.5 to 60.7+ months.
The median PFS was 19.4 months, with 6-month and 12-month PFS rates of 73% and 67%, respectively. Notably, all patients were alive at the 1-year mark, and 13 patients were still alive at the time of analysis, precluding the calculation of median OS.
Regarding safety, all patients experienced treatment-related adverse events, with 50% experiencing grade 3-4 events. The most common side effects included fatigue, nausea, and hypothyroidism. Importantly, there were no treatment-related deaths reported.
This study represents the first prospective evaluation of dual checkpoint inhibition in desmoid tumors, a notoriously challenging malignancy to treat. The results suggest that this immunotherapy combination may offer a new treatment option for patients with these rare tumors, particularly given the durability of responses observed.
However, the study has several limitations that should be considered. The sample size was small, with only 16 evaluable patients, which limits the generalizability of the findings. Additionally, there was no centralized review of pathology or radiology, which could have introduced inconsistencies in tumor evaluations. The lack of a control group also makes it difficult to definitively attribute the observed responses to the treatment rather than the natural history of the disease, as spontaneous regressions have been reported in desmoid tumors.
The authors conclude that the combination of ipilimumab and nivolumab demonstrated meaningful clinical activity in patients with desmoid tumors, with durable responses observed in a subset of patients. They emphasize the need for further research to identify biomarkers of response and resistance, which could help optimize patient selection for this treatment approach.
The potential clinical impact of these findings is significant. For patients with desmoid tumors who have progressed on or are ineligible for standard therapies, dual checkpoint inhibition may offer a new treatment option. The durability of responses is particularly noteworthy, as it suggests the potential for long-term disease control in some patients.
However, it is important to contextualize these results within the evolving landscape of desmoid tumor treatment. Recent approvals of sorafenib and nirogacestat have expanded the therapeutic options for these patients, and comparative studies may be necessary to determine the optimal sequencing or combination of these agents with immunotherapy.
Moving forward, expanded trials with larger patient populations will be crucial to confirm these findings and further elucidate the role of immunotherapy in desmoid tumors. Additionally, correlative studies to identify predictive biomarkers will be essential to refine patient selection and improve outcomes.
In conclusion, this phase II basket trial has provided valuable insights into the potential of dual checkpoint inhibition in desmoid tumors, a rare and challenging malignancy. While the results are promising, they should be interpreted with caution given the study's limitations. Nonetheless, these findings open new avenues for research and may ultimately lead to improved outcomes for patients with this rare disease.
References
Chae YK, Othus M, Patel S, et al. Phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART) SWOG S1609: the desmoid tumors. J Immunother Cancer. 2024;12(9):e009128. Published 2024 Sep 28. doi:10.1136/jitc-2024-009128
