The clinical results of the DeFi trial of nirogacestat excels in adults with progressing desmoid tumors

SpringWorks underscores a win in Desmoid Tumors

Sep 10, 2022 | DelveInsight

Desmoid tumors (DT) are locally aggressive, soft tissue sarcoma. These tumors are originated from the fibroblast cells, mostly found in soft and connective tissues. Fibroblasts are meant for structural support to vital organs. Also involved in wound healing. Desmoid tumors are commonly found in extremities, intra-abdominal and abdominal wall. Tumors could be found in other parts of physiological system as well, since prevalence of soft and connective tissues are wide. Desmoid tumors, generally do not metastasize. Yet, there clinical courses have been unpredictable.  Symptoms of desmoid tumors are nonspecific, like pain, solid outgrowth, etc. at the tumor site. However, quite often display debilitating symptoms, when tumors invade in surrounding healthy, and vital tissues. Delay in diagnosis is quite commonly seen in diagnosis of   DT. Clinical courses are unpredicted like, nearly 20% patients may have spontaneous regression, approximately 50% patients may find stable disease, and in nearly 30% of patient’s tumors grow in size. Historically, surgical resection was the dominant therapeutic approach. But, surgical relapse rate were quite high. Care givers had to perform multiple surgeries and in couple of instances, they used to perform complete surgical removal of involved vital organs. Disfigured body posture and side effects of surgical resections were mojor deterrent for surgery. Evolution of treatment consensus shifted treatment paradigm of DT, more towards nonsurgical practices like active surveillance, off-label therapies like, pain killer, methotrexate (MTX), Tyrosine Kinase Inhibitors(TKIs), Hormonal therapies etc. Mortality rates are not significant, clinicians have to think about quality of life of patients, before providing optimized treatment. Since, toxicities of therapeutic agents or removal of vital organ through surgeries, hampers quality of life of patients.

So far, therapeutic outlook of desmoid tumors are not impressive, by and large care givers have to rely on off-label therapies or surgeries.  Moreover, local relapse or distant recurrence rates are high after treatment.  It clearly reflects, pressing unmet need for novel, efficacious, approved therapeutic options, which can fill therapeutic gaps and sustain remission.

SpringWorks Therapeutics’s nirogacestat demonstrated excellent therapeutic response by gamma secretase inhibition. SpringWorks Therapeutics presented updated results of Phase III, clinical study (DeFi), evaluating efficacy and safety of nirogacestat vs. placebo in adults with desmoid tumors, at ESMO 2022:

  • Overall all response rate  (ORR), in nirogacestat arm compared with placebo arm, were found to be 41% and 8%, respectively (P<0.001)
  • The median time to response with nirogacestat and placebo were found to be, 5.6 months vs. 11.1 months, respectively
  • Median progression-free survival (PFS), in nirogacestat arm  and placebo arm, were found to be, not estimable and 15.1 months, respectively  at a median follow-up of 19.2 months (HR, 0.29; P < 0.001)
  • Patient-reported outcomes (PROs), nirogacestat led to a significant reduction in pain severity at cycle 10 of treatment compared with placebo (P<0.001)
  • Manageable safety profile, despite a high rate of ovarian dysfunction in nirogacestat arm 

Overall, nirogacestat demonstrated sustained and statistically significant improvements in all preset primary and secondary endpoints. Moreover, impressive reductions in pain scores, symptom burden, and improvements in health-related quality of life were seen. As per, updated clinical results from DeFi trial, nirogacestat showed the potential to become the standard of care for patients with desmoid tumors. Driven by positive results, SpringWorks Therapeutics is planning to complete NDA filing by the end of the year 2022. Submission will be done for review under FDA’s RTOR program.

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