To the Editor:
I read with great interest the recent report by Jain et al[1] on nirogacestat in progressing desmoid tumors.[2] While the trial is methodologically sound and demonstrates significant efficacy
of nirogacestat over placebo, I would like to highlight two critical issues that merit
further discussion.
First, the choice of a placebo control arm raises concern, especially given that the
same investigative group had earlier published a landmark randomized trial establishing
the efficacy of sorafenib over placebo in desmoid tumors.[3] With the sorafenib study published in 2018 and patient accrual for the nirogacestat
trial beginning in 2019, it is puzzling why sorafenib was not chosen as the comparator.
If the goal were to establish the therapeutic value of nirogacestat in a post-sorafenib
era, a head-to-head comparison with sorafenib would have been more appropriate. Selecting
placebo as the comparator risks artificially inflating the perceived benefit of nirogacestat,
potentially lowering the threshold for success, and sidestepping an opportunity to
address the more pressing clinical question: Is nirogacestat superior or equivalent
to sorafenib? This trial, while confirming efficacy, does not help the clinician choose
between the two agents.
Second, while nirogacestat demonstrated a higher overall response rate (41 vs. 33%)
and earlier responses compared with historical sorafenib data, the progression-free
survival hazard ratio (HR) with sorafenib (HR: 0.13) appears more favorable than that
of nirogacestat (HR: 0.29). Furthermore, the toxicity profile of nirogacestat, particularly
ovarian dysfunction affecting 75% of premenopausal women, is nontrivial. In contrast,
sorafenib's toxicities, although frequent, are more familiar to clinicians and generally
manageable. Thus, based on existing data, sorafenib may still represent the more pragmatic
first-line choice, especially in young women in whom the disease is more common.
In conclusion, while nirogacestat adds to the armamentarium for desmoid tumors, the
choice of placebo as a comparator limits the trial's clinical utility in guiding therapeutic
decision-making between existing and emerging options. As clinicians, what we need
is not just more drugs or gaps in evidence, but clearer data to guide rational treatment
sequencing.
