Dr Mrinal Gounder: Nirogacestat Approval Provides First-in-Class Option for Desmoid Tumor Treatment

Mrinal M. Gounder, MD, a sarcoma oncologist at Memorial Sloan Kettering Cancer Center and lead investigator of the phase 3 DeFi trial (NCT03785964) assessing nirogacestat for desmoid tumors, discusses the recent FDA approval of nirogacestat and the drug's potential impacts on desmoid tumor treatment.

Transcript

How have desmoid tumors traditionally been treated, and why are new treatments such as nirogacestat important for patients with these tumors?

Desmoid tumors, because they are generally localized, have historically been treated with surgeries. But what we have learned in the last 10 years or so, is that we're really not helping patients with surgeries. So, in general, as a field, we are trying to move away from surgeries. For a small subset of patients, surgery may still be appropriate. But these patients need to be carefully selected, and they need to be discussed in a sarcoma multidisciplinary tumor board to decide whether surgery is the best option for them, or frankly, if any other treatment is the best option for them or not.

The reason surgery is not helpful is that, despite a good surgery, patients can still have a very high recurrence rate, and there are also surgical morbidities that can be lifelong and irreversible. So, as a whole, the field is moving away from surgeries. And increasingly, we are even instituting a initial period of wait and watch for active surveillance with imaging, provided they are not asymptomatic, provided the tumor is not threatening any vital organ, or that it's not progressing rapidly. For those patients who require some form of a systemic treatment, we have many treatments on hand. Historically we've used chemotherapy, typically methotrexate and vinblastine, or vinorelbine combinations. We also continue to use liposomal doxorubicin or other anthracycline-based regimens. These are both quite well used, and they are very active drugs that can be used in the current setting as well.

Over the last 5 years or so, the field has shifted away from chemotherapy a little bit towards more tyrosine kinase inhibitors, particularly sorafenib. Phase 3 clinical trials showed that this had a nice response rate and a profound impact on patients' progression-free survival. But we also know that many of these chemotherapies or tyrosine kinase inhibitors have their own set of side effects, so new drugs such as nirogacestat, which is a new class of drug from the gamma secretase inhibitors, have been evaluated over the last 20 years. And a recent phase 3 clinical trial known as the DeFi study showed that this drug was effective as well as safe in patients, so this adds an extra armamentarium in our toolbox to treat patients with desmoid tumors.

What were the key findings that supported the approval of nirogacestat for desmoid tumors?

Nirogacestat was approved on a phase 3, global, international, randomized, placebo-controlled study. Nirogacestat is an oral pill and it was provided to patients against placebo. What we saw is that the progression-free survival was significantly higher in patients who received nirogacestat compared to placebo. The response rates were also significantly higher, including complete responses, which were seen in the nirogacestat arm but not in placebo. But most importantly, patients who were on nirogacestat, they had an improvement in their quality of life as measured by a desmoid-specific patient-reported outcome called the goddess tool. This showed that patients receiving nirogacestat had improvement in pain, and also all the other metrics that are associated with the desmoid tumor. This includes improvement in range of motion, functionality, mood, sleep, etc. So all 3—the totality of the data about the PFS response rate, as well as the improvement in patient-reported outcomes—led to the approval of this drug in this disease.

How do you expect the FDA approval of nirogacestat to impact the treatment algorithm for desmoid tumors going forward?

As I mentioned, nirogacestat is an additional tool or drug in our toolbox. This does not necessarily mean that this is the very first drug to reach for or that this drug is appropriate for all patients. All desmoid tumor patients ideally should be evaluated whenever possible as part of a sarcoma multidisciplinary tumor board. For some patients, nirogacestat may be first line, or second line, or third line—it really depends on their medical comorbidities as well as their preference. For others, other drugs such as sorafenib, or chemotherapy, cryoablation and other approaches may be equally appropriate. So although this is the first US FDA-approved drug in this disease, ultimately, we have to do what's right for our patients based on their medical comorbidities, but also on patient preferences as well.

Is there anything else you'd like to add?

I would say that one of the side effects of this drug is ovarian dysfunction. Now, this can be ovarian failure or insufficiency, but the number of patients treated are quite small, so this data is evolving. The trial itself showed that some patients who stopped the drug fully recover. Others, while they're still on nirogacestat, can also recover. And others remain to be seen as they're still on treatment. So, the takeaway is that this is an issue that needs to be addressed, especially in women of childbearing potential, just as we would discuss this with patients who are receiving chemotherapy, and sometimes even tyrosine kinase inhibititors, as well.