Patient-Reported Outcomes Confirm Tolerability of Selpercatinib in RET-Driven Thyroid Cancer

Lori J. Wirth, MD

According to the findings from the phase 1/2 LIBRETTO-001 study (NCT03157128), selpercatinib (Retevmo) has durable efficacy and a tolerable safety profile in patients with RET-altered medullary thyroid cancer (MTC) or advanced thyroid cancer. These findings ultimately led to the FDA approval of this RET inhibitor, formerly known as LOXO-292, in May 2020.

The agent received approval specifically for adult and pediatric patients aged 12 years and older with advanced or metastatic RET-mutant MTC who require systemic therapy, as well as those with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine (RAI)-refractory, if RAI was appropriate. A third indication included adult patients with metastatic RET fusion-positive non–small cell lung cancer (NSCLC).

LIBRETTO-001 is the largest trial to date of patients with RET-driven cancers, and this approval is contingent on verification of the clinical benefit of selpercatinib in confirmatory studies. At the 2020 European Society for Medical Oncology (ESMO) Virtual Congress, a poster presentation demonstrated the patient-reported outcomes (PROs) of these patients with thyroid cancer who received selpercatinib. The purpose of the analysis was to evaluate the safety of this agent further among patients with RET-driven MTC or advanced thyroid cancer.

In an interview with Targeted Oncology, Lori J. Wirth, MD, associate professor of Medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers at Massachusetts General Hospital, discussed the findings from an analysis of the PROs observed in the LIBRETTO-001 study of selpercatinib in patients with RET-driven thyroid cancers.

TARGETED ONCOLOGY: Could you first provide an overview of the data from the primary analysis of LIBRETTO-001?

Wirth: LIBRETTO-001 was a phase 1/2 trial investigating cell for catnip, which is a RET-specific inhibitor in cancers that are driven by RET alterations. There were 2 primary cohorts in the trial, patients with non–small cell lung cancer who had RET fusion-positive lung cancer, and then patients with MTC driven by RETmutations. There was also a small cohort of patients with RET fusion-positive, advanced thyroid cancer previously treated.

What we saw in the LIBRETTO-001 study was [interesting] when we looked at the patients with MTC who harbored RET mutations and had been previously treated with either cabozantinib or vandetanib, or both. We saw a very high overall response rate (ORR). The ORR was 69%, and 9% of patients had complete responses. We also saw very durable responses with a 1-year progression-free survival (PFS) rate of 82% in that patient population. When we look at RET-positive MTC, patients who had not received either cabozantinib or vandetanib, the ORR was 73% with a 1-year PFS rate of 92%. We saw similarly high rates of activity in the smaller subset of patients with RET fusion-positive advanced thyroid cancer.

Another thing that I think is important to note in the trial is that overall, we found that selpercatinib is fairly well tolerated, particularly for an oncology drug. We did see treatment-related adverse events (TRAEs), of course, but there was a relatively small number of TRAEs grade 3 or higher. The most common were hypertension, transaminitis, and diarrhea. There were 30% of patients with thyroid cancer who did have dose reductions due to TRAEs, but only 2% of patients had drug discontinuation because of the side effect profile.

TARGETED ONCOLOGY: Why was it important to single out PROs for this study?

In LIBRETTO-001, we took a look at PROs. We evaluated patients every 2 cycles for the first year, and then every 3 cycles thereafter. There were baseline PROs, as well. We looked at the EORTC QLQ-C30, and then for patients with MTC, we also carried out a study with the modified systemic therapy-induced diarrhea assessment tool. The reason that we looked particularly in the MTC patients with this 1 diarrhea-specific tool is because many patients with MTC have diarrhea that's caused by the hormone calcitonin that's secreted by MTC. In fact, 8% of patients at baseline with MTC did have diarrhea at enrollment, and a high percentage of those patients reported their diarrhea as severe at study entry. The reason why it was important, I think, however, is because we anticipated with the drug design with a RET-specific inhibitor, we should see a relatively tolerable drug for patients. We were hoping to have durable responses and hoping to have a therapy that patients are on for a long period of time. I think as we've seen in oncology, our oral therapies that are taken day in and day out every day, week after week, month after month, if there's a significant side effect profile, that can really take a toll on patients over a long period of time. Taking a look at these PROs is very important, particularly if we're claiming that a drug has a well-tolerated safety profile. I think we want to see that in PROs.

TARGETED ONCOLOGY: What were the results presented at ESMO this year?

At ESMO, there was a poster we presented with the PROs, which are preliminary at this point in time, in patients with thyroid cancer on the study, particularly with the diarrhea assessment tool in the MTC patients. What we found was that there was a high rate of compliance with filling out the questionnaires, and when we look at markers of overall performance, such as with physical function or global health status, patients that were enrolled selpercatinib, for the most part, either felt better in terms of physical function and global health status or at least were stable. It was a very small percentage of patients who got worse in those 2 overall subscales, 13% for physical function, and 13% for global health status.

When we also drill down and took a look at various symptom subscales and from the EORTC tool, we found that many patients with diarrhea, pain, and other gastrointestinal symptoms, such as nausea and vomiting, improved over time or at least remained stable. With diarrhea, we saw a 44% improvement in patients over time. With pain, we saw 38% improvement over time. Most of the other patients with those 2 subscales, as examples, remained stable over time, we saw similar rates of improvement and stability with other subscales, such as fatigue, dyspnea, appetite loss, even insomnia, and then as I mentioned, we looked at a diarrhea-specific tool, and we found that most patients had improvement in diarrhea with that tool as well as confirmed that patients who typically are plagued for a long period of time by diarrhea when they have MTC see improvement in that side effect on selpercatinib rather than worsening.

TARGETED ONCOLOGY: What is your key takeaway from these data?

Putting together the data from the PROs with the overall data on efficacy, I think, in patients with thyroid cancer driven by RET alterations, either MTC or advanced thyroid cancer, we have a drug that is very active, and a drug that is very well tolerated.

TARGETED ONCOLOGY: What is next for selpercatinib in this patient population? Do you see it being extended to other patient populations?

What’s next with selpercatinib in the patient population of RET-altered thyroid cancers is more selpercatinib. Most patients originally enrolled on LIBRETTO-001 had responses to therapy and remain in response at this time, so 1 critical question is what will the median PFS be? What will the median duration of response be? It's good that we don't know the answer to that question because so far, we have not yet met those medians despite the length of time that we've had in follow-up thus far.

With this paradigm of gene-specific therapy in oncology, we have seen acquired resistance emerge. In other settings, we are beginning to see that in patients that are treated with the RET-specific inhibitors, such has been reported in NSCLC, with acquired resistance solvent front mutations now being reported. I do think that we will eventually, unfortunately, be seeing more patients progress, so I think we still have a lot to learn about what those mechanisms of escape will be. There are, however, already the second generation of RET inhibitors that are in clinical trials. I think we'll be seeing more drugs come online and in the phase 1 setting as well.

Given the drug has great activity and is well tolerated, an important question in thyroid cancer is how can we best take advantage of this good drug, particularly with MTC when patients can be relatively asymptomatic, or RETfusion-positive advanced thyroid cancer when patients can be relatively asymptomatic? Sometimes we hold off f as long as possible when starting a multikinase inhibitor therapy because of the balance of efficacy and side effect profile that you have to deal with, but when the efficacy is really good, and the side effect profile isn't as troublesome, should we be using these drugs earlier in the course of disease rather than holding off for as long as possible? I think that's a really important question. There are other questions as well, such as if patients present with unresectable thyroid cancer, can we use these drugs even prior to surgery for thyroid cancer to get patients to be able to have a successful operation?