ESMO Data Show Benefit of Approved Thyroid Cancer Regimens in Select Patients

Across subsets of patients with thyroid cancer, an interesting collection of research was shared with oncologists during the 2020 European Society of Medical Oncology (ESMO) Virtual Congress, demonstrating improvement in outcomes for patients with thyroid cancers with newer and established approved regimens.

Larotrectinib Demonstrates Efficacy in TRK Fusion–Positive Tumors

The TRK inhibitor larotrectinib (Vitrakvi) showed activity in patients with TRK fusion–positive thyroid cancers leading to rapid and durable disease control. Although a number of thyroid cancer subtypes were observed in this study, patients with differentiated thyroid cancer (DTC) and anaplastic thyroid cancer (ATC) had the highest responses to treatment, according to findings presented by Maria Cabanillas, MD, an oncologic endocrinologist at The University of Texas MD Anderson Cancer Center during ESMO.¹

“The response rates were very good. We had an overall response rate of 75% for the whole cohort. In patients with differenced thyroid cancer though, the overall response rate was 90%,” Cabanillas told Targeted Oncology, in an interview.

The populations included in the study were patients with papillary thyroid cancer, follicular thyroid cancer, DTC, and ATC. The objective response rate (ORR) of 75% (95% CI, 55%-89%) was observed in the overall population of patients with TRK fusion–positive thyroid cancer (n = 28). It included complete responses (CRs) in 7%, partial responses (PRs) in 68%, and stable disease in 11%.

Among the subgroup of 21 patients with DTC, the ORR of 90% (95% CI, 70%-99%) included CRs in 2 patients, PRs in 17 patients, and stable disease in 2 patients.The ATC subgroup, which included 7 patients, achieved an ORR of 29% (95% CI, 4%-71%) with PRs in 29% and stable disease in 14%.

The treatment duration with larotrectinib ranged from 0.9 months to over 45.4 months. At the time of data cutoff, 68% of patients were still receiving treatment, including 3 patients with disease progression.

Patients has a median time to response of 1.9 months (range, 1.6-5.6). The median duration of response (DOR) was not evaluable ([NE], 95% CI, 14.8-NE), but it was estimated that at 12 months, patients would have a DOR rate of 95% (95% CI, 85%-100%). Overall survival (OS) data in this study were also immature and NE.

The key takeaway from these data were that testing for NTRK gene fusions should be routine for patients with non-medullary, advanced thyroid cancer so that patients with these alterations may benefit from treatment with larotrectinib.

Real-World Data in DTC Similar to Clinical Trials for MKI Use

In the largest ever non-interventional study of patients with asymptomatic radioactive iodine (RAI)–refractory DTC who were treated with multikinase inhibitors (MKIs), it was determined that outcomes in patients treated in the real world were similar to those of patients treated in clinical trials.²

Marcia Brose, MD, PhD, the director of the Center for Rare Cancers and Personalized Therapy, director of the Thyroid Cancer Therapeutics Program, and professor of otorhinolaryngology, Head and Neck Surgery at the Hospital of the University of Pennsylvania, presented the data from the RIFTOS MKI study in a poster during ESMO.

The prospective, open-label, multicenter, non-interventional study analyzed 647 patients who were divided into 2 cohorts of patients who received a prior MKI, either sorafenib (Nexavar) or lenvatinib (Lenvima) and those who did not. The thyroid cancer histologies included in the analysis were papillary (74%), follicular (13%), Hürthle cell (6%), and poorly differentiated carcinoma (6%).

In the overall population, the median OS from the time of initial visit was not evaluable but the rate at 3 years was 77.1%. The median progression-free survival (PFS) was 15.2 months (95% CI, 12.6-17.1) from initial visit and the PFS rate at 3 years was 22.1%. The median OS in the cohort of patients treated with sorafenib (n = 209) was not evaluable, but the rate at 36 months was 68.2% and the median PFS was 16.7 months (95% CI, 14.0-23.2).

These data revealed a pattern of heterogeneity in the patients with RAI-refractory DTC, according to Brose et al.

It was also noted that the safety profile of patients treated with sorafenib observed in the real-world study mirrored the phase 3 clinical trials with the most common adverse events (AEs) of any grade being diarrhea (44%), hand-foot skin reaction (41%), hypertension (26%), fatigue (25%), and alopecia (20%). Brose explained, however, that there is a method for managing these AEs. Notably, the rate of hand-foot skin reaction was lower in the real-world population than was seen in the pivotal trials.

“One of the messages I want to get out it is that with hand-foot skin reaction, nobody ends up being a grade 3 without being a grade 1 or 2 first. If we intervene quickly, they’re unlike to develop grade 3 hand-foot skin reaction,” Brose told Targeted Oncology, in an interview. “We usually handle that in our clinic early on by giving ibuprofen 600 mg 3 times per day. We also have patients keep their skin well hydrated and wear loose-fitting shoes without pressure points. If they still can’t tolerate it, we will sometimes decrease the dose,” Brose added.

PROs Data from LIBRETTO-001 Reported

Lori Wirth, MD, associate professor in medicine at Harvard Medical School and medical director of the Center for Head and Neck Cancers, Massachusetts General Hospital, presented patient-reported outcomes (PROs) from the phase 1/2 LIBRETTO-001 clinical trial (NCT03157128).³

In the primary analysis of LIBRETTO-001, treatment with selpercatinib (Retevmo) was evaluated in patients with solid tumors and RET alterations, including patients with RET-mutant medullary thyroid cancer (MTC) with or without previous vandetanib (Caprelsa) or cabozantinib (Cabometyx) treatment, in addition to those with previously treated RET fusion–positive thyroid cancers. The results showed durable efficacy in the group of patients with MTC with and without previous vandetanib or cabozantinib treatment and tolerable safety.

Findings from LIBRETTO-001 led to the FDA approval of selpercatinib in metastatic non–small cell lung cancer, advanced or metastatic MTC, and advanced RET fusion–positive thyroid cancer.^4,5

“When we looked at patients with medullary thyroid cancer who have RET mutations and have been previously treated with cabozantinib or vandetanib, we saw a very high overall response rate. The overall response rate was 69%, and 9% of patients had complete responses. We also saw very durable responses with a 1-year progression-free survival of 82% of that patient population,” Wirth told Targeted Oncology, in an interview.

“In [patients with] RET-mutant MTC who had not received either cabozantinib or vandetanib, the overall response rate was 73% with a 1-year progression-free survival of 92%. We saw similar activity in the smaller subset of patients with RET fusion–positive advanced thyroid cancer,” Wirth added.

In terms of the PROs exploratory analysis, gastrointestinal symptoms, namely diarrhea, were observed at enrollment per the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire (QLQ-C30). Treatment with selpercatinib significantly reduced symptoms of diarrhea by cycle 3. The PRO analysis was necessary, according to Wirth, because diarrhea is a common symptom associated with MTC.³

“We anticipated with the drug design being a RET-specific inhibitor that we should see a relatively tolerable drug for patients, and we were hoping to have durable responses. I think as we’ve seen in oncology with our oral therapies that are taken day after day, if there is a significant toxicity profile, it can really take a toll on patients,” said Wirth.

Overall, baseline screening in the PRO analysis showed that the mean baseline scale for improvement in symptoms of diarrhea was 40.1 (standard derivation [SD]=38.2), nausea/vomiting was 8.0 (SD=16.6), pain was 29.2 (SD=31.4), and dyspnea was 21.9 (SD=28.2), which met the clinically important threshold. The majority of patients remained stable or had improvement of symptoms on each subscale at each follow-up.

After treatment, diarrhea was improved (mean 18.27, SD=24.9), but the reduction was not clinically significant. The reduction for dyspnea met clinical significance as did all other subsequent assessments.

_References:

_{1. Cabanillas ME, Drilon A, Farago AF, et al. Larotrectinib treatment of advanced TRK fusion thyroid cancer. Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract 1916P.}

_{2. Brose MS, Smit J, Lin CC, et al. Final analysis of RIFTOS MKI, a global, non-interventional study assessing the use of multikinase inhibitors (MKIs) for the treatment of patients with asymptomatic radioactive iodine-refractory differentiated thyroid cancer (RAI-R DTC). Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract 1918P.}

_{3. Wirth L, Robinson B, Boni V, et al. Exploratory patient-reported outcomes among patients with RET-mutant medullary thyroid cancer in LIBRETTO-001: A phase I/II trial of selpercatinib (LOXO-292). Presented at: 2020 ESMO Congress; September 19-21, 2020; Virtual. Abstract 1922P.}

_{4. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in ret-altered thyroid cancers. N Engl J Med. 2020;383:825-835. doi:10.1056/NEJMoa2005651}

_{5. FDA approves first therapy for patients with lung and thyroid cancers with a certain genetic mutation or fusion. News release. FDA. May 8, 2020. Accessed October 9, 2020. https://bit.ly/3dsLuuO​}