Selpercatinib May Be New Standard of Care for RET-Altered Thyroid Cancers, Study Shows

Vivek Subbiah, MD

The treatment landscape for medullary thyroid cancer has lacked selective RET inhibitors, which presents an unmet medical need in the field considering that RET mutations occur in 70% of medullary thyroid cancers (MTC). Researchers suggest that the void could potentially be filled with selpercatinib (formerly known as LOXO-292; Retevmo).

Selpercatinib is the first FDA-approved RET inhibitor for the treatment of MTC.¹ Prior to its approval, targeted therapies, such as the multikinase inhibitors vandetanib (Caprelsa) and cabozantinib (Cabometyx), have been approved by the FDA, but although they target RET, these agents are not specific to this alteration and can cause off-target effects that can be problematic to the patient.

"Before selpercatinib, no selective RET inhibitors were approved for MTC or RET-altered thyroid cancer. Selpercatinib is a novel, highly selective, and highly potent small molecule RET kinase inhibitor," Vivek Subbiah, MD, of the Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, told Targeted Oncology.

Maria E. Cabanillas, MD

According to findings from thyroid cancer cohorts in the phase 1/2 LIBRETTO-001 clinical trial (NCT03157128), selpercatinib demonstrated durable efficacy as treatment of adolescent and adult patients with MTC harboring the RET mutation whether or not they had received prior vandetanib or cabozantinib. These findings were published in the New England Journal of Medicine, further supporting the FDA’s decision to approve selpercatinib earlier this year.²

While the multikinase inhibitors have been a promising option for this patient population, adverse events (AEs) led to dose reductions in 35% of patients receiving vandetanib and 79% receiving cabozantinib, as well as permanent discontinuation of therapy in 12% and 16%, respectively. The data have shown that while 12% to 65% of patients respond to these agents, responses are partially limited by the toxic effects of vandetanib and cabozantinib.

“Considerable enthusiasm in the precision oncology of RET-driven cancers, like RET fusion-positive thyroid cancer and RET-mutant MTC, stems from the successful clinical trial results of the selective RET inhibitors,” Subbiah, an author of the LIBRETTO-001 study, said. “The near future offers us a tantalizing array of opportunities in RET-driven cancer research. The few off-target side effects, more effective growth, and sustained antitumor activity, when compared with these multikinase inhibitors open up a new era of precision oncology in RET-driven cancers.”

More patients with the RET-mutant MTC had an objective response to selpercatinib in the LIBRETTO-001 study compared with what’s been observed in other trials among patients who had objective responses to either of the approved multikinase inhibitors. Selpercatinib also appeared to have a better safety profile.

“It was not compared in the study, but I can tell you from the vast experience that selpercatinib is compared to other RET inhibitors that are multikinase inhibitors, it had far less toxicity,” study author Maria E. Cabanillas, MD, an oncologic endocrinologist, professor, and faculty director in the Department of Endocrine Neoplasia at The University of Texas MD Anderson Cancer Center, told Targeted Oncology. “These patients oftentimes have already been on previous kinase inhibitors, and so once they've seen multiple previous treatments, they're usually not in the best health, and yet they're able to tolerate these drugs. It's quite remarkable.”

The study included 162 patients, 55 of which had MTC and had been previously treated with the multikinase inhibitors, 88 had MTC and had not been treated with either multikinase inhibitor, and 19 had a previously treated thyroid cancer. In the latter group, 13 patients (68%) had papillary thyroid cancer (PTC), 3 (16%) had poorly differentiated thyroid cancer, 2 (11%) had anaplastic thyroid cancer (ATC), and 1 (5%) had Hürthle cell thyroid cancer.

Selpercatinib Appears Efficacious in RET-Altered Thyroid Cancers

The primary end point of LIBRETTO-001 was objective response as determined by an Independent Review Committee, and secondary end points included the duration of response (DOR), progression-free survival (PFS), and safety.

“In the MTC group, the ORR was 70%, which is very high. That's like a dream really for any kind of cancer,” said Cabanillas. “It was regardless of previous treatment, which was another surprising finding. We still had very nice responses.”

In the 55 patients with RET-mutant MTC who had been previously treated, the objective response rate (ORR) 69% (95% CI, 55-81) by independent review, which included 5 patients (9%) with complete response (CR) and 33 (60%) with a partial response (PR). The number of prior lines of multikinase inhibitors did not affect the efficacy in this group, where 67% of patients who had received vandetanib achieved a response, 69% with cabozantinib only, and 71% with both agents. Responses were noted across all qualifying RET mutations, which included 3 patients whose tumors harbored the acquired resistance mutation RET V804.²

At 1 year, 86% of patients remained in an ongoing response (95% CI, 67-95), and 91% of the patients had a biochemical response (95% CI, 80-97), with respect to the calcitonin level in 54 evaluable patients and 66% (95% CI, 52-79) concerning the CEA level in 53 evaluable patients. The median time to calcitonin response was 0.5 months (range, 0.4-1.9), and the median time to CEA response was 1.8 months (range, 0.4-18.8).

According to independent review, the median PFS was not evaluable (NE) in this group (95% CI, 24.4-NE) after a median follow-up of 16.7 months, and the 1-year PFS rate was 82% (95% CI, 69%-90%). The median DOR was also NE (95% CI, 19.1-NE) after a median follow-up of 14.1 months.

In the RET-mutant MTC group that had not been previously treated with vandetanib or cabozantinib, the ORR was 73% (95% CI, 62-82), including 10 patients (11%) with CRs and 54 (61%) with PRs. These responses were observed across all RET mutations. After a median follow-up of 7.8 months, 60 of the 64 responses were still ongoing. At 1-year, 91% of responses were ongoing (95% CI, 72-97), and 92% of patients were progression-free (95% CI, 82-97).

The median PFS was 23.6 months (95% CI, NE-NE) after a median follow-up of 11.1 months, and the 1-year PFS rate was 92% (95% CI, 82%-97%). The median DOR was 22.0 months after a median follow-up of 7.8 months.

Only 19 patients were included in the non-MTC group, which is significantly smaller but reflects the rarity of having a RET fusion in non-MTC compared with MTC. In this study arm, the ORR was 79% (95% CI, 54-94), and activity was observed across multiple histologic types of thyroid cancer in this arm, which included PTC, poorly differentiated, Hurthle-cell, and ATC, as well as across different fusion partners. One of the 2 patients with ATC had an ongoing response for at least 18 months. Seventy-one percent of the responses were ongoing at 1 year (95% CI, 39-88), and 64% of patients were progression-free (95% CI, 37-82).

The median PFS was 20.1 months (95% CI, 9.4-NE) after a median follow-up of 13.7 months, and the 1-year PFS rate was 64% (95% CI, 37%-82%). The median DOR was 18.4 (95% CI, 7.6-NE) after a median follow-up of 17.5 months.

Cabanillas noted significant tumor shrinkage in both the MTC and non-MTC cohorts, but said it was more significant in the non-MTC group. “There were also 2 ATC patients, and so it was very exciting to see responses even in ATC. Not only were these really phenomenal responses, like the type of response rate that every oncologist dreams of, but they were also durable responses.”

Safety Data Suggest Selpercatinib More Tolerable

All 162 patients were also evaluable for safety in the LIBRETTO-001 study, and 100% of patients experience an AE of any grade, regardless of attribution. Treatment-related AEs occurred in 94% of the patients, but only 45 patients (28%) experienced grade 3 AEs and 3 (2%) grade 4.²

“Selpercatinib is quite tolerable,” said Cabanillas. “The major toxicities are the usual things that you would expect from any type of systemic therapy, so we saw fatigue, some nausea, very mild hypertension, and diarrhea. In the MTC patients, diarrhea was 1 of the presenting symptoms, and unfortunately it wasn't measured whether that improved or not on the clinical trial. There's a little bit of liver function elevation, but these tended to be mild. Those were the major toxicities.”

The most common grade 3/4 AEs included hypertension (21%), increased alanine aminotransferase level (9%), hyponatremia (8%), and diarrhea (6%). Grade 5 AEs occurred in 3% of patients, which included hemoptysis, post-procedure hemorrhage, sepsis, cardiac arrest, and cardiac failure, all deemed unrelated to selpercatinib. In RET-altered thyroid cancer, the AE profile of this agent was similar to the overall safety profile in all 531 patients who were treated with selpercatinib. Among those with MTC, grade 3 tumor lysis was observed in 1 patient within 1 week after selpercatinib initiation, which led to intravenous hydration, supportive care, and ultimately permanent discontinuation from treatment.

Among the 531 patients who received selpercatinib, 160 (30%) had a dose reduction due to treatment-related AEs, and 12 (2%) discontinued treatment due to treatment-related AEs, of which the most common AEs were increased alanine aminotransferase level in 2 patients and drug hypersensitivity in 2 patients.

The RET inhibitor ultimately induced fewer toxicities than what has been observed with the multikinase inhibitors historically.

"Although most of the patients have a response to vandetanib or cabozantinib, the non-specificity of the multikinase inhibitors leads to essentially off-target effects, like diarrhea and rash, and this leads to dose reductions and drug discontinuation,” Subbiah said. “The safety and durability of the responses to these agents are hence limited partially by these toxic effects. These AEs are primarily related to the most potent inhibition of non-RET kinases and off-target toxicity.”

In a randomized double-blind phase 3 study, vandetanib was evaluated in patients with MTC in comparison with placebo. The most common AEs of any grade occurring in 30% of patients or more included diarrhea, rash, nausea, and hypertension. Grade 3 or higher AEs included diarrhea (11%), hypertension (9%), ECG QT prolonged (8%), fatigue (6%), decreased appetite (4%), rash (4%), asthenia (3%), dyspnea (1%), and back pain (0.4%).³

Five patients in this study experienced AEs that led to death during the randomized phase, and these were single instances of aspiration pneumonia, respiratory arrest, respiratory failure, staphylococcal sepsis, and arrhythmia, and acute cardiac failure in 1 patient. The 2 patient deaths due to an AE in the placebo arm were isolated cases of gastroenteritis and gastrointestinal hemorrhage, the investigators noted.

In a phase 3 trial of cabozantinib in MTC, AEs of any grade occurring in 30% of patients or more included diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes, and hypertension. The most common grade 3/4 AEs included diarrhea (15.9%), palmar-plantar erythrodysesthesia (12.6%), and fatigue (9.3%).⁴

While these toxicities were generally managed with concomitant medications, dose interruptions, and dose reductions, AEs were the primary reason for treatment discontinuation in 16% of patients treated with cabozantinib. Six percent had discontinued for reasons other than progressive disease, AEs, or death, and 11 patients had ongoing AEs at the time of discontinuation, although AEs were not the primary reason for discontinuation in these patients.

Serious AEs were also observed in the cabozantinib arm, occurring in 42.1% of patients. The most common serious AEs included mucosal inflammation (2.8%), hypocalcemia (2.8%), pulmonary embolism (2.3%), and hypertension (2.3%). Grade 5 AEs also affected 7.9% of patients treated with cabozantinib, which included fistula, respiratory failure, hemorrhage, multiorgan failure, and sepsis.

“If I had a patient today who has MTC with a RET alteration, selpercatinib is FDA approved,” Subbiah said. “Given the toxicity profile when we compare with vandetanib or cabozantinib, I think we will go for the selective RET inhibitor, especially if the patient's tumor harbors the RET alteration.”

Sequencing Selpercatinib With Other Approved Therapies

The FDA granted approval to selpercatinib capsules for the treatment of patients with lung or thyroid cancer harboring RET alterations, specifically including patients 12 years or older with advanced or metastatic RET-mutant MTC who require systemic therapy or those with advanced or metastatic RET fusion-positive thyroid cancer requiring systemic therapy who are radioactive iodine-refractory. This approval, based on the findings from the LIBRETTO-001 study, marks the first treatment approved to target RET alterations.¹ However, investigators must now determine where this agent should be sequenced in the treatment landscape.

“Now that we have a drug that's less toxic, and if the patient has a RET mutation or a RET fusion, I think it makes sense to start with your least toxic drug, but nobody knows the answer to that question,” Cabanillas said.

Selpercatinib has not yet been compared with the other targeted therapies in the clinical trial setting, but there are plans to compare the RET inhibitor to the standard of care agents, vandetanib, and cabozantinib, in a phase 3 study (NCT04211337). This study will randomized patients to receive either selpercatinib or the physician’s choice of vandetanib or cabozantinib. The primary end point of the study is treatment failure-free survival, and secondary end points included PFS, ORR, DOR, and overall survival, among others.

The purpose of this study is to compare the efficacy and safety of selpercatinib to the standard therapies as treatment of patients with RET-mutant MTC that cannot be removed by surgery or has spread to other parts of the body. The trial is expected to enroll 400 patients.

“At MD Anderson, we are also running a study with selpercatinib as neoadjuvant treatment. We are basically using it prior to surgery so that you can do a better resection,” Cabanillas said. “This is going to be a multi-institution trial, so there will be other sites coming on board. We hope to get this trial started in 2021.”

LIBRETTO-001 Highlights Need for Upfront Testing in Thyroid Cancer

The positive results from the LIBRETTO-001 study of selpercatinib and the FDA’s approval of this agent underscore the importance of testing all patients with thyroid cancer for potential RET mutations or fusions.

“Based on this phase 1/2 trial, selpercatinib showed durable efficacy with mainly low-grade toxic effects in patients with MTC with or without previous vandetanib or cabozantinib. In addition, this was active in patients with RET fusion-positive thyroid cancers like PTC and ATC,” Subbiah said.

Cabanillas explained that if the patient appears to require systemic therapy, she will test for RET alterations, and she believes this should be done in for all thyroid cancer patients. “I don't think that that's the practice in other institutions and out in the community, but I do think that now we have a very compelling reason to make that the standard of care for all patients with thyroid cancer that are going to be going on systemic therapy.”

Selpercatinib induced antitumor activity across all RET alterations and histologic types of thyroid cancer, so the implementation of molecular screening is essential to identify patients who may benefit from this therapy.

“Based on this data, a selective RET inhibitor should be standard of care in MTC that harbors a RET alteration or in any other thyroid cancer that harbors a RET alteration. The implementation of effective molecular screening strategies for patients with either germline or somatic RET mutation in non-familial MTC will be essential in identifying these patients who may benefit from RET inhibition,” Subbiah concluded. “The main message is that in these patients who all clinically benefited from a selective RET inhibitor, we have testing for RET mutations or RET rearrangements, so any thyroid cancer patient should be tested for these actionable alterations for them to benefit from this treatment.”

_References

_{1. FDA Approves First Therapy for Patients with Lung and Thyroid Cancers with a Certain Genetic Mutation or Fusion. May 8, 2020. Accessed August 25, 2020. https://bit.ly/3dsLuuO.}

_{2. Wirth LJ, Robinson SB, Solomon B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020; 383;9: 825-835.}

_{3. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012; 30: 134-41.}

_{4. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013; 31: 3639-46.}