Patient With RET-Mutated Thyroid Cancer Is Eligible for Multiple Targeted Therapies

Marc Matrana, MD, MS

Twelve months after a male patient with thyroid cancer was no longer asymptomatic, the patients developed symptoms that led the treating physician to discover metastatic disease. The case became the topic of discussion during a Case-Based Roundtable event led by
Marc Matrana, MD, MS, director, Precision Cancer Therapies (Phase 1) Research Program, endowed professor of Experimental Therapeutics, and associate director of Clinical Cancer Research, Ochsner Cancer Institute.

Targeted Oncology^TM: What are your thoughts on the variety of RET fusions and point mutations associated with oncogenesis, as described by Subbiah and Cote?1 Would you recommend mutational testing for this patient?

MATRANA: [Even] as someone who runs a precision medicine program, I don’t remember all of the mutations.

They change constantly. I look them up every time, and I rely on our molecular pathologist. We also have a molecular tumor board that helps us weed through a lot of the mutations. The variety of cancers that have RET [alterations] was a little surprising to me. For example, I wouldn’t have predicted [the incidence of RET alterations] to be so high in ureteral urothelial carcinoma [16.7%] or meningioma [5.6%].1 It just goes to show that you probably need to test just about everybody with next-generation sequencing because you never know what you’re going to [find].

How does the presence or absence of RET alterations influence therapy recommendations?

According to the National Comprehensive Care Network guidelines, [the preferred regimens] for asymptomatic MTC are vandetanib [Caprelsa] and cabozantinib [Cometriq]; for RET mutation–positive [disease], the preferred regimens are selpercatinib [Retevmo] and pralsetinib [Gavreto]. You can use pembrolizumab [Keytruda] [if the] tumor mutation burden [is] high. The recommendations are the same for [instances of] symptomatic disease or progression.²

What data support the use of vandetanib to treat metastatic MTC?

The ZETA trial [NCT00410761] was a phase 3 trial of vandetanib vs placebo for advanced metastatic MTC in 331 patients with a mean age of 52 years. The primary end point was progression-free survival [PFS], and at a median follow-up of 24 months, vandetanib did prolong PFS [HR, 0.46; 95% CI, 0.31-0.69; P < .001]. The placebo group demonstrated a median PFS of 19.3 months, and the predicted [unreached] median PFS for the vandetanib group was 30.5 months. At 6 months, the percentage of patients with PFS was 63% in the placebo group and 83% in the vandetanib group.³

The objective response rate was 45% [odds ratio [OR], 5.48; 95% CI, 2.99-10.79; P < .001] and the disease control rate was 87% [OR, 2.64; 95% CI, 1.48-4.69; P = .001]. There was calcitonin decrease in 69% of the patients [OR, 72.9; 95% CI, 26.2-303.2; P < .001] and CEA decrease in 52% of the patients [OR, 52.0; 95% CI, 16.0-320.3; P < .001]; . For overall survival [OS], the HR was 0.89 [95% CI, 0.48-1.65]; these data were immature at data cutoff.³

How did various RET mutation subgroups respond to vandetanib therapy?

Subgroup analysis according to RET mutation status [with respect to any RET mutation and with respect to the M918T substitution] showed HRs favoring vandetanib in patients with RET mutation–positive and RET mutation–unknown disease. RET mutation–negative disease was only represented by 2 patients, so that group didn’t have enough power to show [an effect]. An advantage for vandetanib was also demonstrated among patients with the M918T substitution. For patients with no M918T substitution or whose M918T status was unknown, the HR showed an advantage for vandetanib, although the 95% CIs did cross the forest plot line into the region not favoring vandetanib.³

What adverse events (AEs) were reported in this study?

Among the AEs of any grade that occurred in at least 10% of the overall population, those most common in the vandetanib group were diarrhea [occurring in 56% of the vandetanib group vs 26% of the placebo group], rash [45% vs 11%, respectively], nausea [33% vs 16%], hypertension [32% vs 5%], and fatigue [24% vs 23%]. These AEs were not unexpected.³

What data support the use of cabozantinib in a patient with metastatic MTC?

The phase 3 EXAM trial [NCT00704730] of metastatic MTC [looked at] 333 patients [who were randomly assigned] in a 2:1 ratio [to receive] either cabozantinib or placebo. After a minimum follow-up of 42 months, the estimated median PFS was 11.2 months in the cabozantinib group and 4.0 months in the placebo group [HR, 0.28; 95% CI, 0.19-0.40; P < .001]. The objective response rate was 28% in the cabozantinib group and 0% in the placebo group [P < .001].^4,5 No statistically significant increase in OS was observed.⁵

How did various RET mutation subgroups respond to cabozantinib therapy?

Among patients with M918T-positive disease, the objective response rate was 34%; among those with M918T-negative disease, the objective response rate was 20%. Patients with positive, negative, or unknown RET mutation status and those with the M918T substitution all favored cabozantinib treatment vs placebo with respect to OS and PFS. The most pronounced effect was among patients with the M918T substitution, both for median OS [44.3 months] [HR, 0.60; 95% CI, 0.38-0.94; P = .03] and PFS [HR, 0.15; 95% CI, 0.08-0.28; P < .0001].⁵

What AEs were reported in this study?

In the cabozantinib group, the most common AEs of all grades were, as you would expect, diarrhea [in 70.1% of the cabozantinib group vs 35.8% of the placebo group], weight loss [57.9% vs 11.0%, respectively], palmar-plantar erythrodysesthesia [52.8% vs 1.8%], decreased appetite [49.1% vs 15.6%], nausea [46.7% vs 21.1%], and fatigue [42.5% vs 30.3%], and [to a lesser extent various] gastrointestinal [GI] symptoms. Eighty-two percent of the patients who received cabozantinib required dose reduction, and 46% had a second dose reduction.⁵ I use a lot of cabozantinib in renal cell carcinoma [and these results are] consistent with what we see. A lot of our patients get dose reductions but they still achieve efficacy on the drug.

What data support the use of selpercatinib in RET-mutant MTC and RET-fusion–positive thyroid cancer?

The LIBRETTO-001 study [NCT03157128] was a phase 1/2 study of selpercatinib in RET-mutant MTC and RET-fusion–positive thyroid cancer. Among the patients with RET-mutant MTC, one cohort was defined as “previously treated” with cabozantinib [24%], vandetanib [33%], or both [44%]; the remainder [“not previously treated”] had not been previously treated with either cabozantinib or vandetanib [but could have received other prior therapies].6 The most common RET mutation was the M918T [substitution]. All patients with RET fusion–positive thyroid cancer had been previously treated with various therapies.

The arms of the study were well matched, and the median age was 57 in the group with previously treated RET-mutant MTC and 58 in the cabozantinib-vandetanib– naive MTC group.

[The results were analyzed with respect to] whether or not the patients had been previously treated and whether or not they had a RET mutation or RET fusion. [Many] patients achieved complete responses [CR], a majority achieved partial responses [PR], and a large number of patients had stable disease [SD]. Among the patients with previously treated RET-mutant MTC, 9% achieved CR, 60% achieved PR, and 25% had SD. Among patients with RET-mutant MTC that was not previously treated, 11% achieved CR, 61% achieved PR, and 23% achieved SD.

Finally, among patients with previously treated RET fusion– positive thyroid cancer, 5% achieved CR, 74% achieved PR, and 21% achieved SD.

The median duration of response [DOR] was not estimable [NE] [95% CI, 19.1-NE] for the patients with previously treated RET-mutant MTC, 22.0 months [95% CI, NE-NE] among patients with RET-mutant MTC that was not previously treated, and 18.4 months [95% CI, 7.6-NE] among patients with previously treated RET fusion–positive thyroid cancer. The median PFS for the 3 groups was NE [95% CI, 24.4-NE], 23.6 months [95% CI, NE-NE], and 20.1 months [95% CI, 9.4-NE], respectively.

[The tumor response results among patients with RET-mutant MTC that was not previously treated] were impressive; only 1 patient [did not respond], [and even that patient] still had stable disease. Nearly everyone had tumor shrinkage, the great majority met criteria for partial response, and a few achieved CR.

What AEs were associated with selpercatinib therapy?

Twenty-eight percent of patients had a treatment-related AE [TRAE] of grade 3; 2% had a TRAE of grade 4. Hypertension and increased levels of aspartate aminotransferase and alanine aminotransferase were some of the more common serious grade 3 or grade 4 reactions; for grades 3 and 4 together, 12% of patients experienced hypertension, 8% experienced elevated aspartate aminotransferase, and 11% experienced elevated alanine aminotransferase. The most common TRAE of any grade was dry mouth, [which occurred in 39% of patients], followed by hypertension, in 43%, and [then] various GI AEs.6

What is your reaction to the clinical trial data for the treatment of advanced/metastatic RET alteration– positive thyroid cancer with selpercatinib?

I have a patient right now who’s been stable on cabozantinib for a long time, but as soon as he progresses, [I’m going to administer] selpercatinib.

Are there data to show how RET-altered MTC responds to pralsetinib?

The ARROW study [NCT03037385] was a phase 1/2 trial of pralsetinib for MTC in patients with advanced solid tumors that were RET altered but that had no other driving mutations. All patients received pralsetinib, 400 mg daily. The patients were [subdivided into cohorts:] RET-mutant MTC previously treated with cabozantinib, vandetanib, or both; RET-mutant MTC with no prior systemic therapy; RET-mutant MTC previously treated with systemic therapy other than cabozantinib or vandetanib; and other RET-altered tumors, which made up the bulk of the study. The arms were well matched.^7-9

The data were compelling in both situations, both [when the drug was used as] salvage after cabozantinib and vandetanib and [when used] in the cabozantinib-and vandetanib-naïve population. The overall response rate was 60% [95% CI, 46%-73%] in the previously treated group and 66% [95% CI, 46%-82%] in the treatment-naïve group. The CR rate was 1.8% in the previously treated group and 10% in the treatment-naive group; the partial response rates were 58% and 55%, respectively. The median DOR was not reached, although a DOR of at least 6 months was reached by 79% of the patients who received pralsetinib after cabozantinib and vandetanib, and by 84% of those who were treatment naive.⁹

What AEs did patients experience in this study?

The AEs were not surprising and those of all grades that occurred in at least 15% of patients included [various] GI AEs, hypertension [in 40%], fatigue [in 38%], and poor appetite [in 15%]. [These data include both MTC and non-MTC patients with thyroid cancer with RET mutations or alterations.]

[Recently], tumor lysis syndrome was [reported] in patients with MTC treated with pralsetinib; [that is] something to look out for, especially [in patients with] a high tumor burden. It’s recommended that you closely monitor patients, use prophylactic hydration, and treat as clinically indicated.⁹ The FDA approved pralsetinib for RET-altered thyroid cancer based on this data.¹⁰

_REFERENCES:

1. _{Subbiah V, Cote GJ. Advances in targeting RET-dependent cancers. Cancer Discov. 2020;10(4):498-505. doi:10.1158/2159-8290.CD-19-1116}
2. _{NCCN. Clinical Practice Guidelines in Oncology. Thyroid cancer, version 1.2021. Accessed July 26, 2021. https://bit.ly/3Ce3F4r}
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(2):134-141. doi:10.1200/JCO.2011.35.5040}
4. _{Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31(29):3639-3646. doi:10.1200/ JCO.2012.48.4659}
5. _{Schlumberger M, Elisei R, Müller S, et al. Overall survival analysis of EXAM, a phase III trial of cabozantinib in patients with radiographically progressive medullary thyroid carcinoma. Ann Oncol. 2017;28(11):2813-2819. doi:10.1093/annonc/mdx479}
6. _{Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa2005651}
7. _{Hu M, Subbiah V, Wirth L, et al. Results from the registrational phase 1/2 ARROW trial of pralsetinib (BLU-667) in patients with advanced RET mutation-positive medullary thyroid cancer. Paper presented at: European Society for Medical Oncology Congress; September 19-21, 2020; virtual.}
8. _{Hu M, Subbiah V, Wirth LJ, et al. Results from the registrational phase I/II ARROW trial of pralsetinib (BLU-667) in patients (pts) with advanced RET mutation-positive medullary thyroid cancer (RET+ MTC). Ann Oncol. 2020;31(suppl 4):S1084. doi:10.1016/j.annonc.2020.08.1401}
9. _{Gavreto. Prescribing information. Blueprint Medicines Corp; 2021. Accessed July 27, 2021. https://bit.ly/3jeSK1U}
10. _{FDA approves pralsetinib for RET-altered thyroid cancers. News release. FDA. December 1, 2020. Accessed July 27, 2021. https://bit.ly/2VrbWBh}