Expert Highlights Major Advancements in Honor of Thyroid Cancer Awareness Month

Maria E. Cabanillas, MD

The treatment landscape for thyroid cancer has become complex with the increasing awareness of different mutations and fusions that allow physicians to personalize treatment more with targeted therapies, immunotherapies, and more. As September is Thyroid Cancer Awareness Month, it is an important time to review these latest advancements and the importance of genomic testing.

Selpercatinib (Retevmo) recently demonstrated durable efficacy as treatment of patients with MTC (MTC) harboring a RET mutation and differentiated thyroid cancer (DTC) with RET fusion, in the phase 1/2 LIBRETTO-001 study, which support the FDA’s decision to approve this agent earlier this year.¹ The FDA approved the RET inhibitor in May 2020, marking the first treatment approved in this setting to target RETgene alterations. The combination of dabrafenib (Tafinlar) and trametinib (Mekinist) was also approved by the FDA for the treatment of patients with unresectable or metastatic BRAF V600E-positive anaplastic thyroid cancer (ATC).

Although not approved yet, spartalizumab also demonstrated encouraging clinical activity and a satisfactory safety profile as treatment of patients with non-BRAF mutated ATC with PD-L1 expression, as well, in a phase 1/2 clinical trial.² In addition, another RET inhibitor, pralsetinib (BLU-667), is also appearing promising for the treatment of RET-mutant MTC and papillary thyroid cancer (PTC). Clinical trials are also underway looking at different targeted therapies, as well as potential combination regimens.

All of these advancements and more underscore the importance of identifying potential oncogenic drivers in thyroid cancer. With the identification of potential mutations and fusions in patients with thyroid cancer, physicians can tailor their treatments more appropriately to give their patients the best outcomes.

In an interview with Targeted Oncology, 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, discussed the evolution she has observed in thyroid cancer in terms of the use of targeted therapies and other important milestones for this patient population.

TARGETED ONCOLOGY: What would you say have been some of the biggest milestones in the treatment landscape of thyroid cancer within the last few years?

Cabanillas: The majority of patients with thyroid cancer are not going to need systemic therapy. Patients with MTC and DTC are generally treated with surgery. The patients with DTC often will be given adjuvant radioactive iodine (RAI) after surgery, depending on their risk of recurrence. ATC is a very aggressive form of thyroid cancer where the majority of patients cannot have meaningful surgery upfront and therefore most will need systemic therapy and/or radiation. Thus, the biggest advancements have been made in ATC where we are really changing the outcomes of these patients.

At MD Anderson, we are identifying the driver mutation in those patients. About 40% of these patients will have a BRAF V600E mutation. Although rare, we also see RET and NTRK fusions in ATC. However, what has really impacted the treatment of ATC is FDA-approved combination, dabrafenib and trametinib for patients with BRAF mutated ATC. At MD Anderson, we've been using this combination as neoadjuvant treatment so that we can then remove the tumor once it is small enough and no longer invading important structures in the neck such as the carotid artery. We want to see all these patients before they get any treatment because if we can identify the BRAF mutation we can start therapy quickly, and then we take out their tumor a few months later. We are opening a clinical trial with this strategy of neoadjuvant dabrafenib/trametinib.

We are still working on finding better therapies for patients that don't have a BRAF V600E mutation. The recently published study on an immunotherapy (checkpoint inhibitor) drug, spartalizumab, demonstrated efficacy in ATC.² The patients that had high PD-L1 scores. had a higher response rate and good overall survival (OS). At MD Anderson we conducted a trial of a combination of targeted therapy plus immunotherapy trial, and we're seeing good OS even in the non BRAF-mutated patients.

Our recent publication in JAMA oncology looked at nearly 500 patients at MD Anderson with ATC over the past 2 decades.³ This study showed improvement in the median OS from 0.67 years (2000-2013) to 1.31 years (2017-2019). We achieved this by making important changes to how we manage these patients, namely, rapid detection of BRAF mutations, enrollment to clinical trials, combination drug strategies (ie, targeted therapy and immunotherapy), neoadjuvant BRAF/MEK inhibitors, and surgery. The entire work-up and treatment is expedited via the FAST Program at MD Anderson, starting with rapid access to ATC experts. I believe we have shown that the first management option offered to ATC should not go be to hospice. All patients should at least have BRAF testing to determine if they should start the FDA approved drugs mentioned previously, or be considered for a clinical trial.

In DTC and MTC, we now have the selective RET inhibitor, selpercatinib. Two NTRK inhibitors, larotrectinib and entrectinib, for NTRK fusion cancers (present in in PTC, poorly differentiated and ATC) were approved last year.The selectivity of the drug means that there are fewer side effects, making it a very tolerable alternative. This is especially important for patients that are very frail or have uncontrolled hypertension who can't tolerate these multi kinase inhibitors. In DTC, especially PTC, we do see a high frequency of BRAF mutations, and BRAF inhibitors such as vemurafenib and the combination of dabrafenib/trametinib have been studied in that setting.

TARGETED ONCOLOGY: What unmet medical needs or challenges still exist in this space, and how do you think we can overcome these?

Cabanillas: A large proportion of our patients with DTC are refractory to RAI. There is now a better understanding as to why these patients do not take up RAI has led to clinical trials with targeted kinase inhibitors to “redifferentiate” (converting RAI-refractory disease to RAI-sensitive disease). This is a challenging area of study, and I applaud the investigators working in this field.

Probably the biggest unmet need in in the area of Hurthle cell thyroid cancer. This is usually refractory to RAI and a paucity of actionable oncogenes. These patients are usually managed with the FDA approved anti-angiogenic drugs, lenvatinib or sorafenib. However, once these drugs are no longer effective there are few systemic options shown to be effective.

Unfortunately, immunotherapy in MTC and DTC has been underwhelming as single agents. However, at ASCO this year, the data on a clinical trial for DTC patients treated with pembrolizumab and lenvatinib were presented and showed promising results.⁴ A second cohort of patients who progressed on single agent lenvatinib and therefore were started on the combination of lenvatinib/pembrolizumab has not yet been reported. This may be one strategy to overcome resistance to lenvatinib, however results are not yet available.

TARGETED ONCOLOGY: Are there any other new therapies coming down the pipeline right now that you want to highlight?

Cabanillas: There is a second selective RET inhibitor, BLU-667 (pralsetinib) that has shown efficacy in RET mutation/fusion thyroid cancer, but it has not yet been FDA approved.

Combination checkpoint inhibitors are also of interest in thyroid cancer. At ASCO 2020, Jochen Lorch presented a trial in thyroid cancer using nivolumab (Opdivo) plus ipilimumab (Yervoy). He efficacy in Hurthle cell and ATC. I understand that these investigators are going to open a trial with this checkpoint inhibitor combination in ATC.

At MD Anderson we have several trials for thyroid cancer that will be opening within the year. For ATC patients, these include neoadjuvant dabrafenib/trametinib/pembrolizumab in BRAF mutated ATC, lenvatinib/pembrolizumab in non-BRAF mutated ATC, and adjuvant pembrolizumab in non-BRAF mutated ATC patients who have completed external beam radiation. For thyroid cancer patients with RET mutation or fusion, we are opening a trial with neoadjuvant selpercatinib.

TARGETED ONCOLOGY: Is there any advice that you would like to share with community oncologists in the field treating patients with thyroid cancer?

Cabanillas: My advice would be that if you are considering systemic therapy for your thyroid cancer patient, that molecular testing (to include fusions) should be performed if feasible. For ATC, we feel strongly that all patients should have molecular testing and be considered for enrollment on a clinical trial when available (despite the approval of dabrafenib/trametinib).The reason for this is that unfortunately, we see patients starting to progress after about 12 months of dabrafenib and trametinib, so we really want to study strategies to extend survival in these patients. We definitely want to see those patients early and before attempts to remove the tumor have been made. These patients should be seen at centers with ATC experts, such as in our FAST program at MD Anderson. 

TARGETED ONCOLOGY: What message would you like to share with fellow oncologists in the field right now regarding the latest advancements in thyroid cancer in honor of Thyroid Cancer Awareness Month?

Cabanillas: Targeted therapy is the way to go with thyroid cancer patients who need systemic therapy. The field is changing quickly and not all thyroid cancer patients (particularly MTC and DTC patients) will need targeted therapy so it is important to identify appropriate candidates.

<< View more regarding the recent data for selpercatinib in thyroid cancer

_References

_{1. 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}

_{2. Cadevila J, Wirth LJ, Ernst T, et al. PD-1 blockade in anaplastic thyroid carcinoma [Published Online May 4, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02727}

_{3. Maniakas A, Dadu R, Busaidy NL, et al. Evaluation of overall survival in patients with anaplastic thyroid carcinoma, 2000-2019. JAMA Oncol. Published online August 6, 2020. doi:10.1001/jamaoncol.2020.3362}

_{4. Haugen B, French J, Worden FP, et al. Lenvatinib plus pembrolizumab combination therapy in patients with radioiodine-refractory (RAIR), progressive differentiated thyroid cancer (DTC): Results of a multicenter phase II international thyroid oncology group trial. Journ Clin Oncol. 2020, 38:15, 6512-6512. doi: 10.1200/JCO.2020.38.15_suppl.651}2