Multiple Trial Regimens Demonstrate Efficacy for RET-Mutated Medullary Thyroid Cancer

A number of clinical trials have provided evidence of efficacy of combination regimens for the treatment of RET-mutant medullary thyroid cancer (MTC). During a virtual Targeted Oncology Case-based Roundtable event, Lori Wirth, MD, medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, and associate professor in Medicine,Harvard Medical School, discussed the options for a 58-year-old man with RET-mutant MTC.

Targeted Oncology^TM: What additional work-up would you order for a patient like this? Would that include molecular or genetic testing?

WIRTH: With tumor markers of that height, that does predict distant metastatic disease in the patient, so ruling out distant metastases [with a PET scan] is a good idea. [There is] one minor point on PET/CT. When MTCs [medullary thyroid cancers] are not highly FDG [fluorodeoxyglucose] avid, and because they are neuroendocrine tumors with somatostatin receptors, you can do a gallium dotatate PET/CT as a more useful nuclear medicine imaging, and that can be helpful, particularly in finding tiny bone metastases. So if you think your patient may have just local regional disease and you really want to be sure they don’t have distant metastasis, then a gallium dotatate PET can be helpful.

[Genetic testing is] a bit complicated in MTC when we’re talking about germline mutations as well as somatic mutations. Generally, the germline testing takes a while. We will generally send patients to genetics counselors before doing germline testing because of the implications for the patient as well as their family members. So that can be something that can take a while longer, whereas now with NGS [next-generation sequencing] testing we can get testing of the tumor pretty quickly.

For patients with MTC, it is important to rule out a germline alteration because the patient with an MEN2A or MEN2B will be at risk for other malignancies in the syndrome and neoplasias, including pheochromocytoma. So we need to know exactly what their risk is for those other entities, particularly pheochromocytoma.

But the other reason why it’s so important is for the index patients’ first-degree family members. Twenty-five percent of people with MTC will have MEN2A or MEN2B, so their children and siblings are at risk for being carriers of the mutation as well. [Establishing risk is] particularly [important] for children; children can undergo a prophylactic thyroidectomy before they get MTC and be cured of an otherwise deadly disease, just with a simple thyroidectomy. So even in the absence of a family history, it is really important to rule out germline RET mutations in every patient who receives a diagnosis of MTC.

What molecular testing specifically would you recommend in the setting of MTC?

With most NGS testing, similar mutations are seen in germline as well as in sporadic MTC—for example, a RET C634, which is the most common MEN2A mutation, on an NGS test. I think most tests, like Foundation Medicine’s, won’t tell you if it’s a germline or a somatic mutation. So you’d want to go back and rule out a germline mutation if you see a RET mutation in NGS testing.

We send off the somatic testing because we get it back in 10 days. It’s easy to do and we don’t have to do the genetics counseling along with it. Then we’ll circle back and do germline mutational testing as well.

What is the prognosis for this patient?

With the degree of calcitonin and CEA at initial diagnosis and the number of [positive] lymph nodes, I would estimate the risk of recurrent disease probably being about 90%.

Would that be an argument for giving this patient adjuvant therapy?

We are hoping that there will be an adjuvant trial with one of the RET-specific inhibitors to take a look at metastasis-free survival in patients with rapid calcitonin and CEA doubling times in the adjuvant setting, similar to approvals recently in prostate cancer with a similar end point. Then there will be a clinical trial by the International Thyroid Oncology Group, looking at neoadjuvant selpercatinib [Retevmo] in patients with bulky RET-driven thyroid cancer, to see if we can improve on surgical outcomes with neoadjuvant therapy.

What are the currently available treatment options for such a patient?

Selpercatinib was added [to the National Comprehensive Cancer Network (NCCN) guidelines] for MTC with RET mutations, along with vandetanib [Caprelsa] and cabozantinib [Cabometyx], which are both FDA approved.1 Pembrolizumab is in there for TMB-high disease, but we don’t see high TMB in patients with MTC. I think it’s silly that it’s there, but it is. Selpercatinib is also recommended by the NCCN in addition to vandetanib and cabozantinib if there is symptomatic disease or progression. Pralsetinib [Gavreto] was just FDA approved [and added to the guidelines].²

What data support the use of the multikinase inhibitors in this setting?

Vandetanib [data] from the ZETA trial [NCT00410761] in MTC. This was the first randomized trial that was done in MTC, randomizing patients to vandetanib or placebo. This was done early on, and at the time it wasn’t appreciated that we should make sure the patients have disease progression before study entry. So patients did not have to have disease progression, and the placebo progression-free survival [PFS] curve is pretty long as a result of that.³

But vandetanib has an overall response rate [ORR] of 45% in MTC [compared with 13% with placebo; odds ratio, 5.48; P < .001], and there was crossover from placebo to vandetanib, so we wouldn’t expect to see an overall survival [OS] benefit [HR, 0.89], and indeed that was the case.

In terms of PFS, though, there was a significant benefit with a hazard ratio of 0.46. The median PFS with vandetanib had not yet been reached by the time the study was published [vs 19.3 months with placebo].

The forest plot [from the study looked at whether patients] do as well when they have RET mutations versus not. It’s really difficult to tell. Full sequencing of the RET gene was done, so many patients were considered RET unknown, and then only 3% of patients were determined to be RET negative. But it certainly looks like we’re seeing activity in both RET mutation–positive patients and RET-unknown patients. And it’s a multikinase inhibitor, so perhaps you’re getting some activity from the antiangiogenesis aspect of the drug as well as the anti-RET part of the drug.

[In this study], there is a fairly long list of adverse events [AEs] overall. [With] the grade 3 or higher AEs, the list gets smaller, but diarrhea is certainly common with the drug [11% vs 2% with placebo]. We see hypertension [9% vs 0%, respectively]; QTc prolongation is seen [8% vs 1%], and the FDA mandated a risk mitigation program for prescribers of vandetanib as a result of that. Fatigue [6% vs 1%] is certainly something that patients experience as well.

Are there other studies that are relevant in this setting?

The EXAM trial [NCT00704730] was done with cabozantinib in MTC.⁴ This trial required disease progression at study entry, so the placebo PFS was a lot shorter than with the vandetanib trial, at 4 months rather than 19 months. But there was a significant improvement in PFS with cabozantinib compared with placebo [11.2 vs 4.0 months; HR, 0.28; P < .0001]. A response rate of 28% was seen [vs 0% with placebo], and then an OS benefit was not seen in this study [26.6 vs 21.1 months; HR, 0.85; P = .24], despite the fact that there was no crossover.5 But a subsequent analysis took a look at the patients who just had the RET M918 mutation, and there was an OS benefit in that subset of patients [44.3 vs 18.9 months; HR, 0.60; P = .03].

If you look at the forest plot for OS for the patients who had RET M918T, which is the most common RET mutation, there was an OS benefit in those patients [HR, 0.60]. There was a PFS benefit across all the subgroups looked at.

There is a long list of AEs when a patient is on cabozantinib. Diarrhea was very common [any grade, 70.1%], hand-foot syndrome was seen [any grade, 52.8%], and nausea [46.7%], fatigue [42.5%], and weight loss [57.9%] were seen.

So, as a result of the AE profile, 82% of patients on the EXAM trial had to have dose reductions, 46% had second dose reductions, and then there were frequent dose discontinuations as well [AEs or serious AEs, 22%].

How do these trials compare with the data for the selective RET inhibitors?

LIBRETTO-001 [(NCT03157128) included patients with] RET-mutant MTC, and there also was a small group of patients that had RET fusion–positive other follicular-driven thyroid cancers.⁶

For the patients who had RET-mutant MTC, the PAS [primary analysis set included those] previously treated with cabozantinib and/or vandetanib. Then there was a second cohort of patients who were both cabozantinib and vandetanib naive. Patients were, in the previously treated arm, pretty heavily pretreated. The RET M918T mutation was the most common mutation, as expected, and then there were patients with that RET V804 mutation. That was the acquired gatekeeper resistance mutation, and there were a few patients with that mutation who were enrolled.

There were a few patients in both arms of the study who had brain metastases. We see brain metastases in these patients with advanced disease.

In terms of the ORRs in these 2 cohorts that were independently reviewed, the ORR for the previously treated patients [with RET-mutant MTC] was 69%, and we even saw a 9% complete response rate in the previously treated patients. In the patients who had not been previously treated, the independent review ORR was 73%, with an 11% complete response rate. The median duration of response [DOR] and median PFS had not yet been reached at the time of reporting for the PAS patients. The median DOR and PFS for the previously untreated patients [were] straight lines.⁷

We saw activity across all the mutations that were enrolled, including that presumed gatekeeper mutation, RET V804.

Then, when we look at the patients who had been previously treated with a RET fusion–positive follicular-driven thyroid cancer, the ORR in [those] 19 patients was 79% with a median PFS of 20.1 months. [The 8 untreated patients with RET fusion–positive thyroid cancer had an ORR of 100% and the median DOR was not evaluable].

In terms of AEs that were seen in 15% of patients or more, treatment-related grade 3 and grade 4 events [28% and 2%, respectively], it was a really short list of more serious treatment-related AEs and similar to what was seen in the lung group we saw earlier. Only 30% of patients had dose reductions, and the dose discontinuation rate was 2%.

What other trials are important to mention in this setting?

We have a randomized phase 3 trial [LIBRETTO-531;NCT04211337] that’s now under way, comparing selpercatinib with dealer’s choice of cabozantinib or vandetanib in patients with treatment-naive, metastatic progressive MTC. It is worth pointing out that this trial is enrolling patients as young as 12 years of age because we see MTC particularly in kids with germline mutations. This study is open in Boston, so send patients.

I think it’s important to touch upon the pralsetinib data in MTC with the ARROW trial [NCT03037385].⁸ The MTC cohorts [were similar to the LIBRETTO trial with] a treatment-naive cohort and a previously treated cohort, and similar patient profiles in terms of the RET mutations, etc.

For patients previously treated with cabozantinib and/or vandetanib, the ORR was 60%. And for the patients who had not been previously treated—it’s a much smaller number of patients compared with the LIBRETTO-001 trial [19 vs 88]—it was an ORR of 74%. In both the previously treated and untreated patients, we’re seeing very long median DOR and PFS, which haven’t yet been reached.

What kind of response would you expect to see in this patient in the case scenario with a selective RET inhibitor?

What we have seen is very brisk responses. The RET drives the production of calcitonin, so we see rapid declines of calcitonin. We see patients’ diarrhea clearing up in just 1 or 2 days of treatment. After the first couple of patients were treated, we started telling patients to get Senna, because they’re going to be constipated, and I’ve never seen so many happy constipated people in my life.

So we see very early responses and durable responses. We’ve had a number of patients who feel much better right away, so it’s gratifying. We have now seen a few patients who have developed acquired resistance. We have seen now a couple of patients in whom liquid biopsies or tumor biopsies have shown the solvent front acquired resistance mutation. We have a patient in whom we haven’t been able to identify any driver-acquired resistance alterations. So we’re not seeing these responses last forever in everyone, but we’ve got a number of patients in the study who were enrolled when the study opened in early 2018 who remain in the study now.

What are your thoughts on the differences between the 2 selective RET inhibitors? Is there anything that would make you choose one over the other?

I’m a bit surprised that nobody has really talked about the neutropenia [with pralsetinib]. There is some bone marrow suppression that seems to be more of an issue with pralsetinib [than with] selpercatinib. I think maybe we’re all medical oncologists here, so we’re just not too afraid of that particular toxicity. But is it something that’s meaningful?

There are data on neutropenic fever, but the final data are not yet available in manuscript form. Just anecdotally, I did have a patient on pralsetinib who’s had lymphopenia and neutropenia requiring dose reduction, and it wasn’t much of a worry until he got COVID-19. He was admitted, and we held pralsetinib right away, but he had a very long hospital stay. I have no idea if the neutropenia that he had contributed to his more serious illness or not. But I’ve wondered, just until this pandemic is behind us, if my own tendency would be to select selpercatinib rather than pralsetinib because of that one particular AE.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma, version 3.2020. Accessed February 26, 2021. https://bit.ly/3uzMTZL}

_{2. FDA approves pralsetinib for RET-altered thyroid cancers. FDA. December 1, 2020. Accessed February 26, 2021. https://bit.ly/2NLNRl4}

_{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, Drilon A, et al. Registrational results of LOXO-292 in patients with RET-altered thyroid cancers. Ann Oncol. 2019;30(suppl 5):v851-v934. doi:10.1093/annonc/mdz394}

_{7. 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}

_{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 mutationpositive medullary thyroid cancer (RET+ MTC). Ann Oncol. 2020;31(suppl 4):S1084. doi:10.1016/annonc/annonc293}