Multikinase Inhibitor Options Abound for Patients With RET-Mutant Medullary Thyroid Cancer

Marcia S. Brose, MD, PhD

During a Targeted Oncology Case Based Peer Perspectives event, Marcia S. Brose, MD, PhD, director, Center for Rare Cancers and Personalized Therapy, director, Thyroid Cancer Therapeutics Program, Abramson Cancer Center Penn Medicine, and professor of Otorhinolaryngology: Head and Neck Surgery Hospital of the University of Pennsylvania, discussed options for a 58-year-old patient with RET-mutant medullary thyroid cancer.

Targeted Oncology™: What additional work-up would you order?

BROSE: I do somatic RET testing. I don’t know if anybody would necessarily argue with that. In this case, most of the [alterations] in RET are mutations, they’re not translocations, so I’m a little less concerned about whether I can get RNA, but I will make sure. I often send for both, but mostly I’m looking for point mutations on genetic screening for RET.

What do you think about the patient’s disease now that genetic testing has been performed?

One month postoperatively, he had a calcitonin of 112 pg/mL and a CEA of 15 ng/mL. That’s still high compared to what we would have thought. We would have hoped that it would have gone down lower than that. It was already showing that it might be persisting more than we would have expected.

RET aberrations in medullary [thyroid cancer are] mostly point mutations. In papillary thyroid cancer, you can still have point mutations, but it’s mostly translocations. In medullary thyroid cancer, we’re looking just for point mutation.¹

Would you recommend systemic therapy for this patient now?

He had a calcitonin that at 6 months started going up again and lymphadenopathy on the left side. Given that he was short of breath, I probably would have [ordered] a CT scan of his lungs up front around the time of his original surgery. I wouldn’t normally be finding out 6 or 12 months later that he was having positive disease in his lungs. But at 6 months, his calcitonin started to bump and certainly by then it was important to get a CT scan that showed positive lymph nodes, as well as metastatic liver lesions.

One important thing about medullary thyroid cancer and the liver is that the CT scan will often underestimate the involvement of the liver. It’s not as sensitive as an MRI. In medullary thyroid cancer, in general, we screen the liver with an MRI of the abdomen. But in this case, the CT scan picked it up as well. The patient didn’t want systemic therapy up front. I guess they thought they were going to do fine. But 12 months later, his calcitonin had doubled multiple times.

There are data from Douglas W. Ball, MD, who originally published the fact that if patients have a CEA or calcitonin doubling time of [more than] 2 years, they’re going to have low risk for rapid progression.² Those are some patients you might be able to follow. If they don’t have too large a tumor burden up front, you can usually go ahead 2 years or more and follow them with subsequent surveillance scans. If they get to be 1 to 2 years or less than 1 year, those are the patients you’re more likely going to start systemic therapy on. Those scans you want to get on patients every 6 or 3 months, based on whatever the doubling time is. They usually will need treatment within a year.

What would you recommend for systemic therapy for this patient now?

Cabozantinib [Cabometyx] and vandetanib [Caprelsa] were both FDA approved for medullary thyroid cancer in the first-line setting.^3,4 Selpercatinib [Retevmo] was recently approved.⁵

Right now, the current category 1 [recommendations per the National Comprehensive Cancer Network guidelines] are vandetanib and cabozantinib.⁶ Selpercatinib is also [available] for RET mutation–positive disease. Pembrolizumab [Keytruda] is for thyroid cancer with MSI [microsatellite instability]–high status, although I have not seen a role for immunotherapy in medullary thyroid cancer. That’s regardless of whether it’s asymptomatic or symptomatic.

What data support the use of vandetanib in this patient?

The ZETA trial [NCT00410761] was the first trial that was completed. It was with vandetanib versus placebo and did not require progressive disease in order for patients to go on study. The progression-free survival [PFS] from baseline in the placebo arm was long at 19.3 months [vs not reached with vandetanib]. In spite of that, the hazard ratio [for overall survival] was 0.89 [95% CI, 0.48-1.65]. Vandetanib was approved based on the difference in PFS. There was also a statistically significant difference in disease control rate and overall response rate.⁷

Interestingly, vandetanib is both a VEGF receptor inhibitor, and an inhibitor of RET. It was interesting to see that patients’ PFS seemed to be improved if they were RET mutation positive. The number of patients in the RET mutation–negative group wasn’t statistically significantly different because it was such a small number. But interestingly, especially the 918T mutation group, [the group that was mutation positive] seemed to be the ones [who] benefited from vandetanib.

What do we see with the adverse effects (AEs) for vandetanib?

Diarrhea is one of the most common and dose-limiting toxicities. Patients develop that quickly, within the first month or 2. Again, this would be somebody I would monitor. Hypertension is not as big a deal. Patients would be monitored every 2 weeks or so when they start in my clinic. They’d be advised on how to take loperamide prophylactically. Some patients need to go from 300 mg/day to 200 mg/day or even 100 mg/day for this reason because sometimes it’s hard to control [the diarrhea]. Rash and nausea are also quite common.

There are some AEs that overlap with the EGFR inhibitors. Rash is similar, so it’s like an acne-type rash that can respond to acne-type medication. Hypertension is there, but it’s not as significant as with lenvatinib [Lenvima]. It’s more like what we see with sorafenib [Nexavar]. Other AEs of grade 3 or higher included diarrhea and hypertension. Interestingly, there’s a lot of QT prolongation. It wasn’t determined that this was symptomatic; however, 4 patients died unexpectedly, and it was a concern that the QT prolongation could have led to torsades. For that reason, there’s a REMS [Risk Evaluation and Mitigation Strategies] program that people are forced to go through in order to prescribe this and make sure that they know how to monitor electrolytes and echocardiograms for these patients.⁴

Please describe the data that came out of the phase 3 EXAM trial (NCT00704730) supporting cabozantinib in this setting.

PFS for these patients required a central review of progression. The group of patients [treated with cabozantinib] was more active with a PFS of 11.2 months versus the placebo arm at only 4.0 months [HR, 0.28; 95% CI, 0.19-0.40; P < .0001], so a vastly different profile.⁸

Based on the improvement in PFS, cabozantinib was the second [agent] to be approved for the treatment of medullary thyroid cancer. Both vandetanib and cabozantinib were approved regardless of the genotype of the patient.

By RET mutation status, overall survival looked [as though] it favored cabozantinib. The PFS definitely favored patients with both RET as well as RAS mutations. These seem to be the patients who benefited the best, although cabozantinib was indicated for all patients.

What are the toxicity concerns with cabozantinib for these patients?

Diarrhea, weight loss, and hand-foot skin reaction are much more common with cabozantinib compared with vandetanib. I think it’s harder to manage patients. It’s a bit rougher. But especially in a patient who’s symptomatic and who needs a rapid decrease in the [tumor] size, I’ll tend to usually pick cabozantinib in the fi rst-line setting. Personally, I think it also works a little better in the bone, so that’s another reason I might prefer cabozantinib. Nausea and fatigue were signifi cant AEs as well. Grade 3 events you’ll see include diarrhea and weight loss. Diarrhea is the key in cabozantinib management. Nutrition support is important as well for these patients so they don’t lose too much weight.

Can you review the data from the phase 1/2 LIBRETTO-001 trial (NCT03157128) relevant to the selpercatinib approval?

Selpercatinib is the most recently approved agent in medullary thyroid cancer. It was just approved in the last year. Basically, it was approved [to treat] both [patients with] differentiated thyroid cancer [who] have RET fusions or RET point mutations, as well as patients who have medullary thyroid cancer with RET mutations. It’s a selective RET inhibitor, so this is not for all-comers. It’s just for the patients who have RET mutations. It was studied in 4 cohorts. For differentiated thyroid cancer, it looked at systemic therapy–naive or previously treated disease; then for RET point mutations, it was divided by previously treated or cabozantinib and vandetanib naive.

In the group of patients who had medullary thyroid cancer, the vast majority of these patients had RET M918T. That’s the most common mutation, so it’s not surprising. A few patients had the 804 gatekeeper mutations. That’s important because this is expected to confer resistance in some kinase inhibitors. This is the gatekeeper mutation that you’d expect to have resistance to. It turns out, preclinically, selpercatinib is active against 804. Then patients also had other mutations. Many patients, about two-thirds of them, had been previously treated. Then some had had both [prior therapies]. There were 55 patients who had had prior [multikinase inhibitor] therapy.

In patients who were previously treated with medullary thyroid cancer, the objective response rate is at 69%. That’s impressive when you think that some of these patients had been treated with 2 other multikinase inhibitors. In patients not previously treated, it goes up to 73%.

These aberrations tend not to be acquired later. RET mutations are probably present at the start. You can get genotyping before you even start treating these patients. That tends to be what I do because these selective inhibitors have a good AE profile.

Duration of response and PFS were spectacular. Patients are living a long time. One thing I’ll point out is that when you looked at the Kaplan-Meier curves for vandetanib and cabozantinib efficacy, the patients with RET aberration…were not getting duration of response [similar to what is seen here]. But it’s important to remember that this patient population is not the same as the vandetanib and cabozantinib [trial populations], so you can’t directly compare them. Needless to say, duration of responses and PFS curves [on this trial] are impressive.

What are the adverse effects associated with selpercatinib?

For grade 3 events, they are only observed in 28% of patients. Hypertension was the most common with 12%; 3% had some diarrhea. Interestingly, there were grade 3 but asymptomatic increases in AST [aspartate aminotransferase] and ALT [alanine aminotransferase]. Liver function tests…they were noted but asymptomatic; it seemed to fl uctuate, in other words. I could continue patients on the drug even at the same dose and it just seemed to go away periodically.

Is there a confirmatory phase 3 trial under way in these patients?

There’s a phase 3 trial ongoing for RET-mutated disease [LIBRETTO-531; NCT04211337]. We want to know [if it is] better to get selpercatinib or cabozantinib in the first line.⁹ The primary end point is treatment failure-free survival. Secondary end points are PFS, overall survival, and tolerability. Treatment failure incorporates patients who discontinue treatment because of adverse events and toxicity. That’s why this primary end point was chosen.

_References:

_{1. Kato S, Subbiah V, Marchlik E, Elkin SK, Carter JL, Kurzrock R. RET aberrations in diverse cancers: next-generation sequencing of 4,871 patients. Clin Cancer Res. 2017;23(8):1988-1997. doi:10.1158/1078-0432.CCR-16-1679}

_{2. Ball DW. Medullary thyroid cancer: monitoring and therapy. Endocrinol Metab Clin North Am. 2007;36(3):823-837. doi:10.1016/j.ecl.2007.04.001}

_{3. Cabometyx. Package insert. Exelixis, Inc.; 2012. Accessed October 29, 2020. https://bit.ly/34FXwiS}

_{4. Caprelsa. Package insert. Genzyme Corporation; 2011. Accessed October 29, 2020. https://bit.ly/2TAGvQL}

_{5. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. FDA. May 8, 2020. Accessed October 29, 2020. https://bit.ly/31Tk5yR}

_{6. NCCN. Clinical Practice Guidelines in Oncology. Thyroid carcinoma, version 2.2020. Accessed July 15, 2020. https://bit.ly/2TAGexh}

_{7. 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}

_{8. 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}

_{9. Wirth LJ, Sherman E, Robinson B, et al. Effi cacy of selpercatinib in RET-altered thyroid Cancers. N Engl J Med. 2020;383(9):825-835. doi:10.1056/NEJMoa200565}1