An Update on Thyroid Cancer Trials from the European Society of Medical Oncology (ESMO) 2021 Annual Meeting

• MERAIODE:
  • Dr. Sophie Leboulleux presented the results of MERAIODE:
    • A single-group, phase 2 study examining:
    • Re-differentiation with the MEK inhibitor trametinib followed by radioactive iodine:
      • For metastatic RAS-mutant radioactive iodine-refractory differentiated thyroid cancer
  • Attempts to recruit the sodium iodine symporter (NIS) to the cell surface:
    • Through MEK inhibition and render thyroid cancer cells susceptible to radioactive iodine have shown promise in the past:
      • Particularly in RAS-mutant cases:
        • Where significant uptake can be induced by this approach and tumors regress along with drops in serum thyroglobulin levels and/or radiographic responses]
  • The RAS mutations (NRAS, KRAS, and HRAS):
    • Are the second most frequent mutations in thyroid cancer after BRAF
  • In this part of the study, patients with RAS-mutant radioactive iodine (RAI)–refractory thyroid cancer:
    • Received trametinib 2 mg daily for 42 days after a diagnostic RAI scan
    • Patients then received 150 mCi RAI with rhTSH stimulation
  • Eleven patients were enrolled, of whom 10 received RAI
  • At 6 months after treatment, two patients had partial responses (PRs) by RECIST criteria (the primary end point), but no complete responses (CRs) were observed
  • RAI uptake increased from 30% of this cohort to 60% at 35 days after treatment
  • It may be fair to say, however, that the radiographic response rate was unexpectedly low in this selected cohort:
    • For example, BRAF V600E–mutant cases were also part of the same study, for which the results were presented earlier this year:
      • In that part of the trial, among 24 patients, the radiographic response rate was 38%
  • Although this study helps to further shed light on the use of MEK inhibition followed by RAI therapy in iodine-refractory disease:
    • This strategy remains experimental until more robust data from larger trials become available
• COSMIC 311:
  • The final analysis of COSMIC-311, a randomized, phase 3 study of cabozantinib after failure of at least one tyrosine kinase inhibitor (TKI) in RAI-refractory thyroid cancer was presented by Dr. Jaume Capdevila
  • As reported in the preliminary analysis presented at the ASCO meeting this year:
    • 170 patients were randomly assigned to cabozantinib 60 mg daily and 88 to placebo
    • Progression-free survival (PFS):
      • Was again significantly better in the treatment group:
        • HR, 0.2; 95% CI, 0.15–0.32; P = 0.0001
    • Overall survival, however, was not significantly different:
      • Although no difference had been expected in this trial that allowed crossover at disease progression
    • The response rate was 18% for cabozantinib and 0% for placebo
    • Based on these data, cabozantinib was granted approval by the Food and Drug Administration (FDA) for patients with:
      • RAI-refractory thyroid cancer who have previously had no success with one or more multi-TKI drugs
    • While the results were hardly surprising, the data are important:
      • Since they establish cabozantinib:
        • As an appropriate second-line treatment in RAI-refractory thyroid cancer
      • This FDA approval will affect insurance coverage of the drug
  • The difficult question is what to do with patients with NTREK or RET fusions for whom more specific FDA-approved TKIs are available
  • Given the toxicity of cabozantinib:
    • Which was intense (62% of patients suffered grade 3 or 4 toxicity despite the use of a lower dose of 60 mg daily, as compared with the full 140-mg dose):
      • It is likely that most clinicians would prefer NTREK or RET inhibitors for such cases
• STUDY 211:
  • Study 211, presented by Dr. Matthew Taylor,:
    • Examined whether or not a lower starting dose of lenvatinib (18 mg daily):
      • Would be associated with a better safety profile, while being no less effective than the full-dose regimen (24 mg daily)
  • In the pivotal phase 3 study (SELECT), in which lenvatinib had been used at 24 mg daily:
    • Dose interruptions occurred in 82.4%, and 67.8% of patients required dose reductions owing to side effects
  • Previously presented results of Study 211:
    • Had shown similar response rates at 24 weeks of treatment:
      • 57.3% for the 24-mg dose group and 40.3% in the lower-dose group
  • The data presented at this meeting were an update examining whether or not quality of life (QOL) measures, as assessed by standard questionnaires, were different between the lower and full doses:
    • Surprisingly, this was not the case:
      • QOL deteriorated similarly in both the 24- and 18-mg groups
  • The authors, therefore, drew the conclusion that lenvatinib 18 mg daily should not be recommended as a starting dose:
    • Although the study was carefully conducted and the results appear pretty clear, one could question whether the primary end point for this study (the response rate at 24 weeks) was ideal, since response rate and survival are not necessarily linked
  • While QOL measures may not be so different between the 18-mg and the 24-mg groups:
    • Some might argue that lower doses (such as 10 mg or 14 mg) seem to be much better tolerated and that starting at these levels may actually be a reasonable strategy:
      • With the option to escalate the dose regimen as tolerated
  • Nonetheless, this study adds to the current body of knowledge and is a laudable attempt at reducing the intense toxicities associated with this drug
• While no major breakthroughs were on the docket this year at ESMO, important data were presented that help on the quest to find more and better-tolerated treatment options for advanced thyroid cancers
• References:
  • Leboulleux S, Benisvy D, Taieb D, Attard M, Bournaud C, Terroir M, Al Ghuzlan A, Lamartina L, Schlumberger MJ, Godvert Y Borget I 2021 MERAIODE: A redifferentiation phase II trial with trametinib followed by radioactive iodine for metastatic radioactive iodine refractory differentiated thyroid cancer patients with a RAS mutation. Ann Oncol 32(suppl_5): S1205–S1210.
  • Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, Pentlow KS, Zanzonico PB, Haque S, Gavane S, et al. 2013 Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 368:623–632.
  • Leboulleux S, Do Cao C, Zerdoud S, Attard M, Bournaud C, Benisvy D, Taieb D, Bardet S, Terroir-Cassou-Mounat M, Betrian S, et al. 2021 MERAIODE: A redifferentiation phase II trial with trametinib and dabrafenib followed by radioactive iodine administration for metastatic radioactive iodine refractory differentiated thyroid cancer patients with a BRAFV600E mutation (NCT 03244956). J Endocr Soc 5(Suppl 1):A876.
  • Capdevila J, Robinson B, Sherman SI, Jarzab B, Lin C, Vaisman F, Hoff AO, Hitre E, Bowles DW, Sen S, et al. 2021 Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Updated results from the phase III COSMIC-311 trial and prespecified subgroup analyses by prior therapy. Ann Oncol 32(suppl_5):S1283–S1346.
  • Taylor MH, Leboulleux S, Panaseykin S, Konda B, de La Fouchardiere C, Hughes BGM, Gianoukakis AG, Park YJ, Romanov I, Krzyzanowska MK, et al. 2021 Health-related quality-of-life (HRQoL) analyses from study 211: A phase 2 study in patients (pts) with radioiodine-refractory differentiated thyroid cancer (RR-DTC) treated with 2 starting doses of lenvatinib (LEN). Ann Oncol 32(suppl_5):S1205–S1210.
  • Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, et al. 2015 Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621–630.

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