Medullary Thyroid Carcinoma – Recurrent or Persistent Disease Management

Kinase inhibitors:
- May be appropriate for select patients with recurrent or persistent MTC that is not resectable
- Although kinase inhibitors may be recommended for patients with MTC:
  - It is important to note that kinase inhibitors:
    - May not be appropriate for patients with stable or slowly progressing indolent disease
- Vandetanib and cabozantinib:
  - Are oral receptor kinase inhibitors:
    - That increase progression free survival (PFS):
      - In patients with metastatic MTC
RET inhibitors that are FDA-approved for RET-mutated MTC include:
- Selpercatinib and pralsetinib
Vandetanib:
- Is a multi-targeted kinase inhibitor
- It inhibits:
  - RET
  - Vascular endothelial growth factor receptor (VEGFR)
  - Endothelial growth factor receptor (EGFR)
- In a phase III randomized trial in patients with unresectable, locally advanced, or metastatic MTC (n = 331):
  - Vandetanib increased PFS when compared with placebo (HR, 0.46; 95% CI, 0.31– 0.69; P < .001)
  - OS data are not yet available
  - A post-hoc subgroup analysis including 184 patients with symptomatic and progressive disease at baseline:
    - Also showed increased PFS (HR, 0.43; 95% CI, 0.28–0.64; P < .001) in patients who received vandetanib, compared to the placebo:
      - Although time to worsening pain was not significantly different between the two groups (HR, 0.67; 95% CI, 0.43–1.04; P = .07)
      - In this subgroup, the overall response rate (ORR) was:
        37% in the patients who received vandetanib and 2% in patients who received the placebo (P < .001)
- The FDA approved the use of vandetanib for patients with locally advanced or metastatic MTC:
  - Who are not eligible for surgery and whose disease is causing symptoms or growing:
    - However, access is restricted through a vandetanib Risk Evaluation and Mitigation Strategy (REMS) program:
      - Because of potential cardiac toxicity
- The NCCN Panel recommends vandetanib (category 1):
  - As a preferred option for patients with recurrent or persistent MTC
Cabozantinib:
- Is a multi-targeted kinase inhibitor:
  - That inhibits:
    - RET
    - VEGFR2
    - MET
- In a phase 3 randomized trial (EXAM) in patients with locally advanced or metastatic MTC (n = 330):
  - Cabozantinib increased median PFS when compared with placebo:
    - 11.2 vs. 4.0 months:
      - HR, 0.28; 95% CI, 0.19–0.40; P < .001
  - Following long-term follow-up:
    - The median OS for patients treated with cabozantinib was:
      - 26.6 months compared to 21.1 months for placebo:
        Although this difference was not statistically significant (stratified HR, 0.85; 95% CI, .64–1.12, P = .24)
- Exploratory analyses have suggested that cabozantinib:
  - May have a greater clinical benefit:
    - For medullary thyroid cancers harboring:
      - RET M918T or RAS mutations:
        Although prospective trials are needed to confirm
- In 2012:
  - The FDA approved the use of cabozantinib for patients with progressive, metastatic MTC
- The NCCN Panel recommends cabozantinib (category 1):
  - As a preferred option based on the phase III randomized trial and FDA approval
- Rare adverse events with cabozantinib include:
  - Severe bleeding and gastrointestinal perforations or fistulas:
    - Severe hemorrhage is a contraindication for cabozantinib
RET mutations account for a significant percentage of MTC cases:
- Supporting investigation into the impact of recently developed RET inhibitors on RET-mutated MTC
- The phase I–II LIBRETTO-001 study:
  - Evaluated the efficacy of the RET inhibitor selpercatinib in 143 patients with RET-mutant MTC in patients previously treated with vandetanib or cabozantinib (n = 55):
    - The ORR and 1-year PFS rates were:
      - 69% (95% CI, 55%–81%) and 82% (95% CI, 69%–90%), respectively
  - In patients with no previous vandetanib or cabozantinib treatment (n = 88):
    - The ORR and 1year PFS rates were:
      - 73% (95% CI, 62%–82%) and 92% (95% CI, 82%– 97%), respectively
  - The most commonly reported toxicities (grade 3 and 4) were:
    - Hypertension (21%)
    - Increased alanine aminotransferase (11%)
    - Increased aspartate aminotransferase (9%)
    - Hyponatremia (8%)
    - Diarrhea (6%)
  - Dose reductions due to treatment-related adverse events were reported in 30% of patients
- Pralsetinib, another RET inhibitor, was evaluated in the phase I–II ARROW study:
  - Which included 92 patients with RET-mutant MTC
  - The ORR was:
    - 60% (95% CI, 46%–74%) in patients previously treated with vandetanib or cabozantinib (n = 61)
    - 74% (95% CI, 49%–91%) in patients with no previous vandetanib or cabozantinib treatment (n = 22)
  - Pralsetinib was generally well-tolerated, with the most commonly reported grade 3–4 treatment-related adverse events being:
    - Hypertension (11%)
    - Neutropenia (10%)
  - These results are currently reported in abstract form, and the ARROW study is ongoing and continuing to enroll patients
In 2020:
- The FDA approved both of these RET inhibitors for RET-mutated MTC requiring systemic therapy
- Based on the data and the FDA approvals:
  - The NCCN Panel recommends selpercatinib and pralsetinib:
    - As preferred options for patients with RETmutant disease
  - RET somatic genotyping may be done:
    - In patients who are germline wild-type or if germline status is unknown
When locoregional disease is identified in the absence of distant metastases:
- Surgical resection is recommended with (or without) postoperative EBRT or IMRT
For unresectable locoregional disease that is symptomatic or progressing by Response Evaluation Criteria in Solid Tumors (RECIST) criteria:
- The following options can be considered:
  - RT (EBRT or IMRT)
  - Systemic therapy
Treatment can be considered for symptomatic distant metastases (eg, those in bone):
- Recommended options include:
  - Palliative resection, ablation (eg, radiofrequency, embolization), or other regional treatment
  - Vandetanib (category 1)
  - Cabozantinib (category 1)
- These interventions may be considered for asymptomatic distant metastases (especially for progressive disease):
  - But disease monitoring is acceptable given the lack of data regarding alteration in outcome
  - If systemic therapy is indicated, then vandetanib and cabozantinib are category 1 preferred options
  - Selpercatinib or pralsetinib are preferred options for patients with RETmutation positive disease
Pembrolizumab is also an option for patients with:
- TMB-H (metastatic tumor mutational burden-high [≥ 10 mutations/megabase (mut/Mb)]) disease:
  - Based on results of the phase II KEYNOTE-158 trial:
    - Which included two patients with thyroid cancer
The NCCN Panel does not recommend treatment with systemic therapy:
- For increasing calcitonin or CEA alone
In the setting of symptomatic disease or progression:
- The NCCN Panel recommends systemic therapy or enrollment in a clinical trial:
  - As stated above for locoregional disease:
    - Preferred systemic therapy options include:
      - Vandetanib (category 1)
      - Cabozantinib (category 1)
      - Selpercatinib:
        For patients with RET-mutation positive disease
      - Pralsetinib:
        For patients with RET-mutation positive disease
      - Other small-molecule kinase inhibitors (ie, sorafenib, sunitinib, lenvatinib, pazopanib):
        May be considered if clinical trials or the NCCN-preferred systemic therapy options are not available or are not appropriate
If the patient progresses on a preferred option:
- Then systemic chemotherapy can be administered:
  - Using dacarbazine or combinations including dacarbazine
- Pembrolizumab is also an option for patients with TMB-H (≥10 mut/Mb) disease (useful in certain circumstances)
- EBRT or IMRT can be used for local symptoms
- Intravenous bisphosphonate therapy or denosumab can be considered for bone metastases
- Best supportive care is also recommended
Results from clinical trials have shown:
- The effectiveness of novel multi-targeted therapies have shown promise in the management of MTC, these include:
  - Sunitinib
  - Sorafenib
  - Lenvatinib
  - Pazopanib
Severe or fatal side effects from kinase inhibitors include:
- Bleeding, hypertension, and liver toxicity:
  - However, many side effects can be managed
Because some patients may have indolent and asymptomatic disease:
- Potentially toxic therapy may not be appropriate
Calcitonin levels decreased dramatically after vandetanib therapy:
- Which did not directly correlate with changes in tumor volume:
  - Thus, calcitonin may not be a reliable marker of tumor response in patients receiving RET inhibitor therapy
A phase 2 trial in patients with progressive metastatic MTC:
- Assessed treatment using pretargeted anti–CEA radioimmunotherapy with iodine-131:
  - OS was improved in the subset of patients with increased calcitonin doubling times