NCCN Guidelines for First-Line Treatment of RR-DTC

Lori Wirth, MD: The NCCN [National Comprehensive Cancer Network] Guidelines do indicate that for first-line treatment of iodine-refractory progressive differentiated thyroid cancer, lenvatinib is the preferred MKI [multikinase inhibitor] to use. Why is that? My guess is that because of the efficacy data that show a much higher overall response rate with lenvatinib, seen in the SELECT trial, compared with sorafenib, seen in the DECISION trial, that that was taken into account in the NCCN Guidelines committee discussions as well as the improvement in progression-free survival. The improvement in progression-free survival with lenvatinib was greater—14 months—compared with the smaller improvements in progression-free survival seen with sorafenib in the DECISION trial. It’s mostly based on those efficacy differences that led the NCCN Guidelines committee to indicate that lenvatinib is generally the preferred MKI for initial therapy.

When might you want to consider using sorafenib instead, or other drugs for that matter? One of the most common adverse events seen with lenvatinib is hypertension. Hypertension is actually seen in the majority of patients who are started on lenvatinib. For patients who already have hypertension that’s difficult to manage, I may consider starting sorafenib rather than lenvatinib for those patients.

There are other patients where it might be tempting to consider initiating another treatment first in the first-line setting. For example, if we’ve done genotyping, if we have molecular diagnostics and a patient who has a BRAF V600E mutation—which is the most common mutation, driver mutation that is seen in DTC [differentiated thyroid cancer]—should we think about using BRAF-targeted therapy instead of a drug like lenvatinib or sorafenib? Those drugs are not approved by the FDA. I don’t use BRAF-directed therapy as a frontline off-label therapy in my own patients, particularly because in addition to the fact that they’re not FDA approved, the data that we do have don’t suggest that BRAF-directed therapy is better than lenvatinib in the first-line setting. I would reserve thinking about clinical trial participations for BRAF-directed therapy after first-line therapy with a drug like lenvatinib.

We also have seen just recently in the last couple of years some very exciting data, fusion-driven iodine-refractory differentiated thyroid cancer. The first approval was a tumor-agnostic approval for fusion-directed therapy came with larotrectinib. We do see a small percentage of patients with iodine-refractory DTC harboring NTRK fusions. Larotrectinib is approved in that patient population. The activities with larotrectinib is very good, and the tolerability is also very good, and that’s a reasonable therapy to consider as well as entrectinib now that that’s approved as well.

Recently, of course, we’ve seen the approval of selpercatinib in patients with RET fusion-driven iodine-refractory DTC, as well as other RET fusion or RET-mutant driven tumors. Again, there was an approval in patients with non–small cell lung cancer, RET mutation medullary thyroid cancer, and RET-fusion differentiated thyroid cancer.

I think the decision to use selpercatinib or considerations to use selpercatinib in the approximately 10% or 11% of patients with iodine-refractory DTC harboring RET fusions is a reasonable thing to consider.

In terms of the toxicity management of patients on lenvatinib, it’s important to think about 2 things. One is that hypertension is very common, and it can be seen very early in initiating therapy. It’s important to have patients monitoring their blood pressure at home and to actively manage hypertension early. It also is important to note that when we did an analysis taking a look at treatment-emergent hypertension, we found that’s a very important pharmacodynamic marker in how patients will do.

For patients who were on the SELECT trial who developed treatment-emergent hypertension on lenvatinib actually had an overall survival benefit compared with those patients who were treated with lenvatinib and didn’t develop hypertension. The last thing you want to do is stop lenvatinib because the patient has developed hypertension. Instead, you want to manage it.

The other thing I’d say is that we also did an analysis taking a look at how long patients have, the dose of lenvatinib held for toxicity. What we found was that there was a decrement in the progression-free survival, and then also the overall response if lenvatinib was held for too long compared with shorter dose hold for toxicity. Dose holds are a common tool that we have in managing toxicity of patients on lenvatinib. But lenvatinib has a short half-life, and you don’t have to hold the drug for too long before the patients get better, and then you can resume therapy. Sometimes a dose reduction is called for. Sometimes you can resume at the dose that the patient had already been on.

Transcript edited for clarity.

Case: A 67-Year-Old Woman With Differentiated Thyroid Cancer

Initial presentation

• A 67-year-old woman presents with a painless “lump on her neck”
• PMH: unremarkable
• PE: palpable, non-tender solitary right-of-the midline neck mass; otherwise unremarkable

Clinical workup

• Labs: including TSH, anti-Tg antibodies WNL
• Ultrasound of the neck revealed a 3.6 cm suspicious right mass arising from the right thyroid; 3 suspicious supraclavicular largest 2.0 cm in size
• Ultrasound-guided FNAB of the thyroid mass and the largest lymph node confirmed papillary thyroid carcinoma
• Patient underwent total thyroidectomy with central compartment and right selective neck dissection
• Pathology: 3.6 cm papillary thyroid cancer arising in right lobe of thyroid, tall-cell features; extrathyroidal extension present; 2 of 6 positive central compartment lymph nodes, largest 1.6 cm, no extra nodal extension; 3 of 13 right lateral compartment involved nodes largest 2 cm, positive extra nodal extension
• StageT2N1MX; ECOG PS 0

Treatment and Follow-Up

• She was treated with radioactive iodine 150 millicuries
  • Whole body scan showed uptake in neck only consistent with thyroid remnant
• Follow-up at 6 months TSH 0.1 mU/L; thyroglobulin 24 ng/mL
• Chest CT scan showed 10 small bilateral lung nodules largest 1.1 cm
• Follow-up CT neck and chest scan at 3 months was notable for a 1-2 mm growth in several lung nodules and 2 new distinct 8 mm lung nodules
• Lenvatinib 24 mg PO qDay was initiated