Combination Pembrolizumab Plus Lenvatinib May Be Option in Anaplastic and Poorly Differentiated Thyroid Cancers

• Clin Thyroidol 2021;33:131–133.
• Background
  • Anaplastic thyroid carcinoma (ATC) and metas‐ tasized poorly differentiated thyroid carcinoma (PDTC):
    • Are rare aggressive malignancies with low overall survival despite the availability of extensive multimodal therapies
  • Tumors are highly proliferative:
    • With frequently increased tumor mutational burden as compared with differentiated thyroid carcinomas and elevated programmed cell death ligand 1 (PD-L1) levels
• Methods
  • In a retrospective study, the authors analyzed six patients with metastasized ATC and two with PDTC:
    • Who received a combination therapy of lenvatinib and pembrolizumab
  • Lenvatinib was started at 14 to 24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every 3 weeks
  • Maximum treatment duration with this combination:
    • Was 40 months:
      • Three of the six patients with ATC were still on therapy
  • Patients’ tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS], 1–90%)
• Results
  • The best overall response within ATCs was:
    • 66% (4 of 6) with complete remission
    • 16% (1 of 6) with stable disease
    • 16% (1 of 6) with progressive disease
  • The best overall response in PDTCs was:
    • Partial remission (in 2 of 2)
  • Median progression-free survival was:
    • 17.75 months for all patients
    • 16.5 months for ATCs:
      • With treatment durations of 1, 4, 11, 15, 19, 25, 27, and 40 months
  • Grade III of IV toxicities developed in 4 of 8 patients and required dose reduction or discontinuation of lenvatinib
  • The median overall survival was 18.5 months:
    • With three ATC patients still alive without relapse (at 40, 27, and 19 months) despite metastatic disease at the start of treatment (International Union against Cancer [UICC] stage 4C)
  • All patients with long-term (greater than 2 years) or complete responses had either:
    • An increased tumor mutational burden or a PD-L1 TPS greater than 50%
• Conclusions
  • These results suggest that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC or PDTC, leading to complete and long-term remissions
  • The combination treatment is now being systematically examined in a phase two clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab – ATLEP; NCT04171622) in patients with ATC and PDTC
• This small retrospective study demonstrates a rather provocative and high response rate in patients with ATC using the:
  • Multi–tyrosine kinase inhibitor lenvatinib combined with the immune checkpoint inhibitor pembrolizumab
• While there is little doubt that pembrolizumab is active in ATC with activity that is likely comparable to that of spartalizumab (a similar PD-1 inhibitor that was tested in a robust phase two study of ATC and demonstrated a radiographic response rate of 19%), questions remain about the use of lenvatinib in this disease
• Following initial reports from Japan with similarly remarkable response rates and a subsequent phase two study that seemed to confirm some efficacy, an international follow-up study failed to reproduce these results and was terminated after finding only one positive response in 33 patients (3) (NCT02657369)
• Why there was such a discrepancy between those results?
  • At least one possible explanation is that in the Japanese study not all cases might have been anaplastic thyroid cancer, but could have been a mix between anaplastic and poorly differentiated thyroid cancer due to a lack of central pathology review
  • In PDTC, the high response rate to lenvatinib has been well described
  • One could argue that the combination of a checkpoint inhibitor plus lenvatinib could result in synergy:
    • With one drug enhancing the other’s activity perhaps through exposure of a broader range of neoantigens to the immune system
  • This hypothesis was the basis for a recently presented phase two study in radioiodine-refractory differentiated thyroid cancer conducted by the International Thyroid Oncology Group, which also combined pembrolizumab plus lenvatinib and which used the rate of complete responses as the primary end point
  • Unfortunately, there was no signal of synergistic activity, and the results were very much in line with those observed with lenvatinib alone
  • With that in mind, it is somewhat difficult to anticipate that the current data will be reproducible in the planned phase two study, but given the generally bad prognosis in this disease, every possible lead should be explored

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