• The primary endpoint was changed to ORR to improve comparability with other studies. CBR was now a secondary endpoint. • The number of patients in the study was increased from 10 to 18. This was due, among other things, to a request from the Ethics Committee and a revision of the significance level by our statisticians. To achieve a sufficient number of patients, the recruitment period was increased from 12 to 18 months. • Inclusion criterion 4 was changed from ECOG 0-2 to ECOG 0-1. This corresponds to the inclusion criteria of other clinical trials in anaplastic thyroid carcinoma and increased participant safety. • The lenvatinib dosages were changed as follows: Level 1 from 14 to 16 mg; Level 2 from 10 to 12 mg; Level 3 from 8 to 10 mg. These finer dosing options allowed for better and more individualized dose adjustment per patient. • The definitions of 'response' have been changed. Response criteria should be based on the latest irRECIST criteria for immunotherapies. • Inclusion criterion 13 (life expectancy > 1 month) was removed, as our experience had shown that patients with a life expectancy of less than 1 month without treatment also benefit. • Lenvatinib, one of the two study medications, was provided to us by EISAI as part of the ATLEP study. This allowed for the provision of lenvatinib free of charge to all patients within the study for two years. • Consistent description of the dose reduction of lenvatinib.

• Due to the COVID-19 pandemic and the corresponding travel restrictions/ complications we aimed to choose local university hospitals with experience in clinical trials, where our patients could get their 3-weekly pembrolizumab infusions. The 3-monthly study visits still took place in Freiburg. Lenvatinib was surrendered to the patients for the whole 3 months period between two study visits. • Recent clinical data suggested, that the outcome of ATCs (anaplastic thyroid carcinomas) and PDTCs (poorly differentiated thyroid carcinomas) differs regarding response to third-line therapies. Therefore, we aimed to separate the statistical analysis for both entities, and according to our statistical calculations then needed to increase the sample size to 20 ATCs (anaplastic thyroid carcinomas) and 20 PDTCs (poorly differentiated thyroid carcinomas). Enhancement of the recruitment time from 12 to 24 months. • We aimed to change the time point for the PET-CT from 6 months to 3 months and to add another PET-CT at the 12-month time point. Patients suffering from other types of cancer within the last 24 months, which could not be cured by local measures, must be excluded. • In case of hypertension, proteinuria and arterial embolism, it was necessary at first to optimize symptom specific concomitant treatment like antihypertensive medication or anticoagulation; lenvatinib had to be interrupted after outstanding effect of such optimization. • In case of autoimmune hepatitis, pembrolizumab had to be interrupted until transaminases had decreased to CTCAE grade II or below. Pembrolizumab could then be restarted with comedication of budesonide and ursodesoxycholsäure. • Therapy with lenvatinib for a maximum of 4 weeks prior enrolment was permitted. • Duration of the trial was prolonged until 36 months after registration of the last patient.

• Lenvatinib had to be stopped 1 week before and up to 2 weeks after a major surgery • Lenvatinib was shown to induce jaw necrosis as a newly observed side effect, which had to be added • Dr. Cornelius Miething took over the role as Coordinating Investigator (LKP) in Freiburg, Prof. Dr. Christine Dierks is future Scientific Coordinator. Summary of changes to CTP: • Adjustments in trial duration and planned dates as well as on funding • Adjustments in Exclusion criteria concerning consistency • Update of contact details of clinical monitoring (CRA) • Update of patient registration times • Inclusion of further information in “Guidelines for management of medical conditions during the study” • Inclusion of further information in section “Permitted prior/ concomitant treatment/ medication” (stop of lenvatinib treatment before major surgery) • Adjustment on monitoring procedure.

• Starting Dose of Lenvatinib was maintained (according to SmPC) at 20mg/day • Pembrolizumab was administered at the Medical Center – University of Freiburg only

Notification of administrative changes in the conduct of the study: • Update of insurance • Follow-up visits had been updated