Phase 2 Study Spurs Hope for Future Combination Trials in Anaplastic Thyroid Cancer

Lori J. Wirth, MD

The phase 2 Study 213 (NCT02657369) trial may serve as rationale for investigation of multikinase inhibitor and immunotherapy combination studies in patients with anaplastic thyroid cancer (ATC) moving forward after demonstrating a low objective response rate (ORR) when lenvatinib (Lenvima) was used as a single agent to treat this patient population.

Treatment with lenvatinib demonstrated a low objective response rate (ORR) in patients with anaplastic thyroid cancer (ATC) in the phase 2 Study 213 (NCT02657369) trial, but the study may serve as rationale for investigation of the multikinase inhibitor in combination trials going forward.

“The data from this report evaluating lenvatinib as a single agent in anaplastic thyroid cancer will, I think, nonetheless, be helpful in the future,” said Lori J. Wirth, MD, associate professor of medicine, Harvard Medical School, and medical director, Center for Head and Neck Cancers, Massachusetts General Hospital, who presented the findings during the ENDO 2020 virtual meeting. “Due to a lack of efficacy observed with lenvatinib monotherapy in anaplastic thyroid cancer, further investigation of lenvatinib in combination with a checkpoint inhibitor may be warranted rather than pursuing further lenvatinib as a single agent.”

A small Japanese phase 2 study previously showed the potential for lenvatinib in this patient population, demonstrating a partial response in 24% of 17 patients with ATC. The open-label, multicenter, international Study 213 trial was initiated in collaboration with the International Thyroid Oncology Group to further investigate the use of lenvatinib in a larger group of patients with ATC.

Patients were eligible for enrollment if they had histologically confirmed ATC, ≥1 measurable target by RECIST v1.1 criteria, an ECOG performance status of 0 or 1, and adequate organ function. Those who had recently undergone surgery, radiation, or palliative chemotherapy were allowed onto the trial, but patients at high risk for bleeding events were excluded.

The primary end point was ORR by investigator assessment and secondary end points included progression-free survival (PFS), overall survival (OS), duration of objective response (DOR), clinical benefit rate (CBR), and disease control rate (DCR).

According to the study protocol, an interim analysis was completed of the first 20 patients after they had completed ≥2 tumor assessments or had discontinued treatment. If, at the time of the interim analysis, the ORR was ≤15%, enrollment would be halted, and the study would be potentially terminated. Patients were allowed to continue enrolling in the study while the interim analysis was being conducted.

Of the patients in the interim analysis set, half were less than 65 years old and half had an ECOG performance status of 0. Otherwise, the group was predominantly female (65%), from North America (75%), and Caucasian (80%). Wirth noted that the population was fairly heavily pretreated with 20% of patients having received ≥3 prior anticancer treatments; 30% were previously untreated. The most common prior treatments were chemotherapy (55%), including taxanes in 30%, anthracyclines in 30%, and platinum compounds in 25%. Only 2 patients had received prior multikinase inhibitors and 2 received monoclonal antibodies. 

Patient characteristics in the full analysis set (n = 34) were similar with 47% under 65 years, 62% female, 68% from North America, 79% Caucasian, and 47% with an ECOG performance status of 0. Seventy-one percent of the patients were previously treated and 12% had received ≥3 prior treatments. The majority of prior therapies were chemotherapy (62%), consisting of taxanes in 35%, anthracyclines in 29%, and platinum in 32%. Three patients had received prior multikinase inhibitors and 3 had received monoclonal antibodies.

In the interim analysis set, 1 patient achieved a partial response for an ORR of 5.0% (95% CI, 0.1%-24.9%); 9 patients (45%) achieved stable disease. Five patients had progressive disease and the other 5 were unevaluable. The median PFS was 2.6 months (95% CI, 1.2-2.8), and the median OS was 2.9 months (95% CI, 2.7 to not evaluable).

From the full analysis set, the ORR was 2.9% (95% CI, 0.1%-15.3%), and 17 patients (50%) achieved stable disease. Nine patients had progressive disease, and 7 were unevaluable. The CBR, defined as responses and stable disease lasting ≥23 weeks, was 8.8% (95% CI, 1.9%-23.7%). The median PFS and OS were 2.6 months (95% CI, 1.4-2.8) and 3.2 months (95% CI, 2.8-8.2), respectively.

The DOR for 1 responder was 4.1 months. Two other patients also achieved a reduction in total target lesion size of more than 30%, but at their next scan they had progressive disease.

“More than half of the patients did experience tumor shrinkage; however, there were only a few patients who had tumor shrinkage beyond 30%,” Wirth said.

Since the minimum threshold for ORR was not met, the trial was halted for futility, she noted.

Treatment-emergent adverse events (AEs) were reported in all patients and treatment-related AEs were observed in 94%. Grade ≥3 treatment-emergent AEs were reported in 82%, including grade 5 events in 41%, which were due to disease progression in 10 patients, and dysphagia, hypoxia, cardiopulmonary failure, pulmonary edema, renal failure, and septic shock in 1 patient each. These 14 deaths occurred within 28 days of the last dose of lenvatinib. Grade 3/4 treatment-related AEs were observed in 62% of patients, and no major treatment-related bleeding events were noted.

The most common treatment-related AEs of any grade were hypertension (56%), decreased appetite (29%), fatigue (29%), and stomatitis (29%). Wirth noted, “This is what is expected with lenvatinib at this dose in other thyroid cancer settings as well.”

Seventy-four percent of patients required dose adjustment due to treatment-related AEs, 41% required dose reduction, 56% needed dose interruption, and 6% discontinued treatment.

Wirth explained that Study 213 may have shown fewer responses than the Japanese trial due to the larger patient population, many of whom had received prior chemotherapy (62% vs 41%), the requirement for central pathology review to confirm diagnosis, and a shorter durable stable disease definition for the CBR (≥11 weeks vs ≥23 weeks).

Wirth said that 2 phase 2 trials are currently exploring the use of lenvatinib in combination with pembrolizumab (Keytruda) in patients with ATC and poorly differentiated thyroid cancer (ATLEP; NCT02973997) and in patients with unresectable locally advanced or metastatic ATC (NCT04171622). “I think these data will provide a very good historical comparison for those ongoing phase 2 trials,” she commented.

_Reference

_{Wirth LJ, Brose MS, Sherman EJ, et al. An open-label, single-arm, multicenter, phase 2 trial of lenvatinib for the treatment of anaplastic thyroid cancer. Presented at: ENDO Online 2020; June 8-22, 2020.}