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Pazopanib/Trametinib Combo Tolerable, Clinically Active in Differentiated Thyroid Cancer

Darcy Lewis
Published Online:4:11 PM, Thu July 18, 2019
Razelle Kurzrock, MD
Razelle Kurzrock, MD
A combined regimen of pazopanib (Votrient) and trametinib (Mekinist) was tolerable at full single-agent doses in patients with differentiated thyroid cancer (DTC) according to the results of a multicenter phase I trial expansion cohort. The expansion cohort showed that the combination has clinical activity in DTC but did not achieve the pre-specified response rate, according to a new report in Clinical Cancer Research.

“The trial did not meet its pre-specified threshold for activity for the [patients with] follicular thyroid cancer, resulting in closing the trial for enrollment,” the authors, led byRazelle Kurzrock, MD, of The University of Texas MD Anderson Cancer Center, wrote in their report. “Future study of the combination in NRAS-mutated DTC in a larger, randomized trial to truly validate the findings would be meaningful to assess if this strategy has any role in the care of [patients with] DTC.”

The authors hypothesized that the inhibition of receptor tyrosine kinases VEGFR and PDGFR with the multikinase inhibitor pazopanib plus the MEK inhibitor trametinib could improve clinical benefit for patients with DTC compared with pazopanib alone. They enrolled 26 patients with advanced solid tumors at MD Anderson Cancer Center (n = 14) and Johns Hopkins University (n = 12).The later expansion cohort contained 13 patients with DTC at MD Anderson Cancer Center (n = 11) and Johns Hopkins University (n = 2) who were treated at the maximum tolerated dose (MTD).

Adult patients with advanced solid tumors that were refractory to standard-of-care treatment options were eligible for the dose-finding cohort of the study. For the DTC expansion cohort, patients must have had radioiodine non-avid lesions or radioiodine avid lesions that had not responded to treatment with radioactive iodine. They were also required to have adequate organ function and an ECOG performance status of 0 or 1.

In the dose-finding cohort, patients received escalating doses of pazopanib and trametinib with 5 dose levels per drug. For pazopanib, the dose levels (DL) were 400 mg for DL1, 600 mg for DL2, and 800 mg for DL3-5. 

For trametinib, patients received 1 mg at DL1-3, followed by 1.5 mg at DL4, and 2 mg at DL5. Patients took the regimen orally each day in a 28-day cycle. The authors used a standard 3+3 dose-escalation design and defined the MTD as when 0 or 1 dose-limiting toxicities (DLTs) were observed in 6 patients.

The expansion cohort patients were treated at the MTD established in the dose-finding cohort, which was pazopanib 800 mg and trametinib 2 mg daily. The treatment protocol allowed dose delays or reductions if needed. The authors deemed a dose level tolerable if at least 3 patients received it for 4 weeks without developing a DLT prior to treating a new cohort at a higher dose level. They planned to conduct an interim futility analysis after response information was available on the first 12 patients in the expansion cohort.The primary endpoint of the expansion cohort in DTC was objective response rate (ORR) at 6 months of treatment. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. 

In the phase I cohort, 12 (93%) were evaluable for disease response at the primary endpoint of ORR at 6 months. Of these, 4 patients had a RECIST criteria response (33%) and 50% had stable disease. The median follow-up was 37 months. The median PFS was 10.7 months (95% CI, 7.3-NA). The 2-year PFS rate was 25% (95% CI, 9%-67%). The median OS was 29.3 months (95% CI, 18.9-NA).

Overall, 69% of patients discontinued treatment due to disease progression, 19% due to toxicity, and 12% due to physician or patient choice. In the DTC cohort, those numbers were 62%, 8%, and 31%, respectively.Nine patients received dose reductions; 5 had only pazopanib reduced, 1 had trametinib reduced alone, and 3 patients had both therapies reduced. Diarrhea was the most common reason for dose reduction of pazopanib (50%), followed by fatigue and hypertension.

Ten patients with available tumor tissue underwent sequencing and were evaluable for response. All 3 of the 3 evaluable responders had an NRAS mutation, and none of the patients with stable disease or progressive disease had an NRAS alteration (= .008). Additionally, BRAF V600E or TP53 mutations were found in 2 patients. Other alterations noted included PIK3CA, SMO, CDKN2A, ALB1, andRB1 in 1 patient each. 

Regarding treatment-related adverse events (TRAEs) of any grade in the dose-escalation thyroid cohort, all 13 patients had a rash, and a vast majority of the cohort had nausea/vomiting (n = 12, 92%), hypertension (n = 11, 85%), and diarrhea (n = 11, 85%).

The authors reported no treatment-related deaths and no grade 4 toxicities. The most common grade 3 toxicities identified were transaminitis (19%), diarrhea (15%), and hypertension (12%). Common low-grade TRAEs included diarrhea, rash, hypertension, nausea/vomiting, fatigue, and anorexia.

Toxicity was a secondary endpoint of the DTC expansion cohort. Kurzrock et al found that TRAEs were similar in the DTC expansion cohort compared to the dose-escalation cohort. The most common toxicities remained nausea/vomiting, hypertension, rash and diarrhea. In this cohort, 4 patients withdrew from the study due to unrelated AEs and quality-of-life issues due to low-grade diarrhea and fatigue.

As planned, the authors conducted the interim analysis after 12 patients were enrolled and the 6-month ORR data were available.“The posterior probabilities of objective response less than 25% in the papillary and less than 67% in the follicular groups were 0.287 and 0.86, respectively,” Kurzrock et al wrote. “Since there was an 86% probability that the response rate in the follicular group was less than 67%, the study was paused for a futility review, and ultimately halted.”
 
 
Reference:
Kurzrock R, Ball D, Nelkin B, et al. The VEGF receptor tyrosine kinase inhibitor pazopanib in combination with the MEK inhibitor trametinib in advanced solid tumors and differentiated thyroid cancers [published online June 11, 2019]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-18-1881.


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