Sorafenib and sunitinib cause hypothyroidism in a subset of patients. This retrospective study examined the incidence of hypothyroidism and its relationship to progression-free survival in renal cell carcinoma. We found that hypothyroidism occurs more frequently in patients treated with sunitinib and correlates with a longer progression-free survival, which could be useful as a biomarker for response to therapy. Introduction Sunitinib and sorafenib are tyrosine kinase inhibitors used in metastatic renal cell carcinoma and are known to cause hypothyroidism in a subset of patients. The goal of this study was to better characterize the development of hypothyroidism in patients and to examine its relationship to progression-free survival. Patients and Methods A retrospective chart review was performed on patients treated with sunitinib or sorafenib from January 1, 2005, to January 1, 2011. Data pertaining to the treatment course and development of hypothyroidism were extracted. Patients with hypothyroidism at the beginning of treatment were analyzed separately. Results A total of 73 treatment periods had sufficient data to analyze. Among patients with normal baseline thyroid function, 15 (44%) of 34 patients treated with sunitinib and 6 (27%) of 22 patients treated with sorafenib developed hypothyroidism. The hazard ratio for the development of hypothyroidism with sorafenib vs. sunitinib treatment was significant, at 0.38 (95% CI, 0.14–0.97). There was a statistically significant difference in the progression-free survival between patients who developed hypothyroidism while receiving treatment compared with those who did not, 18.2 vs. 10.1 months (P = .01). Conclusions This study demonstrated a significant difference in the incidence of hypothyroidism during treatment with sunitinib and sorafenib, with a higher incidence of hypothyroidism in patients treated with sunitinib. The development of hypothyroidism was associated with a longer progression-free survival.
Patient 1 A woman with renal cell carcinoma (RCC) presented with sudden right sided flank pain and anuria.Two years earlier she was diagnosed with RCC clear cell type and had a left-sided nephrectomy performed at that time. Her initial staging evaluation revealed multiple pulmonary nodules consistent with metastatic disease and she was started on sorafenib therapy. She remained on this therapy for 9 months, but was then found to have progressive disease and high-dose interleukin-2 (IL2) was initiated. The patient developed bilateral pulmonary edema during her initial course of IL2 which was believed to be secondary to IL2-induced capillary leak and required endotracheal intubation. Accordingly, IL2 was abandoned without completing a full course and treatment with sunitinib (50 mg daily for 4 weeks followed by a 2 week break) was pursued.Thirteen months after starting sunitinib, the patient described approximately 12 h of acute right-sided flank pain with no urine output over that time period. Her past history included a tiny calculus in the right kidney. She denied vomiting, diarrhea or recent change in her bowel movements. Laboratory analysis revealed a lactate of 3.5 mmol/l (normal range 0.5-2.2 mmol/l). A computed tomography (CT) exam of the abdomen and pelvis was ordered, showing colonic pneumatosis on the right and pneumoretroperitoneum (Fig. 1a-d). The patient proceeded to surgery, with placement of a ureteral stent and a rightsided hemi-colectomy. Cystoscopy and an intraoperative retrograde ureteropyelogram did not demonstrate an obstructive stone and the anuria was attributed to gastrointestinal perforation (GIP). Pathologic examination of the right colon showed extensive pneumatosis cystoides intestinalis (Fig. 1e) and focal areas of ulceration of the mucosa with transmural acute and chronic inflammation and giant cell reaction (Fig. 1f); microthrombi were observed in the vessels of the lamina propria. Three regional lymph nodes Invest New Drugs (
600 Background: PD-L1- and VEGF-targeted therapies have improved survival for mRCC pts and mechanisms of synergy have been reported. We conducted a phase I/II study to evaluate the safety and efficacy of pembro and cabo in mRCC pts. Phase I data are presented here. Methods: mRCC pts received pembro and cabo in a standard 3+3 dose escalation to determine the dose limiting toxicity (DLT), maximum tolerated dose (MTD), and objective response rate (ORR). Cabo was dosed at 40mg QD and 60mg QD in the first and second cohorts, respectively. Pembro was dosed at 200mg IV Q3W in all cohorts. The DLT window was 21 days. Scans were obtained every 9 weeks. Treatment beyond progression was allowed. Results: Eight pts (6M, 2F) were enrolled in the dose escalation cohort with cabo 40mg (5 pts) or 60mg (3 pts) and pembro 200mg. Two pts were not evaluable for DLT due to missing ≥25% of the planned cabo doses in C1, not related to DLT. Median age was 52.5 yrs (range 40-68). Seven pts had clear cell RCC and 1 pt had non-clear cell RCC. Seven pts had MSKCC intermediate risk and 1 pt had MSKCC poor risk. All pts had prior nephrectomy. Median number of prior therapies was one (range 1-3). No DLTs were observed. Drug-related G1 and G2 adverse effects included fatigue (87.5%), weight loss (75%), anorexia (50%), diarrhea (50%), dysgeusia (50%), and abnormal LFTs (50%). One pt had SAE of G3 reversible posterior leukoencephalopathy syndrome during C4, attributed to cabo. One pt each developed G3 hypertension, G3 anorexia, and G3 confusion, all occurring outside the DLT window. No dose reductions were needed at the 40mg cohort. One pt in the 60mg cohort required dose reduction to 40mg after C5. All patients were evaluable for response: 2 PR (at 60 mg cohort), 5 SD [median duration SD 18 wks (range 9-36+)], 1 PD; ORR 25%; clinical benefit rate 87.5%. No correlation was seen between PD-L1 status (archival tissue) and response. Conclusions: The MTD was determined to be pembro 200 mg Q3W and cabo 60 QD. Enrollment in the phase II dose expansion is ongoing and the MTD may be adjusted based on additional pt experience and long-term tolerability. There was encouraging early efficacy. This is an investigator-initiated study sponsored by Merck. Clinical trial information: NCT03149822.
Increases in the mean corpuscular volume (MCV) have been observed in patients with metastatic renal cell carcinoma (mRCC) on tyrosine kinase inhibitor (TKI) treatment; however, its association with progression‐free‐survival (PFS) is unknown. We aimed to characterize TKI‐associated macrocytosis in mRCC and its relationship with PFS. Retrospective review of data on macrocytosis and thyroid dysfunction on mRCC patients treated with sunitinib and/or sorafenib. These results are evaluated in the context of our previous report on the association of hypothyroidism in this setting. We assessed PFS as clinically defined by the treating physician. Seventy‐four patients, 29 of whom received both drugs, were included. A treatment period was defined as time from initiation to discontinuation of either sunitinib or sorafenib; 103 treatment periods [sorafenib (47), sunitinib (56)] were analyzed. Macrocytosis was found in 55 and 8% of sunitinib‐ and sorafenib‐treated patients, respectively, P < 0.001. The median time to developing macrocytosis was 3 months (m, range 1–7). Median PFS in sunitinib‐treated patients was 11 m (95% CI: 6–19). Median PFS was higher among those with macrocytosis compared to normocytosis (21 m [95% CI: 11–25] vs. 4 m [95% CI: 3–8] P = 0.0001). Macrocytosis and hypothyroidism were two significant predictors of PFS. The greatest difference in PFS among all patients was observed in patients with both macrocytosis and hypothyroidism (25 m), compared to the normocytic and euthyroid patients (5 m) (P < 0.0001). Sunitinib‐related macrocytosis was associated with prolonged PFS, and concurrent development of hypothyroidism and macrocytosis further prolonged PFS. Increased MCV may have a role as a predictive biomarker for sunitinib. Prospective studies accounting for other known prognostic factors are needed to confirm this finding.
We observed more cases of skin cancer during sorafenib treatment than during sunitinib treatment for advanced RCC; median MKI treatment duration before the identification of skin cancer was longer than 1 year.
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