Phase 2 trials of sorafenib in RCC published following the TARGET trial.

<p>Abbreviations: AE = adverse event; CI = confidence interval; CR = complete response; HFSR = hand foot skin reaction; NE = estimable; NR = not reported; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease.</p><p>^a NR for 3 patients.</p><p>^b Tumor assessment was not possible in five patients and they were excluded from the efficacy analysis.</p><p>^c Treatment emergent AEs were reported for the total 202 patients, which included both patients randomized to the sorafenib and to the placebo arm after a 12 week run-in period of sorafenib treatment.</p><p>^d Interim analysis.</p><p>^e Median overall survival was not reached.</p><p>^f Unconfirmed.</p><p>^g All reported AEs were considered treatment related.</p><p>^h Grade ≥3.</p><p>ⁱ Including 2 grade 5.</p><p>Phase 2 trials of sorafenib in RCC published following the TARGET trial.</p

Incidences of select adverse events in TARGET, associated expanded access trials, and subsequent phase 3 trials.

<p>A) Fatigue; B) HFSR; C) Rash, desquamation; D) Diarrhea; E) Hypertension. Data for trials including patients for whom sorafenib was used ≥second-line are indicated by stippling. *Data were not reported.</p

Sorafenib response rates, PFS, and OS in TARGET, associated expanded access trials, and subsequent phase 3 trials.

<p>A) Response rates. B) Median PFS and OS. Data for trials including patients for whom sorafenib was used ≥second line are indicated by stippling. *Data were not reported.</p

A Systematic Review of the Efficacy and Safety Experience Reported for Sorafenib in Advanced Renal Cell Carcinoma (RCC) in the Post-Approval Setting

<div><p>Background</p><p>Sorafenib was FDA approved in 2005 for treatment of renal cell carcinoma (RCC) based on the results of the pivotal phase 3 clinical trial, TARGET (Treatment Approaches in Renal Cancer Global Evaluation Trial). Since that time, numerous clinical studies have been undertaken that substantially broaden our knowledge of the use of sorafenib for this indication.</p><p>Methods</p><p>We systematically reviewed PubMed, Web of Science, Embase, Cochrane Library, and <a href="http://www.clinicaltrials.gov" target="_blank">www.clinicaltrials.gov</a> for prospective clinical studies using single agent sorafenib in RCC and published since 2005. Primary endpoints of interest were progression-free survival (PFS) and safety. PROSPERO International prospective register of systematic reviews #CRD42014010765.</p><p>Results</p><p>We identified 30 studies in which 2182 patients were treated with sorafenib, including 1575 patients who participated in randomized controlled phase 3 trials. In these trials, sorafenib was administered as first-, second- or third-line treatment. Heterogeneity among trial designs and reporting of data precluded statistical comparisons among trials or with TARGET. The PFS appeared shorter in second- vs. first-line treatment, consistent with the more advanced tumor status in the second-line setting. In some trials, incidences of grade 3/4 hypertension or hand-foot skin reaction (HFSR) were more than double that seen in TARGET (4% and 6%, respectively). These variances may be attributable to increased recognition of HFSR, or potentially differences in dose adjustments, that could be consequences of increased familiarity with sorafenib usage. Several small studies enrolled exclusively Asian patients. These studies reported notably longer PFS than was observed in TARGET. However, no obvious corresponding differences in disease control rate and overall survival were seen.</p><p>Conclusions</p><p>Collectively, more recent experiences using sorafenib in RCC are consistent with results reported for TARGET with no marked changes of response endpoints or new safety signals observed.</p></div

Randomized, open-label, phase 3 trials of sorafenib in RCC published following the TARGET trial.

<p>Abbreviations: AE = adverse event; AX = axitinib; CI = confidence interval; CR = complete response; ECOG PS = Eastern Cooperative Oncology Group performance status; DOV = dovitinib; HFSR = hand-foot skin reaction; HR = hazard ratio; MSKCC = Memorial Sloan-Kettering Cancer Center; NR = not reported; OS = overall survival; PFS = progression-free survival; PR = partial response; SAE = serious adverse event; SD = stable disease; SOR = sorafenib; SU = sunitinib; TEM = temsirolimus; TIV = tivozanib.</p><p>^a Data reported only for first-line sorafenib.</p><p>^b Unless otherwise noted, baseline characteristics refer to the overall SU-SO population at study entry (n = 176); characteristics of patients who crossed over are NR</p><p>^c Except adjuvant IFNa.</p><p>^d 1-sided CI.</p><p>^e HR for progression of death.</p><p>^f Occurring in >20% of patients in any phase 3 study.</p><p>^g Data missing for 1 pt.</p><p>^h Reported as grade ≥3.</p><p>ⁱ Data missing for 5 pts.</p><p>^j 18 (7%) had normal thyroid-stimulating hormone levels prior to dosing that increased to >10 IU/mL after treatment; 5 (2%) had low T3 and 2 (1%) had low T4 on or after the date that the increases in thyroid-stimulating hormone were observed.</p><p>Randomized, open-label, phase 3 trials of sorafenib in RCC published following the TARGET trial.</p

TARGET and expanded access trials.

<p>Abbreviations: AE = adverse event; CI = confidence interval; CR = complete response; ECOG PS = Eastern Cooperative Oncology Group performance status; HFSR = hand-foot skin reaction; HR = hazard ratio; MSKCC = Memorial Sloan Kettering Cancer Center; NE = estimable; NR = not reported; OS = overall survival; PBO = placebo; PFS = progression-free survival; PR = partial response; SAE = serious adverse event; SD = stable disease.</p><p>^a Unless otherwise specified, refers to entire study population.</p><p>^b Data missing for 36 pts.</p><p>^c Data missing for 2 pts.</p><p>^d Data missing for 5 pts.</p><p>^e Eligibility criteria included ECOG PS 0–2 with waivers granted to selected pts with PS 3 or 4.</p><p>^f n = 1891.</p><p>^g Considered treatment related.</p><p>^h All reported AEs were considered treatment related.</p><p>TARGET and expanded access trials.</p

Additional small trials and patient series in RCC published since the TARGET trial.

<p>Abbreviations: AE = adverse event; CI = confidence interval; CR = complete response; HFSR = hand foot skin reaction; NR = not reported; OS = overall survival; PFS = progression-free survival; PR = partial response; SD = stable disease.</p><p>^a All 39 pts for which results are posted received 2nd-line sorafenib.</p><p>^b Patients received either 1st-line sorafenib (n = 43), 1st-line sorafenib + IFN (n = 16), or 2nd-line sorafenib (n = 39).</p><p>^c Population who received 2nd-line sorafenib.</p><p>^d Subset of pts with RCC.</p><p>^e Results not reported individually for pts receiving single-agent sorafenib.</p><p>^f Not reached after 278 days mean follow-up.</p><p>^g Median (range).</p><p>^h Grade 1–2.</p><p>Additional small trials and patient series in RCC published since the TARGET trial.</p

Flow of information.

<p>Selection process for included trials.</p