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459
Background: Metastatic UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 (ErbB2), and ...ErbB3 are frequent in UC and may represent viable therapeutic targets. We studied whether afatinib, an oral, irreversible Erb family blocker, has activity in UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC received afatinib 40 mg/day continuously until progression or intolerance.The primary endpoint was 3-mo progression-free survival (PFS3) using a Simon two-stage design, with the trial proceeding to stage II if ≥ 30% pts in stage I had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman) of available archival tumor tissue. Results: The initial enrollment goal of 23 ptswas met: 18 M/5 F, median age 67 (36-82), ECOG 0 in 26%/1 in 74%, Hb < 10 g/dl in 17%, liver metastases in 30%, median time from prior chemotherapy = 3.6 mo. No unexpected toxicities were observed; 2 pts required dose-reduction (grade 3 fatigue, grade 3 rash). 5/23 pts (21.7%) had PFS3 (1 partial response (PR), 4 stable disease). Notably, 5/7 pts (71.4%) with ErbB molecular alterations achieved PFS3 (PFS = 10.3, 7.0, 6.9, 4.6 (ongoing) and 3.9 (ongoing) mo respectively) while 0/16 without alterations reached PFS3 (p < 0.001, Fisher’s exact). The 2 pts with alterations (both HER2 amplified) who did not reach PFS3 had liver metastases. All 3 pts with ErbB3 somatic mutations were responders. One pt with both HER2 amplification and R103G ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. Average time to progression/discontinuation was 4.9 mo in pts with molecular alterations vs 1.7 mo for pts without alterations (p = 0.03). Conclusions: Afatinib demonstrates significant activity in platinum-refractory UC pts with HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. A follow-on phase II study of afatinib in marker-selected refractory UC pts is underway. Clinical trial information: NCT02122172.
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4563
Background: We previously reported no difference in favorable response rate (FRR) or PFS for TIP vs BEP. Here we present results of a pre-planned analysis of biomarkers of outcome. ...Methods: HCG and AFP were drawn on days 1 and 15 of each cycle and rates of decline classified as satisfactory S or unsatisfactory US by MSK (Motzer JCO 2007) and GETUG (Fizazi Lancet Oncol 2014) methods. IHC for ERCC1, RAD51, PARP1, HER-2, and p-AKT was performed on pre-treatment tumor samples. An H-score (0 – 300) was calculated for each stain (H = stain intensity 0 – 3 x % positive cells 0-100). H-score and marker decline category were correlated with FRR (PR + CR) and PFS. Patients (pts) who received disease-stabilizing chemotherapy were excluded from marker analyses. Results: Of 91 pts, 80 did not receive disease-stabilizing treatment with 79 having sufficient marker values for analysis by the MSK method and 75 by GETUG. By MSK, 49 had S decline vs 30 US; by GETUG, 34 S vs 41 US. FRR and PFS were improved for pts with S vs US decline by both methods and remained significant by the MSK method when stratified by IGCCCG group (Table). IHC (n=77) quality was adequate in 71 to 73 pts (varied by stain) and was positive (H >0) for PARP in 68/73, ERCC1 in 54/71, RAD51 in 54/73, p-AKT in 5/72, and HER2 in 4/72. Only PARP1 was associated with outcome with worse PFS for the lowest expression tertile (H < 180; p=0.013). Conclusions: PARP1 expression and tumor marker decline rates, particularly by MSK method, were significantly associated with outcome to initial chemotherapy in int/poor risk GCT. Future trials incorporating marker decline into treatment allocation and validating the prognostic effect of PARP1 expression are warranted. Clinical trial information: NCT01873326. Table: see text
Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma Escudier, Bernard; Eisen, Tim; Stadler, Walter M ...
New England journal of medicine/The New England journal of medicine,
01/2007, Letnik:
356, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The prognosis in metastatic renal-cell cancer, especially of the dominant clear-cell type, is dismal. This trial compared sorafenib, an orally active inhibitor of the proliferation of cancer cells ...and tumor angiogenesis, with placebo in patients with metastatic clear-cell renal cancer. The results with sorafenib were modest but encouraging enough to test the drug as an initial adjuvant treatment.
This trial compared sorafenib, an orally active inhibitor of the proliferation of cancer cells and tumor angiogenesis, with placebo in patients with metastatic clear-cell renal cancer. The results with sorafenib were modest but encouraging enough to test the drug as an initial adjuvant treatment.
The 5-year survival rate for patients with metastatic renal-cell carcinoma is less than 10%.
1
High-dose interleukin-2 therapy rarely induces a durable complete response, and interferon alfa provides only a modest survival advantage. Until recently, there have been no other treatments for patients with renal-cell carcinoma who are ineligible for, or unable to tolerate, these cytokines.
2
–
6
Sorafenib, an orally active multikinase inhibitor with effects on tumor-cell proliferation and tumor angiogenesis, was initially identified as a Raf kinase inhibitor.
7
It also inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3; platelet-derived growth factor receptor β (PDGFRβ); FMS-like tyrosine kinase . . .
Abstract only
317
Background: CDDP-based treatment is limited by AKI. We aimed to test whether a novel AKI biomarker, uCyC, measured before and immediately after CDDP administration could permit ...earlier identification of UC pts at risk for AKI. Methods: In a nested case-control study, pts treated with CDDP were prospectively enrolled. uCyC was measured 2 hours pre- and 3 hours post-CDDP doses, with values normalized to urine creatinine. AKI was defined as an increase in serum creatinine (sCr) by ≥50% (severe cases) or ≥0.3 mg/dL above pre-CDDP baseline. Controls were pts with no significant sCr rise (sCr change <25% and <0.3 mg/dL). A sample size of 98 patients provided 80% power to detect a true difference in biomarker change pre- and post-CDDP between cases and controls. Results: 102 pts were enrolled: 47 had UC, and 55 had other cancers; 76 were male; 82 Caucasians/15 African Americans. 4 pts not providing urine samples were excluded from analysis. For the entire cohort, average pre-CDDP sCr was 0.98 mg/dL and mean cumulative CDDP dose was 220 mg/m
2
. Controls were younger (mean 59.2 vs 65.9 yrs, p=0.01). 25 pts (26%) developed AKI; 15 (15%) were severe cases. UC pts had a significantly increased risk of AKI compared with non-UC pts (UC n=17 37% vs non-UC n=8 16%, Relative Risk 2.2, 95% CI 1.08-4.73; p=0.03). AKI risk did not correlate with total CDDP dose received. In AKI pts, uCyC increased temporally in accordance with sCr and did not increase in controls, but immediate uCyC changes (3 hrs post-CDDP) were not detectable in cases or controls. However, in UC severe cases, pre-CDDP uCyC was consistently higher than in UC controls (183 ng/mg vs 109 ng/mg, p=0.04). Additionally, in UC AKI pts compared to UC controls, average maximum (peak) uCyC was higher (1812 ng/mg vs 244 ng/mg, p=0.04). Baseline uCyC did not correlate with age, and there were no significant differences in age or baseline sCr between UC cases and controls. Conclusions: UC pts are over two times more likely to develop AKI with CDDP chemotherapy than pts with other cancers, even when pre-CDDP sCr is normal. Pre-treatment uCyC levels may have value in predicting which UC pts are at highest risk of developing CDDP-induced renal injury.
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312
Background: Platinum-refractory UC has a dismal prognosis, with no FDA-approved second-line therapies. Somatic mutations and copy number (CN) variation in EGFR (ErbB1), HER2 ...(ErbB2), and ErbB3 are frequent in UC and may represent viable targets for novel therapies. We aimed to investigate whether afatinib, an oral, irreversible Erb family blocker, has clinical benefit in metastatic UC. Methods: In this single arm, phase II trial, patients (pts) with unresectable platinum-refractory UC who received ≤1 chemotherapy in the metastatic setting received afatinib 40 mg/day continuously until disease progression or intolerable toxicity.Primary endpoint was 3-month progression-free survival (PFS3), with drug deemed promising if ≥42% pts had PFS3. Pre-specified analysis for EGFR, HER2, ErbB3, and ErbB4 was conducted using targeted next-generation sequencing (Life Technologies) and CN analysis (Taqman). Results: 15 ptshave enrolled: median age 66 (44-78), 11 M/4 F, ECOG PS 0 in 20%, PS 1 in 80%, Hb<10 g/dl in 20%, liver metastases in 13%, median time from prior chemotherapy=4.4 mo. Rash (73%), diarrhea (33%), and fatigue (13%) were the most common drug-related toxicities; 1 pt required dose-reduction (grade 3 fatigue). 3/14 pts (21%) had PFS3 (1 partial response (PR), 2 stable disease); 1 pt has not reached 3 mo on therapy. All 3 responders had molecular alterations in Erb genes: 1 pt with 4 copies of HER2 achieved PR and responded for 6.9 mo; 1 pt with Gly284Arg ErbB3 mutation responded for 7 mo; and 1 pt with 73 copies of HER2 and Arg103Gly ErbB3 mutation never progressed on therapy, but discontinued after 10.3 mo due to depressed left ventricular ejection fraction. None of the 10 non-responders had alterations in these four genes. Time to progression/discontinuation was 8.1 mo in pts with molecular alterations vs. 1.8 for pts without alterations (p=0.02). Conclusions: Afatinib demonstrates activity in platinum-refractory UC, with all responders bearing HER2 and/or ErbB3 alterations. The potential contribution of ErbB3 to afatinib sensitivity is novel. These data support ongoing testing of afatinib as a potential therapy for refractory UC in marker-selected pts. Clinical trial information: NCT02122172.
