Jennifer M. Tursi

First-line crizotinib versus chemotherapy in ALK-positive lung cancer.

BACKGROUND The efficacy of the ALK inhibitor crizotinib as compared with standard chemotherapy as first-line treatment for advanced ALK-positive non-small-cell lung cancer (NSCLC) is unknown. METHODS We conducted an open-label, phase 3 trial comparing crizotinib with chemotherapy in 343 patients with advanced ALK-positive nonsquamous NSCLC who had received no previous systemic treatment for advanced disease. Patients were randomly assigned to receive oral crizotinib at a dose of 250 mg twice daily or to receive intravenous chemotherapy (pemetrexed, 500 mg per square meter of body-surface area, plus either cisplatin, 75 mg per square meter, or carboplatin, target area under the curve of 5 to 6 mg per milliliter per minute) every 3 weeks for up to six cycles. Crossover to crizotinib treatment after disease progression was permitted for patients receiving chemotherapy. The primary end point was progression-free survival as assessed by independent radiologic review. RESULTS Progression-free survival was significantly longer with crizotinib than with chemotherapy (median, 10.9 months vs. 7.0 months; hazard ratio for progression or death with crizotinib, 0.45; 95% confidence interval [CI], 0.35 to 0.60; P<0.001). Objective response rates were 74% and 45%, respectively (P<0.001). Median overall survival was not reached in either group (hazard ratio for death with crizotinib, 0.82; 95% CI, 0.54 to 1.26; P=0.36); the probability of 1-year survival was 84% with crizotinib and 79% with chemotherapy. The most common adverse events with crizotinib were vision disorders, diarrhea, nausea, and edema, and the most common events with chemotherapy were nausea, fatigue, vomiting, and decreased appetite. As compared with chemotherapy, crizotinib was associated with greater reduction in lung cancer symptoms and greater improvement in quality of life. CONCLUSIONS Crizotinib was superior to standard first-line pemetrexed-plus-platinum chemotherapy in patients with previously untreated advanced ALK-positive NSCLC. (Funded by Pfizer; PROFILE 1014 ClinicalTrials.gov number, NCT01154140.).

Fluorouracil, Leucovorin, and Irinotecan Plus Either Sunitinib or Placebo in Metastatic Colorectal Cancer: A Randomized, Phase III Trial

PURPOSE This double-blind, phase III study aimed to demonstrate that sunitinib plus FOLFIRI (fluorouracil, leucovorin, and irinotecan) was superior to placebo plus FOLFIRI in previously untreated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Patients were randomly assigned to receive FOLFIRI and either sunitinib (37.5 mg per day) or placebo (4 weeks on treatment, followed by 2 weeks off [schedule 4/2]) until disease progression. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, safety, and patient-reported outcomes. The correlation between genotype and clinical outcomes was also analyzed. RESULTS In all, 768 patients were randomly assigned to sunitinib plus FOLFIRI (n = 386) or placebo plus FOLFIRI (n = 382). Following a second prespecified interim analysis, the study was stopped because of potential futility of sunitinib plus FOLFIRI. Final results are reported. The PFS hazard ratio was 1.095 (95% CI, 0.892 to 1.344; one-sided stratified log-rank P = .807), indicating a lack of superiority for sunitinib plus FOLFIRI. Median PFS for the sunitinib arm was 7.8 months (95% CI, 7.1 to 8.4 months) versus 8.4 months (95% CI, 7.6 to 9.2 months) for the placebo arm. Sunitinib plus FOLFIRI was associated with more grade ≥ 3 adverse events and laboratory abnormalities than placebo (especially diarrhea, stomatitis/oral syndromes, fatigue, hand-foot syndrome, neutropenia, thrombocytopenia, anemia, and febrile neutropenia). More deaths as a result of toxicity (12 v four) and significantly more dose delays, dose reductions, and treatment discontinuations occurred in the sunitinib arm. CONCLUSION Sunitinib 37.5 mg per day (schedule 4/2) plus FOLFIRI is not superior to FOLFIRI alone and has a poorer safety profile. This combination regimen is not recommended for previously untreated mCRC.

Intracranial Efficacy of Crizotinib Versus Chemotherapy in Patients With Advanced ALK-Positive Non–Small-Cell Lung Cancer: Results From PROFILE 1014

PURPOSE Intracranial efficacy of first-line crizotinib versus chemotherapy was compared prospectively in the phase III PROFILE 1014 study in ALK-positive non-small-cell lung cancer. PATIENTS AND METHODS Patients were randomly assigned to receive crizotinib (250 mg twice daily; n = 172) or chemotherapy (pemetrexed 500 mg/m(2) plus cisplatin 75 mg/m(2) or carboplatin at area under the curve 5 to 6, every 3 weeks for ≤ six cycles; n = 171). Patients with stable treated brain metastases (tBM) were eligible. Intracranial efficacy was assessed at baseline and every 6 or 12 weeks in patients with or without known brain metastases (BM), respectively; intracranial time to tumor progression (IC-TTP; per protocol) and intracranial disease control rate (IC-DCR; post hoc) were measured. The intent-to-treat population was also assessed. RESULTS Of 343 patients in the intent-to-treat population, 23% had tBM at baseline. A nonsignificant IC-TTP improvement was observed with crizotinib in the intent-to-treat population (hazard ratio [HR], 0.60; P = .069), patients with tBM (HR, 0.45; P = .063), and patients without BM (HR, 0.69; P = .323). Among patients with tBM, IC-DCR was significantly higher with crizotinib versus chemotherapy at 12 weeks (85% v 45%, respectively; P < .001) and 24 weeks (56% v 25%, respectively; P = .006). Progression-free survival was significantly longer with crizotinib versus chemotherapy in both subgroups (tBM present: HR, 0.40; P < .001; median, 9.0 v 4.0 months, respectively; BM absent: HR, 0.51; P < .001; median, 11.1 v 7.2 months, respectively) and in the intent-to-treat population (HR, 0.45; P < .001; median, 10.9 v 7.0 months, respectively). CONCLUSION Compared with chemotherapy, crizotinib demonstrated a significantly higher IC-DCR in patients with tBM. Improvements in IC-TTP were not statistically significant in patients with or without tBM, although sensitivity to detect treatment differences in or between the two subgroups was low.

Dose-Intensive Epirubicin-Based Chemotherapy Is Superior to an Intensive Intravenous Cyclophosphamide, Methotrexate, and Fluorouracil Regimen in Metastatic Breast Cancer: A Randomized Multinational Study

PURPOSE To determine the relative efficacy of a cyclophosphamide epirubicin and fluorouracil (CEF) regimen compared with an intravenous (IV) cyclophosphamide, methotrexate, and fluorouracil (CMF) combination in metastatic breast cancer. PATIENTS AND METHODS Patients were randomized to receive either CEF (cyclophosphamide 400 mg/m(2) IV, epirubicin 50 mg/m(2) IV, and fluorouracil 500 mg/m(2) IV on days 1 and 8), or CMF (cyclophosphamide 500 mg/m(2) IV, methotrexate 40 mg/m(2) IV, and fluorouracil 600 mg/m(2) IV on days 1 and 8). Treatment was given in 3- to 4-week cycles for a total of six to nine cycles. RESULTS A total of 460 patients (223 CEF and 237 CMF) were randomized. Overall response rate was superior for CEF than CMF in all randomized patients (57% v 46%, respectively; P =.01) and in the assessable subset (66% v 52%, respectively; P =.005). With a median follow-up of more than 20 months, time to progression (TTP) was significantly longer with CEF than CMF (median 8.9 v 6.3 months, respectively; P =.0064), as was time to treatment failure (TTF) (median 6.2 v 5.0 months, respectively; P =.01). Significant survival differences were not observed between CEF and CMF (median 20.1 v 18.2 months, respectively; P =.23). Granulocytopenia and infections were similar in both arms. Grade 3/4 nausea/vomiting and alopecia were more frequent with CEF, whereas diarrhea was more frequent with CMF. Cardiac toxicity, primarily asymptomatic, required withdrawal from study of 15 patients on CEF (7%) and one patient on CMF. CONCLUSION This CEF regimen safely provides significantly better tumor control than CMF, manifest as a higher response rate, and longer TTP and TTF, but not survival, when used as first-line chemotherapy for metastatic breast cancer.

A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer

BACKGROUND This study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m2 given over 90 min i.v. and l-leucovorin 200 mg/m2 given over 120 min on day 1, followed by 5-FU 400 mg/m2 bolus and then 2400 mg/m2 infused over 46 h) in untreated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS In this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1-6. Efficacy was a secondary objective. RESULTS Thirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n=1), grade 4 neutropenia (n=4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n=1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5-79.7). CONCLUSIONS The MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.BACKGROUND This study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m2 given over 90 min i.v. and l-leucovorin 200 mg/m2 given over 120 min on day 1, followed by 5-FU 400 mg/m2 bolus and then 2400 mg/m2 infused over 46 h) in untreated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS In this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1-6. Efficacy was a secondary objective. RESULTS Thirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n=1), grade 4 neutropenia (n=4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n=1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5-79.7). CONCLUSIONS The MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.

Abstract C253: PF-06463922, a novel brain-penetrating small molecule inhibitor of ALK/ROS1 with potent activity against a broad spectrum of ALK resistant mutations in preclinical models in vitro and in vivo.

Oncogenic fusions of Anaplastic Lymphoma Kinase (ALK) define a subset of human lung adenocarcinomas. The 1st generation ALK inhibitor XALKORI ® (crizotinib) demonstrated impressive clinical benefit in ALK-fusion positive lung cancers and was approved by the FDA for the treatment of ALK-fusion positive NSCLC in 2011. However, as seen with most kinase inhibitors, patients treated with XALKORI eventually developed resistance to therapy. Acquired ALK kinase domain mutations and brain metastases are significant contributors to the relapse after XALKORI therapy. To date, multiple types of ALK kinase domain mutations have been identified in XALKORI refractory patients including ALKG1269A, ALKL1196M, ALKC1156Y, ALKL1152R, ALKF1174L, ALKS1206Y, ALK1151Tins and ALKG1202R, accounting for about 1/3 of patient samples tested. Currently, a number of 2nd generation ALK inhibitors are under development aiming to overcome XALKORI resistant mutations. Even though in preclinical models, some ALK mutants such as ALKG1202R and ALK1151Tins confer high-levels of resistance to almost all of the 2nd generation ALK inhibitors tested. Here we report PF-06463922, a novel ATP competitive small molecule inhibitor of ALK/ROS1, with potent and selective inhibitory activity against all known acquired XALKORI resistant mutations identified in patients. PF-06463922 is also capable of penetrating the blood brain barrier in preclinical animal models. In vitro, PF-06463922 demonstrated potent inhibition in catalytic activities of ALK and 8 different ALK mutant kinases in recombinant enzyme and cell based assays (cell IC50s = 1 to 65 nM). PF-06463922 also showed potent growth inhibitory activity and induced apoptosis in the NSCLC cells harboring either non-mutant ALK or mutant ALK fusions (IC50s = 1 to 30 nM). In vivo, PF-06463922 demonstrated marked cytoreductive activity in mice bearing tumor xenografts that express EML4-ALK, EML4-ALKL1196M, EML4-ALKG1269A, EML4-ALKG1202R or NPM-ALK at low nM free plasma concentrations. These effects were associated with significant inhibition in cellular Ki67 and increased cleaved-caspase3 levels in tumors. In addition, PF-06463922 achieved brain exposure of 20-30% of its plasma levels in mice, and significantly regressed the brain tumors and prolonged survival of mice bearing orthotopic EML4-ALK and EML4-ALKL1196M positive brain tumor implants. The antitumor efficacy of PF-06463922 was dose dependent and strongly correlated with inhibition of ALK phosphorylation and downstream signaling. Our data indicate that PF-06463922 is the most potent ALK inhibitor reported to date (to our knowledge, against both non-mutant or mutant ALK in cell assays), and it demonstrates great potential for treating ALK fusion positive cancers including patients who relapsed from XALKORI therapy due to various ALK kinase domain mutations and/or brain metastases. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C253. Citation Format: Helen Y. Zou, Lars R. Engstrom, Qiuhua Li, Melissa West Lu, Ruth Wei Tang, Hui Wang, Konstantinos Tsaparikos, Jinwei Wang, Sergei Timofeevski, Dac M. Dinh, Hieu Lam, Justine Lam, Shinji Yamazaki, Wenyue Hu, Timothy Affolter, Patrick B. Lappin, Hovhannes Gukasyan, Nathan Lee, Jennifer M. Tursi, Ted W. Johnson, Valeria Fantin, Tod Smeal. PF-06463922, a novel brain-penetrating small molecule inhibitor of ALK/ROS1 with potent activity against a broad spectrum of ALK resistant mutations in preclinical models in vitro and in vivo. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C253.

Abstract 289: Associations between germline genotype and efficacy and safety outcomes in a phase III study of sunitinib (SU) and FOLFIRI in metastatic colorectal cancer (mCRC)

Introduction: SU is an oral, multitargeted inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET. In a phase III mCRC study, adding SU to FOLFIRI did not improve progression-free survival (PFS) vs. FOLFIRI/placebo. Potential correlations were investigated between germline genotype and safety/efficacy endpoints among patients (pts) in this trial. Methods: Blood sample donation for genotype analysis was optional. Selection of genes and polymorphisms was based on prior reported associations. Twenty-one single-nucleotide polymorphisms (SNPs) in 10 genes (VEGF-A, VEGFR-2, CYP1A1, ABCG2, ABCB1, ABCC2, MTHFR, UGT1A1, FLT1 and FLT3) were analyzed by TaqMan allelic discrimination assay or fragment analysis, using DNA isolated from peripheral blood samples. All 21 polymorphisms were analyzed for associations with efficacy (PFS; overall survival [OS]) and selected safety endpoints. Results were adjusted for multiple testing of SNPs in linkage disequilibrium. Results: Genotyping was performed in 139/768 pts (18%). Age and gender were similar between genotyped and non-genotyped pts, but the genotyped subset had fewer non-Caucasians (13% vs. 39%; Fisher9s exact P Conclusions: Presence of the T allele in the ABCC2 gene at rs717620 was associated with increased risk of grade 3/4 diarrhea in a small number of Caucasian pts receiving FOLFIRI/placebo. No significant associations were identified between genotype and safety/efficacy endpoints in pts who received SU/FOLFIRI. As OS was superior in genotyped vs. non-genotyped pts, correlative findings may not be extrapolated beyond the genotyped subset. Further analysis of baseline characteristics is underway in the genotyped group to investigate this difference. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 289. doi:10.1158/1538-7445.AM2011-289