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Background: The Panitumumab Randomized trial In combination with chemotherapy for Metastatic colorectal cancer to determine Efficacy (PRIME) demonstrated that panitumumab-FOLFOX4 significantly improved progression-free survival (PFS) versus FOLFOX4 as first-line treatment of wild-type (WT) KRAS metastatic colorectal cancer (mCRC), the primary end point of the study. Patients and methods: Patients were randomized 1:1 to panitumumab 6.0 mg/kg every 2 weeks + FOLFOX4 (arm 1) or FOLFOX4 (arm 2). This prespecified final descriptive analysis of efficacy and safety was planned for 30 months after the last patient was enrolled. Results: A total of 1183 patients were randomized. Median PFS for WT KRAS mCRC was 10.0 months [95% confidence interval (CI) 9.3-11.4 months] for arm 1 and 8.6months (95% CI 7.5-9.5 months) for arm 2; hazard ratio (HR) = 0.80; 95% CI 0.67-0.95; P = 0.01. Median overall survival (OS) forWT KRAS mCRC was 23.9 months (95%CI 20.3-27.7 months) for arm 1 and 19.7 months (95% CI 17.6-22.7 months) for arm 2; HR = 0.88; 95% CI 0.73-1.06; P=0.17 (68%OS events). An exploratory analysis of updated survival (>80%OS events) was carried out which demonstrated improvement in OS; HR = 0.83; 95%CI 0.70-0.98; P=0.03 forWT KRASmCRC. The adverse event profile was consistent with the primary analysis. Conclusions: In WT KRAS mCRC, PFS was improved, objective response was higher, and there was a trend toward improved OS with panitumumab-FOLFOX4, with significant improvement in OS observed in an updated analysis of survival in patients with WT KRAS mCRC treated with panitumumab + FOLFOX4 versus FOLFOX4 alone (P = 0.03). These data support a positive benefit-risk profile for panitumumab-FOLFOX4 for patients with previously untreated WT KRAS mCRC. KRAS testing is critical to select appropriate patients for treatment with panitumumab. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

Patients with metastatic colorectal cancer that harbors KRAS mutations in exon 2 do not benefit from anti-epidermal growth factor receptor (EGFR) therapy. Other activating RAS mutations may also be negative predictive biomarkers for anti-EGFR therapy.In this prospective-retrospective analysis, we assessed the efficacy and safety of panitumumab plus oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) as compared with FOLFOX4 alone, according to RAS (KRAS or NRAS) or BRAF mutation status. A total of 639 patients who had metastatic colorectal cancer without KRAS mutations in exon 2 had results for at least one of the following: KRAS exon 3 or 4; NRAS exon 2, 3, or 4; or BRAF exon 15. The overall rate of ascertainment of RAS status was 90%.Among 512 patients without RAS mutations, progression-free survival was 10.1 months with panitumumab-FOLFOX4 versus 7.9 months with FOLFOX4 alone (hazard ratio for progression or death with combination therapy, 0.72; 95% confidence interval [CI], 0.58 to 0.90; P=0.004). Overall survival was 26.0 months in the panitumumab-FOLFOX4 group versus 20.2 months in the FOLFOX4-alone group (hazard ratio for death, 0.78; 95% CI, 0.62 to 0.99; P=0.04). A total of 108 patients (17%) with nonmutated KRAS exon 2 had other RAS mutations. These mutations were associated with inferior progression-free survival and overall survival with panitumumab-FOLFOX4 treatment, which was consistent with the findings in patients with KRAS mutations in exon 2. BRAF mutations were a negative prognostic factor. No new safety signals were identified.Additional RAS mutations predicted a lack of response in patients who received panitumumab-FOLFOX4. In patients who had metastatic colorectal cancer without RAS mutations, improvements in overall survival were observed with panitumumab-FOLFOX4 therapy. (Funded by Amgen and others; PRIME ClinicalTrials.gov number, NCT00364013.).

Background This open-label phase III study assessed the addition of Toll-like receptor 9-activating oligodeoxynucleotide PF-3512676 to gemcitabine/cisplatin chemotherapy in patients with non-small-cell lung cancer (NSCLC). Patients and methods Chemotherapy-naive patients with stage IIIB or IV NSCLC were randomized (1:1) to receive six or fewer 3-week cycles of i.v. gemcitabine (1250 mg/m2 on days 1 and 8) and cisplatin alone (75 mg/m2 on day 1, control arm) or combined with s.c. PF-3512676 0.2 mg/kg on days 8 and 15 of each chemotherapy cycle and weekly thereafter until progression or unacceptable toxicity (experimental arm). No crossover was planned. The primary end point was overall survival (OS). Results A total of 839 patients were randomized. Baseline demographics were well balanced. Median OS (11.0 versus 10.7 months; P = 0.98) and median progression-free survival (PFS) (both 5.1 months) were similar between groups. Grade ≥3 hematologic adverse events (AEs), injection-site reactions, and influenza-like symptoms were more frequently reported among patients receiving PF-3512676. At the first-interim analysis, the Data Safety Monitoring Committee recommended study discontinuation. Administration of PF-3512676 was halted based on efficacy futility and increased grade ≥3 AEs (experimental arm). Conclusions Addition of PF-3512676 to gemcitabine/cisplatin chemotherapy did not improve OS or PFS but did increase toxicity.

Purpose Panitumumab, a fully human anti–epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. Patients and Methods In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. Results KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. Conclusion This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.

Combination of intravenous (i.v.) vinorelbine and docetaxel was shown to be feasible and effective in metastatic breast cancer (MBC). In an effort to improve patient convenience, we investigated in first-line treatment a regimen alternating i.v. and oral vinorelbine in combination with docetaxel.Forty-nine patients (median age, 53 years) with MBC received a maximum of 6 cycles consisting of i.v. vinorelbine 20 mg/m(2) plus docetaxel 60 mg/m(2) given on day 1, and oral vinorelbine 60 mg/m(2) on day 15 every 3 weeks in an open-label, multicentre phase II study (recommended dose established in phase I study [1]).Sixty-three percent of the patient had received prior adjuvant chemotherapy and 78% presented visceral involvement. Twenty-four responses were documented and validated by an independent panel review, yielding response rates of 49% (95% CI: 34-64) in the 49 enrolled patients and 55.8% (95% CI: 40-71) in the 43 evaluable patients. Median duration of response was 9.4 months. Median progression-free survival and median overall survival were 5.5 and 33.2 months, respectively. Neutropenia was the main dose-limiting toxicity but complications were uncommon, four patients having experienced febrile neutropenia and one having developed neutropenic infection. Other frequently reported adverse events included alopecia, fatigue, stomatitis, constipation, diarrhoea and nausea, which were rarely severe.This regimen alternating oral and i.v. vinorelbine in combination with docetaxel is effective and manageable. Vinorelbine i.v. per oral day 1 per day 15-docetaxel day 1 every 3 weeks represents a convenient option to combine docetaxel and vinorelbine for the palliative treatment of MBC.

Purpose Metastatic breast cancer (MBC) remains an incurable illness in the majority of cases, despite major therapeutic advances. This may be related to the ability of breast tumors to induce neoangiogenesis, even in the face of cytotoxic chemotherapy. Sunitinib, an inhibitor of key molecules involved in neoangiogenesis, has an established role in the treatment of metastatic renal cell and other cancers and demonstrated activity in a phase II trial in MBC. We performed a randomized phase III trial comparing sunitinib plus capecitabine (2,000 mg/m2) with single-agent capecitabine (2,500 mg/m2) in patients with heavily pretreated MBC. Patients and Methods Eligibility criteria included MBC, prior therapy with anthracyclines and taxanes, one or two prior chemotherapy regimens for metastatic disease or early relapse after a taxane plus anthracycline adjuvant regimen, and adequate organ function and performance status. The primary end point was progression-free survival, for which the study had 90% power to detect a 50% improvement (from 4 to 6 months). Results A total of 442 patients were randomly assigned. Progression-free survival was not significantly different between the treatment arms, with medians of 5.5 months (95% CI, 4.5 to 6.0) for the sunitinib plus capecitabine arm and 5.9 months (95% CI, 5.4 to 7.6) for the capecitabine monotherapy arm (hazard ratio, 1.22; 95% CI, 0.95 to 1.58; one-sided P = .941). There were no significant differences in response rate or overall survival. Toxicity, except for hand-foot syndrome, was more severe in the combination arm. Conclusion The addition of sunitinib to capecitabine does not improve the clinical outcome of patients with MBC pretreated with anthracyclines and taxanes.

In order to examine which cytokine could be used as a marker of the biological effect of thyroid hormones or anti-thyroid antibodies in Graves' disease (GD) patients, we simultaneously evaluated the concentrations of TSH, free thyroid hormones (fT 3 and fT 4 ), anti-thyroid antibodies (anti-TPO and anti-TG) and a group of cytokines: interleukin-2 (IL-2), tumour necrosis factor α (TNF α ), interleukin-6 (IL-6) and their soluble receptors (sIL-2R, sTNF α R, sIL-6R) as well as interleukin-10 (IL-10) in eight GD females and nine normal controls. We found that serum sIL-2R concentrations of GD patients had only the tendency to be higher versus controls, but strong positive correlations between fT 3 and fT 4 and sIL-2R in peripheral blood of GD subjects were revealed. We showed that sIL-2R was the best cytokine marker, showing very good correlation with the endocrine status of GD patients.

3511 Background: Analysis of a phase III pmab monotherapy study indicated that KRAS and NRAS mutations beyond KRAS exon 2 may be predictive of pmab efficacy (Peeters et al, 2013). Methods: The primary objective of this prospectively defined retrospective analysis of PRIME was to assess the effect of pmab + FOLFOX vs FOLFOX on overall survival (OS) in pts with mCRC based on RAS (KRAS or NRAS) or BRAF mutation status. "Gold standard" bidirectional Sanger sequencing and WAVE-based SURVEYOR Scan Kits from Transgenomic (conducted independently) were used to detect mutations in KRAS exon 3, exon 4; NRAS exon 2, exon 3, exon 4; and BRAF exon 15. Results: RAS ascertainment rate was 90%. Tx HRs for pts with WT RAS were 0.78 (95% CI, 0.62 - 0.99; p = 0.04) for OS (median gain of 5.8 months in the pmab arm) and 0.72 (95% CI, 0.58 - 0.90; p = < 0.01) for PFS. Tx HRs for WT KRAS exon 2/mutant (MT) other RAS were 1.29 (95% CI, 0.79 - 2.10; p = 0.31) for OS and 1.28 (95% CI, 0.79 - 2.07; p = 0.32) for PFS. Tx HRs for pts with WT or MT BRAF were inconsistent with a predictive biomarker (Table). Prognostic effects of the tested biomarkers will be presented. Conclusions: A statistically significant OS benefit was observed in pts with WT RAS mCRC treated with pmab + FOLFOX vs FOLFOX. Pmab is unlikely to benefit pts with any RAS mutations. In this analysis, BRAF mutation had no predictive value. Clinical trial information: NCT00364013. [Table: see text]

8020 Background: The SATURN (BO18192) study investigated whether erlotinib maintenance therapy improved PFS in patients (pts) with advanced NSCLC who had obtained clinical benefit from 1st-line chemotherapy. This study included a prospective analysis of the prognostic/predictive value of several molecular markers. Methods: 889 pts with advanced NSCLC whose disease had not progressed following 4 cycles of 1st-line platinum-doublet chemotherapy were randomized to erlotinib 150 mg/day or placebo. Mandatory tumor specimens were collected at baseline and tested for EGFR protein expression using immunohistochemistry (IHC), EGFR gene copy number using fluorescent in-situ hybridization (FISH), and EGFR and KRAS somatic mutations using DNA sequencing. Pts were stratified according to EGFR IHC status (any membranous staining in ≥10% tumor cells used as cut-off); the co-primary endpoint was PFS in EGFR IHC+ pts. Baseline whole blood samples were obtained for genotyping of EGFR (intron 1 CA-repeat polymorphisms). Results: In the overall population, erlotinib significantly prolonged PFS vs placebo (HR 0.71, p [Table: see text] [Table: see text]

To comparatively assess first-line treatment with cladribine single (C) or in combination with cyclophosphamide (CC), and COP (cyclophosphamide, vincristine, prednisone) in low grade B-cell non-Hodgkin lymphoma (NHL), previously untreated patients (pts) with Ann Arbor stage II-IV were randomly allocated to receive 6 monthly courses of either C, CC, or COP. End points were treatment response, freedom from progression (FFP) and overall survival (OS), and tolerance. From June 1, 2000 to June 30, 2005, 196 pts were randomized in 17 centers. Of 153 pts for whom data is available, 55 (36%) were diagnosed as small lymphocytic, 11 lymphoplasmocytoid (7%), 37 marginal-zone (24%), 42 follicular (27.5%), and 8 not otherwise specified low grade B-cell NHL (5.5%). Randomization constituted comparable groups, including International Prognostic Index variables. Compared to C and CC, COP induced lower overall response rates (75%, 90%, 50%, χ2 =7.9 p

The purpose of the study was to evaluate response, duration of response, and toxicity of fludarabine (F), mitoxantrone (M), and dexamethason (D) (FMD) in patients (pts) with relapsed or refractory low-grade non-Hodgkin lymphoma (LGNHL). 26 pts with advanced relapsed/refractory LGNHL exposed to previous chemotherapy (CHT) received 3–6 monthly cycles of FMD. The median age was 60 years (range 34–73), included 13 male (50%) and 13 female (50 %). The regimen consisted of F (25 mg/m2 i.v., day 1–3), M (10 mg/m2 i.v., day 1) and D (20 mg p.o., day 1–5). Parameters analyzed included response, toxicity and infection rates, number of previous CHT lines, performance status (ECOG), Ann Arbor scale, LDH, International Prognostic Index score, freedom from progression (FFP) and overall survival (OS). In total 78 cycles of FMD was administered. This induced 25% complete and 37,5% partial response, with a total response rate of 62,5%. After 14 months of the median follow-up of the pts remaining alive, median FFP was 11 months and median OS has not been achieved yet. Out of 78 administered cycles 16 (20%) were associated with toxicity, including 8 (10%) severe infections despite prophylaxis and 6 (8%) grade III/IV neutropenias. In addition, one case of grade III/IV thrombocytopenia and acute noninflammatory renal dysfunction were observed. Toxicity rate was not correlated with the number of previous CHT lines or ECOG, but IPI >2 was significant factor predictive for FMD-related toxicity (p=.037). Shorter OS was observed for the pts with ECOG>1 (p=.049), IPI>2 (p=.005) and FMD-related toxicity (p=.036). FMD is an active regimen for relapsed and refractory LGNHL. Toxicity rate is substantial and seems to predict survival.

The aim of the study was to comparatively assess first-line treatment with cladribine alone or in combination with cyclophosphamide (CCR, cladribine-containing regimens) and COP (cyclophosphamide, vincristine, prednisone) in different subtypes of low-grade lymphoma. End points were complete remission (CR), overall response rate (ORR), incidence of chemotherapy-related side effects as well as freedom from progression (FFP) and overall survival (OS). From June’2000 to June’2005, 178 previously untreated patients (pts) were randomly allocated to receive 6 monthly courses of either CCR or COP in 17 centers in Poland. This analysis included 107 pts who have completed scheduled chemotherapy, including 45 pts with small lymphocytic (SLL, median age=64 years), 26 marginal zone (MZL, median age=58 years) and 36 follicular (FL, median age=65 years) lymphoma. Compared to COP, CCR induced higher CR rates in all treated groups (65% vs 15%, p=.005; 57% vs 10%, p=.02; 58% vs 12%, p=.03, respectively) but differences in ORR were not significant (92% vs 69%; 92% vs 60%; 79% vs 62%, respectively). Incidence of side effects did not differ significantly in CCR- as compared to COP-treated pts, e.i. infections (10% vs 7%; 14% vs 20%; 15% vs 0%, respectively), myelosuppression (31% vs 7%; 21% vs 20%; 30% vs 0%, respectively), and non-hematological adverse events (10% vs 14%; 7% vs 30%; 7% vs 22%, respectively). With a median follow-up of 12 months, median FFP was superior in CCR- as compared to COP-treated treated pts with SLL (43 vs 12 months, log-rank p

The aim of this study was to assess humoral response to influenza vaccination in 47 patients with non-Hodgkin lymphoma (NHL) in comparison with 45 healthy individuals (age 12–76 years, median 41 years; 13 males and 32 females). Patients (age 36–82, median 60 years; 24 males and 23 females) consisted of two groups, previously treated with chemotherapy (group A, n=32) or untreated (group B, n=15). In autumn 2003, all subjects were vaccinated with influenza vaccine ([Isquo]influvac’, Solvay Pharmaceuticals B.V.). Antibody responses to influenza hemagglutinin and neuraminidase were determined in sera collected before and 1 month after vaccination by hemagglutination and neuraminidase inhibition tests. Statistical analysis was performed using the Mann-Whitney unpaired and Wilcoxon paired tests. After vaccination geometric mean antibody titers (GMTs) of antihemagglutinin (HI) antibodies significantly increased (p1:40, ranged from 0% to 9.4% in group A, 0% to 13.3% in group B and from 2.2% to 20% in the controls. After vaccination protection rates increased and ranged from 78.1% to 87.5%, 73.3% to 93.3% and 66.7% to 82.2%, respectively. Response rates, i.e. the number of subjects with at least 4-fold increase of HI antibody titers after vaccination, ranged from 59.4% to 84.4%, 73.3% to 86.7% and from 51.1% to 66.7%, respectively. In both study groups and in the controls, post-vaccination antineuraminidase (NI) antibody titers were higher (p

We assessed humoral response to influenza vaccination (vacc) in two consecutive seasons 2003/2004 and 2004/2005 in 123 NHL patients. In season 03/04 50 patients (29 previously treated with chemotherapy - group A03/04 and 21 not treated - group B03/04) and 73 patients in season 04/05: 34 treated - A04/05, 39 not treated - B04/05 were vaccinated with trivalent subunit influenza vaccine. Antibody responses to influenza hemagglutinin (HI) and neuraminidase (NI) were determined in sera collected before vacc, after 1 month and after 6 months. One month after vacc geometric mean antibody titers (GMTs) of antiHI antibodies significantly increased (p1:40, ranged from 3.4 to 10.3% in A03/04, 2.9-8.8% in A04/05, 0–4.6% in B03/04 and 0–5.1% in B04/05. After 1 month protection rates ranged from 78.1 to 87.5% in A03/04, 61.8–70.6% in A04/05, 73.3–93.3% in B03/04 and 66.7–74.4% in B04/05 and decreased after 6 months to 24.1–37.9% in A03/04, 32.4–35.3% in A04/05, 19–47.6% in B03/04 and 17.9–35.9% in B04/05. Response rates, i.e. the number of subjects with at least a 4-fold increase of antiHI antibody titers after vacc, ranged from 58.6–75.9% in A03/04, 50–67.6% in A04/05, 57.1–81% in B03/04 and 61.5–71.8% in B04/05. Six months after vacc it decreased to 17.2–34.5% in A03/04, 20.6–29.4% in A04/05, 19–38.1% in B03/04 and 15.4–33.3% in B04/05. In all patients’ groups, post-vacc antiNI GMTs were significantly higher (p