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On December 18, 2020, the FDA approved osimertinib as adjuvant therapy in patients with non–small cell lung cancer (NSCLC) whose tumors have EGFR exon 19 deletions or exon 21 (L858R) mutations, as detected by an FDA-approved test. The approval was based on the ADAURA study, in which 682 patients with NSCLC were randomized to receive osimertinib (n = 339) or placebo (n = 343). Disease-free survival (DFS) in the overall population (stage IB–IIIA) was improved for patients who received osimertinib, with an HR of 0.20; 95% confidence interval (CI), 0.15–0.27; P < 0.0001. Median DFS was not reached for the osimertinib arm compared with 27.5 months (95% CI, 22.0–35.0) for patients receiving placebo. Overall survival data were not mature at the time of the approval. This application was reviewed under FDA's Project Orbis, in collaboration with Australia Therapeutic Goods Administration, Brazil ANVISA, Health Canada, Singapore Health Sciences Authority, Switzerland Swissmedic, and the United Kingdom Medicines and Healthcare products Regulatory Agency. This is the first targeted therapy adjuvant approval for NSCLC and has practice-changing implications.

In 2019, the FDA Oncology Center of Excellence launched Project Orbis, a global collaborative review program to facilitate faster patient access to innovative cancer therapies across multiple countries. Project Orbis aims for concurrent submission, review, and regulatory action for high-impact clinically significant marketing applications among the participating partner countries. Current Project Orbis partners (POP) include the regulatory health authorities (RHA) of Australia, Brazil, Canada, Singapore, and Switzerland. Project Orbis leverages the existing scientific and regulatory partnerships between the various RHA under mutual confidentiality agreements. While FDA serves as the primary coordinator for application selection and review, each country remains fully independent on their final regulatory decision. In the first year of Project Orbis (June 2019 to June 2020), a total of 60 oncology marketing applications were received, representing 16 unique projects, and resulting in 38 approvals. New molecular entities, also known as new active substances, comprised 28% of the received marketing applications. The median time gap between FDA and Orbis submission dates was 0.6 months with a range of −0.8 to 9.0 months. Across the program, the median time-to-approval was similar between FDA (4.2 months, range 0.9–6.9, N = 18) and the POP (4.4 months, range 1.7–6.8, N = 20). Participating countries have signified a strong commitment for continuation and growth of the program. Project Orbis expansion considerations include the addition of more countries and management of more complex applications.

Background We assessed the novel MACC1 gene to further stratify stage II colon cancer patients with proficient mismatch repair (pMMR). Patients and methods Four cohorts with 596 patients were analyzed: Charite 1 discovery cohort was assayed for MACC1 mRNA expression and MMR in cryo-preserved tumors. Charite 2 comparison cohort was used to translate MACC1 qRT-PCR analyses to FFPE samples. In the BIOGRID 1 training cohort MACC1 mRNA levels were related to MACC1 protein levels from immunohistochemistry in FFPE sections; also analyzed for MMR. Chemotherapy-naive pMMR patients were stratified by MACC1 mRNA and protein expression to establish risk groups based on recurrence-free survival (RFS). Risk stratification from BIOGRID 1 was confirmed in the BIOGRID 2 validation cohort. Pooled BIOGRID datasets produced a best effect-size estimate. Results In BIOGRID 1, using qRT-PCR and immunohistochemistry for MACC1 detection, pMMR/MACC1-low patients had a lower recurrence probability versus pMMR/MACC1-high patients (5-year RFS of 92% and 67% versus 100% and 68%, respectively). In BIOGRID 2, longer RFS was confirmed for pMMR/MACC1-low versus pMMR/MACC1-high patients (5-year RFS of 100% versus 90%, respectively). In the pooled dataset, 6.5% of patients were pMMR/MACC1-low with no disease recurrence, resulting in a 17% higher 5-year RFS [95% confidence interval (CI) (12.6%–21.3%)] versus pMMR/MACC1-high patients (P = 0.037). Outcomes were similar for pMMR/MACC1-low and deficient MMR (dMMR) patients (5-year RFS of 100% and 96%, respectively). Conclusions MACC1 expression stratifies colon cancer patients with unfavorable pMMR status. Stage II colon cancer patients with pMMR/MACC1-low tumors have a similar favorable prognosis to those with dMMR with potential implications for the role of adjuvant therapy.

A greater understanding of disease biology processes, the opportunity to develop targeted drugs leading to further improved patient outcomes and technology advances, as well as increasing pressure on healthcare budgets have led to a shift towards personalised healthcare solutions. Personalised medicine has tremendous potential benefits for patients and healthcare providers, as well as for regulatory agencies and pharmaceutical and diagnostic companies, but the advancement of this innovative therapeutic strategy depends on identifying biomarkers functioning as companion diagnostics for the targeted drug. However, considerable practical, methodological, regulatory and economic issues must be addressed to fully realise the potential of this approach.

Purpose: Prognostic markers that identify patients with stage II colon cancers who are at the risk of recurrence are essential to personalize therapy. We evaluated the potential of GIV/Girdin as a predictor of recurrence risk in such patients. Experimental Design: Expression of full-length GIV was evaluated by IHC using a newly developed mAb together with a mismatch repair (MMR)-specific antibody panel in three stage II colon cancer patient cohorts, that is, a training (n = 192), test (n = 317), and validation (n = 181) cohort, with clinical follow-up data. Recurrence risk stratification models were established in the training cohort of T3, proficient MMR (pMMR) patients without chemotherapy and subsequently validated. Results: For T3 pMMR tumors, GIV expression and the presence of lymphovascular invasion (LVI) were the only factors predicting recurrence in both training (GIV: HR, 2.78, P = 0.013; LVI: HR, 2.54, P = 0.025) and combined test and validation (pooled) cohorts (GIV: HR, 1.85, P = 0.019; LVI: HR, 2.52, P = 0.0004). A risk model based on GIV expression and LVI status classified patients into high- or low-risk groups; 3-year recurrence-free survival was significantly lower in the high-risk versus low-risk group across all cohorts [Training: 52.3% vs. 84.8%; HR, 3.74, 95% confidence interval (CI), 1.50–9.32; Test: 85.9% vs. 97.9%, HR, 7.83, 95% CI, 1.03–59.54; validation: 59.4% vs. 84.4%, HR, 3.71, 95% CI, 1.24–11.12]. Conclusions: GIV expression status predicts recurrence risk in patients with T3 pMMR stage II colon cancer. A risk model combining GIV expression and LVI status information further enhances prediction of recurrence. Further validation studies are warranted before GIV status can be routinely included in patient management algorithms. Clin Cancer Res; 22(14); 3488–98. ©2016 AACR.

Background In vitro diagnostic (IVD) investigations are indispensable for routine patient management. Appropriate testing allows early-stage interventions, reducing late-stage healthcare expenditure (HCE). Aim To investigate HCE on IVDs in two developed markets and to assess the perceived value of IVDs on clinical decision-making. Physician-perceived HCE on IVD was evaluated, as well as desired features of new diagnostic markers. Methods Past and current HCE on IVD was calculated for the US and Germany. A total of 79 US/German oncologists and cardiologists were interviewed to assess the number of cases where: physicians ask for IVDs; IVDs are used for initial diagnosis, treatment monitoring, or post-treatment; and decision-making is based on an IVD test result. A sample of 201 US and German oncologists and cardiologists was questioned regarding the proportion of HCE they believed to be attributable to IVD testing. After disclosing the actual IVD HCE, the physician’s perception of the appropriateness of the amount was captured. Finally, the association between physician-rated impact of IVD on decision-making and perceived contribution of IVD expenditure on overall HCE was assessed. Results IVD costs account for 2.3% and 1.4% of total HCE in the US and Germany. Most physicians (81%) believed that the actual HCE on IVDs was >5%; 19% rated the spending correctly (0–4%, p

Purpose Thromboembolism is a major source of morbidity and mortality in patients with cancer. The contribution of anti–vascular endothelial growth factor therapy to these events remains controversial. Patients and Methods Individual patient data were available for 6,055 patients in 10 randomized studies. Unadjusted and exposure-adjusted incidence of venous thromboembolisms (VTEs) was estimated for the overall population and by tumor type. Multivariate analysis was performed to identify risk factors for development of VTE. The safety of anticoagulant therapy in patients undergoing bevacizumab treatment was also examined. Results There were no statistically significant increases in the unadjusted or exposure-adjusted incidences of all-grade VTEs for bevacizumab versus controls in the overall population or by tumor type. The unadjusted incidence in the overall population was 10.9% with bevacizumab versus 9.8% with controls (odds ratio, 1.14; 95% CI, 0.96 to 1.35; P = .13); the rate per 100 patient-years was 18.5 for bevacizumab and 20.3 for controls (rate ratio, 0.91; 95% CI, 0.77 to 1.06; P =.23). Incidences of grade 3 to 5 events were similar in both groups. Several risk factors for VTEs were identified, including tumor type, older age, poorer performance status, VTE history, and baseline oral anticoagulant use. No interactions between bevacizumab treatment and these factors were observed. For patients who had a VTE and received full-dose anticoagulation therapy, the risk of severe bleeding was low (< 1%) and unaffected by bevacizumab treatment. Conclusion The addition of bevacizumab to chemotherapy did not statistically significantly increase the risk of VTEs versus chemotherapy alone. The risk for VTEs is driven predominantly by tumor and host factors.

Background Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest. Patients and methods This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged

Summary Objective Adrenocortical carcinoma (ACC) is a rare malignancy associated with a dismal prognosis. Dendritic cells (DCs) are professional antigen-presenting cells leading to an antitumour immune response. The aim of this study was to elaborate two methods of antigen delivery to DCs and to evaluate an immunotherapy protocol in ACC patients. Design/patients Autologous DCs were pulsed with autologous tumour lysate (TL). Fusion of DCs with tumour cells was based on a polyethylene glycol method. Two patients with metastasized hypersecretory ACC were vaccinated twice. Measurements In vitro data were quantified by measurement of PBMC (peripheral blood mononuclear cell) responses and cytokine secretion and by flow cytometry analyses. Clinical response was monitored by CT scan of tumour mass and measurement of angiogenic factors. Results The maximum loading of TL was obtained at 24 h as 48·2% ( ± 26·8%) of DCs were TL-positive. The DC/tumour cell fusion efficacy was ∼ 45% as shown by double positive staining for ACTH receptor and DC-specific CD83. In vivo DC vaccination resulted in positive delayed-type hypersensitivity skin reactions reflecting specific memory T-lymphocyte reaction. In vitro analyses revealed specific T-cell proliferation in patient 1 (stimulation index: 5·7 compared to pretreatment) and induction of cytotoxic granzyme B secreting T cells in patient 2 (0·41% CD8 + cells vs. 0·06% pretreatment) as indicators of specific cytotoxic T cells. Although angiogenic serum markers could be stabilized, no impact on tumour growth could be observed. Conclusion Our data demonstrate that autologous dendritic cells induce antigen-specific Th1 immunity in adrenocortical carcinoma. The clinical outcome, however, was not improved in the patients studied here.

BACKGROUND: Current regimens for peripheral blood progenitor cell (PBPC) mobilization in patients with multiple myeloma are based on daily subcutaneous injections of granulocyte‐colony-stimulating factor (GCSF) starting shortly after cytotoxic therapy. Recently a polyethylene glycol‐conjugated G-CSF (pegfilgrastim) was introduced that has a substantially longer t1/2 than the original formula. STUDY DESIGN AND METHODS: The use of pegfilgrastim was examined at two dose levels for PBPC mobilization in patients with Stage II or III multiple myeloma. Four days after cytotoxic therapy with cyclophosphamide (4 g/m 2 ), a single dose of either 6 mg

In a retrospective analysis of 203 patients with small cell lung cancer (SCLC), we examined the prognostic value of c-kit expression on survival. Expression of c-kit was examined immunohistochemically in formalin-fixed, paraffin-embedded tissue sections. c-kit was observed in 87.7% of SCLC tumors. Using the Kaplan-Meier model, we found that lack of c-kit expression was associated with significantly shorter survival time compared to the presence of c-kit expression (mean survival 151 +/- 27 vs. 358 +/- 49 days, p = 0.0084). Moreover, the proportion of c-kit(+) cells within the tumor was also related to survival time. Patients with tumors in which >75% of cells stained positive for c-kit had a mean overall survival time of 424 (+/-72) compared to 295 (+/-67) days for patients with 25-75% c-kit(+) tumor cells. Patients with tumors containing

We have previously identified the gene Metastasis-Associated in Colon Cancer 1 (MACC1). MACC1 acts a prognostic biomarker for tumor progression, metastasis and patient survival for a broad variety of solid cancer types. Here we assessed if the MACC1 gene could separate stage II colon cancer patients with proficient mismatch repair (pMMR) into high- and low-risk groups who might benefit from or be spared adjuvant chemotherapy based on their prognosis. In the Charité 1 discovery cohort (n=61), MACC1 expression and MSI status were assayed by qRT-PCR in cryo-preserved tumors from CRC patients. MSS/MSI-low/MACC1-low tumors showed better survival vs. MSS/MSI-low/MACC1-high (P Citation Format: Ulrich-Peter Rohr, Pia Herrmann, Katharina Ilm, Hai Zhang, Sabine Lohmann, Astrid Reiser, Andrea Muranyi, Janice Smith, Susen Burock, Marc Osterland, Katherine Leith, Shalini Singh, Patrick Brunhoeber, Rebecca Bowermaster, Jeanne Tie, Michael Christie, Hui-Li Wong, Paul Waring, Kandavel Shanmugam, Peter Gibbs, Ulrike S. Stein. Combination of DNA mismatch repair status and MACC1 expression in patients with stage II colon cancer: The BIOGRID studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2778. doi:10.1158/1538-7445.AM2017-2778

e15118 Background: STEAM (NCT01765582) evaluated the efficacy and safety of concurrent (c) and sequential (s) FOLFOXIRI-bevacizumab (BEV) versus FOLFOX-BEV for first-line treatment of mCRC. Methods: The AVENIO ctDNA Expanded Kit (Research Use Only) was used to identify somatic mutations in 77 cancer-related genes by next-generation sequencing (NGS) in both pre- and post-induction plasma samples (n = 118 for both groups) from STEAM. Demographics for patient tested were similar to the overall cohort. The mutant allele fraction (mAF) represents the mutation frequency in ctDNA for single nucleotide variants (SNVs) and indels detected per patient. Results: Overall, patients with a pre-induction mAF below the median had longer PFS compared to patients with mAF above the median (13.4 vs 9.5 mo, HR 0.49, p = 0.002). A similar trend was seen for overall survival (OS). Within the below median mAF group, longer PFS was observed in patients treated with cFOLFOXIRI-BEV versus FOLFOX-BEV (25.2 vs 9.5 mo, HR 0.34, p = 0.020). In contrast, no differences in PFS were observed in the treatment arms in the above median mAF group. Patients with a post-induction mAF below the median had longer PFS compared to patients with mAF above the median (15.3 vs 8.1 mo, HR 0.51, p = 0.0064). Correlations of post-induction genomic changes with outcomes, according to treatment groups, will also be presented. Conclusions: The level of pre- and post-induction mAF appears to correlate with PFS in STEAM overall. Furthermore, a lower median pre-induction mAF suggests PFS benefit for cFOLFOXIRI-BEV versus FOLFOX-BEV. Thus, plasma analysis of mAF via the AVENIO ctDNA Expanded Kit may identify patients who benefit from specific treatment in mCRC. These results are hypothesis generating and require further clinical validation. Clinical trial information: NCT01765582.

3591 Background: Adjuvant chemotherapy is offered to most pts with Stage III CRC, and to a subset with Stage II disease deemed at high-risk for recurrence. Nevertheless, risk stratification strategies remain suboptimal. Detection of minimal residual disease (MRD) through ctDNA analysis has been shown to identify pts at high recurrence risk in Stage II CRC, but not Stage III disease. Methods: The next-generation sequencing based AVENIO ctDNA Surveillance Kit (Research Use Only) was used to identify single nucleotide variants (SNVs) in tumor tissue within a cohort of 145 Stage II and III CRC pts following R0 surgical resection (n = 86 and 59 respectively; median follow-up = 32.1 mo). The same assay was used to monitor ctDNA with a single post-operative blood sample (mean surgery-to-phlebotomy time: 10 days). Regions from 197 genes recurrently mutated in CRC were interrogated, and pts were classified as ctDNA positive (+) or negative (-) in plasma based on the detection of SNVs previously identified in tumor tissue. Results: Variants were identified in 99% of tumors (n = 144) with a median of 4 SNVs/sample (range 1-24) and all post-operative plasma samples were successfully profiled. Pts with detectable ctDNA (n = 12) displayed a significantly shorter 2-year relapse-free survival (RFS; 17% vs 88%; HR 10.3; 95% CI 2.3-46.9; p < 0.00001), time to recurrence (TTR; HR 20.6; 95% CI 3.1-139.0; p < 0.00001) and overall survival (OS; HR 3.4; 95% CI 0.5-25.8; p = 0.041) than ctDNA- pts (n = 132). 11 (92%) of ctDNA+ pts developed recurrence compared to 9 (7%) of ctDNA- pts. Monitoring multiple variants doubled sensitivity of MRD detection compared to tracking a single driver mutation. TTR was shorter in ctDNA+ vs ctDNA- Stage II (HR 23.1, 95% CI 0.28-1900.4; p < 0.00001) and stage III pts (HR 17.9; 95% CI 2.7-117.3, p < 0.00001). TTR of Stage II and III ctDNA- pts was similar (p = 0.7). Conclusions: Our results indicate that ctDNA analysis can detect MRD within days after complete resection of CRC and accurately identifies pts at high risk of recurrence in both Stage II and III CRC. MRD detection via ctDNA sequencing may allow personalization of adjuvant treatment strategies.

11510 Background: STEAM (NCT01765582) assessed the efficacy and safety of concurrent (c) and sequential (s) FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for first-line treatment of mCRC. Methods: The AVENIO ctDNA Expanded Kit (Research Use Only) was used to assess somatic mutations in 77 cancer-related genes by NGS in tissue, and both pre- and post-induction plasma samples (n = 182, 150 and 118 respectively) from STEAM. Four mutation classes including single-nucleotide variants (SNVs), indels, copy number amplifications (CNAs) and fusions were identified. SNVs and indels were called in tissue and plasma at allele frequencies of 5% and 0.25% respectively. Results: Overall concordance of mutations in pre-induction plasma with tissue was 83%. Concordance for the seven most mutated genes ranged from 91.5%-100%. In pts with matched samples (n = 118), RAS WT pts showed significantly longer progression-free survival (PFS) in both cFOLFOXIRI-BEV (A) and sFOLFOXIRI-BEV (B) arms versus FOLFOX-BEV (C), using genotyping of either tissue or plasma. This was not seen in RAS MUT pts. In contrast, TP53 WT showed no significant treatment differences while TP53 MUT showed longer PFS for cFOLFOXIRI-BEV versus FOLFOX-BEV. A list of mutation frequencies for all samples, as well as hierarchical clustering analysis of tissue mutations will be presented. Conclusions: The AVENIO ctDNA Expanded Kit identified mutations in 77 cancer-related genes, in both plasma and tissue, with high overall concordance. Compared to FOLFOX-BEV, longer PFS was observed for c- or s- FOLFOXIRI-BEV in RAS WT pts and for cFOLFOXIRI-BEV in TP53 MUT pts, irrespective of sample type. These results are hypothesis generating and require further clinical validation. Clinical trial information: NCT01765582. [Table: see text]

Acute graft-versus-host disease (aGVHD) is a serious complication of allogeneic peripheral blood stem cell transplantation (PBSCT). Patients with severe aGVHD not responding to treatment with steroids have a poor prognosis. We treated four patients with severe aGVHD refractory to steroids with infliximab, a chimeric human/mouse antiTNFalpha antibody. Patients (CML 2, MM 1, AML 1) developed grade III-IV GVHD at a median of 34 days (range 15-76) after myeloablative PBSCT (two), donor lymphocyte infusion for relapsed CML (one) or non-myeloablative PBSCT (one), respectively. All patients had severe intestinal involvement in addition to skin and/or liver disease and had received treatment with high-dose steroids (four) for a median of 11 days (range 5-17) in addition to CsA (four) and MMF (three). Infliximab (10 mg/kg) was given once a week until clinical improvement. In three of four patients a complete resolution of diarrhea and significant improvement of skin and liver disease were observed. Two patients received one, one patient two and one patient three infliximab infusions. At present two patients are alive >200 days after therapy, one with limited cGVHD. Two patients died, one of progressive malignant disease without GVHD and one of refractory GVHD. Infliximab is apparently an active drug for the treatment of aGVHD.

Purpose: Patients with central nervous system (CNS) metastases were excluded from bevacizumab trials following a case of fatal cerebral hemorrhage in a patient with hepatocellular carcinoma in 1997. Safety information for bevacizumab-treated patients with CNS metastases was reviewed to determine whether general exclusion of these patients from bevacizumab treatment is still justified. Experimental Design: A retrospective exploratory analysis was conducted using datasets from 13 randomized controlled phase II/III trials (dataset A), two open-label single-arm safety trials (dataset B), and two prospective studies including patients with treated CNS metastases (dataset C). In datasets A and B, known CNS metastasis was an exclusion criterion; patients with CNS metastasis had unrecognized CNS metastases at study entry or developed them during the trial. All reported cerebral hemorrhage grades in patients with CNS metastases were quantified. Results: In dataset A, occult brain metastases were identified in 187 of 8,443 patients (91 in bevacizumab arms and 96 in non-bevacizumab arms). Three bevacizumab-treated patients (3.3%) developed grade 4 cerebral hemorrhage, whereas one control-arm patient (1.0%) developed grade 5 cerebral hemorrhage. In dataset B, 321 of 4,382 patients had initially occult CNS metastases, in whom two grade 1 and one grade 3 cerebral hemorrhage (0.9%) were reported. In 131 patients with treated CNS metastases in dataset C, one bevacizumab-treated patient (0.8%) developed grade 2 cerebral hemorrhage. Conclusions: In this selected population, patients with CNS metastases are at similar risk of developing cerebral hemorrhage, independent of bevacizumab therapy. Consequently, such patients with CNS metastases from advanced/metastatic breast cancer, non–small cell lung carcinoma, and renal and colorectal cancer should not be generally excluded from bevacizumab therapy or clinical trials. Clin Cancer Res; 16(1); 269–78

s S387 Material and Methods: Formalin-fixed, paraffin-embedded tissue sections from 186 primary colorectal carcinomas and four normal colorectal tissues were immunostained using specific monoclonal antibodies against Tn and sialyl-Tn antigens. Baseline clinicopathological characteristics and overall 5-year survival were correlated with antigen expression. Results: Of the 186 colorectal carcinomas, Tn antigen is expressed in 70 (37.6%) and sialyl-Tn antigen is expressed in 141 (75.8%). There is no staining for these antigens in normal colorectal tissues. Immunostaining measurements for Tn antigen were significantly associated with the differentiation degree (p = 0.017) of the tumors, but independent of age, gender, tumor location, depth of penetration, status of lymph nodes, lymphovascular invasion, perineural invasion and TNM stage. The expression results of sialyl-Tn antigen revealed more significant associations with the degree of differentiation (p = 0.006) and perineural invasion (p = 0.041). The poor overall survival rate of patients was significantly associated with the positive expression of sialyl-Tn (p = 0.013) but not with the expression of Tn (p = 0.650). Survival at 5 years for patients with sialyl-Tn-negative versus sialyl-Tn-positive tumors was 72.1% versus 49.2%. Cox regression multivariate analysis confirmed that TNM stage (p = 0.001) and sialyl-Tn expression (p = 0.038) were the two most important variables of for predicting overall survival. Conclusions: These results indicate that Tn and sialyl-Tn antigens appear to be useful biomarkers of poorly differentiated adenocarcinomas and mucinous carcinomas. Moreover, the positive expression of sialyl-Tn antigen is an independent predictor of poor prognosis in human colorectal carcinoma. No conflict of interest.

Following induction therapy and 4 g/m(2) cyclophosphamide, a single dose of 12 mg polyethyleneglycol-conjugated G-CSF (pegfilgrastim; n=12) or daily doses of unconjugated G-CSF (8.5 mug/kg/day) (n=12) were administered to myeloma patients. Pegfilgrastim was associated with an earlier leukocyte recovery (12 vs 14 days) and peripheral blood CD34+ cell peak (12 vs 15 days). The peripheral blood CD34+ cell peak was lower in the pegfilgrastim group (78 vs 111/mul). Following high-dose melphalan (200 mg/m(2)) and autografting, leukocyte and platelet reconstitution was similar in both groups and stable blood counts were observed 100 days post transplant. In summary, a single dose of pegfilgrastim after chemotherapy is capable of mobilizing a sufficient number of CD34+ cells for successful autografting with early engraftment and sustained hematological reconstitution in patients with myeloma. These data provide the basis for randomized studies evaluating the optimal dose and time of pegfilgrastim as well as long-term outcome in larger cohorts of patients.

Aim: There is an evident unmet need to better define recurrence risk for patients with stage II colon cancer (CC), particularly those with mismatch repair proficient (pMMR) tumors, to determine the subgroup of patients that may benefit from adjuvant chemotherapy. GIV/Girdin is a novel metastasis associated protein that triggers tumor cell invasion by enhancing PI3K/AKT signaling downstream of multiple oncogenic receptors. We explored the potential of GIV as a prognostic marker in stage II CC. Methods: A MMR antibody panel and a GIV specific antibody were developed by Ventana and evaluated by immunohistochemistry (IHC) on a cohort of stage II CC from Melbourne (n = 192), enriched for patients with recurrent disease (n = 44, 25%). Log rank test was used to assess the association of GIV IHC expression status with the recurrence risk. Evaluation of alternative GIV scoring algorithms, combining staining intensity and percent staining, and statistical predictive modeling including the analysis of distant recurrence free survival (DRFS) was undertaken for the chemo-naive cases, stratified by MMR and AJCC tumor (T) status. The association between GIV IHC status and standard histopathologic criteria was also assessed. Results: The distribution of deficient MMR (dMMR) vs pMMR cases were 20.8% and 79.2%, respectively. Within the chemo-naive population (n = 103), expected associations between pathologic features and DRFS were observed, including pMMR vs dMMR (HR 4.12, p = 0.052), T4 vs T3 (HR 2.39, p = 0.055) and lymphovascular invasion (LVI) vs no LVI (HR 2.62, p = 0.021). GIV positivity, defined as >10% of tumor cells stained or any staining of 3+ intensity, was present in 45 (44.0%) of pMMR chemo-naive cases. For T3 pMMR chemo-naive cases (n = 91), GIV positivity was associated with significantly reduced DRFS (HR 2.49, p = 0.022). Adding LVI as an additional parameter to the algorithm for this group increased the HR to 4.74 (95% CI 1.90-11.85). Conclusions: GIV IHC expression status has been found to be associated with T3 disease, pMMR, and DRFS in an initial cohort of stage II CC. This exploratory diagnostic algorithm currently undergoes validation in two independent clinical stage II CC cohorts, with promising preliminary data. Disclosure: P. Waring: received research grant funding from F. Hoffmann-La Roche; B. Lafleur, A. Muranyi, S. Singh and P. Brunhoeber: Employee of Ventana Medical Systems, Inc., a member of the Roche Group; S. Hu, V. Teichgraber, U. Rohr, R. Ridder:. and K. Shanmugam: Employee of F. Hoffmann-La Roche Ltd. All other authors have declared no conflicts of interest.

2007 Background:. The background rate of CNS hemorrhage (CH) in cancer patients with brain metastases not receiving bevacizumab (BV) treatment is 5%-29%, depending on tumor type. Patients with CNS metastases were routinely excluded from most BV late-stage clinical trials, following the occurrence of CH in one hepatocellular carcinoma patient with occult CNS metastasis in a BV phase I trial. In this particular tumour type, up to 87.5% has been reported as a background rate of CH without BV use. Available safety information in BV-treated patients with CNS metastases has been reviewed to determine whether the exclusion of these patients from trials is still justified. Methods: A retrospective exploratory analysis was conducted using safety data from three datasets: A.) 13 randomized controlled phase II or III trials (RCTs); B.) Two ongoing open-label trials MO19391 (ATHENA) and MO19390 (SAIL). While patients with known CNS metastases, based on imaging or clinical signs and symptoms, were excluded from trial in A and B datasets, patients who were found to have CNS lesions had either unrecognized CNS metastases at study entry or had developed these during the trial.; C.) 2 ongoing open-label studies AVF3752g and AVF3671g in patients with NSCLC, where inclusion of patients with treated CNS metastases was allowed. Incidence of CH in patients with brain metastases was quantified in each dataset. Results: A.) In 13 RCTs, with a total of 8443 patients with locally advanced, unresectable, or metastatic breast, renal, pancreatic, colorectal cancer, or NSCLC, brain metastases were identified in 187 patients (91 in BV-arms and 96 in control arm). Three of 91 (3.29%) BV-treated patients developed grade 4 CH, and one in 96 patients in the control arm (1.04%) developed grade 5 CH; B.) In open-label studies no CH was reported in 68 patients with CNS metastases, out of 3,252 patients enrolled. C.) In two studies in patients with treated CNS metastases, one subject in 83 (1.2%) BV treated patients developed a grade 2 CH. Conclusions: In this retrospective review, the rates of CH in BV-treated patients with CNS metastases is low, and appears consistent with historical rates of CH in these patient populations. Ongoing trials are expected to provide additional data regarding the risk of CH in patients with primary and metastatic CNS tumors. [Table: see text]

Bortezomib has improved the outcome of patients with multiple myeloma. Nevertheless, bortezomib monotherapy achieves responses in less than 50% of patients with advanced disease. Combination therapy can improve response rates but is associated with more adverse events such as neuropathy or myelosuppression. Therefore, we evaluated a step-wise escalation treatment algorithm for patients with relapsed or refractory myeloma. The initial treatment (step1) consisted of bortezomib monotherapy (1.3mg/m2 on day 1,4,8,11). Patients who did not show a at least 25% reduction of paraprotein at the beginning of cycle 2 received an escalated treatment (step2) with bortezomib and dexamethasone (40mg on day 1,4,8,11). The next treatment escalation (step3) was performed by addition of bendamustine (50–100mg/m2 on day 1 + 8) to bortezomib and dexamethasone. Step3 was used for patients who did respond with less than a minor response to one cycle of step2 treatment. We report on 48 patients who have been treated at our institution according to this regimen. Patients median age was 59 years with a median β2-microglobuline level of 3.8 g/dl and median albumine level of 3.7 g/dl. All patients were heavily pre-treated with in median three prior treatment regimen including high-dose therapy and thalidomide in more than 90% of patients. Escalation therapy was applied as planned to 36 (75%) patients, whereas 12 (25%) patients received step2 at the beginning of treatment due to physicians decision because of fulminant disease progression with hypercalcemia or severe tumor burden. Toxicity was as expected for bortezomib monotherapy and was manageable with escalated treatment steps. Response rates for patients in step1 were 11% nCR, 36% PR and 11% MR. In step2 (n=26) response rates were 31% PR, 15% MR and in step3 (n = 7) 43% PR and 29% MR. This results in an overall response rate of 80% for all patients. Patients with fulminant progressive disease who needed upfront treatment with step2 had an inferior overall response rate of 42% in comparison to 90% for patients who were treated according to the planned treatment schedule. With a median follow-up of 26 months the median time to progression and overall survival was 9 months and not reached for patients in the planned program and 2 and 4 months for the patients with upfront escalated therapy. Univariate analysis including several conventional prognostic parameters revealed physicians decision for upfront escalated treatment and age >60 years as the only bad prognostic factors. Interestingly, for patients within the planned treatment schedule, response to previous therapies, the extent of paraprotein reduction and the required escalation step had no impact on response duration. Another interesting observation of our single center study was that re-exposure of step3 treatment at the time of relapse (n=8) resulted in a new remission in 50% and in stable disease in 38% of patients. In conclusion, escalating therapy with bortezomib, dexamethasone and bendamustine induces durable remissions in the majority of patients, even in the presence of poor prognostic parameters. However, this treatment algorithm is not applicable for patients presenting with fulminant disease progression, as these patients need more aggressive regimens.

17066 Background: The primary objective of the ongoing phase II study was to find clinical and molecular predictors for survival. Consequently, we prospectively examined gene and protein expression and EGFR mutation profiles of tumor cells, and clinical variables. Methods: Pts with advanced NSCLC (stage IIIb/IV) previously treated with platinum-based chemotherapy received 150mg/day erlotinib (Tarceva an EGFR tyrosine-kinase inhibitor) orally until disease progression. For molecular analyses, biopsies were taken from the primary lung tumor prior to erlotinib treatment. Pure tumor cells were isolated using laser-capture microdissection. For expression analysis, a microarray of 8793 genes (Human Focus Array, Affymetrix) was used. Data were analyzed using VSN method and significance analysis of microarrays. Results: In an interim analysis, clinical data were available for 36 of 43 so far included pts in the ongoing phase II study. For 36 pts, the tumor responses were: 1 CR (3%), 4 PR (11%), 11 SD (30%) and 19 PD (53%), and the median survival was 20 wks. Overall survival was significantly better in pts with rash than without rash: 9.2 vs 4.3 months. In a 14 months follow up, all of the responding pts survived while the median survival for pts with SD or PD was 11.4 and 4.0 months, respectively. Comparing gene expression profiles of tumors from 6 pts with a response or SD with those from 13 pts with tumor progression, we could not identify genes that were differentially expressed with sufficient significance. In 20 tumor samples evaluated for EGFR protein expression and mutation analysis, 19 expressed EGFR (IHC). A base exchange in exon 18 (2166G>A; A722A) and 20 (2547A>G; Q787Q) of the EGFR already described as a single nucleotide polymorphism was seen in 4 samples performing SSCP gel electrophoresis and sequencing. Conclusions: Rash, a side effect with erlotinib, was significantly associated with better survival. No activating EGFR mutations were found indicating that the response in 14% of pts is independent of mutations. For identification of genes predictive for response to erlotinib, a larger sample number is necessary. No significant financial relationships to disclose.

17033 Background: We evaluated the therapeutic efficacy of tandem high-dose chemotherapy followed by autologous peripheral stem-cell transplantation (PBSCT) in patients with newly diagnosed SCLC in complete remission or very good partial response after induction chemotherapy. Methods: Between 1996 and 2000, 19 patients with newly diagnosed SCLC in CR or very good PR after two cycles of induction chemotherapy (cisplatin 90 mg/m2 day 1, etoposide 120 mg/m2 day 1–3, ifosfamide 1500 mg/m2 day 1–4) received a tandem high-dose chemotherapy (cyclophosfamide 2000 mg/m2 day 1 and 2, etoposide 700 mg/m2 day 1–3, carboplatin 1200 mg/m2 day 1) followed by PBSCT. Following transplantation, patients received concurrent chest and cranial radiotherapy to a total dose of 45 Gy and 30 Gy, respectively. Results: Of 19 patients with SCLC, 18 had stage III and one stage IV disease. The median age was 50.7 years. Median time to leukocyte-recovery above 1000/μl and platelet-recovery above 20.000/μl was 12 days and 9 days, respectively. The median follow-up was 6.38 years (range 5.11–7.23) for surviving patients. There were no transplant-related deaths and toxicity was moderate. Using the Kaplan-Meier method, the 2- and 5-year survival rates after high-dose therapy were 42% and 32% respectively. Median time to relapse was 0.7 years (range 0.2–4.6). The mean survival was 36.8 months. This outcome compared favourably to a group of 77 patients who did not receive high-dose therapy but responded to conventional chemotherapy (mean survival 11.4 months). Using the Cox regression model, among all patients response to induction, normal LDH and PBSCT were associated with favourable outcome. Conclusions: Our findings suggest that patients with or near complete response after conventional therapy might benefit from tandem high-dose therapy with PBSCT with tolerable toxicicity. No significant financial relationships to disclose.

PTTG-1 (pituitary tumor transforming gene) is a novel oncogene that is overexpressed in tumors, such as pituitary adenoma, breast and gastrointestinal cancers as well as in leukemia. In this study, we examined the role of PTTG-1 expression in lung cancer with regard to histological subtype, the correlation of PTTG-1 to clinical parameters and relation on patients' survival.

Background: High-dose chemotherapy with autologous stem cell transplantation has improved outcome and survival of patients with multiple myeloma. However, the majority of patients suffer from relapse. Using real-time quantitative (RQ) PCR we have shown before (Haematologica 89,2004) that the amount of residual tumor cells in the bone marrow of patients before transplantation is of prognostic relevance. In this study we evaluated in a larger group of patients with multiple myeloma whether a pre-transplantation level of clonotypic cells in the bone marrow is predictive for time-to-progression (TTP) and overall survival (OS). Further, we compared results with known prognostic factors. Patients and Methods: Bone marrow samples of 19 patients with stage II/III multiple myeloma were obtained after induction therapy but before transplantation. Immunoglobulin heavy chain (IgH) RQ-PCR using patient-specific Taqman probes was performed to quantify pre-transplantation tumor levels. The proportion of clonotypic cells was assessed as IgH/2 beta-actin ratio in percent. Medical records of patients were reviewed for prognostic factors and outcome. Results: The median level of residual tumor cells in bone marrow of all patients at the time before transplantation was 0.3 %. At 23 month median follow-up after transplantation the median TTP and OS in our study were 14 and 36 month, respectively. The threshold level of 0.03% clonotypic cells identified two prognostic groups (p Conclusion: Quantitative molecular assessment of pre-transplantation tumor level in the bone marrow is an independent prognostic parameter for the progression-free survival of patients with multiple myeloma and thus helps to guide therapeutic interventions

BACKGROUND: Treatment for patients with breast cancer (BC) is guided by human epidermal growth factor receptor 2 (HER2) status. The patient's HER2 status is assessed using US Food and Drug Administration-approved in vitro diagnostic (IVD) immunohistochemical (IHC) tests and laboratory-developed IVD tests. We analysed HER2 testing accuracy using data from the Nordic Immunohistochemistry Quality Control (NordiQC) HER2 IHC programme; results were used in an economic BC treatment model.METHODS: Data were obtained from NordiQC HER2 BC surveys performed from 2008 to 2012. False-negative (FN) and false-positive (FP) rates for approved and laboratory-developed IVDs were used to estimate direct costs, loss of survival, productivity benefit and quality-adjusted life-years. In the absence of consistent and accessible clinical and economic data from countries participating in the NordiQC programme, United States productivity data, healthcare costs and patient numbers were used as a surrogate in order to estimate the potential impact of selecting an approved or laboratory-developed IVDs.RESULTS: In total, 1703 tests were performed. Pooled FN rates were 11 % for approved IVDs and 25 % for laboratory-developed IVDs; FP rates were 0 % and 5 %, respectively. Using these FP and FN rates in the economic model and applying them to the United States BC population, approved IVD tests would result in better clinical outcomes, i.e., better survival and fewer disease recurrences/progressions, and lower costs, i.e., total direct costs and lost productivity, versus laboratory-developed IVD tests. Every $1 saved by laboratories by using cheaper reagents could potentially result in approximately $6 additional costs to the healthcare system.CONCLUSIONS: The results of this analysis suggest that incorrect HER2 test results have far-reaching clinical and economic consequences.