bluuebunny/crossref_metadata_2025 huggingface dataset:
Graft-versus-tumor effect following reduced-intensity allogeneic stem cell transplantation in prostate cancer
Authors: Bregni M. , Bernardi M. , Ciceri F. , Rigatti P. , Peccatori J.
Published: March 2020

6551

Background: Allogeneic transplantation has been utilized as adoptive immunotherapy for patients with solid tumors resistant to conventional therapy. Methods: In 2001 we started a pilot study of allogeneic hematopoietic cell transplantation after a reduced-intensity regimen in patients with metastatic, androgen-independent prostate cancer, aged 18–70, ECOG PS 0–1. Planned sample size was 10 patients. Primary endpoint was feasibility of the procedure. The conditioning regimen included thiotepa, fludarabine, and cyclophosphamide. Patients received allogeneic peripheral blood cells from an HLA-identical sibling. A median of 6.9×10e6 CD34+ cells/kg were infused (range 4.8–11.8). Graft-versus-Host Disease (GvHD) prophylaxis consisted of cyclosporine A and short-course methotrexate. All the patients were evaluable for engraftment and chimerism. Results: Six patients have been enrolled. The median age was 61 years (range 51–66). The median time to reach an absolute neutrophil count of 1.0×10e9/l and a platelet count of 20×10e9/l was 11 and 12 days respectively (range 10–14 and 11–16). All patients achieved complete lymphoid- and myeloid-chimerism at day +90 by cytogenetics or by VNTR polymorphism analysis. Median day of cyclosporine A withdrawal was +85. Three patients developed acute GvHD grade ≥2, usually soon after cyclosporine withdrawal. At a median follow-up of 401 days (range 93–682), 2 patients are alive and 4 died, 2 for disease progression (+214 and +275), one for CMV disease (+93) and one for hemorrhagic cystitis (+527). This last patient achieved an almost complete response confirmed on choline-PET scan after cyclosporine withdrawal and limited chronic GvHD. In other 4 patients we observed a PSA reduction, concurrently with cyclosporine withdrawal or development of GvHD. Conclusions: The close association between GvHD and/or cyclosporine withdrawal and tumor responses strongly suggests that tumor regression was associated with an immune-mediated reaction related to allografting. Future strategies will aim at enhancing the anti-tumor effect and at decreasing GvHD and transplant-related mortality.

No significant financial relationships to disclose.
Clinicopathological correlation (CC) and outcome of breast cancer patients (pts) with resected brain metastasis (BM)
Authors: Ibrahim N. K. , Nguyen G. , Suki D. , Hennessy B. , Montero A. , Sarriera J. E. , Symmans F. , Valero V. , Sawaya R. , Aldape K.
Published: March 2020

656

Background: We aimed at determining the pathologic features of metastatic breast lesions to the brain, and their correlation with the primary tumor, and their effect on postneurosurgical survival (PNS). Methods: Tissue samples from 123 pts who underwent surgical resection of BM at MDACC between 1984–2004, were examined for estrogen receptor-α (ER) by IHC and HER2 by FISH or IHC. Pts’ medical records were retrospectively reviewed for CC. Results: Median (med) age at BM diagnosis was 51 years. The med time from primary diagnosis to BM was 33 months (Range (R)0–304). Infiltrating ductal cancers were found in 89%. ER was negative and HER2 amplified in 73% and 37% of BM, respectively; ER-/Her2- was seen in 43%, ER-/Her2+ in 30%, ER+/Her2+ in 6%. Concordance of ER and HER2 status between primary and BM were both 88% (p=NS, for discordance). ER positivity was associated with a longer primary diagnosis to BM interval [med 39 months (R, 0–213) vs. 29 months (R, 0–304) in the ER- pts; p=0.02]; HER2 amplification was not (p=0.82). The med PNS was 11.2 months (R, 9.0–13.5) for 112 pts with no pre- craniotomy brain radiation. Pts with ER+ metastases experienced apparent longer PNS survival than ER- pts [med 18.9 months (95% CI, 4.8–33.1) vs. 9.9 months (95% CI, 7.6–12.1 months), respectively, p=0.06], as did those with HER2-amplified BM [med 13.8 months vs. 9.9 months, respectively; p=0.10]. Pts aged 45 to <60 years had significantly longer pns survival (med 15.5 months) than younger or older pts (med 9.5 and 5.1 months, respectively), p≤.05 for all pair- wise comparisons. In mutivariate analyses correcting for age, functional status, and systemic tumor burden, neither ER nor HER2 status were independent predictors of pns. Of the 38 patients with HER2-amplified tumors and no pre- craniotomy radiation, 14 received trastuzumab (Tz) prior to initial neurosurgery. These 14 pts had longer PNS compared to those with HER2-amplified tumors not receiving Tz [median, 25.4 months vs. 10.7 months, respectively, p=NS). Conclusions: ER and HER2 positivity were highly concordant between primary and BM. Resected BM were more likely to be ER- or HER2-amplified. ER positivity and HER2 amplification were not significant independent predictors of PNS, though both showed a strong trend in univariate analyses. Middle age group pts had the best PNS survival.

No significant financial relationships to disclose.
Darbepoetin alfa for treating anemia in low-risk myelodysplastic syndrome patients: Interim results after 27/28 weeks
Authors: Paquette R. , Gabrilove J. , Lyons R. , Mushtaq C. , Sekeres M. , Lam H. , Dreiling L.
Published: March 2020

6564

Background: Patients (pts) with myelodysplastic syndrome (MDS) disorders often develop anemia, resulting in increased transfusions and fatigue. Using the erythropoiesis-stimulating agent (ESA) epoetin alfa to treat anemia in low-risk MDS pts results in an average response rate of 30% (40% when used with G-CSF). Pilot studies suggest that 150 or 300 mcg/week (wk) darbepoetin alfa (DA) can raise hemoglobin (Hb) levels in anemic MDS pts. Methods: This fully enrolled (n = 209), phase 2, single-arm, 52-wk ongoing study is examining DA 500 mcg every 3 weeks (Q3W) for treating anemic pts (Hb ≤ 11 g/dL) with low- or intermediate-risk MDS (IPSS definition). The study’s primary endpoint is the proportion of pts achieving an erythroid response by 13 wks. Other endpoints include the proportion of pts achieving an erythroid response by 27/28 wks and change in both Hb levels and FACT-F scores. Results are stratified by whether pts received ESA therapy before enrollment: ESA-naïve (ESA-N) vs ESA-treated (ESA-T). Results: Previous interim data suggested that low-risk MDS pts can achieve a major erythroid response after 13 wks of DA 500 mcg Q3W. This is the first reported summary of results from a planned interim analysis after 27/28 wks of treatment (n = 129). Of 84 ESA-N pts, 51% were men, 86% were white, and the average (SD) age was 74.1 (9.7) years; the 45 ESA-T pts had similar demographics. During 27/28 wks of treatment, a majority of pts achieved a major erythroid response. ESA-N pts had a mean (SD) 1.2 (1.4) g/dL rise in Hb levels from BL and a clinically significant increase in FACT-F score from BL ( Table ). Of the 129 pts analyzed after 27/28 wks, 83% reported an adverse event (AE) and none reported serious treatment-related AEs or thrombotic events (of 189 pts analyzed after 13 wks, 1 pt reported a serious treatment-related AE). Conclusions: These interim results suggest that DA 500 mcg Q3W is well tolerated and can raise Hb levels in anemic, low-risk MDS pts. Final 27/28-wk data from all enrolled pts (n = 209) will be shown.

[Table: see text]

[Table: see text]
A study of factors determining outcome of patients receiving third line chemotherapy for metastatic breast cancer: The Royal Marsden Hospital experience
Authors: Kuciejewska A. , Banerji U. , Walsh G. , Ashley S. , O’Brien M. , Johnston S. , Smith I.
Published: March 2020

657

Background: Metastatic breast cancer is increasingly treated with multiple lines of chemotherapy. We studied the factors determining the outcome of patients receiving third line chemotherapy for metastatic breast cancer Methods: This is retrospective study of 149 consecutive patients from the Royal Marsden Hospital chemotherapy database recorded to have received third line chemotherapy for metastatic breast cancer. The chemotherapy regimens and best response to chemotherapy for all three lines of chemotherapy were recorded. The time to progression (TTP) and survival after third line chemotherapy were also studied. Chi square and log rank tests were used to analyse differences in response rates (RR) and (TTP)/survival respectively. Results: 149 patients were studied with a median age of 52 (range 25 -80). The median TTP and survival was 4 months (range 1–25) and 8 months (range 1–52) respectively. Eighteen different chemotherapy regimens were used. The RR for third line chemotherapy was 30.2% (45/149). There was no significant difference in the TTP and survival of patients treated with different chemotherapy regimens (p= 0.82 and 0.44) respectively. We identified a subgroup of patients who had a poor outcome after third line chemotherapy. These patients did not respond to the first two lines of chemotherapy and had a response rate of 20.2% (10/49) compared to the rest of the cohort, 35% (35/100), p= 0.068. The TTP (3 Vs 4 months, p = 0.033) and survival, (6 Vs 9 months, p = 0.027) of this subgroup was significantly shorter than the rest of the cohort. The median time to death after progression in this subgroup was 2 months. Conclusions: The chemotherapy regimen used does not influence RR, TTP or survival in patients receiving third line chemotherapy for metastatic breast cancer. Patients not responding to the first two lines of chemotherapy have a significantly shorter TTP and survival. Best supportive care or experimental chemotherapy should be considered as options for these patients.

No significant financial relationships to disclose.
Prognostic significance of bcl-2 expression in stage III breast cancer patients who received doxorubicin and cyclophosphamide followed by paclitaxel as adjuvant chemotherapy
Authors: Lee K. , Kim B. , Lee S. , Han W. , Kim D. , Im S. , Kim T. , Park I. A. , Noh D. , Bang Y.
Published: March 2020

670

Background: Bcl-2 is an anti-apoptotic marker and regulated by hormonal receptor pathways in breast cancer. We performed this study to assess the prognostic significance of ER, PR, p53, c-erbB2, bcl-2, Ki-67, and EGFR as a marker for relapse in breast cancer patients who received same adjuvant therapy in a single institution. Methods: A cohort of 154 curatively resected breast cancer patients who had 4 lymph nodes or more and received doxorubicin and cyclophosphamide followed by paclitaxel (AC/T) as adjuvant chemotherapy was analyzed for clinicopathologic characteristics including disease-free survival (DFS). Patients with ER and/or PR expression received 5 years of tamoxifen following AC/T. The markers were analyzed by immunohistochemistry. Results: Median f/u duration was 25 months and 32 patients (20.8%) had recurrences. Stage (IIIa vs. IIIc) affected recurrences significantly, however, types of surgery, histology, histologic grade, presence of endolymphatic emboli, or close resection margin did not. Among the immunohistochemical markers, bcl-2 expression was the only one to be associated significantly with prolonged DFS (median 54 mo in bcl-2 (−) vs. not reached in bcl-2 (+); p=0.016). Furthermore, bcl-2 was an independent prognostic factor for DFS in multivariate analysis. Bcl-2 expression was significantly correlated with ER expression (p<0.001), and inversely correlated with c-erbB2 overexpression (p=0.027). Patients with both ER and bcl-2 expression had a longer DFS compared to the other patients (not reached vs. 54 mo, p=0.019). Patients with bcl-2 expression had a significantly longer DFS even in ER (+) subgroups (not reached vs 54 mo; p=0.011). Patients with c-erbB2 overexpression, ER (−) and bcl-2 (−) had a shorter DFS than the others (38 mo vs. not reached; p=0.029). Conclusions: In our homogenous patient cohort, bcl-2 expression was correlated with ER expression, and inversely correlated with c-erbB2 overexpression. Bcl-2 was an independent prognostic factor for DFS in curatively resected stage III breast cancer patients.

No significant financial relationships to disclose.
Same day administration of pegfilgrastim with dose dense doxorubicin in early breast cancer patients
Authors: Vance K. T. , Carpenter J.
Published: March 2020

671

Background: Pegfilgrastim is indicated to decrease the incidence of febrile neutropenia in patients with non-myeloid malignancies receiving myelosuppressive chemotherapy. In licensing studies, patients received a single dose of pegfilgrastim on day 2 of each chemotherapy cycle, which added an extra visit for day 2 administration. We administered pegfilgrastim to a series of early breast cancer patients on the same day of chemotherapy. We reviewed charts retrospectively to assess both efficacy and safety. Methods: Data on blood counts, toxicity and chemotherapy dosing was collected from July 1, 2003 to May 6, 2005 for all patients with early breast cancer who received sequential or combination doxorubicin, cyclophosphamide and paclitaxel on a 14 day schedule. Herceptin was given with paclitaxel and/or cyclophosphamide in 2 patients. Results: 64 patients with a median age of 50 years (range 22–67 years) were treated. 14 patients had stage I disease, 39 stage II and 11 stage III disease. Forty-one patients were treated postoperatively and 23 preoperatively. 211 cycles of doxorubicin were administered. After administration of doxorubicin, pegfilgrastim 6 mg s.c. was given on the same day. The lowest absolute neutrophil count on day 14 after doxorubicin was 1693/mm3 with no episodes of febrile neutropenia. The highest absolute neutrophil count was 23,671/mm3. The only dose reductions were five doxorubicin doses for grade 1–2 mucositis. Grade 1–2 nausea and vomiting was the most common toxicity seen after doxorubicin. Grade 1 bone pain was the most common side effect seen after pegfilgrastim occurring in 13/64 patients. There was no grade 3 or 4 toxicity of any kind. Conclusion: Pegfilgrastim administered on the same day as doxorubicin on a 14 day schedule was both safe and effective. Side effects were mild and included bone pain most likely attributable to pegfilgrastim. Neither granulocytopenia nor febrile neutropenia were seen and no treatments were delayed or postponed. Pegfilgrastim given on the same day as chemotherapy was effective in maintaining adequate granulocyte counts to allow treatment 14 days later and to avoid infection from granulocytopenia. Toxicity from pegfilgrastim was mild and tolerable.

[Table: see text]
Neoadjuvant chemotherapy (NCT) in 710 patients for operable breast cancer: Variation changing in hormonal receptors (HR) status
Authors: Tacca O. , Penault-Llorca F. , Abrial C. , Raoelfils I. , Mouret-Reynier M. A. , Bougnoux P. , Achard J. L. , Dauplat J. , Chollet P. , Curé H.
Published: March 2020

673

Background:
Positive HR constitutes by their presence a favourable prognosis factor and predicts response to an adjuvant hormonal therapy. In breast cancer treated by NCT, HR expression has been shown to be modified in residual disease after induction chemotherapy (
Miyoshi Y and al., Clin Cancer Res. 2004
).
Methods:
A second centralized comparative lecture of oestrogenic and progestative receptors was realized by IHC. HR status was evaluated in a blinded fashion by two pathologists, on 414 out of 710 patients from several prospective phase II trials. Cut off value for positivity was 10% tumor cells
(Amat et al, Breast Cancer Res Treat 2005)
. Median age of patients was 49.5 years. 555 (78%) patients had a ductal, 90 (13%) a lobular and 65 (9%) other type carcinoma, with a median size of 40 mm. Response was evaluated before, during and after a median number of 6 courses (1–9) of NCT. Study is curently ongoing.
Results:
Among these414 tumors, 157 (38%) were HR negative and 257 (62%) positive before NCT. HR status was changed in 105 patients (25%): 75 patients (48%) initially HR negative became HR positive. This HR positive switch was significantly correlated with a better overall survival (OS), compared with the unchanged HR negative tumors (p=0.032). However, HR positive switch had no effect on the disease free survival (p=0.085). More details concerning RH status and effect on hormonal adjuvant treatment will be presented.Conversely, Among the 257 HR positive tumors, 30 (12%) became negative after NCT, without effect on OS (p=0.28).
Conclusions:
We have previously shown that residual disease after NCT, rather than parameters evaluated on initial biopsy, must be considered for patients’ prognosis. NCT induced variations in HR status in 25% of patients; a positive switch was a strong prognostic indicator for patients outcome.

No significant financial relationships to disclose.
Lung Adjuvant Cisplatin Evaluation (LACE): A pooled analysis of five randomized clinical trials including 4,584 patients
Authors: Pignon J. P. , Tribodet H. , Scagliotti G. V. , Douillard J. Y. , Shepherd F. A. , Stephens R. J. , Le Chevalier T.
Published: March 2020

7008

Background: Several recent trials have shown a benefit of adjuvant cisplatin-based chemotherapy on overall survival (OS) in patients with non-small cell lung cancer (NSCLC). The aim of the Lung Adjuvant Cisplatin Evaluation (LACE) is to identify treatment options associated with a higher benefit, or groups of patients benefiting more from adjuvant chemotherapy. Methods: Individual patient data were collected and pooled from the five largest trials (ALPI, ANITA, BLT, IALT and JBR10) of cisplatin-based chemotherapy in completely resected patients, conducted after the NSCLC-meta-analysis (BMJ 1995, update ongoing). The interactions between patient subgroups or treatment types and chemotherapy effect on OS were analysed using hazard ratios (HR) and logrank tests stratified by trial. Results: With a median follow-up of 5.1 years, the overall HR of death was 0.89 (95% confidence interval [CI]: 0.82–0.96; p<0.005) corresponding to a 5-year absolute benefit of 4.2% with chemotherapy. There was no heterogeneity of chemotherapy effect among trials. The benefit varied with stage (test for trend, p=0.046) with the HR for stage I-A 1.41 [95% CI: 0.96–2.09], stage I-B 0.93 [0.78–1.10], stage II 0.83 [0.73–0.95] and stage III 0.83 [0.73–0.95]. The effect of chemotherapy did not vary significantly (test for interaction, p=0.10) with the associated drugs: vinorelbine (HR=0.80 [0.70–0.91]) etoposide/vinca-alcaloide (0.93 [0.80–1.07]) or other (0.98 [0.84–1.14]). There was no interaction between chemotherapy and sex, age, planned radiotherapy or planned total dose of cisplatin. Conclusions: Adjuvant cisplatin-based chemotherapy improves survival in patients with NSCLC. This benefit depends on stage and is greatest in patients with stages II and III. Our analysis suggests that platinum-based adjuvant chemotherapy may not benefit stage I-A patients. Results of disease-free survival will be presented at the meeting. Supported by PHRC and LNLCC

[Table: see text]
Immunohistochemical staining of the Excision Repair Cross-Complementing 1 (ERCC1) protein as predictor for benefit of adjuvant chemotherapy (CT) in the International Lung Cancer Trial (IALT)
Authors: Soria J. , Haddad V. , Olaussen K. A. , Fouret P. , Dunant A. , Filipits M. , Popper H. H. , André F. , Le Chevalier T. , Brambilla E.
Published: March 2020

7010

Background: Adjuvant cisplatin-based chemotherapy improves survival in patients with completely resected non-small-cell lung cancer, but no clinical or biological predictor of the benefit of CT has yet been validated in large trials. ERCC1 is a highly conserved excision nuclease within the nucleotide excision repair (NER) pathway and is essential for efficient repair of DNA-adducts induced from alkylating agents. Methods: Using a standard protocol of immunohistochemistry, we evaluated ERCC1 expression in 783 resected tumor tissues from patients enrolled in the IALT. For each case, a semi-quantitative histology score (H-score) was calculated on the basis of both the percentage of positive tumor nuclei and staining intensity. The median value of H-scores was a priori chosen as the cut-off point to classify ERCC1 positive and negative tumors. Overall survival was analyzed with a Cox model adjusted on clinical and pathological factors. Results: After immunostaining, 761 out of 783 cases (97%) were of sufficient quality for analysis. For 335 patients (44%), ERCC1 status was positive (H-score exceeding 1.0, i.e. tumors with a staining intensity score of 2 and 50% or more positive nuclei or a staining intensity score of 3 and 10% or more positive nuclei). The benefit of cisplatin-based adjuvant CT was correlated with the ERCC1 status (test for interaction, P<0.009). Patients with ERCC1-negative tumors randomized to CT had significantly prolonged survival compared with patients with ERCC1-negative tumors randomized to observation (adjusted hazard ratio for death, 0.67; 95% confidence interval [0.51–0.89], P<0.006). There was no survival difference with CT among ERCC1 positive patients (adjusted hazard ratio for death, 1.18; [0.87–1.61], P=0.29). When analyzing only patients randomized to observation, the subgroup with ERCC1 positive tumors had a better survival compared to those with ERCC1 negative tumors (0.65; [0.48–0.89], P<0.008). Conclusions: Patients with completely resected NSCLC and ERCC1-negative tumors derive a substantial benefit from adjuvant cisplatin-based CT. Unrestricted grants: Eli-Lilly, PHRC, Cancéropôle Rhône-Alpes, Austrian Science Fund

No significant financial relationships to disclose.
A phase II trial of ZD6474 plus docetaxel in patients with previously treated NSCLC: Follow-up results
Authors: Heymach J. V. , Johnson B. E. , Prager D. , Csada E. , Roubec J. , Pesek M. , Spasova I. , Hou J. , Kennedy S. , Herbst R. S.
Published: March 2020

7016

Background: ZD6474, a once-daily oral agent, targets key signaling pathways in cancer by inhibiting VEGF, EGF and RET receptor tyrosine kinases. ZD6474 in combination with docetaxel (Doc) was assessed in patients (pts) with refractory non-small-cell lung cancer (NSCLC). Methods: Pts eligible for this randomized, double-blind study had locally advanced or metastatic (stage IIIB/IV) NSCLC after failure of 1st-line platinum-based chemotherapy. The primary objective was to determine whether once-daily oral ZD6474 (100 or 300 mg) + Doc (75 mg/m2 i.v. infusion every 21 days) prolonged progression-free survival (PFS) vs Doc alone (80% power to detect 50% prolongation at P<0.2). Overall survival was a secondary objective. Results: A total of 127 pts (73 male/54 female; median age 59 yrs, range 29–82) received ZD6474 100 mg + Doc (n=42), ZD6474 300 mg + Doc (n=44) or Doc (n=41). The study met its primary objective of PFS prolongation with the addition of ZD6474: median PFS was 19 wks for ZD6474 100 mg + Doc (HR=0.64; P=0.074); 17 wks for ZD6474 300 mg + Doc (HR=0.83; P=0.461); and 12 wks for Doc. A total of 64 pts (50%) presented with histology other than adenocarcinoma, including 37 with squamous, and 13 pts (10%) entered with CNS metastases. Exploratory subgroup analyses suggest advantages in PFS for ZD6474 + Doc vs Doc both for adenocarcinoma and for other lung cancer histologies. Common adverse events (AEs) included diarrhea, rash and asymptomatic QTc prolongation, all responded to standard management or dose interruption/reduction. Four pts with squamous experienced hemoptysis (ZD6474 100 mg + Doc, n=2 CTC grade 1/2; Doc, n=2 CTC grade 3/4). No fatal episodes of hemoptysis or any CNS hemorrhage AEs were reported in pts receiving ZD6474. Overall survival data were immature at the time of PFS analysis, and a mature survival analysis will be conducted at ∼75% of deaths (anticipated April 2006, and will be presented at the meeting). As of December 2005, 40/127 (31%) pts were alive, 5 of whom continue to receive ZD6474. The minimum follow-up of pts still alive was 17 months. Conclusions: ZD6474 + Doc prolonged PFS vs Doc alone, and these promising data have led to the initiation of Phase III evaluation of ZD6474 + Doc in 2nd-line NSCLC.

[Table: see text]
Multi-center, double-blind, randomized, placebo-controlled phase II study to assess the efficacy of recombinant MAGE-A3 vaccine as adjuvant therapy in stage IB/II MAGE-A3-positive, completely resected, non-small cell lung cancer (NSCLC)
Authors: Vansteenkiste J. , Zielinski M. , Dahabre J. , Linder A. , Malinowski W. , Jassem J. , Lopez-Brea M. , Passlick B. , Lehmann F. , Brichard V.
Published: March 2020

7019

Background: About half of the patients with completely resected early-stage NSCLC will relapse. Adjuvant chemotherapy reduces the number of relapses at the expense of substantial toxicity. Activity of MAGE-A3 vaccination (i.e. recombinant MAGE-A3 protein and a potent GSK immunological adjuvant) has been proven in advanced melanoma. As about 35% of NSCLCs express the MAGE-A3 antigen, post-operative MAGE-A3 vaccination may be a targeted, well tolerated, and effective adjuvant therapy. Methods: Patients with completely resected, MAGE-A3 positive (assessed by quantitative RT-PCR), stage pIB or pII were 2:1, double-blind, randomly assigned to postoperative MAGE-A3 vaccination or placebo. Vaccination was started ≥6 weeks after surgery, with 5 vaccinations at 3-week intervals, followed by 8 vaccinations every 3 months. Randomization was stratified for stage (IB vs. II), histology (squamous vs. other), and lymph node procedure (sampling vs. dissection). Other anti-cancer adjuvant therapy was not allowed. Primary endpoint was time-to-recurrence, other endpoints were recurrence rates at different times, and survival. A sample size of 180 patients (120 active, 60 placebo) was chosen, to achieve 48% power (α=10%) to detect a 10% difference, assuming a 40% recurrence rate at month 30 in the placebo group (log rank test). A thorough interim efficacy analysis by an independent statistician (blinded to investigators and sponsor) is planned for 18 months after completion of recruitment. Results: 35% of 1,089 biopsies from 59 sites were MAGE-A3 positive. In two years, 182 patients were randomized (121 stage IB, 61 stage II). Overall, treatment was well tolerated, with high protocol compliance. Data collection for the interim efficacy analysis was initiated on December 19th, 2005. Median follow-up was 21 months, with 62 recurrences recorded. Conclusions: This study confirms expression of MAGE-A3 antigen in 35% of early NSCLC cases, and demonstrates good tolerability of postoperative MAGE-A3 vaccination. Efficacy results of the interim analysis will be available in February 2006.

[Table: see text]
Prospective trial with preoperative gefitinib to correlate lung cancer response with EGFR exon 19 and 21 mutations and to select patients for adjuvant therapy
Authors: Kris M. G. , Pao W. , Zakowski M. F. , Ladanyi M. , Heelan R. T. , Schwartz L. , Zhao B. , Venkatraman E. , Rusch V. , Rizvi N. A.
Published: March 2020

7021

Background: Induction therapy provides a unique opportunity for the objective assessment of therapies in patients with NSCLC to facilitate care and advance research. We designed this 40 patient prospective trial to measure gefitinib’s ability to induce regressions preoperatively in individuals with NSCLC and to simultaneously correlate response with mutations in EGFR exons 19 and 21. Patients with ‘in-vivo‘ gefitinib sensitivity and/or mutations receive gefitinib postoperatively as well. To facilitate our goals, we enriched the population studied to select individuals with tumors more likely to harbor mutations in EGFR. Methods: At diagnosis, patients with stage I or II NSCLC had baseline chest CT imaging and a core-needle biopsy to detect EGFR mutations. All participants smoked cigarettes ≤ 10 pack years and/or had tumors with bronchioloalveolar features. All received gefitinib 250 mg daily. After 21 days, CT imaging was repeated and resection followed. Surgical specimens were agained assayed for EGFR mutations. Patients with mutation and/or a ≥ 25% regression (WHO) were given gefitinib 250 mg for 2 years. Results: 20 patients enrolled to date. EGFR mutations were detected in both pre and post gefitinib specimens in 4/19 tested (21%). Five of 19 (26%) had a ≥ 25% bidimensional tumor reduction after 3 weeks. Regressions ≥ 25% were seen in 2/4 (50%) with exon 19 and 21 EGFR mutations and 3/15 (20%) with WT EGFR. The other 2 patients with mutations had 11% and 23% tumor regressions. The 6 patients who had either a ≥ 25% lesion reduction and/or mutation received gefitinib postoperatively. No perioperative complications related to gefitinib occurred. All patients are relapse free. Conclusions: In this ongoing trial, 1) Our ‘enrichment strategy‘ resulted in the detection of twice the expected number of EGFR mutations in USA patients with NSCLC. 2) Gefitinib sensitivity can be assessed by CT in 3 weeks. 3) Results of mutation detection were identical in pre- and post-treatment specimens. 4) The rate of response is numerically higher in patients with EGFR mutations in exons 19 and 21. 5) We are using the surgical specimens to elucidate determinants of gefitinib sensitivity in the absence of EGFR mutation. Support: CA05826, CA113653.

[Table: see text]
Prospective correlative assessment of biomarkers in E4599 randomized phase II/III trial of carboplatin and paclitaxel ± bevacizumab in advanced non-small cell lung cancer (NSCLC)
Authors: Dowlati A. , Gray R. , Johnson D. H. , Schiller J. H. , Brahmer J. , Sandler A. B.
Published: March 2020

7027

Background: E4599 was a phase II/III trial, in which 878 patients with advanced NSCLC were randomized to carboplatin + paclitaxel (PC arm) or PC + bevacizumab (PCB arm). Survival and progression free survival (PFS) were superior on the PCB arm (Sandler, ASCO 2005). The rationale for markers used in this correlative study were based on elevated vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (ICAM) in NSCLC and changes in response to endothelial apoptosis. Methods: Prospective laboratory correlates included measurements of pretreatment plasma VEGF as well as pretreatment and week 7, bFGF, ICAM, and E-Selectin. 166 patients had pre- and 112 had post-treatment measurements. Measurements were made by ELISA. Low and high levels were defined as ≤ or > than the median. Results: There were significant associations between E-Selectin and ICAM (p = .003) and between bFGF and VEGF (p = .01). E-Selectin (p = .01) and bFGF (p = .004) showed significant decreases from baseline at week 7 in both arms (Wilcoxon signed-rank tests). Only baseline ICAM showed a significant association with response. Patients with low baseline ICAM in both arms had a higher response rate of 29% vs 13% in high ICAM group (p=0.03, Fisher’s exact test). Patients with low baseline ICAM levels had a significantly better overall survival (p=0.00005) compared to patients with high ICAM levels as well as a better 1-year survival (65% vs 25%). No other factor predicted survival. Tests for treatment by factor interactions, which test whether the effect of treatment (the addition or not of bevacizumab) is different within the low and high levels were significant only for baseline ICAM where treatment interaction is significant for PFS (p=.04). This suggests a benefit from bevacizumab (53% reduction in the PFS hazard rate) in the group with low baseline ICAM levels vs no benefit from bevacizumab for patients with high levels. Conclusions: Baseline ICAM levels are strongly prognostic for survival and response to chemo. This exploratory correlative study suggests that improvements in PFS from the addition of bevacizumab occur mainly in patients with low baseline ICAM levels.

[Table: see text]
Low dose spiral computed tomography for early diagnosis of lung cancer. Results of baseline screening in 5,000 high-risk volunteers
Authors: Veronesi G. , Bellomi M. , Spaggiari L. , Pelosi G. , Maisonneuve P. , Paganelli G. , De Fiori E. , Leo F. , Rotmensz N. , Veronesi U.
Published: March 2020

7029

Background: The high lethality of lung cancer is related to the advanced stage at diagnosis. Early studies have demonstrated that screening with CT is effective to diagnose lung cancer at earlier stage but the optimal clinical approach for the management of patients identified with nodules during screening has yet to be defined. We report the first-year results of our CT screening trial. Method: Between October 2004 and October 2005, 5,189 asymptomatic current or former smokers of more than 20 packs/year, older than 50 years, were enrolled in a single-institution screening trial using annual low-dose multidetector CT for 5 years. A protocol for the diagnostic work-up of nodules identified by CT was LD-CT at 1 year for nodules with maximum diameter less than 5 mm, LD-CT at 3 months for lesions between 5.1 and 8 mm and FDG-PET for lesions larger than 8.1 mm. Trans cutaneous biopsy was not routine part of this protocol. End-points were: prevalence and incidence rates of lung cancer, stage distribution, resectability, recall rate and invasive procedure for benign disease. Results: Median age of volunteers was 57 years, 66% were males and 80% current smokers. The prevalence of lung cancer diagnosed at first CT was 1.0% (54 cases; 65% stage I; 9% stage II; 22% stage III and 4% Stage IV). Forty-seven tumors (87%) were radically resected (45 lobectomies, 1 pneumonectomy, 1 atypical segmentectomy). Major surgical morbidity and mortality were 4% and 2% respectively. Recall rate was 10%. Seven patients (1.3% of all recalled subjects) underwent surgical diagnostic procedures for non-malignant disease representing 12% of all screening surgical procedures versus 16% in a non-screening control group treated in the same unit and period. Conclusions: Our results confirmed that screening with low-dose CT allows the detection of early stage lung cancer in a high proportion of cases increasing the probability of cure. Although follow-up is necessary to confirm the efficacy of the proposed work-up protocol, the initial results are promising, with a very low number of invasive procedures performed for benign lesions.

No significant financial relationships to disclose.
Adding oral talactoferrin to first-line NSCLC chemotherapy safely enhanced efficacy in a randomized trial
Authors: Wang Y. , Raghunadharao D. , Raman G. , Doval D. , Advani S. , Julka P. , Parikh P. , Patil S. , Nag S. , Madhavan J. , Varadhachary A.
Published: March 2020

7095

Background: Talactoferrin alfa (TLF) is an oral immunomodulatory protein with a novel mechanism. TLF showed preclinical anti-cancer activity alone and in combination with chemotherapy. In Phase I/II trials, TLF was safe with apparent single-agent anti-cancer activity in non-small cell lung cancer (NSCLC). Methods: 110 chemo-naive patients with advanced or metastatic NSCLC were randomized (1:1) in a multi-center trial to carboplatin/paclitaxel (C/P) therapy plus either TLF or placebo. Starting the day after C/P (C:AUC 5 mg/mL/min; P:175 mg/m2) in chemo-cycles 1, 3 and 5, oral TLF (1.5 g BID) or placebo was administered in 35-day cycles for up to three cycles or until progression. Primary endpoint was Confirmed Response Rate (RR; PR+CR) by CT using RECIST. Secondary endpoints included Progression Free Survival (PFS) and Overall Survival (OS). Results: Baseline patient and disease characteristics were comparable in both groups. All 110 patients were included in the Intent To Treat (ITT) population. 100 patients with at least one CT scan after starting treatment were prospectively defined as the Evaluable population. Adding oral TLF to C/P enhanced efficacy on all endpoints examined including RR, PFS and OS. Confirmed RR in the 100 evaluable patients significantly increased from 29% to 47% (P = 0.05). Confirmed RR in the 110 ITT patients improved from 27% to 42% (P = 0.08). Median PFS in both evaluable and ITT patients improved by 2.8 months (67%). Median OS improved by 31% and 18% in evaluable and ITT patients, respectively. A landmark analysis comparing survival in patients with and without a PR showed a significant difference (P < 0.01), suggesting a strong association between RR and survival. TLF appeared to be very safe and well tolerated with no drug-related SAEs. Fewer AEs were observed in the TLF arm than in the placebo arm, 346 and 432 AEs, respectively (P = 0.0023). The number of Grade 3/4 AEs was also lower in the TLF arm, 60 versus 91 (P = 0.0144). Conclusions: Adding oral TLF to standard C/P chemotherapy in NSCLC was safe and increased efficacy in a randomized, multi-center, double-blind, placebo-controlled trial, with apparent improvements in RR, PFS and OS. Results with TLF compare favorably to other anti-cancer agents. Oral TLF will be further evaluated in a Phase III trial.

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Randomized phase II study of gemcitabine-oxaliplatin or gemcitabine-cisplatin in chemonaive patients with advanced non-small cell lung cancer (NSCLC)-CLEO 05
Authors: Le Chevalier T. , Thezenas S. , Breton J. , Pujol J. , Coudert B. , Sun X. , Laza M. , Quoix E. , Schott R. , Geneve J.
Published: March 2020

7097

Background: Gemcitabine-cisplatin is one of the reference doublets used in NSCLC. Oxaliplatin is a platin analog which offers a promising efficacy/tolerance profile in NSCLC. The combination of gemcitabine and oxaliplatin has been proven feasible and active in solid tumors. Methods: Patients with chemonaive, measurable, PS 0 or 1, stage IIIB/ IV NSCLC were randomized to receive either gemcitabine 1,250 mg/m2 day 1 & 8 plus oxaliplatin 130 mg/m2 day 1 (GEMOX) or gemcitabine 1,250 mg/m2 day 1 & 8 plus cisplatin 80 mg/m2day 1 (GEMCIS). Cycles were given every 3 weeks. The primary endpoint of the study was the response rate according to the RECIST criteria. Secondary endpoints included tolerance, survival and quality of life. Results: Between October 2003 and December 2004, 130 patients (66 in GEMOX and 64 in GEMCIS) were accrued at 12 centres. Baseline patient characteristics were similar in the 2 groups. Mean age was 61. There were 96 males and 34 females; 27% of patients were PS 0 and 73% were PS 1; 15% had stage IIIB and 85% had stage IV. Median number of cycles was 5 in each group. Objective response rates were 36% in GEMOX (CI 95%: 25%-50%) and 39% in GEMCIS (CI 95%: 28%-54%) respectively. Time to progression was 173 days in the GEMOX group and 163 days in the GEMCIS group. Median survival was 10.8 months in the GEMOX group and 10.4 months in the GEMCIS group. Grade III/IV neutropenia was observed in 38% of patients after GEMOX and 41% after GEMCIS; thrombocytopenia was observed in 40% and 33% of cases respectively. Grade 2+ neurotoxicity was more frequent after GEMOX (18% vs 3%). Conclusions: GEMOX has an activity comparable to GEMCIS and may be an alternative for those patients with advanced NSCLC who have a contra-indication to cisplatin.

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Final results of a phase II trial of bexarotene capsules as 3rd or subsequent line therapy in patients with advanced non-small cell lung cancer (NSCLC)
Authors: Govindan R. , Crowley J. , Schwartzberg L. , Kennedy P. , Williams C. , Ekstrand B. , Sandler A. , Jaunakais D. , Ghalie R.
Published: March 2020

7099

Background: Bexarotene, a rexinoid that binds to RXR nuclear receptors, has antiproliferative, differentiating, and apoptotic effects. Phase II studies of bexarotene plus chemotherapy in previously untreated NSCLC suggested improved patient survival. This study evaluated bexarotene for relapsed advanced NSCLC. Methods: Patients were eligible if they had NSCLC Stage IIIB wet/IV, had failed ≥ 2 prior systemic therapies, had previously received a taxane and platinum, had ECOG performance status (PS) 0–2, and had adequate organ function. Bexarotene 400 mg/m2 daily plus prophylactic levothyroxine and a lipid-lowering agent were given until disease progression or unacceptable toxicities occurred. The primary efficacy endpoint was survival. To detect a 50% increase in median survival from 4 months, as shown with 3rd line chemotherapy, to 6 months, 125 evaluable patients were required for a 90% power at a 1-sided 5% significance. Results: A total of 146 patients were enrolled at 32 sites. Median age = 66 (range, 34–87), male = 51%, PS 2 = 23%, adenocarcinoma = 54%, and median prior therapies = 3 (range 1–7) with 55% having failed gefitinib. Bexarotene was usually well tolerated and there were no therapy-related deaths. For the 124 patients who were treated for at least 14 days and were considered evaluable for efficacy, median and 1-year survival were 6 months and 25%, respectively. Baseline albumin < 3 g/dL and PS = 2 were significantly associated with shorter survival. For 26 patients who developed hypertriglyceridemia plus skin rash by Day 21, median and 1-year survival were 12 months and 44%, respectively, vs. 2 months and 12% in 36 patients with neither (p = 0.0003). Partial response was reported in 1 patient. When assessed by FACT-G, quality of life was improved or stabilized in 65% of patients. Conclusions: Survival of patients with heavily pretreated NSCLC may be extended with oral bexarotene therapy. Confirmation of these results with a randomized trial is warranted. Ongoing investigations attempt to explain the notable outcome reported in this and other bexarotene trials in the subset of patients who developed hypertriglyceridemia with or without skin rash.

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Efficacy and safety of patupilone in non-small cell lung cancer (NSCLC): A phase I/II trial
Authors: Sánchez J. M. , Mellemgaard A. , Perry M. , Zatloukal P. , Hamm J. , Belani C. P. , Kim E. , Felip E. , Berton M. , Johri A.
Published: March 2020

7104

Background: Based on its activity in a wide range of tumors including those that are taxane resistant, the novel microtubule stabilizer patupilone (EPO906; epothilone B) has the potential to treat NSCLC. Fifty patients were enrolled in phase I to evaluate safety, efficacy, and optimal dose. The phase II part of this study is investigating the antitumor activity of patupilone in 53 patients with stage IIIB/IV NSCLC. Methods: Patients with histologically or cytologically confirmed unresectable, locally advanced, or metastatic NSCLC documented before 1st-line therapy without symptomatic or uncontrolled brain metastases received patupilone at a starting dose of 10.0 mg/m2 q3wk by 20-minute IV infusion. Additional inclusion criteria: age ≥18 years; WHO performance status 0–1; prior treatment with a platinum-containing regimen. Primary objective of the phase II, single-arm, 2-stage, multicenter trial: to determine activity of patupilone q3wk (overall response using modified RECIST) in NSCLC. An additional cohort with recurrent brain metastases from NSCLC is being accrued to evaluate safety, pharmacokinetics, and activity. Results: In phase I, all patients received prior treatment with platinum therapy; 28% had received taxanes and 78% nontaxanes. Patupilone dose was escalated from 6.5 to 13.0 mg/m2 q3wk. Dose-limiting toxicities occurred in 4 patients: 1 with grade 3 asthenia and 3 with grade 3 diarrhea at various dose levels. The most frequent adverse events (AEs) were diarrhea (66%), nausea (40%), vomiting (34%), paraesthesia (32%), abdominal pain (30%), and fatigue (30%). The most frequent grade 3 AE was diarrhea (14%); a grade 4 AE (asthenia) occurred in 1 patient. Overall phase I response: 5 PR, 16 SD, and 26 PD. Based on risk-benefit analyses, 10.0 mg/m2 q3wk was recommended as the phase II dose. Phase II is ongoing: 25 of 53 patients (15 men and 6 women with NSCLC; 2 men and 2 women with brain metastases) have been enrolled. Conclusions: In phase I, patupilone q3wk was safe and well tolerated, with antitumor activity in patients with advanced pretreated NSCLC. Data from phase II will be available at time of presentation.

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Front line therapy with gemcitabine(G) administered immediately prior to pemetrexed (P) for patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC): Final report of a phase II clinical trial
Authors: West H. J. , Belt R. J. , Wakelee H. A. , Monberg M. J. , Frye L. A. , Ye Z. , Obasaju C. K.
Published: March 2020

7116

Background: P and G have well demonstrated, single-agent activity in pts with locally advanced or metastatic NSCLC. This phase II study was designed to determine the activity of the combination of PG when G was administered immediately prior to P on day 8 of a 21-day cycle. Methods: Pts with Stage IIIB/IV NSCLC were enrolled. Treatment was G 1250 mg/m2 on D 1 and 8, with P 500 mg/m2 on D 8, immediately following G. Treatment was repeated every 21 days for 6 cycles. Pts received folic acid, vitamin B12 and steroid prophylaxis. Results: 54 pts (32 M/22 F) were enrolled in the study. Median age was 65.0 (range = 43 - 87) years, ECOG PS 0: 1 = 35.2%: 57.4%; Stage IIIB (9.3%), Stage IV (90.7%); Histology: adeno (61.1%) squamous (18.5%), and large cell (5.6%). Median dose intensity was 83.2% for P and 82.2% for G. Grade 3 toxicities were neutropenia (12.0%), thrombocytopenia (8.0%), dyspnea (16.0%), febrile neutropenia (10.0%), anemia (4.0%), fatigue (18.0%), nausea (10.0%), vomiting (8.0%), and rash (2.0%). Grade 4 toxicities were neutropenia (28%), thrombocytopenia (4%), dyspnea (6%), anemia (0%), fatigue (4%), nausea (0%), vomiting (0%), rash (0%). Five patients (10%) experienced Grade 1 alopecia. Median TTPD was 4.4 months and survival was 10.6 months. There were 0 CR, 16 PR (35.6%), 16 SD (35.6%), and 12 PD (26.7%), for an overall best response rate of 35.6%. Conclusions: In this study, PG had a disease control rate (ORR + SD) of 71.1% in the front-line treatment of NSCLC, suggesting that this is an active doublet. Administering P on D 8 rather than D 1 did not seem to negatively impact the therapeutic index.

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Phase II trial of cisplatin (C), etoposide (E) and radiation (RT) followed by gemcitabine (G) vs G and docetaxel (D) in stage III A/B unresectable non-small cell lung cancer (NSCLC)
Authors: Movsas B. , Langer C. , Wang L. H. , Jotte R. M. , Xu F. , Huang C. , Hood K. E. , Ye Z. , Monberg M. , Obasaju C. K.
Published: March 2020

7120

Background: SWOG 9504 demonstrated the benefit of D consolidation after E + C with radiation therapy in pts with locally advanced NSCLC. This study was developed to assess the feasibility and efficacy of consolidation with either G alone or with D after the same chemoradiation schedule as SWOG 9504. Methods: The treatment schema included concurrent C 50 mg/m2 Day 1, 8 + E 50 mg/m2 Day 1–5 for two 28-day cycles + RT 180 cGy daily for 7 weeks after which pts were randomized to consolidation treatment of either G 1000 mg/m2 Day 1, 8 (Arm A) or G 1000 mg/m2 Day 1, 8 + D 75 mg/m2 Day 1 (Arm B) every 21 days for 3 cycles. Forty-six pts have been accrued; data is currently available in 28. Conclusions: Preliminary data indicate that G or G + D following chemoradiation in locally advanced NSCLC is well tolerated. The doublet, as expected, results in more toxicity, particularly myelosuppression and fatigue. Response, survival and TTP data will be presented at the time of the meeting.

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