Frontline Phase Research Articles

Risk-stratification in frontline CLL therapy: standard of care.

The treatment of chronic lymphocytic leukemia (CLL) has been transformed over the past decade based on a better understanding of disease biology, especially regarding molecular genetic drivers and relevant signaling pathways. Agents focusing on B-cell receptor (in particular Bruton tyrosine kinase [BTK]) and apoptosis (BCL2) targets have replaced chemoimmunotherapy (CIT) as the treatment standard. BTK and BCL2 inhibitor-based therapy has consistently shown prolonged progression-free survival and in some instances even increased overall survival against CIT in frontline phase 3 trials. This improvement is particularly pronounced in high-risk CLL subgroups defined by unmutated IGHV, deletion 17p (17p-), and/or the mutation of TP53, making CIT in these subgroups essentially obsolete. Despite remarkable advances, these markers also retain a differential prognostic and predictive impact in the context of targeted therapies, mandating risk-stratification in frontline management. Furthermore, BTK- and BCL2-targeting agents differ in their adverse event profiles, requiring adjustment of treatment choice based on patient characteristics such as coexisting conditions, comedications, and delivery-of-care aspects.

Dual HER2 inhibition: Is two better than one?

Li etal. present data from a randomized frontline phase II trial in HER2+ gastroesophageal cancers exploring dual targeting of HER2 with HLX22 (a novel HER2-specific antibody) with HLX02 (a trastuzumab biosimilar) and capecitabine/oxaliplatin chemotherapy. While the objective response and progression-free survival are encouraging, the future development of the combination in a crowded HER2 space remains unclear.

Identifying eligibility criteria that perpetuate race/ethnic disparities in acute myeloid leukemia (AML) clinical trial participation.

1589 Background: The extent to which eligibility criteria perpetuate race/ethnic disparities in adult AML clinical trial participation is unknown. Methods: This multicenter cohort study counterfactually assessed race/ethnic disparities in trial eligibility between Non-Hispanic Whites (NHW) and Minoritized Individuals (MI: Hispanic, Black, Asian, and/or Other) diagnosed with AML between 2010-2022 at six hospitals in Chicago, IL and one in Boston, MA. All newly diagnosed patients were catalogued; those with complete data were analyzed. Eligibility criteria were obtained from 190 front-line phase II/III therapeutic studies active during the same period (1). Common sets of criteria for intensive and non-intensive trials were generated based on prevalent criteria and medians of any associated limits (e.g., QTc ≤480 ms). Proportions of MI and NHW that would have been eligible based on these common criteria sets were assessed using X2 tests with odds ratios (OR). Mann-Whitney U tests assessed differences in the median number of trials for which each MI and NHW patient would have been eligible. Analyses with MI groups disaggregated were also performed. Results: There were 1283 patients (405 MI, 878 NHW) with a median age of 60 years (57 MI, 61 NHW; p<0.001); 44% were female. According to the common set of 23 intensive trial criteria that was generated, similar proportions of MI and NHW were eligible (24.7% and 24.5%, OR 1.01, 95% CI [0.77,1.33]). With the age limit criterion removed, fewer MI than NHW were eligible (42.7% and 36.0%, OR 0.76, 95% CI [0.59,0.96]). In this set of criteria, prior malignancy (excluding 22.5% and 17.5%, p=0.04), prolonged QTc (17.0% and 8.7%, p<0.001), and coronary artery disease (CAD; 8.6% and 4.1%, p=0.002) generated the largest disparity individually. According to the non-intensive set (14 criteria), fewer MI were eligible than NHW (42.2% and 54.4%, OR 0.61, 95% CI [0.48,0.78]); there was no age criterion in this set. Prior malignancy (22.5% and 17.5%, p=0.04), prolonged QTc (20.5% and 12.8%, p<0.001), and hepatitis B infection (4.0% and 1.0%, p=0.001) generated the largest disparities in this set. Overall, individuals were eligible for a mean of 51.6% of the 190 trials (median: 98 trials, IQR [59,115]). MI were eligible for 6.8% fewer trials than NHW (median difference: 13 trials [88 and 101], p<0.001). Asian, Black, and Other were eligible for 7.7%, 4.8%, and 16.9% less trials than NHW, respectively (all p<0.05). Criteria with the largest individual disparities in median eligibility were lower age limits, hepatitis B, and CAD (all p<0.01). Conclusions: Eligibility criteria disparately exclude minoritized individuals from AML clinical trial participation. Based on ASCO recommendations ( 2), several of the criteria driving disparate eligibility (hepatitis, prior malignancy) are modifiable or removable. 1. Hantel, Haematologica, 2023. 2. ASCO, Clin Cancer Res, 2021.

Are enrollment criteria for phase II and III clinical trials in acute myeloid leukemia arbitrarily restrictive?

6525 Background: Ethical clinical research requires fair subject selection and a favorable risk-benefit ratio. Enrollment criteria can unfairly exclude patients if they are not based in safety. There are few data regarding variability within criteria, which can also represent unfair exclusion, or for acute myeloid leukemia (AML). Methods: We assessed enrollment criteria use and variability for frontline phase II and III therapeutic AML trials from 2010-2019 listed on Clinicaltrials.gov. Drug safety profiles were obtained from protocols, publications, and FDA labels. FDA publications guided a standardized abstraction and coding process. Associations between criteria and safety profiles were identified using X2 and t-tests. Regression modeling identified differences in infectious disease (ID) exclusion by sponsor adjusted for trial phase, year, size, and safety profiles. Results: 190 trials were eligible; 159 (84%) were phase II and 32 (17%) phase III. Trials were sponsored by the National Institutes of Health (NIH; 50; 26%), industry (109; 57%), and academic investigators (AI; 108; 57%). Exclusions and variability are shown in the table. ID exclusions were for HIV (96; 51%) and hepatitis B (60; 32%) and C (64; 34%). Older adults were considered as over 60 (42 trials; 39%), 65 (23; 21%), 70 (13; 12%), or 75 years (18; 17%). There was no association between QTc limits and the use of QTc prolonging drugs (criteria presence p=0.2; mean 450 vs 474 ms, p=0.3) or renal function limits and nephrotoxic drugs (presence p=0.2; mean 1.65 vs 1.67 ULN, p=0.8). Hepatitis B and C exclusions were associated with the use of drugs linked to viral reactivation (OR 2.1 [95% CI 1.1,3.9], 2.0 [95% CI 1.1,3.7]). This was not the case for HIV (OR 1.2 [95% CI 0.7,2.2]). Industry sponsorship was independently associated with hepatitis B and C exclusion (OR 3.0 [95% CI 1.2,7.3], 3.3 [95% CI 1.4,4.7]) and AI sponsorship with HIV exclusion (OR 2.5 [95% CI 1.4,5.5]). Conclusions: There is substantial variability in enrollment criteria for AML clinical trials. Many criteria are related to risks, but some exclusions and variability are not clearly based in safety. Avoiding arbitrary exclusions will likely enhance trial representativeness and enrollment rates. [Table: see text]

Combination of Lenalidomide and Rituximab (R2) Targets Immune Dysfunction in FL By Activating T and NK Cells Ex Vivo and Is Differentiated from Chemotherapy

▪Introduction: Follicular lymphoma (FL) is an indolent disease characterized by a dysfunctional immune compartment. The standard of care in FL is chemotherapy-based treatment (R-CHOP/R-CVP or R-Bendamustine), with a high overall response rate of >90% but low complete response (CR) rates between 25% to 31% (Flinn 2014). The majority of patients still relapse and often experience immune suppression resulting from chemo-related cytotoxicity that may ultimately impact outcomes. Lenalidomide (Len) has both potent direct antineoplastic and immunomodulatory activity. Len in combination with rituximab (Rtx) has shown enhanced antibody-dependent cellular cytotoxicity (ADCC) and direct apoptosis in B-cell lymphoma in vitro and in animal models (Wu 2008; Hernandez-Ilizaliturri 2005). Multiple phase II studies showed that R2 therapy achieves clinical synergy in treatment naive (Fowler 2014; Martin ICML 2017) and relapsed/refractory settings (Leonard 2015; Andorsky ASCO 2017). Here we provide a mechanistic rationale beyond ADCC for the activity observed in the clinical setting using patient samples. We show T and NK cell activation by Len in FL patients ex vivo and demonstrate R2activity in FL cell lines providing clear differentiation from immunochemotherapy.Methods: Peripheral blood mononuclear cells (PBMCs) from FL patients were treated with Len (1nM-10µM), analyzed for cytokine production by ELISA, T and NK-cell activation on day 3 and proliferation of T and NK-cells on day 5 by flow. Len, idelalisib, bendamustine (1nM-10µM), and ibrutinib (0.1nM-1µM) were each used in combination with Rtx in an ADCC and cell autonomous assay to measure apoptosis by Annexin V/ToPro-3 flow cytometry against FL cell lines DoHH2 and RL. For cell autonomous assay, cells were treated with therapeutic agents for 7 days followed by 24hr Rtx treatment. Synergy of Rtx in combination with each therapeutic agent was calculated using fractional product method (Chou, 1984). For ADCC assays, healthy donor (HD) or FL PBMC were treated with therapeutic agent for 3 days followed by a 4-hr incubation with Rtx-treated CFSE labeled target tumor cells. PBMC viability was measured immediately prior to co-culture by Annexin V/To-Pro.Results: In ex vivo FL PBMCs, Len significantly enhanced proliferating CD4+and CD8+ T cells by up to 3 and 7-fold respectively (p<0.001) and proliferating NK and NKT by up to 2 and 5-fold vs DMSO. In FL PBMCs, Len significantly increased the production of TNF-α, IFN-γ and GMCSF up to 4, 6 and 10-fold respectively (p≤0.01) vs DMSO. Len increased IL-2 and RANTES by up to 3-fold vs DMSO. Len activates NK cells by a 2-fold increase in expression of CD56, CD25, NKp30, OX40 and Granzyme B in FL PBMCs vs DMSO. Len significantly enhanced expression of CD154, HLA-DR, CD278 and CD134 on CD8+T cells by up to 2-fold (p≤0.05) vs DMSO. The R2 combination was more potent than R-chemo in Rtx mediated ADCC. Combination of Len (1µM) and Rtx (1µg/mL) significantly increased ADCC to 44% (p≤0.01) in DOHH2 and RL cells vs Rtx alone (4% in DoHH2 and 17% in RL) using HD PBMCs. Combination of Len (1µM) and Rtx (10ng/mL) significantly increased ADCC by 41% in DOHH2 and 31% in RL (p≤0.05) vs Rtx alone (12% in DoHH2 and 21% in RL cells) using FL PBMCs. Combination of Rtx with idelalisib, ibrutinib and bendamustine demonstrated no effect or an antagonistic effect on Rtx mediated ADCC against FL cells. In direct apoptosis assay, combination of Len (1µM) and Rtx (10µg/mL) was significantly synergistic and increased apoptosis to 77% (p≤0.0001) vs Len (29%) or Rtx alone (40%). In RL cells, R2 was significantly additive and increased apoptosis by 55% (p≤0.001) vs Len (37%) or Rtx alone (34%). No synergy was observed with Rtx in combination with the other chemo agents in ADCC assays. In PBMC viability assays, Len had no effect whilst idelalisib (2µM), ibrutinib (1µM) and bendamustine (10µM) significantly decreased viability by 25, 37 and 46 % respectively (p≤0.01-0.05).Conclusion: R2 is a novel and effective combination immunotherapy in FL. The mechanism of action of this combination results in T and NK cell activation, which leads to enhanced ADCC and addresses the known immune dysfunction in FL. This combination is clearly differentiated from chemo-immunotherapy. The R2 combination immunotherapy is currently being assessed in the FL frontline phase 3 RELEVANCE trial (NCT01476787) and in the relapsed FL setting in the AUGMENT trial (NCT01938001). DisclosuresChiu:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Trisal:Celgene: Employment, Equity Ownership. Waldman:Celgene: Employment, Equity Ownership, Patents & Royalties: US 9,587,281 B2. Cavanaugh:Celgene: Employment. Gandhi:Celgene Corporation: Employment, Equity Ownership.

ABC Subtype, TP53 Mutation and BCL2 Overexpression are Associated with a Worse Outcome in Untreated Poor-Risk Young Diffuse Large B-Cell Lymphoma: Results from the Frontline Phase III BIO-DLBCL04 Study of the Fondazione Italiana Linfomi

ABC Subtype, TP53 Mutation and BCL2 Overexpression are Associated with a Worse Outcome in Untreated Poor-Risk Young Diffuse Large B-Cell Lymphoma: Results from the Frontline Phase III BIO-DLBCL04 Study of the Fondazione Italiana Linfomi

IMbrave150: Updated overall survival (OS) data from a global, randomized, open-label phase III study of atezolizumab (atezo) + bevacizumab (bev) versus sorafenib (sor) in patients (pts) with unresectable hepatocellular carcinoma (HCC).

267 Background: Atezo + bev has been approved globally for pts with unresectable HCC who have not received prior systemic therapy, based on results from IMbrave150 (NCT03434379). At a median of 8.6 mo follow-up, both coprimary endpoints were met, with statistically significant and clinically meaningful improvements observed with atezo + bev vs sor for OS (HR, 0.58 [95% CI, 0.42, 0.79]; P&lt;0.001) and independently-assessed progression-free survival (PFS; per RECIST 1.1; HR, 0.59 [95% CI, 0.47, 0.76]; P&lt;0.001) (Finn, et al. N Engl J Med 2020). Here, we report an updated OS analysis for IMbrave150. Methods: The global, multicenter, randomized, open-label, Phase III study IMbrave150 enrolled 501 systemic treatment–naive pts with unresectable HCC, ≥1 measurable untreated lesion (RECIST 1.1), Child-Pugh class A liver function and ECOG PS 0/1. Pts were randomized 2:1 to receive either atezo 1200 mg IV q3w + bev 15 mg/kg IV q3w or sor 400 mg bid until unacceptable toxicity or loss of clinical benefit per investigator. This post hoc, descriptive OS analysis was conducted with 12 mo of additional follow up from the primary analysis. Results: 501 pts were enrolled, including 336 to atezo + bev and 165 to sor. At the clinical cut-off date of Aug 31, 2020, median follow-up was 15.6 mo and 280 OS events were observed. Median OS was 19.2 mo with atezo + bev vs 13.4 mo with sor (HR, 0.66 [95% CI, 0.52, 0.85]; P=0.0009). Survival at 18 mo was 52% with atezo + bev and 40% with sor. Survival benefit with atezo + bev over sor was generally consistent across subgroups and with the primary analysis. The updated objective response rate (ORR; 29.8% per RECIST 1.1) with atezo + bev was in line with the primary analysis, with more pts achieving complete response (CR; 7.7%) than previously reported. Additional response data are in Table. Safety was aligned with the primary analysis, with no new signals identified. Conclusions: IMbrave150 showed consistent clinically meaningful treatment benefit and safety with 12 mo of additional follow-up. The combination provides the longest survival seen in a front-line Phase III study in advanced HCC, confirming atezo + bev as a standard of care for previously untreated, unresectable HCC. Clinical trial information: NCT03434379. [Table: see text]

Quizartinib for the treatment of acute myeloid leukemia

ABSTRACT Introduction . Up to 30% of patients with acute myeloid leukemia (AML) have a mutation in the FLT3 receptor. Molecular targets have acquired a significant interest in the treatment of AML and are changing patient outcomes, including improvement of overall survival (OS) and remission rates. FLT3 inhibitors have obtained a central role in how we treat AML. Areas covered . This article reviews the mechanism of action, pharmacology, clinical efficacy, and safety of quizartinib, a FLT3 inhibitor, for the treatment of acute myeloid leukemia. Expert opinion . Quizartinib yielded an improvement in OS and complete remission (CR) rates in a phase 3 trial for relapsed/refractory FLT3-mutated AML. The toxicities are manageable; however, it is associated with significant QTc prolongation and myelosuppression. The FDA and EMA did not grant drug approval to quizartinib in the relapsed/refractory setting due to the lack of a significant benefit – to-risk ratio, safety concerns and concerns with credibility and generalizability of the trial data. Results from the frontline phase 3 study evaluating quizartinib with intensive chemotherapy are eagerly awaited. Ongoing studies are investigating its toxicity and efficacy with other therapeutic agents and will help to clarify its role in the treatment of FLT3-ITD-mutated AML.

Abstract 3656: The mTOR-activating GATOR2 complex is essential in PAX3-FOXO1-positive rhabdomyosarcoma

Abstract Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, and can be genomically classified into fusion-positive and fusion-negative subsets. The former is driven by PAX3-FOXO1 or related chimeric transcription factors and has few other genetic alterations; the latter harbors recurrent mutations within the PI3K-RAS pathway. Despite these fundamental differences in cancer initiating events, current therapeutic approaches are identical between the two groups aside from chemotherapy intensification for some fusion-positive patients given their poorer outcomes. Current pharmacologic strategies do not permit direct targeting of the PAX3-FOXO1 oncoprotein, so we undertook a CRISPRi genetic screen to identify genes whose loss was toxic to PAX3-FOXO1+ RMS cells, but tolerated in cells with knockdown of the fusion protein. We hypothesized that this would identify targetable dependencies created by PAX3-FOXO1 expression that might permit precision therapy for fusion positive RMS. Through this screen, we identified two genes within the mTOR-activating GATOR2 complex, MIOS and WDR24, as essential for the growth of PAX3-FOXO1 positive RMS cells. We find that loss of MIOS is toxic to fusion-positive RMS cells due to a loss of mTORC1 signaling that normally initiates from signals of amino acid sufficiency. Restoration of mTORC1 activation by amino acids could be achieved by genetic suppression of either DEPDC5, a component of the RAG GAP GATOR1 complex that is normally inhibited by GATOR2, or of TSC1, which suppresses mTORC1 activity in the absence of PI3K signaling. Either genetic alteration completely rescued fusion positive RMS cells from the deleterious effects of MIOS loss. Correspondingly, we found that a fusion-negative RMS cell line with an activating NRAS mutation was insensitive to MIOS loss, suggesting that in this genetic context, amino acid signaling through GATOR2 is no longer necessary to activate mTORC1 and promote RMS survival. In contrast, loss of WDR24 was toxic to both fusion positive and fusion negative RMS cells, and could not be rescued by genetic reactivation of mTORC1. Preliminary data demonstrate alterations in lysosome size and quantity after WDR24 suppression, adding to existing data in Drosophila that this gene plays a critical, mTOR-independent role in lysosome biogenesis, and showing that this role supports RMS survival. As mTOR inhibitors are being tested in frontline phase 3 studies in North America, our work lends timely molecular insight into how the genetic basis of distinct RMS subtypes can influence the signals that promote mTORC1 function to support cancer cell survival. Based on our finding that amino acid activation of mTORC1 is a fusion-positive dependency, we are now testing combined mTOR inhibition with amino acid depletion as a precision therapeutic strategy in preclinical models of this aggressive childhood cancer. Citation Format: Amit J. Sabnis, David V. Allegakoen, Trever G. Bivona. The mTOR-activating GATOR2 complex is essential in PAX3-FOXO1-positive rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3656.

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Final Analysis of the Front-Line Phase III Randomized ACT-1 Trial in Younger Patients with Systemic Peripheral T-Cell Lymphoma Treated with CHOP Chemotherapy with or without Alemtuzumab and Consolidated By Autologous Hematopoietic Stem Cell Transplant

Low Peripheral Blood NK Cell Count Is Associated with Worse Clinical Outcome in Patients with Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Immunochemotherapy: Results from the Frontline Phase 3 GALLIUM and GOYA Trials

Low Peripheral Blood NK Cell Count Is Associated with Worse Clinical Outcome in Patients with Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Immunochemotherapy: Results from the Frontline Phase 3 GALLIUM and GOYA Trials

Current challenges in the management of follicular lymphoma.

Although typically indolent in nature, follicular lymphoma remains an ongoing challenge for practicing oncologists. While response rates >90% can be achieved with rituximab-based chemoimmunotherapy in advanced stage patients, the complete remission rates are substantially lower and patients inevitably relapse. The inability to achieve a complete remission and an early progression of disease have recently been determined to be indicative of poorer long-term outcomes. A greater understanding of the pathogenesis of follicular lymphoma has enabled the development of targeted therapies, which may improve standard treatment approaches. Examples include lenalidomide and obinutuzumab, which are currently in front-line Phase III investigation. Other therapies of interest include small molecule inhibitors, immune checkpoint inhibitors and chimeric antigen receptor T cells.

Phase II study of low-dose methotrexate to reduce the incidence of human anti-mouse antibodies in patients receiving I-131 tositumomab as first-line treatment for follicular lymphoma.

e19519 Background: I-131 tositumomab is a radiolabeled murine anti-CD20 antibody. In a frontline phase II follicular lymphoma (FL) trial, treatment with I-131 tositumomab produced a 95% ORR with 75% CR (NEJM 352:441, 2005). Median PFS was 6.1 yrs. However, 30% of patients (pts) developed high levels of human anti-mouse antibodies (HAMA) and a serum sickness syndrome within 7 weeks of treatment (early onset HAMA). The 5-yr PFS for this group was 35% compared to 70% for the others (p = 0.003). Low-dose oral methotrexate (mtx) reduces the incidence of human anti-chimeric antibody (HACA) formation in rheumatoid arthritis pts receiving infliximab. We hypothesized that low-dose mtx would likewise reduce the incidence of early onset HAMA when given in combination with I-131 tositumomab. Methods: This is a single arm, phase II study in pts with FL, grade 1-2, stage III or IV disease without limits on marrow involvement, and ≥ 1 of the GELF criteria. Prior therapy, other than focal radiotherapy, is not allowed. Pts must have adequate hematologic, hepatic and renal function, and serum HAMA levels ≤ ULN. I-131 tositumomab is given as a dosimetric dose followed within 1-2 weeks by a therapeutic dose of 75cGy of total body radiation. Pts take mtx 7.5 mg orally once weekly for 3 weeks prior to their dosimetric dose, followed by 7 additional weekly doses. The primary endpoint is the rate of HAMA formation within 7 wks of I-131 tositumomab treatment. Secondary endpoints are overall HAMA incidence, ORR, CR, PFS OS, and safety. Results: Between 8/2011 and 10/2012, 15 pts were enrolled. Median age was 56 (39-83); 11 were male. Three pts had serum HAMA levels &gt;ULN at baseline. One pt had a spontaneous remission prior to starting treatment, leaving 11 evaluable pts. One pt developed early onset HAMA (9%). ORR = 82%, CR = 64%. Two pts progressed with DLBCL. Grade 3 or 4 toxicities included thrombocytopenia n = 3, neutropenia n = 2 and pain n = 3. Conclusions: These preliminary results show that concurrent low-dose oral mtx appears to reduce the incidence of early onset HAMA in FL patients receiving first- line I-131 tositumomab (9% vs. 30% in historical controls) while preserving efficacy. Clinical trial information: NCT01389076.

Does histology predict survival of advanced non-small cell lung cancer patients treated with platin-based chemotherapy? An analysis of the Eastern Cooperative Oncology Group Study E1594

IntroductionWe conducted this analysis to determine whether survival of advanced NSCLC patients treated with platin-based chemotherapy doublets involving paclitaxel, docetaxel or gemcitabine was dependent on histological subtypes and treatment regimen. MethodsWe retrospectively analyzed data from E1594, a front-line phase III study in which advanced NSCLC patients were randomized to receive one of four regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, and carboplatin-paclitaxel. Patients were classified into four histology groups: squamous cell (SCC), adeno- (AC), large cell (LCC) and others including not otherwise specified (O/NOS) carcinoma. Logrank test was performed to compare overall survival (OS) and progression free survival (PFS) distributions according to histology as well as treatment. ResultsOf 1139 patients including 716 men and 423 women, AC was the most common subtype (56.8%), followed by SCC (19.7%), O/NOS (17.0%) and LCC (6.5%). Men were more likely to have SCC and women were more likely to have AC (p=0.002). Among the four histology groups, there was no imbalance in regard to race, performance status, weight loss, brain metastasis or treatment. In each histology group, we found no significant difference in OS and PFS between the four chemotherapy regimens. Conversely, in each treatment arm, the survival outcome was similar between the four histology subtypes. ConclusionsOur analysis suggests that histology does not predict survival benefit in advanced NSCLC patients treated with first-line platin-based doublets involving paclitaxel, docetaxel or gemcitabine.

Should studies of maintenance therapy be maintained in women with ovarian cancer?

Should studies of maintenance therapy be maintained in women with ovarian cancer?

Exploring counter-theoretical instances of graduate learners’ self-regulatory processes when using an online repository

Academic self-regulation theories have proposed that learning involves a complex set of cognitive and metacognitive mechanisms that are enacted in phases. These phases include task understanding, strategy adoption, monitoring, and reflection. Whereas classical approaches to self-regulation contend that these phases work together to influence academic performance, the empirical research reported herein reveals that, for essay writing in an online learning environment, improved self-regulation is not necessarily associated with improved learning outcomes. We begin by reviewing frameworks for academic self-regulation, specifically in the context of learners’ experiences in online repositories equipped with Topic Maps (ISO 13250) indexes. We then offer explanations for counter-theoretical interactions found between task understanding (a frontline phase of self-regulation) and academic performance in 38 graduate learners who used Topic Maps to tackle ill-structured essay tasks. Our investigation sheds light not only on how learners’ perceptions of feedback facilitate task understanding, but also on the complex relationship between task understanding and monitoring proficiencies.

OCEANS: A randomized, double-blinded, placebo-controlled phase III trial of chemotherapy with or without bevacizumab (BEV) in patients with platinum-sensitive recurrent epithelial ovarian (EOC), primary peritoneal (PPC), or fallopian tube cancer (FTC).

LBA5007 Background: BEV, a humanized anti-VEGF monoclonal antibody, has shown a progression-free survival (PFS) benefit in 2 frontline phase III trials in patients with EOC, PPC and FTC. The therapeutic impact of BEV in combination with carboplatin (C) and gemcitabine (G) followed by single agent BEV to disease progression (PD) was evaluated in this phase III trial in the platinum-sensitive recurrent setting. Methods: Patients had recurrent, platinum-sensitive EOC, PPC or FTC, 1 prior regimen, no prior BEV, ECOG performance status 0-1, measurable disease. Subjects were randomized to: Arm A: [IV C (AUC 4, Day (D) 1) + G (1,000 mg/m2 D1 and 8) + placebo (PL) D1] q21D x 6 cycles (c) → PL q21D until PD or unacceptable toxicity (tox) Arm B: [CG + BEV (15 mg/kg) D1] q21D x 6 c → BEV q21D until PD or tox primary endpoint was investigator assessed PFS (RECIST). Secondary endpoints included objective response (OR), overall survival (OS), duration of response and safety. The design provided 80% power to detect a 27% reduction in the hazard of progression or death in Arm B vs A, limiting the overall type I error of 5%. Results: OCEANS enrolled 484 patients (242 per arm) from 4/07 - 1/10, median follow up of 24 months. BEV plus CG followed by single agent BEV to PD significantly increased PFS compared to CG alone (HR=0.484, p&lt;0.0001). OR increased by 21% (p&lt;0.0001). OS data is immature with only 29% of patients having had an event. The safety profile was consistent with other BEV trials. Conclusions: Results show a statistically significant and clinically relevant benefit when bevacizumab is added to chemotherapy in patients with recurrent, platinum sensitive EOC, PPC, and FTC. This is the first phase III trial of an antiangiogenic to demonstrate a clinical benefit to these patients. [Table: see text]

Evolving strategies for ovarian cancer: gynecologic oncology in ASCO's 46th annual meeting

during induction, followed by placebo maintenance; and 3) CP plus concurrent bevacizumab during induction, followed by bevacizumab maintenance. Bevacizumab was not administered during the first 21-day induction cycle so as to limit post- surgical bleeding complications. The entire treatment sched- ule took 15 months to complete. Although overall survival was originally selected as the primary endpoint, this was changed to progression-free survival (PFS) to accord with international consensus as a more appropriate endpoint for frontline phase III trials in this patient population, as well as pressure by pa- tients to unblind their treatment assignment in the event of disease progression. The investigators monitored disease pro- gression based on radiographic evidence, CA-125 measure- ments, and global clinical deterioration. Overall survival, safe- ty, and quality of life comprised the secondary endpoints.

Trials With Impact on Clinical Management: First Line

Advanced-stage epithelial ovarian cancer is generally managed with cytoreductive surgery and chemotherapy consisting of carboplatin and paclitaxel. Although initially responsive, most tumors recur and demonstrate progressive chemotherapy resistance. During the last 20 years, many thousands of women have participated in international front-line phase 3 trials that have contributed to our understanding of ovarian cancer biology and helped to define optimal treatment strategies. Emerging data from these trials need to be interpreted within an evolving paradigm of cancer biology, disease management, and availability of clinical resources. Survey of recent phase 3 trials and emerging principles of ovarian tumor biology. There is no evidence that adding a third cytotoxic agent improves clinical outcomes. However, weekly dose-dense scheduling of paclitaxel appears superior to standard dosing. Primary therapy with carboplatin and paclitaxel remains a well-tolerated standard regimen, including the option of weekly paclitaxel dosing. Data are awaited from completed trials incorporating bevacizumab. Emerging biological paradigms will contribute to individualized treatment options in the future.

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.

Erlotinib: CP 358774, NSC 718781, OSI 774, R 1415.