US Cooperative Group Research Articles

Minimal Residual Disease Status in Multiple Myeloma 1 Year After Autologous Hematopoietic Cell Transplantation and Lenalidomide Maintenance Are Associated With Long-Term Overall Survival.

Prognostic Immunophenotyping in Myeloma Response (PRIMeR) is an ancillary study of minimal residual disease (MRD) assessment for multiple myeloma by next-generation multiparameter flow cytometry (MFC). Patients were enrolled on a three-arm randomized control trial (Blood and Marrow Transplants Clinical Trials Network 0702 Stem Cell Transplant for Myeloma in Combination of Novel Agents [STaMINA]; ClinicalTrials.gov identifier: NCT01109004). Four hundred and thirty-five patients consented to the MRD panel, which included 10 monoclonal antibodies measured via six-color MFC. MRD was measured at baseline/preautologous hematopoietic cell transplant (BL/preAutoHCT), premaintenance (PM), and 1 year (Y1) after AutoHCT with a sensitivity of 10-5 to 10-6. The primary objective was to assess MRD-negative (MRDneg) at 1 year after AutoHCT and progression-free survival and overall survival (PFS/OS). Similar to the STaMINA results, at a median follow-up of 70 months, there was no significant difference in PFS/OS by treatment arm in the PRIMeR patients. MRDneg at all three time points was associated with significantly improved PFS, and MRDneg at Y1 had significantly longer OS. Multivariate analysis of PFS, adjusting for disease risk and treatment arm, demonstrated hazard ratios (HRs) in MRD-positive patients compared with MRDneg patients at BL, PM, and Y1 of 1.55 (P = .0074), 1.83 (P = .0007), and 3.61 (P < .0001), respectively. Corresponding HRs for OS were 1.19 (P = .48), 0.88 (P = .68), and 3.36 (P < .001). Patients with sustained MRDneg or who converted to MRDneg by Y1 had similar PFS/OS. To our knowledge, this first, prospective US cooperative group, multicenter study demonstrates that MRDneg at Y1 after AutoHCT with lenalidomide maintenance is prognostic for improved 6-year PFS and OS. Serial MRD measurements may direct trials to test how further therapy may improve long-term PFS and OS.

Radiotherapy Use and Locoregional Recurrence Rates on SWOG 1007, a US Cooperative Group Trial Enrolling Patients with Favorable-Risk Node-Positive Breast Cancer

<h3>Purpose/Objective(s)</h3> Trials suggest benefit from regional nodal irradiation (RNI) in node-positive breast cancer patients (pts), but absolute benefit is not uniform. SWOG S1007 randomized pts with hormone receptor-positive, HER2-negative breast cancer and 21-gene assay recurrence score (RS) ≤25 to endocrine therapy alone (ET) vs chemotherapy then ET. Little is known about modern RNI practice patterns or rates of locoregional recurrence (LRR) in such pts. Here, we report use of radiation therapy (RT) and patterns of LRR on S1007. <h3>Materials/Methods</h3> RT receipt, targets, and dose were prospectively collected. For analysis of LRR, invasive disease-free survival (IDFS) was separated into local/regional events while other IDFS events were competing risks in a Cox model. Since RT occurred after randomization, landmarked analysis starting at 1 year was used for analysis of LRR incidence and IDFS. Analyses adjusted for menopausal status, treatment arm, RS, tumor size, and number of positive nodes. <h3>Results</h3> Of the 4,983 eligible pts, 4,871 (97.8%) had RT forms and 3,947 (81.0%) reported RT receipt. Of pts who had breast conservation (BCS), 95.7% received RT. Of pts who received BCS+RT, 52.7% had RNI (at least a supraclavicular field). Predictors of RNI after BCS were larger tumor (p<0.0001) and more positive nodes (p<0.0001), but not RS (p=0.92). For pts who had mastectomy (mast), 54.2% received RT, of whom 81.1% had RNI. Significant predictors of RT among mast pts were being premenopausal (p=0.022), larger tumor size (p<0.0001), and more positive nodes (p<0.0001), but not RS (p=0.33). The cumulative incidence of LRR between 1-5 years was 0.85% among pts with BCS+RT with RNI, 0.55% after BCS+RT w/o RNI, 0.11% after mast+RT, and 1.7% after mast w/o RT. In premenopausal pts, BCS+RT had reduced LRR compared to mast w/o RT (HR=0.41, 95% CI 0.19-0.91, p=0.028) adjusting for RS, systemic treatment, tumor size, and # of positive nodes. The reduction in postmenopausal pts was not significant (HR=0.48, 95% CI 0.20-1.13, p=0.09) with similar adjustment. IDFS did not differ among BCS+RT, mast w/o RT, mast+RT groups in premenopausal (p=0.14) or postmenopausal (p=0.98) pts after adjustment for other factors. IDFS also did not differ in these 3 groups in the ET arm after adjustment for other factors. <h3>Conclusion</h3> On S1007, practice was evenly divided for use of RNI in the setting of N1 disease & favorable biology. Rates of LRR were low even in pts who did not receive RNI. IDFS did not differ across locoregional treatment groups, even in the ET only arm. Omission of chemotherapy among pts eligible for this trial does not appear to be an indication for use of RNI. These findings reinforce the importance of prospective trials like NCIC MA-39, randomizing pts with RS ≤25 to RNI or not.

Four-year follow-up from a phase 2 study of obinutuzumab, ibrutinib, and venetoclax in CLL.

7540 Background: Targeted agent combinations for chronic lymphocytic leukemia (CLL) have resulted in safe regimens with improved progression-free survival (PFS) compared to chemoimmunotherapy. The optimal regimen and long-term outcomes remain unknown. We conducted a phase 2 study of obinutuzumab (OBIN), ibrutinib (IBR), and venetoclax (VEN) in relapsed/refractory (RR) and treatment-naïve (TN) CLL patients (pts) and report extended follow up on two previously reported cohorts (RR, TN 1) and a new cohort of identically treated TN pts (TN 2). Methods: Pts with TN or RR (≥1 prior treatment) CLL requiring treatment were eligible. Treatment was given for 14 28-day cycles (C). OBIN was started C1, IBR C2, and VEN C3 with standard dose escalation. Response was assessed 2 months (mos) after C14 (EOT) by iwCLL 2008 criteria. Minimal residual disease (MRD) was measured by 10-color flow cytometry with a cutoff of &lt; 1x10-4. The primary endpoint was complete remission (CR) with undetectable MRD (uMRD) in blood and bone marrow at EOT. A sample size of 25 pts per cohort achieves 90% power to test the null hypothesis of 10% against 30% with 1-sided α of 10%. The Kaplan-Meier method was used to estimate PFS and overall survival (OS). Results: 75 pts were treated in 3 cohorts (Table). Data are as of 1/3/2022. In the TN 2 cohort, the overall response rate (ORR) at EOT was 96% (95% CI: 80-100) and CR with uMRD was 20% (95% CI: 7-41). The ORR for TN 1 and TN 2 combined was 90% (95% CI: 78-97) and CR with uMRD was 24% (95% CI: 13-38). Median follow up was 56 (0-65), 57 (7-63), and 30 (24-35) mos, respectively, for RR, TN 1, and TN 2. There were 3 deaths (RR = 1, TN 1 = 1, TN 2 = 1) and 6 disease progressions (RR = 4, TN 1 = 2, TN 2 = 0). Estimated 48-month PFS for TN 1 and RR cohorts were both 96% (95% CI: 72-99) and OS was 85% (95% CI: 60-95) and 100%, respectively. The estimated 24-month PFS and OS for TN 2 were both 96% (95% CI: 75-99). The most frequent adverse events were neutropenia (95%, 73% grade ≥3), leukopenia (95%, 45% grade ≥3), lymphopenia (93%, 40% grade ≥3), and thrombocytopenia (91%, 28% grade ≥3). The only grade ≥3 non-hematologic toxicity occurring at ≥20% was hypertension (85%, 39% grade ≥3). Atrial fibrillation occurred in 11% of pts. Conclusions: At extended follow-up, remissions remain durable after fixed duration OBIN, IBR, and VEN. The efficacy and acceptable safety justify further study and are being compared to IBR and OBIN in 2 phase 3 US cooperative group trials. Clinical trial information: NCT02427451. [Table: see text]

Financial relationships between industry and principal investigators of US cooperative group randomized cancer clinical trials.

Financial conflicts of interest (FCOIs) could bias the potentially practice-changing oncologic randomized clinical trials (RCTs) of tomorrow. This investigation characterized the FCOIs of the principal investigators (PIs) of all currently accruing trials of the four (adult) cooperative groups of the National Clinical Trials Network. For our study, the PI list was first compiled, and each name was then searched in the CMS Open Payments database. For each transaction (general payments (GPs) or research funding (RF)), the amount/number/source of payments was recorded. Results showed that from 2014 to 2019, the 91 PIs collectively accepted nearly one-third of a billion dollars ($10 477 023 GPs and $320 096 233 RF). The mean and median GP was $6505 and $945, respectively, and $301 693 and $49 824 RF, respectively. Multivariable Gamma regression analysis revealed that higher GP sums were associated with RCTs involving any type of systemic therapy, and higher RF sums with medical oncologist PIs, trials with phase III components, and RCTs involving radiotherapy (P < .05 for all). Both higher-volume GPs and RF were predicted by PIs having accepted payment(s) from the manufacturer of the drug utilized in their RCT (P < .001 GP, P=.008 RF). Taken together, the main message of this investigation is that FCOIs may be particularly high in PIs of phase III systemic therapy trials, especially if the PI accepted payments from the manufacturer of the drug utilized in their trial. Such RCTs should be thoroughly scrutinized by medical journals, the FDA, and insurance companies for potential "industry bias" that could influence the integrity of their conclusions.

Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer:NRG-GI005 (COBRA).

TPS148 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms:standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. The trial is actively accruing towards the phase II endpoint across all US and Canadian cooperative groups. Support:U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103.

Phase II/III study of circulating tumor DNA as a predictive biomarker in adjuvant chemotherapy in patients with stage II colon cancer: NRG-GI005 (COBRA).

TPS4121 Background: There are currently no validated predictive biomarkers for stage II resected colon cancer (CC) after adjuvant chemotherapy. However, circulating tumor DNA (ctDNA) that is shed into the bloodstream represents a highly specific and sensitive approach for identifying microscopic or residual tumor cells. For patients (pts) with CC, the detection of ctDNA is associated with persistent disease after resection and may outperform traditional clinical and pathological features as a prognostic factor to assess risk for recurrence. We hypothesize that for pts whose stage II colon cancer has been resected and who have no traditional high-risk features, a positive ctDNA status may identify those who will benefit from adjuvant chemotherapy. Methods: In this prospective phase II/III clinical trial, pts (N=1,408) with resected stage II CC without traditional high-risk features and whom the evaluating oncologist deems suitable for no adjuvant chemotherapy will be randomized 1:1 into 2 arms: standard-of-care/observation (Arm A), or prospective testing for ctDNA (Arm B). Postoperative blood will be analyzed for ctDNA with the GuardantHealth LUNAR panel, covering CC-relevant mutations and CC-specific methylation profiling. Pts in Arm B with ctDNA detected will be treated with 6 months of adjuvant (FOLFOX) chemotherapy. For all pts in Arm A, ctDNA status will be analyzed retrospectively at the time of endpoint analysis. The primary endpoints are clearance of ctDNA with adjuvant chemotherapy (phase II) and recurrence-free survival (RFS) for “ctDNA-detected” pts treated with or without adjuvant chemotherapy (phase III). Secondary endpoints will include time-to-event outcomes (OS, RFS, TTR) by ctDNA marker status and treatment, prevalence of detectable ctDNA in stage II CC, and rates of compliance with assigned intervention. Archived normal and matched tumor and blood samples will be collected for exploratory correlative research. The trial is actively accruing towards the phase II endpoint across all US and Canadian cooperative groups. Support: U10-CA-180868, -180822; UG1CA-189867; GuardantHealth. Clinical trial information: NCT04068103 .

Outcomes in adolescents and young adults with Hodgkin lymphoma treated on US cooperative group protocols: An adult intergroup (E2496) and Children's Oncology Group (COG AHOD0031) comparative analysis

There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL). Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study. Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study. Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2018;124:136-44. © 2017 American Cancer Society.

P1.05-027 Novel Prognostic Gene Expression Signatures for Squamous Cell Lung Carcinoma: A Study by the SPECS Lung Consortium

A multi-institutional squamous lung cancer consortium of investigators is developing prognostic signatures through the US NCI Lung SPECS (Strategic Partnership for Evaluation of Cancer Signatures) program. Six institutions contributed tumor specimens and published/unpublished expression-based prognostic signatures for validation using standardized sample cohorts (a primary validation cohort comprising institutional cases, and additional validation cohorts from two prospective cooperative group studies) and quality controlled assessment in independent laboratory and statistical cores. Here, we report on de novo prognostic signatures derived using the pooled institutional dataset. Highly quality-controlled cases of primary SCC from the pooled cohort (N=249) were analyzed to generate de novo prognostic signatures from among the 147 genes comprising pre-existing signatures, and from among all profiled genes. Minimax Concave Penalty (MCP) selection and Ward’s minimum variance clustering yielded survival analyses with 2 clusters that were evaluated using Cox regression and bootstrap cross validation (bCV; 500 iterations). Two significantly prognostic models were generated (see Figure): Pooled Model A (PMA) was the optimal 2-cluster model using probesets representing 6 genes selected from components of pre-existing signatures: CASP8, MDM2, SEL1L3, RILPL1, LRR1, COPZ2. Pooled Model B (PMB) was the optimal 2-cluster model using probesets representing 6 genes selected from among all those profiled: SSX1, DIAPH3, LOC619427, CASP8, EIF2S1, HSPA13. PMA and PMB each remained independently prognostic in multivariable analyses incorporating an a priori baseline model (age, sex, stage; c-index = 0.641). Two de novo prognostic signatures were derived using a pooled multi-institutional cohort of SCC assembled for validation of pre-existing signatures. PMA and PMB were each found to be independently prognostic, accounting for established clinical predictors. Both now move forward, along with validated pre-existing signatures, to additional assessment of discrimination, calibration and clinical usefulness using additional independent prospective US co-operative group cohorts of cases.

P2.03a-055 Predicting Risk of Chemotherapy-Induced Severe Neutropenia in Lung Patients: A Pooled Analysis of US Cooperative Group Trials: Topic: Clinical Trials

P2.03a-055 Predicting Risk of Chemotherapy-Induced Severe Neutropenia in Lung Patients: A Pooled Analysis of US Cooperative Group Trials: Topic: Clinical Trials

Outcomes in Adolescents and Young Adults (AYA) with Hodgkin Lymphoma (HL) Treated on US Cooperative Group Protocols: An Adult Intergroup (E2496) and Children's Oncology Group (COG AHOD0031) Comparative Analysis

▪Introduction: There is no clear consensus regarding the optimal therapeutic approach for AYAs with HL. Prior registry data showed that HL AYA patients treated with ABVD had similar outcomes to their older counterparts (Foltz JCO 2006). However, SEER data have suggested that advances in HL survival among AYAs may be less robust compared with older populations (Bleyer NCI 2006). We sought to examine AYA patients treated on two recent, randomized pediatric and adult North American HL clinical trials (i.e., 17-21 years; the age group of those typically eligible for both pediatric- and adult-based HL clinical trials) by comparing outcomes of different age cohorts within E2496 as well as across the two different studies.Methods: We examined characteristics and outcomes of 114 newly diagnosed AYA HL patients aged 17-21 years treated on E2496 (ABVD vs. Stanford V [SV] chemotherapy, Gordon JCO 2013) trial and compared the failure free survival (FFS) and overall survival (OS) with patients ages >21 years. In addition, we compared presenting features, planned treatment, FFS, and OS of these ECOG AYA patients with 391 newly diagnosed AYA HL patients between ages 17-21 years treated on the COG AHOD0031 (ABVE-PC backbone, Friedman JCO 2014). Unstratified and stratified log-rank tests as well as propensity score analysis were utilized to compare differences in patient outcomes.Results: In E2496, the 5-year FFS and OS rates for AYAs were 68% and 89%, respectively, with significant variations identified by patient age (see Table). There was no FFS difference between ECOG AYAs treated with ABVD vs. SV (P =0.66). However, FFS in AYAs were inferior to those ages 21 to 44 years in E2496 (P =0.005; see Figure, sections A and B). Interestingly, AYA outcomes on E2496 appeared more similar to patients aged 45-59 years. In examining COG and E2496 AYA patient characteristics, there was no significant difference in sex, race, or histology. Due in part to trial design differences, a larger proportion of E2496 AYAs were stage III or IV vs. COG AYAs (63% vs. 29%, P <0.001) and had B symptoms (63% vs. 27%, P <0.001); fewer E2496 patients had bulk disease (33% vs. 77%, P <0.001). There was no significant difference in presentation with extralymphatic disease, anemia, or hypoalbuminemia. In terms of therapy, more COG AYAs received radiotherapy (76% vs. 66%, P =0.03), though in smaller doses (21 Gy vs. 36 Gy). In each group, 3 AYAs developed a second cancer. The 5-year FFS and OS for AYAs on the COG study were 80% and 97%, respectively (see Figure, sections C and D). For survival comparison across studies, COG AYAs appeared to have superior FFS compared with E2496AYAs (P =0.001). In stratified multivariable analyses (controlled for stage, anemia, and bulk), E2496 AYAs appeared to have worse FFS compared with COG AYAs in all strata except among the subgroup of patients with stage I/II without anemia. Furthermore, propensity score analysis with patients exactly matched on stage, anemia, and bulk disease confirmed the inferior FFS for E2496 AYAs compared with COG AYAs (P =0.004). Moreover, the AYA survival disparity across studies persisted after additional covariates were incorporated into the propensity score (i.e., age, gender, B symptoms, and hypoalbuminemia; P =0.026).Conclusions: AYA HL patients treated on E2496 had inferior outcomes compared with older patients (i.e., ages 22 to 44 years) treated within the same study, for unclear reasons, as well as to similarly matched AYA patients treated on COG AHOD0031. These outcomes may result from treatment regimen differences or dose-intensity, differing patient populations or risk profiles, biology, and/or other factors. Prospective examination of these issues in AYA HL patients is warranted.Table 1Survival Outcomes Within E2496 by Age.PFS3-yr5-yrP17-2170%68%0.00521-4479%76%45-5968%68%>=6056%48%OSP17-2193%89%<.000121-4496%93%45-5979%76%>=6070%58% [Display omitted] DisclosuresSmith:Pharmacyclics: Consultancy; Celgene: Consultancy. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy. Horning:Genentech: Employment. Shah:Seattle Genetics: Research Funding; Rosetta Genomics: Other: Grant support; Acetylon: Other: Advisory board; Plexus Communications: Honoraria; Pharmacyclics: Speakers Bureau; Spectrum: Other: Advisory board, Speakers Bureau; Bayer: Honoraria; Celgene: Other: Advisory board, Speakers Bureau; DeBartolo Institute for personalized medicine: Other: Grant support. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Leonard:Weill Cornell Medical College: Employment; Genentech: Consultancy; Medimmune: Consultancy; AstraZeneca: Consultancy; Spectrum: Consultancy; Boehringer Ingelheim: Consultancy; Vertex: Consultancy; ProNAI: Consultancy; Biotest: Consultancy; Seattle Genetics: Consultancy; Pfizer: Consultancy; Mirati Therapeutics: Consultancy; Gilead: Consultancy; Novartis: Consultancy. Gordon:Northwestern University: Employment; Dr Leo I. Gordon: Patents & Royalties: Patent for gold nanoparticles pending.

Addition of Sorafenib to Chemotherapy Improves the Overall Survival of Older Adults with FLT3-ITD Mutated Acute Myeloid Leukemia (AML) (Alliance C11001)

Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of kinases including the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse and in combination with chemotherapy for newly diagnosed AML. Historical Cancer and Leukemia Group B results using standard chemotherapy for older patients (pts) with FLT3-ITD have demonstrated a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr overall survival (OS) of 30% (Whitman et al., Blood 2010). More recently, sorafenib was demonstrated to significantly prolong event-free (EFS) and disease-free survival (DFS) of younger adults irrespective of FLT3 mutation status (Rollig, et al., ASH 2014). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older pts with FLT3-mutated AML.The Alliance for Clinical Trials in Oncology conducted a multicenter, single-arm phase 2 study in pts ≥ 60 years old with AML and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA, core-binding factor AML or who had received prior treatment for AML were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive a second cycle of cytarabine and daunorubicin (5+2) plus sorafenib 400 mg bid on days 1-7. Post-remission therapy consisted of intermediate-dose cytarabine 2 g/m2 on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles followed by maintenance sorafenib 400 mg bid for 12 28-day cycles. The primary endpoint of the study was 1-yr OS. With a sample size of 39 FLT3-ITD patients and type I error rate of 10%, this design provided 90% power to distinguish between true 1-yr OS rate of 50% compared to our historical rate of 30% for the FLT3-ITD pts.A total of 474 pts were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 83 subjects (17.5%). Fifty-four pts with a median age of 67 years (60.3-82.7) were enrolled, including 39 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). All pts have now completed protocol treatment. Of the 54 pts, 37 achieved a CR or CRi (69%). The 30-day induction mortality was 9% with no additional deaths occurring between days 30-60. With a median follow up of 28.3 months, the observed 1-yr OS (95% CI) was 62% (45-78) for the FLT3-ITD pts and 71% (42-92) for the FLT3-TKD pts. The median DFS and OS was 12.5 mo (7.7-17.4) and 15.0 mo (10.4-20.1) respectively in the FLT3-ITD group and 9.0 (1.6-NA) and 16.2 mo (5.0-NA) for the FLT3-TKD group. For all subjects, the 2-yr OS was 28% (17-43) and DFS was 27% (15-46). There were no treatment-related deaths during consolidation or maintenance. For pts receiving sorafenib maintenance, the most commonly reported related adverse events were Grade 1 diarrhea, fatigue, transaminitis, and Grade 2 palmar-plantar erythodyesthesia. The mean plasma inhibitory activity (PIA) for FLT3 was 94% (n=25) on day 6 of induction, 93% (n=15) on day 15 of consolidation and 99.2% (n=6) on day 15 of maintenance demonstrating robust inhibition of FLT3 in vivo.This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. The study met the primary endpoint demonstrating that the addition of sorafenib to chemotherapy for FLT3-ITD AML improves the survival of older adults more than doubling the 1-yr OS compared to historical controls (62% vs 30%, p <0.0001). DisclosuresUy:Novartis: Research Funding. Off Label Use: Sorafenib for AML. DeAngelo:Novartis: Consultancy; Ariad: Consultancy; Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Incyte: Consultancy; Agios: Consultancy; Celgene: Consultancy. Stock:Gilead: Membership on an entity's Board of Directors or advisory committees. Byrd:Acerta Pharma BV: Research Funding. Stone:Celator: Consultancy; Celgene: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Amgen: Consultancy; Karyopharm: Consultancy; Abbvie: Consultancy; AROG: Consultancy; Merck: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding; Juno: Consultancy; Agios: Consultancy. Larson:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy; Ariad: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Long Term Follow up of SWOG S0313: Ibritumomab Tiuxetan Consolidation after 3 Cycles of CHOP Plus Radiotherapy for High Risk Limited Stage Aggressive B-Cell Lymphoma

Introduction: Patients with limited stage aggressive B-cell non-Hodgkin lymphoma (LS-NHL) and at least one stage-modified adverse risk factor have an excessive relapse rate leading to a 5-year overall survival (OS) of 50-77% and 10-year OS of 0-50%. In SWOG S0014 we have shown that the addition of rituximab to 3 cycles of CHOP plus involved field radiation therapy (IFRT) resulted in an improved estimated 4-year progression-free survival (PFS) of 88% and OS of 92%. Relapses were largely systemic (5 of 6 evaluable) and continued to be seen with longer follow-up. Ibritumomab tiuxetan (Zevalin ®) is a radiolabeled anti-CD20 antibody that has excellent single agent activity in diffuse large B-cell lymphoma and could prevent systemic relapse of disease. We now report long term results of SWOG S0313, a phase II study of ibritumomab tiuxetan consolidation after 3 cycles of CHOP plus IFRT in patients with LS-NHL.Methods: Patients with LS-NHL and at least one stage-modified adverse risk factor (non-bulky stage II, age > 60 years, elevated LDH, or WHO performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40-50 Gy of IFRT. Ibritumomab tiuxetan regimen was initiated 3 – 6 weeks following IFRT.Results: Forty-six patients were registered and eligible, with median follow-up of 7.3 years. Median age was 61, 37% of patients had elevated LDH, and 20% had systemic symptoms. Grade 4 adverse events occurring more than once included neutropenia (8 patients), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. Eleven patients progressed and 8 patients died. The PFS estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. OS estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. These outcomes compare favorably to matched cohorts on prior SWOG trials, with 7-year PFS estimate of 68% on S0014 and 65% on S8736 (original pre-Rituximab trial); and 7-year OS estimate of 80% on S0014 and 73% on S8736 cohorts.Conclusions: Patients with high-risk LS-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. A US cooperative group study of R-CHOP and response-adapted IFRT followed by consolidative ibritumomab tiuxetan is ongoing. DisclosuresOff Label Use: ibritumomab tiuxetan in diffuse large B-cell lymphoma.

Resistance prediction in AML: analysis of 4601 patients from MRC/NCRI, HOVON/SAKK, SWOG and MD Anderson Cancer Center

Therapeutic resistance remains the principal problem in acute myeloid leukemia (AML). We used area under receiver operator characteristic curves (AUC) to quantify our ability to predict therapeutic resistance in individual patients where AUC=1.0 denotes perfect prediction and AUC=0.5 denotes a coin flip, using data from 4,601 patients with newly diagnosed AML given induction therapy with 3+7 or more intense standard regimens in MRC/NCRI, HOVON, SWOG, and MD Anderson Cancer Center studies. Age, performance status, white blood cell count, secondary disease, cytogenetic risk, and FLT3-ITD/NPM1 mutation status were each independently associated with failure to achieve complete remission despite no early death (“primary refractoriness”). However, the AUC of a bootstrap-corrected multivariable model predicting this outcome was only 0.78, indicating only fair predictive ability. Removal of FLT3-ITD and NPM1 information only slightly decreased the AUC (0.76). Prediction of resistance, defined as primary refractoriness or short relapse-free survival (RFS), was even more difficult. Our ability to forecast resistance based on routinely available pre-treatment covariates provides a rationale for continued randomization between standard and new therapies and supports further examination of genetic and post-treatment data to optimize resistance prediction in AML.

The 41st David A. Karnofsky Memorial Award Lecture: Academic research worldwide--quo vadis?

Academiaplaysavitalrole inrandomizedclinical trials; by counterbalancing commercial interests, it can act as a guardian to protect patients’ needs. Moreover, the relationship between investigators and patients enrolling onto clinical trials can be viewed as one based on an implicit ethical contract. Its premise is that the primary objective of randomized clinical trials is to improve patient outcome, free from bias, whether commercial or academic. Indeed, more than 50 years of sustained commitment to randomized clinical trials in early breastcancerhavecontributedtothedecliningmortality from the disease in the Western world and would not have been possible without this understanding. The Breast International Group (BIG), created in 1996, is an umbrella organization harnessing the efforts and supporting the activities of its almost 50 national and international cooperative group members worldwide. It has become a major actor in the conduct of early breast cancer trials, particularly those run in partnership with the pharmaceutical industry for the global registration of new anticancer drugs in the adjuvant setting. The HERA (Herceptin Adjuvant) trial (NCT00045032) is one such example, contributing to the registration of adjuvant trastuzumab in 39 countries in fewer than 4 years. BIG also supports clinical trials sponsored by its academic member groups and facilitates collaboration between international researchers and US cooperative groups. The International Breast Cancer Study Group (IBCSG) –led SOFT (Suppression of Ovarian Function Trial) and TEXT (Tamoxifen and Exemestane Trial) trials (NCT00066690 and NCT00963417, respectively) evaluating endocrine therapies for 5,738 premenopausal women are cases in point. BIG is therefore uniquely positioned to examine how academic research in oncology has evolved over the last two decades, to alert the oncology community about the dangerous shift toward commercially oriented research, and to propose some new routes for empowering academics at a critical time when the remarkable progress in elucidating cancer complexity, stemming from The Cancer Genome Atlas (TCGA) project, needs to be translated into new and effective clinical applications.

Initial Results Of a Phase II Trial Of Sorafenib Plus Standard Induction In Older Adults With Mutant FLT3 Acute Myeloid Leukemia (AML) (Alliance trial C11001)

Sorafenib is an oral multikinase inhibitor that blocks the autophosphorylation and activation of a number of tyrosine kinases; it has potent activity against the FLT3 tyrosine kinase with an internal tandem duplication mutation (FLT3-ITD). Sorafenib has activity against AML with FLT3-ITD mutations as a single agent in the setting of post-transplant relapse (Metzelder et al., Blood 2009) and in combination with chemotherapy for newly diagnosed AML (Ravandi et al., JCO 2010). The prevalence of FLT3 mutations among older adults (>60 years) with AML is not yet well defined. Historical CALGB results using standard chemotherapy for older AML patients with FLT3-ITD have shown a complete remission (CR) rate of 67%, median survival of 0.8 yrs, and 1-yr survival of 30% (Whitman et al., Blood 2010). We hypothesized that the addition of sorafenib to induction and post-remission therapy would improve the overall survival of older patients with FLT3-mutated AML.We conducted a multicenter, single-arm phase 2 study in patients ≥ 60 years old with newly diagnosed AML (including therapy-related AML) and either a FLT3-ITD or a point mutation in the activation loop of the kinase domain (FLT3-TKD). Subjects with PML-RARA or CBF leukemias were excluded. Induction chemotherapy consisted of cytarabine 100 mg/m2 CIVI on days 1-7 and daunorubicin 60 mg/m2 IV on days 1-3 (7+3) with oral sorafenib 400 mg bid on days 1-7. Those not achieving a hypoplastic bone marrow on day 14 were to receive 5+2 plus sorafenib 400 mg bid on days 1-7. Patients achieving CR were encouraged to undergo allogeneic HSCT if possible. For all others, consolidation consisted of intermediate-dose cytarabine 2 g/m2 over 3 hours on days 1-5 with sorafenib 400 mg bid on days 1-28 for 2 cycles. Following consolidation, maintenance sorafenib 400 mg bid was administered daily for 12 28-day cycles. The primary endpoint for this study is the 1-year overall survival of the FLT3-ITD patients.A total of 459 older adults were screened for FLT3 mutations though a central laboratory. FLT3 mutations were identified in 81 subjects (17.6%). The median turn-around time for FLT3 testing was 46 hours, with 99.1% of cases returned within the cutoff time of 48 hours. Fifty-two patients to date have enrolled on the study, including 37 with FLT3-ITD (71%) and 15 with FLT3-TKD (29%). The median age is 67 years (range, 60-83) and 19 pts were > 70 years (37%). The median follow up is 4.5 months. Of the 52 evaluable patients, 36 have achieved a CR or CRi (69%) of which 4 were CRi (8%). The CR/CRi rate did not differ between subjects with an ITD (26 of 37, 70%) vs a TKD (10 of 15, 67%). The CR/CRi rate was 58% for those >70 years old. Eight pts are known to have received a second induction course. Four of 52 patients (8%) died within 30 days of starting their most recent induction course with no additional deaths occurring within 60 days. Treatment-related toxicities were those typical during AML induction, and no additional or unexpected toxicities were attributed to sorafenib. There were 2 grade 5 nonhematologic adverse events (lung infection; oral mucositis) and 7 grade 4 events among the first 40 evaluable patients, including infection, cardiac, respiratory, metabolic, and kidney injury.This study represents the first prospective clinical trial for older adults with AML targeting a specific mutational profile within the US cooperative group setting. It demonstrates the feasibility of rapid screening for FLT3 mutations prior to initial remission induction chemotherapy. The addition of sorafenib to chemotherapy for older adults with AML is associated with a high rate of CR, relatively low risk of mortality during induction, and an acceptable toxicity profile. Disclosures:Off Label Use: sorafenib for AML.

Wither the Cooperative Groups?

The cooperative groups sponsored by the National Cancer Institute (NCI) were formed beginning in the mid-1950s and have provided a publicly funded standing infrastructure to conduct cancer clinical trials ever since (Appendix Fig A1, online only). The accomplishments of the US cooperative groups, often in collaboration with similar organizations in Europe and Canada, are notable for the development of curative therapies for most pediatric cancers; the introduction of effective combined modality treatments for many diseases, including head and neck cancer, cervical cancer, esophageal cancer, non–small-cell lung cancer, and anal cancer; the development of adjuvant chemotherapy as a standard of care for many solid tumors, particularly breast cancer and colorectal cancer; and the introduction of chemoprevention strategies for patients at high risk of developing breast and prostate cancer. The groups have also worked collaboratively with the pharmaceutical industry to introduce new cancer drugs into medical practice and to develop new indications for already approved drugs. Indeed, more than 20 new indications for cancer drugs have resulted directly from cooperative group studies. Clinical trials performed by the cooperative groups have also provided important insights into optimal scheduling and sequencing of chemotherapy drugs and the preferred route of drug administration that have established new standards of care, such as the introduction of dose-dense chemotherapy as part of adjuvant treatment of breast cancer and the demonstration of improved survival when intraperitoneal administration of chemotherapy is used for treatment of ovarian cancer. Importantly, cooperative groups have also rigorously evaluated purported advances in cancer care that were popularized by single individuals or centers and, in some cases, such as high-dose chemotherapy and autologous stem-cell transplant for breast cancer, have proven them ineffective. Finally, many important advances in supportive care for patients with cancer have come from cooperative group studies, such as the recent demonstration of the value of duloxetine to relieve symptoms of chemotherapyinduced painful peripheral neuropathy. In the current era of molecular medicine, the cooperative group biospecimen repositories, populated with specimens from clinical trial participants who received uniform treatments and have welldocumented outcomes, are invaluable resources for the development of new prognostic, predictive, and response biomarkers across a range of cancer types. These repositories will support a new generation of biomarker-driven clinical trials currently in development by the cooperative groups. And, with the heightened public interest in comparative effectiveness and cost, the cooperative groups, as publicly funded entities free from commercial bias, are ideally positioned to directly compare therapeutic approaches or drugs from competing commercial firms, combine drugs from different sponsors, develop treatments for rare diseases with small commercial markets, and rigorously examine the cost effectiveness of new treatments and their impact on patient quality of life. Beyond their scientific contributions, the cooperative groups have developed many of the standard methods to conduct multicenter clinical trials, extended clinical trials to community oncologists, and provided a fertile training ground for generations of clinical investigators and countless research staff. Despite their many contributions to cancer care and research, the cooperative groups have been subjected to scrutiny and criticism for nearly their entire existence. In the last 15 years alone, no fewer than five committees have been convened by NCI or at the request of NCI to evaluate the cooperative group program. Most recently the Institute of Medicine (IOM) of the National Academy of Sciences produced a report at the request of the NCI entitled, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program,” which identified the many challenges faced by the cooperative groups at the present time, including stagnant funding; inefficient and redundant processes; excessive and complex government oversight, with many layers of review performed by multiple agencies; long delays in the launch of clinical trials; and increasing competition from the pharmaceutical industry for patient accrual to studies. When the IOM report was issued, the time required to activate a phase III trial in the cooperative groups averaged nearly 2 years, and JOURNAL OF CLINICAL ONCOLOGY S P E C I A L A R T I C L E VOLUME 32 NUMBER 3 JANUARY 2

Clinical, genomic, and imaging predictors of malignancy: Analysis of the first U.S. cooperative group prospective clinical trial in asymptomatic monoclonal gammopathies (SWOG S0120).

8515 Background: Asymptomatic monoclonal gammopathies (AMG) are the most common plasma cell dyscrasia classified as either monoclonal gammopathy of undetermined significance (MGUS) or asymptomatic multiple myeloma (AMM). Clinical outcome in AMGs can be highly variable and there is an unmet need to identify newer clinical, genomic and imaging parameters from prospective studies to guide patient management. Methods: We analyzed clinical, genomic and imaging data from AMG patients (n=334) enrolled in a prospective observational clinical trial (S0120) conducted under the auspices of SWOG. Baseline data from clinical variables, as well as gene expression profiles of purified tumor cells and the findings on magnetic resonance imaging (MRI) were correlated with the risk of progression to symptomatic myeloma (MM) requiring therapy. Results: In addition to serum M spike, percent bone marrow plasma cells and the ratio of involved/uninvolved serum free light chains, the level of serum beta-2-microglobulin was associated with an increased risk of progression to clinical myeloma requiring therapy. Gene expression profiles (GEP) of purified tumor cells revealed that all of the known molecular GEP subtypes of human MM are also represented in the precursor phase. An increased risk score (&gt; - 0.26) based on a 70-gene signature (GEP70) was an independent predictor of the risk of progression to clinical MM requiring therapy. The presence of focal lesions on MRI also conferred an increased risk of disease progression but was not independent of other clinical and genomic features. Conclusions: These data represent the first comprehensive evaluation of clinical, genomic and imaging features of AMGs in the context of a prospective US-cooperative group trial, and demonstrate that while all genetic subtypes of MM have a precursor phase, genetic signatures previously associated with high risk myeloma also predict the risk of progression to clinical malignancy requiring therapy. These findings suggest the need to integrate both clinical assessment of tumor bulk and genomic properties of tumor cells in the clinical management of these patients. Clinical trial information: NCT00900263.

Significance of FAB subclassification of “acute myeloid leukemia, NOS” in the 2008 WHO classification: analysis of 5848 newly diagnosed patients

AbstractThe World Health Organization (WHO) classifies acute myeloid leukemia (AML) via genetic, immunophenotypic, biological, and clinical features. Still, “AML, not otherwise specified (NOS)” is further subdivided based on morphologic criteria similar to those of the French-American-British (FAB) classification. We analyzed the relevance of this practice in patients with newly diagnosed “AML, NOS” with available FAB information undergoing curative-intent therapy in trials of 3 cooperative study groups (Dutch-Belgian Cooperative Trial Group for Hematology/Oncology [HOVON], UK Medical Research Council/National Cancer Research Institute [MRC/NCRI], and the US cooperative group Southwest Oncology Group [SWOG]) or at MD Anderson Cancer Center. Ignoring information on NPM1 and CEBPA, 5848 patients met criteria for “AML, NOS.” After multivariate adjustment, FAB M0 was independently associated with significantly lower likelihood of achieving complete remission and inferior relapse-free and overall survival as compared with FAB M1, M2, M4, M5, and M6, with inconclusive data regarding M7. However, restricting attention to known NPM1neg patients, FAB M0 was no longer associated with worse outcomes; restricting attention to patients known to be NPM1neg/CEPBAneg (ie, honoring the provisional entities of “AML with mutated NPM1” and “AML with mutated CEBPA”) did not affect this result. In conclusion, in the 2008 WHO classification scheme, FAB subclassification does not provide prognostic information for “AML, NOS” cases if data on NPM1 and CEBPA mutations are available.

Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL

AbstractThanks to modern treatment with all-trans retinoic acid and chemotherapy, acute promyelocytic leukemia (APL) is now the most curable type of leukemia. However, this progress has not yielded equivalent benefit in developing countries. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) was established to create a network of institutions in developing countries that would exchange experience and data and receive support from well-established US and European cooperative groups. The IC-APL formulated expeditious diagnostic, treatment, and supportive guidelines that were adapted to local circumstances. APL was chosen as a model disease because of the potential impact on improved diagnosis and treatment. The project included 4 national coordinators and reference laboratories, common clinical record forms, 5 subcommittees, and laboratory and data management training programs. In addition, participating institutions held regular virtual and face-to-face meetings. Complete hematological remission was achieved in 153/180 (85%) patients and 27 (15%) died during induction. After a median follow-up of 28 months, the 2-year cumulative incidence of relapse, overall survival (OS), and disease-free survival (DFS) were 4.5%, 80%, and 91%, respectively. The establishment of the IC-APL network resulted in a decrease of almost 50% in early mortality and an improvement in OS of almost 30% compared with historical controls, resulting in OS and DFS similar to those reported in developed countries.

Combined-modality therapy in gastrointestinal cancers

Charles Richard Thomas Jr speaks to Theo Bond, Assistant Commissioning Editor: Charles Richard Thomas Jr is Professor and chair of the Department of Radiation Medicine and Professor of Hematology/Oncology in the Department of Medicine at the Oregon Health and Science University (OHSU) in Portland (OR, USA). He is also an active member of the OHSU Knight Cancer Institute (OR, USA). Thomas has received triple-board certification in Radiation Oncology (American Board of Radiology), Medical Oncology and Internal Medicine (American Board of Internal Medicine). He is a member of the NCI Rectal Anal Cancer Task Force. He also has an interest in cancer disparities and was one of the editors for the special edition on cancer disparities published in the Journal of Clinical Oncology in 2006. He is also active in protocol development either as chair or co-chair within the US co-operative group mechanism, with a focus on novel therapeutic and translational clinical research on gastrointestinal and thoracic malignancies that have tested incorporation of novel antiproliferative systemic agents with radiotherapy. Currently, Thomas has served as the chair of the Radiation Oncology Committee of the American College of Surgeons Oncology Group (ACOSOG). He has served as editor-in-chief of Radiation Medicine Rounds (Demos Medical Publishing), as well as on the Editorial Boards of a number of peer-reviewed journals. Thomas has served as an oral and written examiner for the gastrointestinal section of The American Board of Radiology Certification Examination, as well as on multiple committees within the American Society of Clinical Oncology (ASCO), American Association for Cancer Research (AACR), Radiological Society of North America (RSNA), American College of Radiology (ACR) and the American Society of Radiation Oncology (ASTRO). He is the author or co-author of over 145 journal articles and is a co-editor of multiple textbooks, including Mediastinal Tumors (1995), Biliary Tract &amp; Gallbladder Cancers: Diagnosis and Therapy (2008) and Esophagus Cancers: Practice and Principles (2009). His passion resides with mentoring the best and brightest talent, especially individuals from historically under-represented populations, in order to further develop the pipeline of highly skilled oncologists.