Search

PURPOSE Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2–overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.

TPS264 Background: Clinical improvements for locally advanced rectal cancer have been relatively static over the past few decades. While immunotherapy shows no benefit in microsatellite stable (MSS) colorectal cancer, preclinical models suggest that radiotherapy (RT) can enhance neoantigen presentation, modulate the microenvironment, and improve the likelihood of anti-tumor activity with checkpoint inhibitor use. Using a “window-of-opportunity” study design, this prospective phase II trial will determine the safety and activity of this approach with the anti-PD-L1 agent durvalumab (MEDI4736). Methods: This multi-center phase II trial is currently enrolling patients (pts) with rectal cancer who are undergoing standard NCCN guideline-compliant neoadjuvant chemoradiotherapy (CRT). Eligibility includes pts with MSS stage II-IV rectal cancer with adequate organ function and pre-treatment diagnostic tumor available for profiling with intent to proceed to surgical resection after CRT. Stage IV disease must be limited such that the primary pelvic tumor requires definitive management. Standard ineligibility criteria include active infections, systemic steroid use, or other conditions making immunotherapy use unsafe. Treatment includes durvalumab (750mg IV infusion once every 2 wks) for 4 total doses beginning within 3-7 days after CRT completion. Surgery must be within 8-12 wks of the final CRT dose. Primary endpoint is a demonstrated improvement in Neoadjuvant Rectal Cancer (NAR) score compared to historical controls targeting a 20% relative risk reduction in DFS and 3-4% absolute OS improvement. Secondary endpoints include OS, DFS, toxicity, pCR, cCR, therapy completion, negative surgical margins, sphincter preservation, off-target “abscopal” effects for the subset of stage IV pts, and exploratory assessments of tumor infiltrating lymphocytes, tumor Immunoscore, circulating immunologic profiles, and molecular predictors of response. A safety run-in phase has completed as a precedent to full enrollment. Enrollment now continues to 47 total pts to achieve 41 surgically evaluable pts. Support: AstraZeneca-Medimmune, NSABP Foundation. Clinical trial information: NCT03102047.

Purpose To determine the optimal dose and schedule of anthracycline and taxane administration as adjuvant therapy for early-stage breast cancer. Patients and Methods A 2 × 2 factorial design was used to test two hypotheses: (1) that a novel continuous schedule of doxorubicin-cyclophosphamide was superior to six cycles of doxorubicin-cyclophosphamide once every 2 weeks and (2) that paclitaxel once per week was superior to six cycles of paclitaxel once every 2 weeks in patients with node-positive or high-risk node-negative early-stage breast cancer. With 3,250 patients, a disease-free survival (DFS) hazard ratio of 0.82 for each randomization could be detected with 90% power with two-sided α = .05. Overall survival (OS) was a secondary outcome. Results Interim analyses crossed the futility boundaries for demonstrating superiority of both once-per-week regimens and once-every-2-weeks regimens. After a median follow-up of 6 years, a significant interaction developed between the two randomization factors (DFS P = .024; OS P = .010) in the 2,716 patients randomly assigned in the original design, which precluded interpretation of the two factors separately. Comparing all four arms showed a significant difference in OS (P = .040) but not in DFS (P = .11), with all treatments given once every 2 weeks associated with the highest OS. This difference in OS seemed confined to patients with hormone receptor–negative/human epidermal growth factor receptor 2 (HER2) –negative tumors (P = .067), with no differences seen with hormone receptor–positive/HER2-negative (P = .90) or HER2-positive tumors (P = .40). Conclusion Patients achieved a similar DFS with any of these regimens. Subset analysis suggests the hypothesis that once-every-2-weeks dosing may be best for patients with hormone receptor–negative/HER2-negative tumors.

521 Background: S0221 investigated weekly vs q 2 week dosing of doxorubicin/cyclophosphamide (AC) and paclitaxel (P) in patients (pts) with high risk early breast cancer as previously reported (JCO 33:58-64, 2015). After enrollment of 2716 pts randomization to the two AC arms was stopped for futility and an additional 578 pts received 4 cycles of q 2 week AC and were randomized to P weekly (Pw) or P q 2 weeks (P2). We report updated results of the original trial design and the first report of the 578 pts treated with AC x 4 and Pw x 12 or P2 x 6. Methods: Between December 2003 and November 2010, 2716 pts were randomized in a 2x2 factorial design to 1) 15 weeks of weekly AC (A 24 mg/m2/week and C 60 mg/m2/day po) vs 6 cycles of q 2 week AC (A 60 mg/m2 and C 600 mg/m2) and 2) Pw (paclitaxel 80 mg/m2/week x 12) vs P2 (paclitaxel 175 mg/m2 q 2 weeks x 6), with growth factor support as previously described. After study amendment 578 patients received 4 cycles of q 2 week AC followed by Pw or P2. Updated survival was assessed using log-rank tests and Cox regression models. Results: At a median follow-up of 8.5 years, among the pts treated in the original protocol, there were no significant differences among the four treatments for DFS (p=0.21) or OS (p=0.08). The triple-negative subset had worse DFS (P

Purpose An anthracycline-based combination followed by, or combined with, a taxane is the sequence used in most adjuvant chemotherapy regimens. We hypothesized that administering the taxane before the anthracycline combination would be associated with fewer dose reductions and delays than the reverse sequence. To test this hypothesis, a randomized phase II multicenter adjuvant chemotherapy trial was performed. Patients and Methods Fifty-six patients with axillary node-positive, nonmetastatic breast cancer were randomly assigned either to group A (docetaxel [DOC] 75 mg/m2 intravenously [IV] every 14 days for four cycles followed by doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 [AC] IV every 14 days for four cycles); or to group B (AC followed by DOC) at the identical doses and schedule. Pegfilgrastim 6 mg subcutaneous injection was administered 1 day after the chemotherapy in all treatment cycles. The primary objective was to administer DOC without dose reductions or delays before or after AC and calculate the relative dose intensity (RDI) of DOC and AC. Results The majority of toxicities were grade 0 to 2 irrespective of sequence. The RDI for DOC was 0.96 and 0.82, respectively, in groups A (DOC followed by AC) and B (AC followed by DOC), with more frequent dose reductions occurring in group B (46% v 18%). The RDI for AC was 0.95 and 0.98 in groups A and B, respectively. Conclusion The administration of DOC before AC results in fewer DOC dose reductions and a higher RDI than the reverse sequence. Larger trials evaluating the sequence of DOC before anthracyclines are justified.

AMF Consulting Incorporated, Los Angeles, Cal-ifornia.The authors thank William Carter, Ph.D., and theOncology Practice Pattern Study Group for provid-ing the historic-control database. MaryAnn Foote,Ph.D., assisted with the writing of this article.Additional members of the Neutropenia Risk ModelStudy Group include: Mitchell Alden, M.D., Bux-Mont Oncology/Hematology Medical Associates,Sellersville, PA; Francis P. Arena, M.D., Arena On-cology Associates, Great Neck, NY; John A. Axel-son, M.D., Hematology/Oncology Association ofSouthern Michigan, Jackson, MI; Suzanne T. Ber-lin, M.D., Addison-Gilbert Hospital, Gloucester, MA;Stephanie Bernstein, M.D., Faulkner Hospital, Ja-maica Plains, MA; Rachel Borson, M.D., MidwestCancer Center, St. Louis, MO; Albert M. Brady,M.D., St. Joseph Mercy Oakland, Pontiac, MI; Mi-chael S. Buchholtz, M.D., Hematology/Oncology,Huntington, NY; Janak E. Choksi, M.D., AlamanceCancer Center, Burlington, NC; Patrick Colarusso,M.D., Pottstown Memorial Cancer Center, Potts-town, PA; Elliot Dickman, M.D., Hillcrest HospitalCancer Center, Mayfield Heights, OH; David Dun-ning, M.D., Northern Virginia Oncology Group, Fair-fax,VA;LeroyJ.Essig,M.D.,MedicalSpecialistsofFredericksburg, Fredericksburg, VA; Frank J.Forte, M.D., Staten Island University Hospital,Staten Island, NY; Julio M. Garcia, M.D., Oncology/RadiationAssociates,Miami,FL;JeremyR.Geffen,M.D., Geffen Cancer Center, Vero Beach, FL;Charles D. Graham, M.D., Trident Palmetto Hema-tology/Oncology, Charleston, SC; Andrew A.Hertler, M.D., Maine General Health, Waterville,ME; Karen L. Hoelzer, M.D., Springfield Clinica,Springfield, IL; Anthony D. Hoffman, M.D., SciodeMedical Association, Bronx, NY; Leonard A. Kal-man, M.D., Oncology/Hematology Group of SouthFlorida, Miami, FL; Edward H. Kaplan, M.D., NorthShoreCancerResearch,Skokie,IL;JosephKaplan,M.D., Community Hematology/Oncology, Olney,MD; Kapisthalam S. Kumar, M.D., Pasco HernandoOncology Associates, New Port Richey, FL; StevenS. Larmon, M.D., Dartmouth-Hitchcock Hospital,Keene, NH; James J. Lechner, M.D., WesternWashington Oncology, Olympia, WA; William A.Lerner, M.D., Topilow, Lerner & Mencel, Man-asquan, NJ; James E. Liebmann, M.D., New Mex-ico Oncology/Hematology Consultants, Albuquer-que, NM; Robert J. March, M.D., Hematology/Oncology Associates, New City, NY; Leslie A.Martin, M.D., St Elizabeth’s Medical Center, Brigh-ton, MA; Edward T. O’Brien, M.D., The RegionalCancer Center, Erie, PA; John A. Okerbloom, M.D.,Heartland Oncology & Hematology, Council Bluffs,IA; James M. Orsini, M.D., Essex Hematology/Oncology Group, Belleville, NJ; Stuart H. Packer,M.D., Hematology/Oncology, Langhorne, PA; Sig-urdur R. Petursson, M.D., Western PennsylvaniaHospital, Pittsburgh, PA; Debra M. Prow, M.D.,Texas Cancer Center, Fort Worth, TX; Jane M.Raymond, M.D., Western Pennsylvania Hospital,Pittsburgh, PA; Joseph A. Readling, M.D., LourdesRegional Cancer Center, Binghamton, NY; Joel H.Schwartz, M.D., North Shore Cancer Center, Pea-body, MA; David Shiba, M.D., Gould Medical Group,Modesto, CA; Michael J. Stender, M.D., Hematology/Oncology Consultants, Royal Oak, MI; N. SimonTchekmedyian, M.D., Pacific Shores Medical Group,Long Beach, CA; Kathleen Toomey, M.D., SomersetHematology/Oncology, Somerset, NJ; Dean Tsar-whas, M.D., North Shore Oncology/Hematology, Lib-ertyville, IL; Stephen A. Volk, M.D., Oncology/Hema-tology of Lehigh Valley, Bethlehem, PA; PivapongVongkovit, M.D., Northwestern Carolina Oncology/Hematology, Hickory, NC; and Marjorie A. Vukelich,M.D., Kettle Moraine Oncology, West Bend, WI.Address for reprints: Edgardo Rivera, M.D., Univer-sity of Texas M. D. Anderson Cancer Center, 1515Holcombe Blvd., Unit 424, Houston, TX 77030-0056; Fax: (713) 794-4385; E-mail: erivera@mail.mdanderson.orgReceived January 15, 2003; revision receivedMarch 28, 2003; accepted April 11, 2003.

1016 Background: Assessment of the outcome of minority populations within clinical trials may give insight into important tumor and host factors relevant to those populations. Methods: S0221 is a p...

CRA1008 Background: S0221 is a SWOG-coordinated phase III adjuvant chemotherapy intergroup trial in node-positive and high-risk node-negative operable breast cancer which hypothesized that 1) the weekly AC+G regimen is superior to ddAC x 6 and 2) 12 weeks of weekly paclitaxel (wP) is superior to q 2 week paclitaxel x 6 (ddP). Methods: Between December 2003 and November 2010, 2,716 patients were randomized in a 2 x 2 factorial design to 1) AC+G vs ddAC and 2) P 80 mg/m2/week x 12 vs P 175 mg/m2 q 2 weeks x 6. If there was no significant interaction between the factors, the trial was powered to find a disease-free survival hazard ratio (HR) ≤ 0.82 for weekly vs q 2 week for each factor. At the first interim analysis, the AC randomization was halted for futility, and S0221 was closed to accrual 10 November 2010. S0221 reopened 15 December 2010, after which time all patients received 4 cycles of ddAC and randomization to P weekly x 12 and ddP x 6 continued. Accrual halted at a total of 3,294 in January 2012. Results: By September 7, 2012, 487 events and 340 deaths had occurred, prompting the third planned interim analysis. The Data Safety and Monitoring Committee recommended reporting the results since the futility boundary was crossed. A Cox model adjusting for the AC arms had a HR = 1.08 (95% CI 0.90-1.28; p=0.42), with the 99.5% CI excluding the original alternative hypothesis that the HR=0.82. There was no significant interaction of the two factors. Estimated 5-year progression-free survivals were 82% for weekly P and 81% for ddP. Toxicity data were available for 1,385 patients treated with ddP and 1,367 treated with weekly P. Grade 5 toxicity occurred in 4 patients on ddP and 2 on weekly P. Percent grade 3-4 toxicity per arm are shown in the Table. Conclusions: Either ddPx6 or weekly P x 12 are acceptable schedules of P administration. The differences in leukopenia likely reflect ascertainment bias against weekly P. If this is accepted, weekly P x 12 produces less overall toxicity than 6 cycles of ddP. Support: NCI grants CA32102, CA38926, CA21115, CA21076, CA77597, CA25224, CA77202, CCSRI15469, and Amgen, Inc. Clinical trial information: NCT00070564. [Table: see text]

TPS3110 Background: With the knowledge that Bcl-2 facilitates drug resistance and cell survival, a DNA interference (DNAi) strategy was applied to silence Bcl-2 in cancer cells and promote apoptosis. DNAi differs from cytoplasmic mRNA targeting (antisense, RNAi, and miRNA targets) as it targets genomic DNA, blocking transcription. PNT100, a first in class DNAi, is a novel single-stranded 24-base unmodified DNA designed to bind to an upstream region of the Bcl-2 promoter. The drug product (PNT2258) is PNT100 encapsulated in a specialized pH tunable liposome and is being assessed for safety and tolerability in a phase I trial. PNT2258 avoids the toxicities associated with modified oligonucleotides and double-stranded RNAs; since the liposome formulation is anionic and contains no surface spacers, vehicle toxicities are minimal. Xenograft experiments demonstrated marked single agent activity in a diffuse large cell lymphoma, and therapy potentiation when combined with either rituximab in Daudi-Burkitt’s Lymphoma or docetaxel in A375 melanoma. Methods: An open-label, single-arm, first-in-man phase I dose-escalation study of PNT2258 in patients with advanced solid tumors was designed to evaluate safety, tolerability, dose-limiting toxicities, pharmacokinetics, and pharmacodynamics of PNT2258 to recommend a dose for phase II studies. In this phase I study, pharmacodynamic effects of PNT2258 will be evaluated through analyses of soluble serum and plasma markers and peripheral blood mononuclear cells. Patients will receive PNT2258 as an intravenous infusion over 2 hours once daily for 5 consecutive days (days 1-5) of each 21-day treatment cycle (3 weeks). The starting dose of 1 mg/m2 with PNT2258 administered to one patient per cohort and dose-escalation will proceed by dose-doubling in each successive cohort until a dose level of 64 mg/m2 is attained, provided no dose-limiting toxicities are observed in cycle 1. Thereafter, dose escalations shall proceed at 33% increments of the previous cohort dose-level to 85, 113, and 150 mg/m2 with expansions of up to six patients per cohort as needed. The ten planned dose cohorts have been completed with all patients enrolled.

1004 Background: AC+G (doxorubicin 24 mg/m2/week x 15, cyclophosphamide 60 mg/m2/day po, and filgrastim daily except on the days of doxorubicin administration) produced encouraging results in a SWO...