Neoadjuvant Period Research Articles

Double-blind, randomized phase III study to compare the efficacy and safety of CT-P6, trastuzumab biosimilar candidate versus trastuzumab as neoadjuvant treatment in HER2 positive early breast cancer (EBC).

510 Background: CT-P6 (C) is a proposed biosimilar to trastuzumab. This trial (NCT02162667) evaluated the similarity of C and trastuzumab in efficacy and safety for HER2+ EBC. Methods: 549 patients with HER2+ EBC were randomized to receive C (n=271) or trastuzumab (n=278) in combination with docetaxel (Cycles 1-4) and 5-fluorouracil, epirubicin, and cyclophosphamide (Cycles 5-8). C or trastuzumab was administered at 8 mg/kg (Cycle 1 only) followed by 6 mg/kg every 3 weeks. The primary endpoint was pathological complete response (pCR) rate at surgery. Secondary endpoints were overall response rate (ORR), PK, PD and safety. After surgery, patients received adjuvant C or trastuzumab to complete a total of 1-year treatment. Results: The pCR rate was 46.8% for C and 50.4% for trastuzumab. The 95% CIs for the risk ratio estimate were within the equivalence margin (0.74, 1.35) in PPS and ITT analyses. Other efficacy endpoints were similar between C and trastuzumab. The proportion of patients with at least 1 treatment-emergent SAE was 6.6% for C and 7.6% for trastuzumab. Only 1 patient in each group withdrew treatment due to significant LVEF decrease. Infusion-related reaction was reported for 8.5% of patients in C and 9.0% of patients in trastuzumab. Conclusions: This study demonstrated the similarity of efficacy in terms of pCR between CT-P6 and trastuzumab in EBC patients. Secondary efficacy endpoints also supported the similarity between CT-P6 and trastuzumab. CT-P6 was well tolerated with a similar safety profile to that of trastuzumab during the neoadjuvant period. Clinical trial information: NCT02162667. [Table: see text]

A randomized, double-blind, phase III study comparing SB3 (trastuzumab biosimilar) with originator trastuzumab in patients treated by neoadjuvant therapy for HER2-positive early breast cancer.

509 Background: SB3, a proposed biosimilar to the originator trastuzumab (TRZ), demonstrated similarity to its originator in terms of biological activities and pharmacokinetic (PK) equivalence. This study compared SB3 to TRZ in terms of efficacy, safety, PK, and immunogenicity in patients treated by neoadjuvant therapy for HER2 positive early breast cancer (NCT02149524). Methods: Phase III, randomized, double blind, multicenter study compared neoadjuvant SB3 or TRZ for 8 cycles concurrently given with chemotherapy (docetaxel followed by 5-fluorouracil/epirubicin/cyclophosphamide). Then patients underwent surgery followed by 10 cycles of SB3 or TRZ. The primary endpoint was breast pathologic complete response (bpCR) rate. Equivalence was declared if the 90% confidence interval (CI) of the ratio or the 95% CI of the difference of the bpCR rates in the per-protocol set (PPS) were contained within the pre-defined equivalence margins (0.785, 1.546) and (-13%, 13%), respectively. Secondary endpoints were total pathologic complete response (tpCR), overall response rate (ORR), event-free survival, PK, immunogenicity, and safety. Results: 800 patients were included in PPS. The bpCR rates were 51.7% for SB3 and 42.0% for TRZ. The ratio of bpCR rate was 1.259 and its 90% CI was 1.112-1.426, within the pre-defined equivalence margin. The difference of bpCR rate was 10.70% and its 95% CI was 4.13-17.26; the lower margin was contained within, the upper margin was outside the pre-defined equivalence margin. Secondary endpoints were comparable between SB3 vs TRZ: tpCR rate (45.8% vs 35.8%); ORR (96.3% vs 91.2%). Safety was comparable between SB3 vs TRZ during neoadjuvant period: incidence of treatment-emergent adverse events (96.6% vs 95.2%), most commonly neutropenia, alopecia, and nausea; incidence of serious adverse events (10.5% vs 10.7%). PK equivalence was demonstrated and immunogenicity between SB3 vs TRZ was comparable (0.7% vs 0.0%). Conclusions: Equivalence was demonstrated between SB3 and TRZ based on the ratio of bpCR rates. Safety, PK, and immunogenicity were similar. Complete safety and survival data will follow. Clinical trial information: NCT02149524.

Comparison of two different neoadjuvant chemoradiatiotherapy regimens for locally advanced rectal cancer: Results of a phase II, multicenter, randomized trial.

3614 Background: The aim of this study is to compare clinical outcomes between two groups of different chemoradiation Regimens. Methods: Eligible patients were randomly assigned to Patients received either IMRT to the pelvis of 50 Gy/25Fxs concurrent with oxaliplatin 50 mg/m2 weekly and capecitabine 625 mg/m2 bid d1–5 weekly (Arm A), or IMRT to the pelvis of 50 Gy/25Fxs and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, followed by a cycle of XELOX two weeks after the completion of chemoradiotherapy (Arm B). Surgery was scheduled eight weeks after the completion of CRT. All patients were recommended to receive adjuvant CT regardless of pathological stages. A total of six cycles of XELOX chemotherapy was recommended including neoadjuvant and adjuvant period. The primary end point was pCR. Results: From February 2010 to December 2011, a total of 120 patients were randomly assigned to Arm A (n = 60) or Arm B (n = 60). One hundred and ten patients (Arm A = 53, Arm B = 57) underwent surgery, the other 10 patients didn’t receive surgery because of unresectable disease. Eight and 14 cases were evaluated as pCR in two groups respectively ( p= .157). Tumor response was further classified into good response and poor response, the former was defined as ypT0N0, ypT1-2N0 and ypT0N1a. The rate of good responses were 30.0% and 55% ( p= .006). No significant differences were found in grade 3 or 4 acute adverse events during the treatment between the two groups. However, number of patients who had delayed incision healing was 13 and 3 patients ( p= .007). There were no statistical differences in OS ( p= .553), DFS ( p= .349) and local-regional control ( p= .856) between the two groups. In the univariate analysis, N stage, MRF involvement and tumor response had significant impacts on OS, DFS and LC. In the multivariate analysis, MRF involvement had significant impacts on OS ( p= .02), DFS ( p= .01) and LC ( p= .01). Conclusions: A dose-intensified radiotherapy in neoadjuvant chemoradiotherapy demonstrated contribution to tumor regression with acceptable toxicity, but led delayed incision healing after surgery. The impact of MRF involvement on survival merits further investigation. Clinical trial information: NCT01064999.

A double blinded, placebo-controlled pilot study to examine reduction of CD34 +/CD117 +/CD133 + lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma.

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and "slow proliferation" molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

Changes in multiparametric prostate MRI and immune subsets in patients (Pts) receiving neoadjuvant immunotherapy and androgen deprivation therapy (ADT) prior to radiation.

30 Background: Endorectal(er) MRI is an emerging tool in assessing intraprostatic tumors. Immunotherapy development in prostate cancer has been limited due to the lack of intermediate (bio)markers of response. Methods: Untreatedpts with high-risk prostate cancer were randomized in a trial (NCT01496131) of standard ADT+Radiation + an immunotherapy targeting MUC1 (tecemotide, aka L-BLP25). Pts had erMRI at baseline and after 2 months of ADT+/- biweekly immunotherapy. Low dose (300 mg/m2, maximum 600 mg) cyclophosphamide for regulatory T-cell depletion preceded first immunotherapy. Multiparametric MRI included evaluation of apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI. Monthly peripheral blood assessments utilized flow cytometry to evaluate immune cell subsets. This analysis focuses on the 2 month neoadjuvant period of ADT+/-immunotherapy before radiation. Results: 28 pts (n = 14/arm) with high risk prostate cancer (Gleason 8-10, PSA > 20, or stage T3) were enrolled. PSA declined in all pts 2 months after ADT. erMRI findings at 2 months indicated greater improvements in ADC values in pts receiving immunotherapy+ADT vs. ADT alone. Improved ADC on MRI suggests improvements in intratumoral diffusion and has been associated with decreased tumor density. This relative improvement between the groups occurred both per patient (p = 0.16) and per lesion (p = 0.031). Relative to baseline, pts receiving immunotherapy+ADT had increases in CTLA4+ CD8+ T-cells consistent with immune activation (p = 0.0134) and decreases in myeloid derived suppressor cells (MDSCs; p = 0.0353) during the neoadjuvant period corresponding to the erMRI changes. These immune findings were not seen in the ADT alone group. Conclusions: Pts who received immunotherapy+ADT for 2 months had greater improvements in ADC values on erMRI, consistent with decreased tumor density, relative to pts receiving ADT alone. Corresponding increases in activated CD8+ T-cells and decreases in MDSCs were seen in pts receiving vaccine+ADT. These preliminary findings suggest that ADC on MRI may be useful in assessing immunologic impact. Further study is warranted. Clinical trial information: NCT01496131.

Abstract P4-21-41: Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer

Abstract Background: Neoadjuvant pertuzumab (P)+trastuzumab (H)+standard chemotherapy (CT) significantly increases pathologic complete response (pCR) rates v H+CT. However, anti-HER2 therapy following anthracyclines can cause heart failure, and data are limited or lacking on combining P+H after epirubicin or doxorubicin. We report cardiac and overall safety as well as total pCR (tpCR) rates with widely used but understudied anthracycline-containing regimens. Methods: BERENICE (NCT02132949), a non-randomized, open-label, phase II study, enrolled patients (pts) with centrally confirmed HER2-positive, locally advanced, inflammatory, or early-stage, unilateral, and invasive breast cancer, Eastern Cooperative Oncology Group performance status ≤1, and baseline left ventricular ejection fraction (LVEF) ≥55%. In the neoadjuvant period, Cohort A pts received four q2w dose-dense doxorubicin+cyclophosphamide cycles (60 mg/m2/600 mg/m2 with granulocyte-colony stimulating factor support as needed) followed by 12 qw paclitaxel doses (80 mg/m2) + four q3w P+H cycles (P 840 mg, then 420 mg; H 8mg/kg, then 6 mg/kg). Cohort B received four q3w fluorouracil/epirubicin/cyclophosphamide cycles (500 mg/m2/100 mg/m2/600 mg/m2) followed by four q3w docetaxel cycles (75 mg/m2 escalated to 100 mg/m2) + four q3w P+H cycles. Surgery was performed after cycle 8 for both cohorts. The primary objective was to evaluate cardiac safety during the neoadjuvant period, assessed by incidence of 1) New York Heart Association (NYHA) Class III/IV heart failure and 2) significant LVEF declines (≥10% from baseline with a value of <50%). Secondary objectives included assessments of adverse event (AE) rates and tpCR (ypT0/Tis ypN0; NX was considered non-tpCR). Results are descriptive; no statistical hypothesis testing was planned. Results: Four hundred one pts were enrolled between Jul 2014–Aug 2015. Clinical cutoff was Mar 3, 2016. Demographics and baseline characteristics were generally balanced between cohorts; 64.3% v 61.7% of pts had centrally confirmed hormone receptor (HR)-positive disease and 95.0% v 93.0% had T1–T3 primary tumors. Three pts in Cohort A and none in Cohort B experienced NYHA Class III/IV heart failure during neoadjuvant treatment (table). Thirteen pts in Cohort A v four in Cohort B had significant LVEF declines (table). One Cohort B pt's LVEF decline was prior to anti-HER2 treatment. AE and serious AE (SAE) rates were well balanced between cohorts. The most common AEs were nausea, diarrhea, and alopecia. The most common SAE was febrile neutropenia. tpCR rates were similar between cohorts (table). Neoadjuvant periodCohort ACohort BSafety: Pts, n (%)N=199N=198NYHA Class III/IV heart failure3 (1.5%)0Significant LVEF decline13 (6.5%)4 (2.0%)tpCR (ypT0/Tis ypN0): Pts, n/N (%) Intention-to-treat123/199 (61.8%)122/201 (60.7%)HR-positive66/128 (51.6%)71/124 (57.3%)HR-negative53/65 (81.5%)51/75 (68.0%) Conclusion: Cardiac and general safety of the two anthracycline-containing regimens in BERENICE were as expected and were consistent with the known P+H+CT profiles. Both regimens were active, and tpCR rates were high. Citation Format: Swain SM, Ewer MS, Viale G, Delaloge S, Ferrero JM, Verrill M, Colomer R, Vieira C, Werner TL, Douthwaite H, Bradley D, Waldron-Lynch M, Eng-Wong J, Dang C. Primary analysis of BERENICE: A phase II cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with locally advanced, inflammatory, or early-stage, unilateral, and invasive HER2-positive breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-41.

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

Phase I study of neoadjuvant chemotherapy with xeloda and oxaliplatin (G-XELOX) for locally advanced gastric cancer.

149 Background: Prognosis for locally advanced gastric cancer, such as clinical T4 disease, bulky nodal involvement, type 4 and large type 3 gastric cancer, remains unsatisfactory, even with D2 gastrectomy followed by adjuvant chemotherapy. Neoadjuvant chemotherapy is a promising approach, and combination chemotherapy with Xeloda and oxaliplatin (G-XELOX) is recognized as a potentially promising regimen for gastric cancer. However, the use of neoadjuvant chemotherapy consisting of G-XELOX for locally advanced gastric cancer has not been reported. The aim of this study was to evaluate the incidence of dose limiting toxicities (DLTs) during the neoadjuvant chemotherapy and to determine the maximum tolerated dose (MTD) and recommended dose of preoperative chemotherapy combined with oxaliplatin with a fixed Xeloda dose for locally advanced gastric cancer. Methods: Patients received two cycles of neoadjuvant chemotherapy with oxaliplatin on day 1, as well as Xeloda (2000 mg/m2/day, b.i.d.) for 14 days, repeatedly every 3 weeks. They then underwent gastrectomy with curative D2/3 lymph-node dissection followed by adjuvant S-1 (80 mg/m2/day, b.i.d.) for one year. A decrease of oxaliplatin dose was planned (starting at level 1, 130 mg/m2). Results: Six patients (5 male, 1 female) with a median age of 72 (range 68-79) were enrolled. MTD was not reached at level 1. Oxaliplatin 130 mg/m2 in combination with Xeloda 2000 mg/m2/day, b.i.d. could be administered with acceptable toxicity. No treatment-related death was observed. Most frequent drug-related AEs during the neoadjuvant chemotherapy period were G1 anemia, G1/2 thrombocytopenia and G1 peripheral neuropathy. One patient refused surgical resection, therefore five received resection with curative intent. Of the five patients, all achieved a pathological downstaging after neoadjuvant G-XELOX therapy. The incidence of operative morbidity was tolerable. Conclusions: Neoadjuvant chemotherapy with G-XELOX regimen was feasible by patients with locally advanced gastric cancer. Clinical trial information: UMIN000015950.

A double blinded, placebo-controlled pilot study to examine reduction of CD34 +/CD117 +/CD133 + lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1 + cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

Venous thromboembolism in patients with esophageal or gastric cancer undergoing neoadjuvant chemotherapy.

There is a well-established link between cancer and venous thromboembolism (VTE), and patients receiving chemotherapy for esophageal or gastric cancer appear at high risk of developing VTE. The incidence of VTE in the neoadjuvant setting in these patients is poorly understood, as is the role for thromboprophylaxis during neoadjuvant chemotherapy. A PubMed search was conducted using a combination of terms including; esophageal & gastric cancer, deep venous thrombosis (DVT), VTE, neoadjuvant, chemotherapy and chemoradiotherapy. One hundred and fifty-four articles were retrieved and a narrative review was conducted. For patients with esophageal and gastric cancer the incidence of VTE ranged from 4 to 19%. Gastric cancer (Odds Ratio [OR] 6.38, [95% CI: 1.96-20.80]) and Stage III/IV disease, (OR 5.16 [95% CI: 1.29-20.73]) were identified as risk factors for developing VTE. Neoadjuvant chemotherapy was identified as an independent risk factor for developing VTE. Symptomatic and asymptomatic VTE have a similar effect on mortality. Median overall survival for asymptomatic VTE was 13.9months (95% CI: 5.0-∞) versus 12.8months (95% CI: 4.7-30.3) if the VTE was symptomatic. Neoadjuvant chemotherapy is a significant risk factor for VTE in patients with esophageal and gastric cancer. Intervention to minimize the risk using pharmacological and mechanical thromboprophylaxis should be considered, and this should start in the neoadjuvant period.

Abstract P1-14-16: Weekly paclitaxel, trastuzumab, carboplatin is a highly effective neoadjuvant regimen in HER2-positive breast cancer: Results from the TRAIN-study

Abstract Background A trastuzumab/carboplatin/docetaxel regimen is an established alternative for the more commonly used and toxic anthracycline/cyclophosphamide containing regimen in HER2-positive breast cancer. Weekly paclitaxel, however, may be more effective and better tolerable than three-weekly docetaxel. Aim To assess the efficacy and safety of an anthracycline/cyclophosphamide-free neoadjuvant treatment regimen with weekly paclitaxel, carboplatin and trastuzumab in HER2-positive breast cancer. Patients and methods The TRAIN-study is a multicenter phase II trial which was developed during the 9th ECCO/AACR/ASCO Workshop on "Methods in Clinical Cancer Research" in Flims, Switzerland. Patients with stage II or III HER2-positive breast cancer were eligible. Treatment consisted of weekly administrations of paclitaxel ([P], 70mg/m2), trastuzumab ([T], 2mg/kg, loading dose 4mg/kg), and carboplatin ([C], AUC = 3mg/ml/minute) for a total of 24 weeks. In cycles 7, 8, 15, 16, 23 and 24 only trastuzumab was administered. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive tumor cells in the breast and axilla. Event-free survival was evaluated as a secondary endpoint. In addition, we report efficacy results in an additional cohort of patients treated with the same regimen after study closure. Toxicity data were only recorded for the study population. Results Baseline characteristics of 109 study patients and 72 additional patients were similar. The pCR rate in the study population was 43% (95% confidence interval [CI] 33-53%) and in all evaluable patients combined 47% (95% CI 39-54%). The median follow-up was 41 months (interquartile range [IQR] 20-53). The 3-year event-free survival estimate was 89% (95% CI 84-95%). Patients who achieved a pCR had a better prognosis than patients who did not (hazard ratio [HR] 0.33; 95% CI 0.11-1.00, p<0.05). In the study population the most common grade 3-4 adverse events were neutropenia (67%) and thrombocytopenia (43%). Febrile neutropenia occurred in less than five percent of patients. During the neoadjuvant treatment period no symptomatic left ventricular systolic dysfunction was observed. Dose reductions were implemented in 56% of study patients and at least one chemotherapy dose was skipped in 67% of patients. Conclusion Weekly paclitaxel, trastuzumab, and carboplatin is a highly effective neoadjuvant regimen in HER2-positive breast cancer with manageable toxicity. In the currently running randomized TRAIN-2 study this regimen will be directly compared to an anthracycline/cyclophosphamide containing neoadjuvant regimen in the setting of dual HER2-blockade with pertuzumab (clinicaltrials.gov NCT01996267). Pathologic complete response rate according to population and hormone receptor status All patientsER- and PR-ER+ and/or PR+Study population (n=108)43%53%34%Additional cohort (n=70)53%71%36%Combined population (n=178)47%60%35% Citation Format: van Ramshorst MS, van Werkhoven E, Mandjes IAM, Schot M, Wesseling J, Vrancken Peeters M-JTFD, Rodenhuis S, Oosterkamp HM, Bos MEM, Meerum Terwogt JM, Linn SC, Sonke GS. Weekly paclitaxel, trastuzumab, carboplatin is a highly effective neoadjuvant regimen in HER2-positive breast cancer: Results from the TRAIN-study. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-16.

Abstract OT3-1-01: A two-cohort, phase II, cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive, locally advanced, inflammatory, or early breast cancer

Abstract Background: In HER2-positive early breast cancer (BC), neoadjuvant pertuzumab (P) + trastuzumab (T) + docetaxel (D) significantly increased pathologic complete response (pCR) rates compared with T+D (Gianni L, et al. Lancet Oncol 2012); high pCR rates were also seen with P+T in combination with anthracycline- and non-anthracycline-based regimens (Schneeweiss A, et al. Ann Oncol 2013). Neoadjuvant P+T + chemotherapy was well tolerated, with little increased toxicity associated with the addition of P. Although there was a higher rate of cardiac adverse events (AEs), left ventricular systolic dysfunction (LVSD), and left ventricular ejection fraction (LVEF) declines in P+T-containing arms compared with arms without P, these events were generally asymptomatic, reversible, and patients (pts) recovered with no sequelae. No data are available for neoadjuvant P-based regimens that include paclitaxel (Ptx) and dose-dense doxorubicin plus cyclophosphamide (ddAC), despite these being widely used in (neo)adjuvant BC therapy. This study will evaluate the cardiac safety of two anthracycline-based neoadjuvant regimens in combination with P+T. Following surgery, all pts will receive adjuvant P+T. Trial design: In this non-randomized, open-label, phase II study, two parallel cohorts of pts receive different P-based neoadjuvant treatment regimens. In Cohort A, pts receive four 2-weekly cycles of ddAC, followed by 12 doses of weekly Ptx, plus four 3-weekly (q3w) cycles of P+T from the start of Ptx. In Cohort B, pts receive four q3w cycles of 5-fluorouracil, epirubicin, and cyclophosphamide, followed by four q3w cycles of D, plus four q3w cycles of P+T from the start of D. Following surgery, both cohorts receive 13 cycles of P+T. Eligibility: Pts with HER2-positive, locally advanced, inflammatory, or early BC (size >2 cm or >5 mm and node-positive) are eligible if they have a baseline LVEF ≥55% and an ECOG performance status ≤1. Among the exclusion criteria are prior incisional biopsy or excision of the primary tumor, prior systemic or radiation therapy for cancer, and prior chemopreventive agents. Pts are also excluded if they have poorly controlled hypertension, angina requiring medication, a history of congestive heart failure, serious or uncontrolled cardiac arrhythmia requiring treatment, or myocardial infarction within 6 months prior to enrollment. Aims: The primary objective is cardiac safety during the neoadjuvant period, assessed by incidence of symptomatic LVSD and LVEF changes. Secondary objectives include cardiac safety in the adjuvant and post-treatment periods, incidence of all AEs, pCR rate, event-free survival, invasive disease-free survival, and overall survival. Statistical methods: No statistical hypothesis testing will be performed. Safety and efficacy results will be summarized descriptively. A sample size of 200 pts per cohort is expected to provide sufficient data to evaluate the cardiac safety of each regimen with acceptable precision (exact Clopper-Pearson 95% CIs) around the expected rates. Accrual: The first patient in is planned for August 2014. Citation Format: Sandra M Swain, Michael S Ewer, Hannah Douthwaite, Tania Szado, Maeve Waldron-Lynch, Chau Dang. A two-cohort, phase II, cardiac safety study of pertuzumab, trastuzumab, and neoadjuvant anthracycline-based chemotherapy in patients with HER2-positive, locally advanced, inflammatory, or early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-1-01.

A double blinded, placebo-controlled pilot study to examine reduction of CD34+/CD117+/CD133+ lymphoma progenitor cells and duration of remission induced by neoadjuvant valspodar in dogs with large B-cell lymphoma

We previously described a population of lymphoid progenitor cells (LPCs) in canine B-cell lymphoma defined by retention of the early progenitor markers CD34 and CD117 and “slow proliferation” molecular signatures that persist in the xenotransplantation setting. We examined whether valspodar, a selective inhibitor of the ATP binding cassette B1 transporter (ABCB1, a.k.a., p-glycoprotein/multidrug resistance protein-1) used in the neoadjuvant setting would sensitize LPCs to doxorubicin and extend the length of remission in dogs with therapy naïve large B-cell lymphoma. Twenty dogs were enrolled into a double-blinded, placebo controlled study where experimental and control groups received oral valspodar (7.5 mg/kg) or placebo, respectively, twice daily for five days followed by five treatments with doxorubicin 21 days apart with a reduction in the first dose to mitigate the potential side effects of ABCB1 inhibition. Lymph node and blood LPCs were quantified at diagnosis, on the fourth day of neoadjuvant period, and 1-week after the first chemotherapy dose. Valspodar therapy was well tolerated. There were no differences between groups in total LPCs in lymph nodes or peripheral blood, nor in event-free survival or overall survival. Overall, we conclude that valspodar can be administered safely in the neoadjuvant setting for canine B-cell lymphoma; however, its use to attenuate ABCB1+ cells does not alter the composition of lymph node or blood LPCs, and it does not appear to be sufficient to prolong doxorubicin-dependent remissions in this setting.

897P - Neoadjuvant Therapy in Advanced Ovarian Cancer Patients: Efficiency of Screening By Laparoscopy for Clinical Trial Recruitment

ABSTRACT Aim: There is an important literature supporting the role of staging laparoscopy to predict the chances of optimal cytoreduction but its role to screen patient for inclusion in neoadjuvant therapy clinical trial is unknown. We report here the results of screening by laparoscopy for inclusion in a clinical trial testing the efficacy of bevacizumab in the neoadjuvant settting (Anthalya: A Randomized, Open-label, Phase II Study Assessing the Efficacy and the Safety of Bevacizumab in Neoadjuvant Therapy in Patients With FIGO Stage IIIC/IV Ovarian, Tubal or Peritoneal Adenocarcinoma, Initially Unresectable. NCT01739218). Methods: We are currently conducting a clinical trial to evaluate the efficacy of neoadjuvant bevacizumab and chemotherapy measured by the rate of complete resection, defined as the removal of all macroscopic residual tumour at interval debulking surgery (IDS). Secondary objectives are: safety, Objective Response Rate for the neoadjuvant period and after all courses of treatment and monitoring of CA 125. Before randomization, patients with suspicion of stage IIIC-IV ovarian cancer had a laparoscopy to have a histological assessment of the tumor, to document the FIGO stage and to evaluate resectability for inclusion. Standard pictures and scoring are performed during this laparoscopy and during IDS. We report here the results of screening by laparoscopy. Results: This multicenter study is conducted in 14 centers. Over a 16 month period, 182 and 82 patients have been screened and randomized, respectively. The proportion of screening/inclusion in the paticipating centers ranged from 16% to 100% (mean: 46%). Reasons for non inclusion were resectable tumor (60%), non ovarian/tubal/peritoneal adenocarcinoma histology or contra-indication to carboplatin/taxol/bevacizumab (29%), patient refusal (1%). The screening success was not statistically related to the specialty of the PI in each center (medical oncologist vs surgical oncologist, p = 0.09) or to the volume of patients screened (p = 0.09). Conclusions: In patients with suspicion of ovarian cancer (based on imaging, CA125 and clinical data), screening by laparoscopy resulted in eligibility of 46% of patients for inclusion in a neoadjuvant therapy clinical trial. Resectable tumors was the first reason for non inclusion in this neoadjuvant therapy trial. Disclosure: R. Rouzier: membership on an advisory board; V. Menguy: Employee; Y. Ghazi: Employee;. All other authors have declared no conflicts of interest.

Bicalutamide (150 mg) monotherapy versus LHRHa as neoadjuvant treatment in intermediate- and high-risk prostate cancer: A case matched study.

226 Background: The role of neo-adjuvant Lutenising Hormone Releasing Hormone Agonist (LHRHa) therapy prior to radical radiotherapy of intermediate and high risk prostate cancer (PC) has been clearly defined. Anti-androgen (AA) monotherapy is often used as an alternative to castration therapy in this setting due to a more favorable toxicity profile, however the evidence base is weaker. We compared biochemical failure free survival (BFFS) and prostate-specific antigen (PSA) kinetics in men receiving radical radiotherapy for localised prostate cancer and neo-adjuvant hormones with either AA or LHRHa therapy. Methods: All men with intermediate and high risk PC treated with AA monotherapy prior to radical prostate radiotherapy between April 2004 and December 2008 were individually case matched for key prognostic factors with men treated with neoadjuvant LHRHa monotherapy at our institution. BFFS, PSA kinetics, and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level were analyzed. Results: Sixty five men treated with AA monotherapy were matched to with 65 men treated with LHRHa. The median follow-up was 74 months and 67 months, respectively. Phoenix BFFS was seen in 14 (23.4%) and nine (13.8%) of AA and LHRHa patients respectively with the log rank test indicating no statistically significant difference between the groups. Statistically significant differences were seen between groups in the PRPH-PSA with a geometric mean of 2.0ng/ml (range 0.1 – 11.2) for AA patients and 1.0ng/ml (range 0.1 – 11.1) for LHRHa patients (p<0.001). There was no significant difference between groups in the geometric mean PSA halving time or velocity during the neo-adjuvant period. A PRPH-PSA of less than 1.0ng/ml and less than 0.1ng/ml was seen in 16 (24.6%) and two (3%) of the AA patients and 34 (52.3%) and three (4.6%) of LHRHa patients, respectively. Conclusions: Our case matched study demonstrates that there was no statistical difference in BFFS between patients receiving neo-adjuvant AA versus LHRHa at median follow-up of 72 months. AA monotherapy resulted in less PRPH-PSA suppression when compared to neo-adjuvant LHRHa alone. Longer follow-up is required to determine if the differences in PSA kinetics translate into clinically meaningful differences.

Abstract P1-15-03: Preoperative endocrine treatment with letrozole ± triptorelin in patients with ER (estrogen receptor) and PgR (progesterone receptor) positive locally advanced breast cancer

Abstract Background: Neoadjuvant endocrine therapy demonstrated activity in endocrine responsive locally advanced breast cancer. Proper duration of neoadjuvant therapy has not yet established. We aimed to assess the efficacy and safety of longer duration of letrozole alone or combined with triptorelin in pre-or postmenopausal breast cancer patients. Methods: Premenopausal and postmenopausal patients (pts) with ER and PgR-positive > 50% of the cells, HER2-negative, T2-T4b breast cancer were considered eligible. Patients received letrozole 2,5 mg per day (plus triptorelin 3,75 mg/month in premenopausal pts) for 3-9 months. Tumor response was measured by caliper, ultrasound (US) and mammography. The primary endpoint was overall tumour response (ORR) (complete response plus partial response), during the neoadjuvant treatment period for the intention-to-treat population. Results: Between 2009 and 2013, 54 pts were enrolled and 46 (34 pre- and 12 post-menopausal) pts were evaluable for ORR. Median age was 44 and 55 years, respectively. 44 patients are evaluable. The ORR was 77% in the premenopausal group and 67% in the postmenopausal group. One premenopausal patient had a pathological complete response (pCR). The mean time to complete/partial response was 4.9 months (95% CI: 3.8-6.0) in the premenopausal group and 3.6 months (95% CI: 0.8-6.4) in the postmenopausal group. Overall, 56% of premenopausal and 58% of postmenopausal pts underwent breast conservative surgery. Ki67-LI after surgery had a mean decrease of 33% (95% CI: 16%-50%, p-value = 0.0005) and 42% (95% CI: 18%-65%, p-value = 0.0030) in pre-and postmenopausal pts, respectively. Therapy was well tolerated in both groups with no grade 3/4 toxicity. The most common adverse events in both groups were hot flashes, fatigue, arthralgias/stiffness, and myalgias. Conclusions: The results of this preliminary analysis support neoadjuvant endocrine therapy for a duration of up to 9 months. The combination of letrozole plus triptorelin might represent an alternative neoadjuvant treatment option for premenopausal women with early stage endocrine-responsive breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-15-03.

Factors associated with improved biochemical response to neoadjuvant androgen deprivation therapy before definitive radiation therapy in prostate cancer patients.

In prostate cancer patients treated with androgen deprivation therapy (ADT) and radiation therapy (RT), a pre-RT PSA level 0.5 ng ml(-1), determined after neoadjuvant ADT and before RT, predicts for worse survival measures. The present study sought to identify patient, tumor and treatment characteristics associated with the pre-RT PSA in prostate cancer patients. We reviewed the charts of all patients diagnosed with intermediate- and high-risk prostate cancer and treated with a combination of neoadjuvant (median, 2.2 and 2.5 months, respectively), concurrent, and adjuvant ADT and RT between 1990 and 2011. A total of 170 intermediate- and 283 high-risk patients met inclusion criteria. On multivariate analysis, both intermediate- and high-risk patients with higher pre-treatment PSA (iPSA) were significantly less likely to achieve a pre-RT PSA <0.5 ng ml(-1) (iPSA 10.1-20 ng ml(-1): P=0.005 for intermediate risk; iPSA 10.1-20 ng ml(-1): P=0.005, iPSA >20 ng ml(-1): P<0.001 for high risk). High-risk patients undergoing total androgen blockade were more likely to achieve a pre-RT PSA <0.5 ng ml(-1) (P=0.031). We observed an interaction between race and type of neoadjuvant ADT (P=0.074); whereas African-American men on total androgen blockade reached pre-RT PSA <0.5 ng ml(-1) as frequently as other men on total androgen blockade (P=0.999), African-American men on luteinizing hormone-releasing hormone (LH-RH) agonist monotherapy/orchiectomy were significantly less likely to reach pre-RT PSA <0.5 ng ml(-1) compared with other men on LH-RH monotherapy/orchiectomy (P=0.001). Our findings suggest that total androgen blockade in the neoadjuvant period may be beneficial compared with LH-RH monotherapy for achieving a pre-RT PSA <0.5 ng ml(-1) in African-American men with high-risk prostate cancer. In addition, men with higher iPSA are more likely to have a pre-RT PSA greater than 0.5 ng ml(-1) in response to neoadjuvant ADT and are therefore candidates for clinical trials testing newer, more aggressive hormone-ablative therapies.

Biliary stents for pancreas cancer with obstruction: the problem with plastic.

Biliary stents for pancreas cancer with obstruction: the problem with plastic.

1261P - Erlotinib as Neoadjuvant Treatment in Patients with IIIA-N2 Non-Small Cell Lung Cancer(NSCLC) With Activating Epidermal Growth Factor Receptor (EGFR) Mutation (NCT01217619, ESTERN)

ABSTRACT Background Patients with stage IIIA N2 NSCLC have poor outcomes with 5-year survival rate of approximately 15% after treatment with surgical resection or chemo-radiotherapy. Tyrosine kinase inhibitor monotherapy have been demonstrated a significant improvement in tumor response rate and progression free survival as the first line treatment for metastatic NSCLC patients with activating EGFR mutation. The objective of this trial is to explore the efficacy and safety profile of erlotinib as neoadjuvant treatment in patients of stage IIIA-N2 NSCLC with activating EGFR mutation. Material and methods This is a single arm, one center, phase II study of erlotinib as neoadjuvant treatment in patients with Endobronchial Ultrasound (EBUS) confirmed stage IIIA-N2 NSCLC with activating EGFR mutation in exon 19 or 21. The primary endpoint is to evaluate radical resection rate. A total of 44 patients will be enrolled. Major inclusion criteria: IIIA-N2 NSCLC Patients with pathologically confirmed ipsilateral mediastinal metastasis by EBUS. The biopsy specimen shows activating EGFR mutation in exon 19 or 21. Treatment schedule All the recruitment patients will be treated by erlotinib 150mg orally per day for 56 days for neoadjuvant period. Patients will be assessed by Chest CT for the efficacy evaluation in day 29 and right after day 56. All the post-operative patients will receive standard adjuvant treatment which will be decided by the investigator. Current enrollment 48 patients have been screened, and 7 patients met the inclusion criteria and were enrolled. 2 patients are still on neoadjuvant treatment, 5 patients have completed the neoadjuvant therapy, and RECIST evaluation showed partial response in 2 patients, disease progression in 2 patients, and disease stable in 1 patient. Due to active hepatitis and technical infeasibility, 2 patients with PR didn't receive surgery, only one SD patient received R0 surgery. Disclosure All authors have declared no conflicts of interest.

Neoadjuvant Hormone Therapy for Radical Prostate Radiotherapy: Bicalutamide Monotherapy vs. Luteinizing Hormone–Releasing Hormone Agonist Monotherapy: A Single-Institution Matched-Pair Analysis

BackgroundThe purpose of this study was to compare the prostate-specific antigen (PSA) response to either neoadjuvant bicalutamide (BC) monotherapy or neoadjuvant luteinizing hormone–releasing hormone agonist (LHRHa) monotherapy and the subsequent effect on biochemical failure–free survival (BFFS) in men receiving radical radiotherapy (RT) for localized prostate cancer. Patients and MethodsThis was a retrospective review of consecutive men treated with BC monotherapy before radical prostate RT who were individually case-matched to men treated with neoadjuvant LHRHa monotherapy. PSA kinetics and absolute pre-RT posthormone PSA (PRPH-PSA) level and subsequent BFFS were analyzed. ResultsSixty-five men treated with BC monotherapy with a median follow-up of 44 months were individually matched with 65 men treated with LHRHa with a median follow-up of 54 months. Statistically significant differences were noted between groups in the PRPH-PSA, with a mean of 2.9 ng/mL (0.1-11.2 ng/mL) for patients receiving BC treatment and 1.8 ng/mL (0.1-11.1 ng/mL) for patients receiving LHRHa treatment (P < .001). A PRPH-PSA of < 1.0 and < 0.1 ng/mL was seen in 16 (24.6%) and 2 (3%) of the patients receiving BC and 34 (52.3%) and 3 (4.6%) patients receiving LHRHa, respectively. There were no significant differences between groups in either PSA halving time or velocity. Phoenix biochemical failure occurred in 10 (15.4%) and 8 (12.3%) patients receiving BC and patients receiving LHRHa, respectively. Neither PRPH-PSA level nor PSA kinetics during the neoadjuvant period predict for subsequent BFFS at this duration of follow-up. ConclusionsAlthough neoadjuvant BC therapy did not result in equivalent PRPH-PSA suppression when compared with neoadjuvant LHRHa alone, there was no difference in biochemical failure rates between cohorts at 50 months' median follow-up. Longer follow-up is required.