SC Arm Research Articles

Neoadjuvant Docetaxel, Oxaliplatin, and S-1 Plus Surgery and Adjuvant S-1 for Resectable Advanced Gastric Cancer: Updated Overall Survival Outcomes From Phase III PRODIGY.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The phase III PRODIGY study demonstrated that neoadjuvant chemotherapy with docetaxel, oxaliplatin, and S-1 (DOS) followed by surgery and adjuvant S-1 chemotherapy (CSC) improved progression-free survival (PFS) compared with surgery followed by adjuvant S-1 (SC) for patients with resectable locally advanced gastric cancer (LAGC) with clinical T2-3N+ or T4Nany disease. The primary end point was PFS. Overall survival (OS) was the secondary end point. We herein report the long-term follow-up outcomes, including OS, from this trial. A total of 238 and 246 patients were randomly assigned to the CSC and SC arms, respectively, and were treated (full analysis set). As of the data cutoff (September 2022), the median follow-up duration of the surviving patients was 99.5 months. Compared with SC, CSC significantly increased the OS (adjusted hazard ratio [HR], 0.72; stratified log-rank P = .027) with an 8-year OS rate of 63.0% and 55.1% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (HR, 0.70; stratified log-rank P = .016). In conclusion, neoadjuvant DOS chemotherapy, as part of perioperative chemotherapy, prolonged the OS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1. It should be considered one of the standard treatment options for patients with LAGC in Asia.

P686 Comparison between therapeutic sequences starting with IV induction-biologic versus SC-induction biologic in bionaïve-patients with ulcerative colitis: results from the APPETISER study

Abstract Background Recent data suggest that infliximab and vedolizumab would be more effective than subcutaneous anti -TNF as 1st line-biologic, leading therapeutic sequencing challenging. We compared the effectiveness of a strategy starting with a first-line bologic with IV induction (IFX or VDZ = IV group) compared to a biologic with SC induction (adalimumab or golimumab = SC group) to induce and maintain steroid-free clinical remission during the first 24 months. Methods From a database of IBD referral center, all consecutive UC patients ≥ 18 years-old who started a first line of biologic (IFX, VDZ, ADAor GLM) for active UC with follow-up > 6 months were included. Prior colectomy or severe acute colitis were excluded. The primary endpoint was remission defined according to PRO2 (PRO2-remission) as the absence of bleeding, normalization of transit (Mayo stool frequency subscore = 0) and no steroid. PRO2-remission was defined as a binary criterion each month (the statistical unit being the month and not the patient). The secondary endpoints concerned the analysis by patient and were CFREM (partial Mayo score ≤ 2 without steroid) and endoscopic remission (CFREM + score Endoscopic Mayo ≤ 1) at week 12 . All comparisons were adjusted using propensity scores on potential confounders. Analysis by month was performed using mixed models to account for repeated data. Results Overall, 130 patients were included including 60 patients in the IV group (IFX= 50 and VDZ= 10) and 70 in the SC group (ADA= 48 and GLM= 22). The populations had similar characteristics at baseline apart from concomitant immunosuppressant more frequent in IV group (55.9% vs 21.7%). 2nd line treatment was started in 26.7% of patients in IV group (ADA in 48.8%, VDZ 25.5% and ustekinumab 18.8%) and 87.1% of patients in SC group (IFX in 54.1%, VDZ 31.1%). After adjustment, the rate of CFREM at week 12 was significantly higher in the IV arm (70.8%) than in the SC arm (33.0%) (p < 0.001). The rate of endoscopic remission at W12 was 22.1% and 10.0% in the IV and SC arms, respectively (p =0.18). In this study, 3350 months were analyzed (1180 in the IV arm and 1175 in the SC arm). The percentage of months spent in PRO2-CFREM in the first 24 months (primary endpoint) was greater in the IV arm than in the SC arm (74.2% vs 46.6%; p<0.001). The percentage of months spent in CFREM was higher in the IV arm in the first 6 months (60.4% vs 18.9%), but also between M7 and M12 (73.1% vs 38.6%), M13 and M18 (79.9% vs 57.0%) or M19 and M24 (83.3% vs 64.6%) (p < 0.001 for all comparisons). Conclusion A therapeutic sequence starting with IV induction biologic (IFX or VDZ) was more effective than starting with a SC induction anti-TNF (ADA and GLM ) to induce and maintain remission at short and long-term in UC.

DNA mismatch repair deficiency and outcomes of patients with locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery plus postoperative S-1: a sub-analysis of the phase 3 PRODIGY trial.

The benefit of adjuvant chemotherapy for locally advanced gastric cancer (LAGC) patients with DNA mismatch repair (MMR) deficiency (D-MMR) is controversial due to concerns about its potential detrimental effect. The PRODIGY trial showed the survival benefit of adding preoperative docetaxel, oxaliplatin, and S-1 (DOS) to surgery plus postoperative S-1 for LAGC patients. In this sub-analysis, we evaluated the benefit of preoperative DOS according to MMR status. Among patients enrolled in the PRODIGY trial treated with either preoperative DOS followed by surgery and postoperative S-1 (CSC arm), or surgery and postoperative S-1 (SC arm) at Asan Medical Center (n = 249), those in the full analysis set with available tissue to assess MMR status were included in the present analysis. A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included (median age, 58years [range, 27-75]), and 21 patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had D-MMR tumors. Progression-free survival and overall survival tended to be superior in the CSC arm than in the SC arm among D-MMR patients (HR 0.48 [95% CI 0.09-2.50]; log-rank P = 0.37 and HR 0.55 [95% CI 0.11-2.86]; log-rank P = 0.46, respectively), as well as among proficient MMR (P-MMR) patients (HR 0.68 [95% CI 0.46-1.03]; log-rank P = 0.07 and HR 0.75 [95% CI 0.49-1.14]; log-rank P = 0.17, respectively). Preoperative DOS followed by surgery and postoperative S-1 may be considered a treatment option for LAGC patients regardless of MMR status.

Neoadjuvant docetaxel, oxaliplatin, and S-1 plus surgery and adjuvant S-1 for resectable advanced gastric cancer: Final survival outcomes of the randomized phase 3 PRODIGY trial.

30 Background: The phase 3 PRODIGY study compared neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy followed by surgery followed by adjuvant S-1 with surgery followed by adjuvant S-1 for Korean patients with resectable locally advanced gastric cancer (LAGC) (Kang et al. J Clin Oncol. 2021). The planned analysis of the primary endpoint of PRODIGY showed that the addition of neoadjuvant DOS to surgery and adjuvant S-1 improved progression-free survival (PFS). We herein report the long-term follow-up outcomes, including overall survival (OS), from this trial. Methods: Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma with clinical T2-3N+ or T4Nany disease were enrolled from 18 Korean study sites. Patients were randomly assigned to D2 surgery followed by adjuvant S-1 (40–60 mg orally twice a day, days 1–28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1–14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS. OS was the secondary endpoint. This analysis presents the final assessment of the outcomes after 5 years. Results: A total of 266 and 264 patients were randomly assigned to the CSC and SC arms, respectively, among which 238 and 246 patients were treated and included in the full analysis set. As of the data cut-off date (SEP-2022), the median follow-up duration of the surviving patients was 99.5 months (range, 68.6–127.7 months). As compared to SC, CSC significantly increased the OS (adjusted hazard ratio, 0.72; 95% CI, 0.54 to 0.97; stratified log-rank P=0.028) with a 5-year OS rate of 66.8% and 63.0% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (adjusted hazard ratio, 0.71; 95% CI, 0.53 to 0.94; stratified log-rank P=0.019) with a 5-year PFS rate of 60.6% and 56.9% for the CSC and SC arms, respectively. Among the patient subgroups determined based on different clinical T/N categories, a patient subgroup with cT4Nany disease showed the greatest relative risk reduction in OS with neoadjuvant chemotherapy (HR 0.69, 95% CI 0.51–0.95). Conclusions: The addition of neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, to surgery and adjuvant S-1 prolonged the OS and PFS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1 alone. Neoadjuvant DOS chemotherapy should be considered one of the standard treatment options for patients with LAGC in Asia. Unlike in the Western setting, neoadjuvant chemotherapy may be preferentially considered for patients with cT4 disease in Asia. Clinical trial information: NCT01515748 .

370-OR: Optimized Weight Loss with Bimagrumab—Reduced Fat Mass with Increased Muscle Mass by Appetite-Independent Mechanisms

Background: Obesity is managed with lifestyle changes or incretin Tx to produce wt loss that is challenging to maintain long-term, perhaps because lean mass loss accounts for 20-40% of total wt loss. Semaglutide Tx results in rapid wt loss with 35% lower caloric intake, no further wt loss after 1 yr and rapid wt regain post-Tx. Bimagrumab (bima), a mAb to ActRIIA/ActRIIB, blocks activin pathways, leading to increased lean mass/decreased fat mass in numerous clinical studies (N=1561). Effects of bima IV or SC on fat and muscle were evaluated by DXA and MRI. Results: In a Ph2 study of bima 10 mg/kg IV q4wks vs placebo (respectively) in persons with overweight/obesity and T2DM (N=75), LS mean change at Wk 48 in body wt was −5.9 vs −0.8 kg (p<0.001; −7.5% vs −1.1%), with minimal change in daily caloric intake. DXA: LS mean change at Wk48 in total body (TB) fat mass was −7.5 vs −0.2 kg (p<0.001; −22.2% vs −0.3%), TB lean mass +1.7 vs −0.4 kg (p<0.001; +3.6% vs -0.9%), and appendicular lean mass +0.5 vs −0.3 kg (p=0.009; +2.5% vs −1.1%); fat mass loss was maintained 12 wks post-last dose. MRI: LS mean change at Wk24 in visceral adipose tissue was −1.5 vs +0.2 L (p<0.001; −36.1% vs +3.6%), absolute hepatic fat fraction (FF, %) −4.6 vs +0.2 (p=0.006; -23.6% vs +14.3%), and paravertebral muscle (PVM) mass +363.3 vs −331.0 mm2 (p=0.003; +6.4% vs -4.6%); a trend for decreased PVM fat fraction and intermuscular adipose tissue was observed (p=NS). Bima improved HbA1c (%) by -0.76 vs +0.04. AEs included diarrhea, muscle spasms. In a Ph1 study comparing bima 525 mg SC (N=12) and 700 mg IV (N=8), q4wks X3, fat mass loss and lean mass (total body and appendicular) increase were similar, with fat mass loss maintained 12 wks post-last dose; SC arm had fewer AEs than IV arm. Conclusions: Bimagrumab Tx results in decreased fat deposition in tissues and increased muscle mass despite minimal change in caloric intake, which could lead to durable, high quality wt loss. A study of bima in obesity without T2DM is ongoing (NCT05616013). Disclosure K.M.Attie: Employee; Versanis Bio. S.B.Heymsfield: None. L.Mindeholm: Consultant; Versanis Bio, Novartis AG, Stock/Shareholder; Novartis AG, Alcon Research, LLC, Novo Nordisk A/S. S.Spruill: None. M.Pruzanski: None. L.Klickstein: None.

Neoadjuvant docetaxel, oxaliplatin, and s-1 plus surgery and adjuvant s-1 for resectable advanced gastric cancer: Final survival outcomes of the randomized phase 3 PRODIGY trial.

4067 Background: The phase 3 PRODIGY study compared neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy followed by surgery followed by adjuvant S-1 with surgery followed by adjuvant S-1 for Korean patients with resectable locally advanced gastric cancer (LAGC) (Kang et al. J Clin Oncol. 2021). The planned analysis of the primary endpoint of PRODIGY showed that the addition of neoadjuvant DOS to surgery and adjuvant S-1 improved progression-free survival (PFS). We herein report the long-term follow-up outcomes, including overall survival (OS), from this trial. Methods: Patients with histologically confirmed primary gastric or gastroesophageal junction adenocarcinoma with clinical T2-3N+ or T4Nany disease were enrolled from 18 Korean study sites. Patients were randomly assigned to D2 surgery followed by adjuvant S-1 (40–60 mg orally twice a day, days 1–28 q6w for eight cycles; SC group) or neoadjuvant DOS (docetaxel 50 mg/m2, oxaliplatin 100 mg/m2 intravenously day 1, S-1 40 mg/m2 orally twice a day, days 1–14 q3w for three cycles) before D2 surgery, followed by adjuvant S-1 (CSC group). The primary endpoint was PFS. OS was the secondary endpoint. This analysis presents the final assessment of the outcomes after 5 years. Results: A total of 266 and 264 patients were randomly assigned to the CSC and SC arms, respectively, among which 238 and 246 patients were treated and included in the full analysis set. As of the data cut-off date (SEP-2022), the median follow-up duration of the surviving patients was 99.5 months (range, 68.6–127.7 months). As compared to SC, CSC significantly increased the OS (adjusted hazard ratio, 0.72; 95% CI, 0.54 to 0.97; stratified log-rank P=0.028) with a 5-year OS rate of 66.8% and 63.0% for the CSC and SC arms, respectively. CSC also significantly improved the PFS (adjusted hazard ratio, 0.71; 95% CI, 0.53 to 0.94; stratified log-rank P=0.019) with a 5-year PFS rate of 60.6% and 56.9% for the CSC and SC arms, respectively. Conclusions: The addition of neoadjuvant docetaxel, oxaliplatin and S-1 (DOS) chemotherapy, as part of perioperative chemotherapy, to surgery and adjuvant S-1 prolonged the OS and PFS of Asian patients with LAGC relative to patients treated with surgery and adjuvant S-1 alone. Neoadjuvant DOS chemotherapy should be considered one of the standard treatment options for patients with LAGC in Asia. Clinical trial information: NCT01515748 .

DNA mismatch repair deficiency and outcomes of patients with resectable locally advanced gastric cancer treated with preoperative docetaxel, oxaliplatin, and S-1 plus surgery and postoperative S-1 or surgery and postoperative S-1: A sub-analysis of the phase 3 PRODIGY trial.

431 Background: Benefit of perioperative or postoperative chemotherapy for resectable locally advanced gastric cancer (LAGC) with DNA mismatch repair (MMR) deficiency is controversial due to concerns about the potential detrimental effect of perioperative chemotherapy. In this sub-analysis of the phase 3 PRODIGY trial, we evaluated the association between the MMR status and outcomes of resectable LAGC treated with perioperative or postoperative chemotherapy. Methods: Among 249 patients with resectable LAGC enrolled in the PRODIGY trial treated with either perioperative chemotherapy (preoperative docetaxel, oxaliplatin, and S-1 [DOS] followed by surgery and postoperative S-1; CSC arm) or surgery and postoperative S-1 (SC arm) at Asan Medical Center, those in the full analysis set with available tissue for MMR status assessment by immunohistochemistry were included in this study. Progression-free survival (PFS) was compared according to the MMR status and treatment arm. In the CSC arm, the pathologic complete response (pCR) rate was compared according to the MMR status. Results: A total of 231 patients (CSC arm, n = 108; SC arm, n = 123) were included in the study (median age, 58 years [range, 27–75]). Twenty-one patients (CSC arm, n = 8 [7.4%]; SC arm, n = 13 [10.6%]) had deficient MMR (D-MMR) tumors while the rest had proficient MMR (P-MMR) tumors. There was no significant difference in the baseline characteristics including the clinical stage according to the MMR status. Among patients with P-MMR tumors, PFS tended to be superior in the CSC arm than in the SC arm (hazard ratio [HR] 0.67 [95% confidence interval (CI) 0.44–1.03]; log-rank P = 0.07). Among patients with D-MMR tumors, the PFS of the CSC arm was not inferior to that of the SC arm (HR 0.50 [95% CI 0.10–2.60]; log-rank P = 0.41). In the CSC arm, the pCR rate was 5.0% (5/100) and 12.5% (1/8) in patients with P-MMR and D-MMR tumors, respectively. Conclusions: In this sub-analysis of the PRODIGY trial, the PFS of the CSC arm was not inferior to that of the SC arm among patients with D-MMR LAGC. Among patients who received preoperative DOS, the pCR rate was not lower in patients with D-MMR tumors compared with those with P-MMR tumors. Perioperative chemotherapy consisting of preoperative DOS followed by surgery and postoperative S-1 may be recommended for patients with LAGC regardless of the MMR status.

Population pharmacokinetic and exploratory exposure\u2013response analysis of the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection in patients with HER2-positive early breast cancer in the FeDeriCa study

PurposeTo characterize pertuzumab pharmacokinetics (PK) in FeDeriCa (NCT03493854: fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection [PH FDC SC] versus intravenous pertuzumab plus trastuzumab); derive individual pertuzumab exposures in the PH FDC SC arm for subsequent pertuzumab exposure–response (ER) analyses; compare observed trastuzumab PK with predicted exposures from a previous SC trastuzumab model; assess whether pertuzumab affects trastuzumab PK; evaluate pertuzumab exposure–efficacy and –safety relationships and support the approved SC dosing regimen.MethodsPopulation pharmacokinetic modeling and simulations were used to describe the data. Standard goodness-of-fit diagnostics and prediction-corrected visual predictive checks were used for model performance assessment. Covariates were included from previously reported models. ER analysis was conducted using logistic regression.ResultsSC pertuzumab PK was described adequately by a two-compartment model with first-order absorption; significant covariates included in the final model were albumin, lean body weight, and Asian region; however, these appeared not to be clinically relevant. Trastuzumab concentrations were described adequately by the previous model; there was no evidence of a pertuzumab effect on trastuzumab PK as part of PH FDC SC and higher model-predicted pertuzumab exposure was not associated with differences in pathologic complete response rate or an increased probability of selected grade ≥ 3 adverse events of interest.ConclusionThe approved PH FDC SC dose [loading: 1200/600 mg pertuzumab/trastuzumab (15 mL); maintenance: 600 mg pertuzumab/trastuzumab (10 mL) and 2000 U/mL recombinant human hyaluronidase every 3 weeks] provides a positive benefit–risk profile with comparable efficacy and safety to intravenous pertuzumab plus trastuzumab.

724. Gastrointestinal (GI) PCR vs Stool Cultures: Impact on Length of Hospital Stay (LOS) and Antibiotic Use

BackgroundGI PCR can detect 22 pathogens (bacteria, parasites and viruses) from a single stool sample. Stool cultures are labor intensive and only target the most common diarrheal pathogens (such as Campylobacter, E. coli and a few parasites). We hypothesized that implementation of GI PCR would result in decreased LOS and lower antibiotic use.MethodsThis retrospective study utilized data from review of electronic medical records and included patients aged > 18 years old who were admitted with diarrhea over a 3-year period from 2016 to 2019. LOS and antibiotic use data was collected for patients who had GI PCR from 2017–2019 (GIP arm) and compared with data from patients who had stool cultures from 2016–2017 (SC arm). Differences were assessed using Chi-square or Fisher’s exact test for categorical variables and the Mann Whitney Rank Sum test for continuous variables.ResultsThe analysis included a total of 338 patients, 225 (66.6%) in the GI PCR arm and 113 (33.4%) in the SC arm. A significantly higher proportion of patients in the GIP arm had a positive result compared with the SC arm (26.2% vs. 9.7%, P < .0001; Table 1). Table 2 shows the most frequently isolated organisms. Median LOS was 6 days (IQR: 4–13) for the GIP arm and 5 days (IQR: 3–7) for the SC arm (p=.060); 8 patients in the GIP arm had average LOS of 75 days due to comorbidities and disposition issues. However, within the GIP arm, median LOS was much shorter for patients detected with viruses by PCR vs. those with non-viral pathogens (3.5 days (IQR: 3-7) vs. 6 days (3-12)) There was no difference in antibiotic use between the GIP and SC arms (84.9% vs. 84.1%, P=.844). Patients in GIP arm were more commonly given Piperacillin-tazobactam and Carbapenems, whereas patients in the SC arm received metronidazole more often. Within the GIP arm, antibiotic use was lower among patients detected with viruses vs. those detected with non-viral pathogens (73.1% vs. 81.8%).Table 1 Table 2 ConclusionLOS was longer in patients in GIP arm vs SC arm, which may have been influenced by the presence of outliers in the GIP arm. No differences in antibiotic use was observed between the two groups. However, within the GIP arm, detection of viruses by GI PCR significantly shortened LOS and lowered antibiotic use.Disclosures All Authors: No reported disclosures

Inotuzumab ozogamicin for relapsed/refractory acute lymphoblastic leukemia: outcomes by disease burden

Adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) have a poor prognosis, especially if disease burden is high. This post hoc analysis of the phase 3 INO-VATE trial examined the efficacy and safety of inotuzumab ozogamicin (InO) vs. standard of care chemotherapy (SC) among R/R ALL patients with low, moderate, or high disease burden, respectively, defined as bone marrow blasts (BMB) < 50% (n = 53 vs. 48), 50–90% (n = 79 vs. 83), and >90% (n = 30 vs. 30). Patients in the InO vs. SC arm with low, moderate, and high BMB%, respectively, had improved rates of complete remission/complete remission with incomplete hematologic recovery (74% vs. 46% [p = 0.0022], 75 vs. 27% [p < 0.0001], and 70 vs. 17% [p < 0.0001]), and improved overall survival (hazard ratio: 0.64 [p = 0.0260], 0.81 [p = 0.1109], and 0.60 [p = 0.0335]). Irrespective of BMB%, cytopenias were the most common treatment-emergent adverse events, and post-transplant veno-occlusive disease was more common with InO vs. SC. Patients with extramedullary disease or lymphoblastic lymphoma showed similar efficacy and safety outcomes. This favorable benefit-to-risk ratio of InO treatment irrespective of disease burden supports its use in challenging and high disease burden subpopulations. INO-VATE is registered at www.clinicaltrials.gov: #NCT01564784.

ACUFOCIN: Randomized clinical trial of ACUpuncture plus standard care versus standard care alone FOr Chemotherapy Induced peripheral Neuropathy (CIPN).

12003 Background: CIPN is a dose limiting toxicity, and a major clinical challenge. This study aims to explore the use of acupuncture with standard care (Acu +SC) against SC alone, to reduce symptoms of CIPN. Methods: A phase II, randomised, parallel group design was used to investigate the effectiveness of a 10 week course of acupuncture to manage CIPN. Patients experiencing CIPN ≥ Grade II (CTCAE v4.03), recording a ‘Most Troublesome’ CIPN symptom score of ≥ 3 using the "Measure Yourself Medical Outcome Profile" (MYMOP 2), were randomised (1:1) to either Acu+SC or SC alone. The primary end-point was a ≥ 2 point improvement in MYMOP2 score at week 10 (logistic regression adjusted for stratification factors and baseline MYMOP2 score). The necessary sample size was 100 patients;120 were randomised to allow for attrition (90% power; 10% one-sided alpha), for a hypothesised improvement in success proportions from 30% to 55%. Results: 120 patients were randomised to ACUFOCIN; diagnosis: breast 61 (51%), multiple myeloma 9 (8%), GI 48 (40%), gynaecological 2 (2%). MYMOP2 score for most troubling CIPN symptom at baseline: 3-4 33 (28%), 5-6 87 (73%). CTCAE CIPN at baseline; grade II 103 (86%), grade III 17 (14%). Baseline characteristics were balanced between arms. Primary outcome data were available for 108 participants with 36/54 (67%) successes in the Acu+SC arm compared to 18/55 (33%) in the SC arm. Adjusted success odds ratio was 4.3 (95% CI 1.9-9.6; p &lt; 0.001; Acu+SC vs SC). Additionally, 27/53 (51%) participants achieved a CIPN success (grade ≤ I) in the Acu+SC arm compared to 4/56 (7%) in the SC arm with adjusted odds ratio 13.1 (95% CI 4.1-41.7; p &lt; 0.001; Acu+SC vs SC). Significant reduction in week 10 pain score; mean difference (SC+Acu – SC alone) -1.45 with 95% CI (-2.25, -0.65) after adjustment for week 1 pain, breast cancer diagnosis and treatment complete status. (note pain on a 0-10 scale). Significant increase in the EORTC QLQ-C30 summary score; mean difference (SC+Acu – SC alone) 9.51 with 95% CI (5.01, 14.02) after adjustment for the baseline score, breast cancer diagnosis and treatment complete status. (note summary score on a 0-100 scale). Significant effects seen at week 10 are also present at week 6. The week 6 effect estimates are consistently less than the week 10 effects (but not usually statistically significantly so). Conclusions: In this patient cohort, a 10 week course of acupuncture significantly improved symptoms of CIPN. These results support further investigation within a phase III trial. Clinical trial information: NCT02275403 .

Characterization of Response and Transfusion Independence in Patients with FLT3-Internal Tandem Duplication (FLT3-ITD)-Mutated Relapsed/Refractory Acute Myeloid Leukemia Treated with Quizartinib or Salvage Chemotherapy in the Quantum-R Trial

Characterization of Response and Transfusion Independence in Patients with FLT3-Internal Tandem Duplication (FLT3-ITD)-Mutated Relapsed/Refractory Acute Myeloid Leukemia Treated with Quizartinib or Salvage Chemotherapy in the Quantum-R Trial

Efficacy and Safety Outcomes in the Phase 3 INO-Vate Trial By Baseline CD22 Positivity Assessed By Local Laboratories

Efficacy and Safety Outcomes in the Phase 3 INO-Vate Trial By Baseline CD22 Positivity Assessed By Local Laboratories

Quizartinib in FLT3-ITD-Mutated Relapsed/Refractory Acute Myeloid Leukemia: QuANTUM-R Trial Results

Abstract Background FLT3-ITD mutations occur in about 25% of patients (pts) with acute myeloid leukemia (AML) and are associated with poor outcomes. Pts with relapsed/refractory (R/R) FLT3-ITD AML have worse prognosis and high unmet medical need. Quizartinib (Q) is a potent and selective FLT3i with promising activity and a manageable safety profile. QuANTUM-R was a global, phase 3, randomized trial of Q vs chemotherapy (SC) in pts with R/R FLT3-ITD AML (NCT02039726). Methods Pts with R/R FLT3-ITD AML w/wo hematopoietic stem cell transplant (HSCT) were randomized to receive Q or a preselected investigator choice SC: low-dose cytarabine; mitoxantrone, etoposide, and intermediate-dose cytarabine (MEC); or fludarabine, cytarabine, and G-CSF with idarubicin (FLAG-IDA). Prior midostaurin was allowed. Pts receiving HSCT after Q could resume Q after HSCT. Primary and secondary endpoints were overall survival (OS) and event-free survival (EFS), respectively. Exploratory endpoints included response rate, time to and duration of response, and transplant rate. Results 367 pts were randomized; 245 to Q and 122 to SC. Median follow-up was 23.5 mo. OS hazard ratio (HR) of Q relative to SC was 0.76 (95% CI, 0.58-0.98; P=.0177). Median OS was 6.2 (95% CI, 5.3-7.2) vs 4.7 (95% CI, 4.0-5.5) mo in Q and SC arms, respectively. EFS HR was 0.90 (95% CI, 0.70-1.16; P=.1071); median EFS was 1.4 (95% CI, 0.0-1.9) vs 0.9 (95% CI, 0.4-1.3) mo, respectively. Sensitivity analyses and OS subgroup analyses supported Q vs SC. Composite complete response (CRc) was 48% and 27% in Q and SC arms, respectively. Transplant rate was 32% (Q) and 12% (SC). Median time to first CRc was 4.9 wk for Q. The most common grade ≥ 3 TEAEs in both arms were infections and those associated with cytopenia. Conclusion OS benefit was observed with single-agent Q vs SC in pts with R/R FLT3-ITD AML with a favorable Q safety profile, providing evidence of meaningful clinical benefit in pts with limited treatment options.

LBA41 - Phase III randomized study of neoadjuvant chemotherapy (CT) with docetaxel(D), oxaliplatin(O) and S-1(S) (DOS) followed by surgery and adjuvant S-1, vs surgery and adjuvant S-1, for resectable advanced gastric cancer (GC) (PRODIGY)

BackgroundAdjuvant CT after D2 gastrectomy is standard therapy for resectable advanced GC in Asia. We investigated whether added neoadjuvant (NA) CT can further improve outcomes. Methods530 pts with newly diagnosed locally advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma (cT2,3/N[+]M0 or cT4/N[any]M0, AJCC 7th ed), ECOG PS 0-1, were randomized 1:1 to NA DOS then surgery and adjuvant S-1 (CSC; n=266), or surgery and adjuvant S-1 (SC; n=264). NA CT was D 50mg/m2 iv and O 100mg/m2 iv on day 1, S 40mg/m2 twice po on days 1–14 every 3 weeks for 3 cycles. Standard surgery was D2 gastrectomy. Adjuvant CT was S 40mg/m2 twice po on days 1–28 every 6 weeks for 8 cycles. Primary endpoint: 3-year progression free survival (PFS) in full analysis set (FAS). ResultsWith 46 pts excluded due to ineligibility or consent withdrawal, FAS was 484 pts (238 in CSC, 246 in SC). Baseline characteristics were balanced. In CSC arm, 214 pts (90.0%) completed 3 cycles of NA DOS. Main ≥grade3 toxicities: neutropenia in 12.6%, febrile neutropenia 9.2%, diarrhea in 5.0%, 1 treatment related death. 222 CSC (93.3%) and 246 SC (100%) pts underwent surgery. R0 resection rates: 96.4% vs 85.8%, p<0.0001; lower pathologic stage in CSC with pathologic CR 10.4% vs 0%, p<0.0001. Major surgical complication rates: 6.3% vs 8.5% with 1 surgical mortality in CSC arm. 204 CSC pts started adjuvant S-1, 170 (83.3%) completed 8 cycles; SC arm: 187 started, with completion of 8 cycles in 157 (84.0%). Main ≥grade3 toxicities: neutropenia (6.4% CSC, 5.4% SC), diarrhea (2.9% CSC, 3.2% SC). With median follow up of 37.4 months and 37.8% of PFS events, 3-year PFS rate (FAS) was 66.3% for CSC, 60.2% for SC; hazard ratio (HR) 0.70 (95% CI 0.52–0.95), stratified log-rank p=0.023. Sensitivity analyses (intent to treat set and landmark analysis) confirmed these results. ConclusionsAddition of NA DOS to D2 gastrectomy and adjuvant S-1 led to significant tumour downstaging and improved PFS with acceptable safety in PRODIGY study. Neoadjuvant DOS chemotherapy followed by D2 gastrectomy and adjuvant S-1 should be considered as a treatment option for resectable advanced GC. Clinical trial identificationNCT01515748. Legal entity responsible for the studySanofi Korea. FundingSanofi Korea. DisclosureY. Kang: Advisory / Consultancy: Ono; Advisory / Consultancy: BMS; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Merck Serono; Research grant / Funding (institution): Roche; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSKBiopharma; Advisory / Consultancy: Taiho; Advisory / Consultancy: Blueprint; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Hengrui. G. Kim: Shareholder / Stockholder / Stock options, Full / Part-time employment: Sanofi. Y. Lee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Sanofi. All other authors have declared no conflicts of interest.

P763Home Monitoring is associated with fewer gastrointestinal bleeding events following ventricular assist device implantation

Abstract Introduction Patients (pts) treated with a continuous flow left ventricular assist device (LVAD) are at increased risk for both bleeding and thromboembolic events. Maintenance of oral anticoagulation (AC) in the therapeutic range is difficult to achieve. Hypothesis Increased frequency of international normalized ratio (INR) home monitoring (HM) decreases the incidence of gastrointestinal bleeding and thromboembolic events (stroke, pump thrombosis) compared to standard of care (SOC). Methods We analyzed the efficacy of outpatient AC monitoring in consecutive pts who underwent VAD implantation at our institution between 2008–2018. Time in therapeutic range (TTR) was defined as percent of time with INR 2.5–2.8. HM pts had biweekly INR measurements using the Coagucheck XS ROCHE, while SOC pts had INR measured every 1–3 weeks. Gastrointestinal bleeding (GIB) and thromboembolic events were assessed by retrospective blinded chart review. Logistic regression was used to model the impact of TTR on the risk of GIB and THROMB. Results There were 85 pts: 44 in HM and 40 in SC arm with similar characteristics. SOC patients were more likely to have ischemic cardiomyopathy (63% vs 30%, p=0.006) and an LVAD (60% vs 25%, p=0.002). The use of HM was associated with a 19.7% reduction in the risk of GIB (8.8% vs 28.5%, p=0.043) and a trend towards lower risk of THROMB (6.8% vs 14.9%, p=0.19). HM pts had significantly longer TTR (52±20% vs 39±22%, p=0.007). Each percentage increase in TTR was associated with a 5.2% decrease in the risk of GIB [Odds Ratio (OR) 0.95, 95% Confidence Interval (CI) 0.91–0.99, p=0.009] even after adjustment for aspirin use and monitoring duration (OR 0.95, 95% CI 0.91–0.99, p=0.020). There was a similar decrease in the risk of overall bleeding (OR 0.94, 95% CI 0.90–0.98, p=0.008). Conclusions Increased frequency of home INR monitoring achieved a higher TTR and was associated with a 20% reduction in risk of gastrointestinal bleeding.

PS949 INOTUZUMAB OZOGAMICIN (INO) TREATMENT IN PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA (R/R ALL): OUTCOMES OF PATIENTS TREATED IN SALVAGE ONE WITH A LONG DURATION OF FIRST REMISSION

Background:In R/R ALL, data are limited supporting targeted therapies like InO as first salvage in patients (pts) who achieved a long duration of first complete remission (CR1). InO, a calicheamicin‐conjugated antibody, targets CD22 on ALL blasts.Aims:Here we report outcomes in pts with ALL in first salvage (S1) who had a long CR1 before receiving InO vs standard of care chemotherapy (SC).imageMethods:Adults with CD22+ R/R ALL, stratified by salvage and length of remission (CR1 ≥ or &lt;12 mos), were randomized to receive InO (n = 164) or SC (n = 162). Methods were previously described (Kantarjian et al, NEJM 2016), with data shown up to the last patient last visit (January 4, 2017). Outcomes including complete remission (CR)/CR with incomplete hematologic recovery (CRi) and overall survival (OS) were determined for S1 pts who achieved CR1 ≥ 12 mos and CR1 ≥ 18 mos.Results:For S1 pts with CR1 ≥ 12 mos or CR1 ≥ 18 mos, InO and SC arms had generally comparable baseline characteristics. For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos, fewer pts had received a prior stem cell transplant in the InO vs SC arm (10.4% vs 25.0% and 9.7% vs 21.4%). For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos respectively, InO vs SC treatment led to a higher CR/CRi rate (85.4% vs 27.5% [P &lt; 0.0001] and 83.9% vs 32.1% [P &lt; 0.0001]) and improved OS (HR = 0.547 [P = 0.0086] and 0.504 [P = 0.0163]), with veno‐occlusive liver disease reported in 12.5% and 12.9% of InO pts.Summary/Conclusion:Improved outcomes were seen with InO vs SC among S1 pts who had a long first complete remission (CR1 ≥ 12 mos or CR1 ≥ 18 mos), supporting the benefit of InO vs SC in this population.

Inotuzumab ozogamicin (InO) treatment in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL): Outcomes of patients treated in salvage one with a long duration of first remission.

7029 Background: In R/R ALL, data are limited supporting targeted therapies like InO as first salvage in patients (pts) who had a long first complete remission (CR1). InO, a calicheamicin-conjugated antibody, targets CD22 on ALL blasts. Here we report outcomes in pts with ALL in first salvage (S1) who had a long CR1 before receiving InO vs standard of care chemotherapy (SC). Methods: Adults with CD22+ R/R ALL, stratified by salvage and length of remission (CR1 ≥ or &lt; 12 mos), were randomized to receive InO (n = 164) or SC (n = 162). Methods were previously described (Kantarjian et al, NEJM 2016), with data shown up to the last patient last visit (January 4, 2017). Outcomes including complete remission (CR)/CR with incomplete hematologic recovery (CRi) and overall survival (OS) were determined for S1 pts who achieved CR1 ≥ 12 mos and CR1 ≥ 18 mos. Results: For S1 pts with CR1 ≥ 12 mos or CR1 ≥ 18 mos, InO and SC arms had generally comparable baseline characteristics. For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos, fewer pts had received a prior stem cell transplant in the InO vs SC arm (10.4% vs 25.0% and 9.7% vs 21.4%). For S1 pts with CR1 ≥ 12 mos and CR1 ≥ 18 mos respectively, InO vs SC treatment led to a higher CR/CRi rate (85.4% vs 27.5% [ P&lt; 0.0001] and 83.9% vs 32.1% [ P&lt; 0.0001]) and improved OS (HR = 0.547 [ P= 0.0086] and 0.504 [ P= 0.0163]), with veno-occlusive liver disease reported in 12.5% and 12.9% of InO pts Clinical trial information: NCT01564784. Conclusions: Improved outcomes were seen with InO vs SC among S1 pts who had a long first complete remission (CR1 ≥ 12 mos or CR1 ≥ 18 mos), supporting the benefit of InO vs SC in this population.[Table: see text]

Vitrified macaque ovarian cortical tissue transplanted to heterotopic sites produces fertilizable oocytes

To determine which heterotopic transplantation sites produce competent oocytes from vitrified ovarian cortical tissue. Randomized, longitudinal, in vivo. Ovarian cortical pieces (3x6x0.5 mm3) from adult (n=4; 6-9 yrs) and peripubertal (n=4; 4-5 yrs) rhesus macaques were vitrified using glycerol:ethylene glycol containing non-permeating polymers, placed into straws and cooled in LN2 with cryoprotectants removed in sucrose [1]. Within the same animal, pieces were transplanted to subcutaneous (sc) sites [2,3] in the arm (n=4); sc abdomen (n=4); sc abdomen + omental tissue (n=2) or retroperitoneal + omentum (n=2); and bilateral mesosalpinx sites (n=2). Serum was analyzed for estradiol (E) and progesterone (P) to determine ovarian cyclicity during one year post-transplantation. When E reached at least 100 pg/ml and the preovulatory follicle was 3-6 mm diameter, hCG (1000 IU, im) was given [3]. In alternate cycles, follicles were aspirated 30 hr later. Mature oocytes were inseminated in vitro. All animals resumed cyclic ovarian cyclicity based on midcycle E rise and luteal phase P. There was no difference in the time to the first cycle post-transplantation between adult (5.9±0.8 mos) and peripubertal (6.0±0.8) animals, or the number of ovarian cycles displayed during the year (7±1 vs 6±1, respectively). The total number of preovulatory follicles seen in the sc arm (2) and sc abdomen (2) was less (P<0.01) than those seen in the sc abdomen + omentum (14), retroperitoneal + omentum (10) and mesosalpinx (11). A single preovulatory follicle typically developed at a single site within each animal during a given month despite the presence of multiple transplants. The numbers of preovulatory follicles observed and oocytes collected were similar between adults and peripubertal animals. Of 38 total follicles that developed, 31 were aspirated yielding 21 oocytes (68%); 52% metaphase II, 24% metaphase I, 24% degenerated and no immature oocytes. Three oocytes fertilized, and two cleaved to the 4-cell (from mesosalpinx) and 8-cell stage (retroperitoneal + omentum), and one developed to a morula (sc abdomen + omentum). Vitrified ovarian cortical tissue transplanted to retroperitoneal or sc abdominal sites containing omentum and in the mesosalpinx consistently developed a single preovulatory follicle and produced steroid hormones typical of normal ovarian cycles. A competent oocyte was retrieved from each of these sites and efforts to produce offspring are ongoing. Heterotopic transplantation of vitrified ovarian tissue is promising for cancer survivors seeking fertility who sustain extensive ovarian damage after cancer therapy that may preclude re-vasculariztion to support orthotopic transplantation.

Abstract PD3-11: Efficacy and safety of subcutaneous or intravenous trastuzumab in patients with HER2-positive early breast cancer after 5 years' treatment-free follow-up: Final analysis from the phase III, open-label, randomized HannaH study

Abstract Background HannaH (NCT00950300) compared subcutaneous and intravenous trastuzumab (H SC and H IV) as neoadjuvant–adjuvant therapy for HER2-positive breast cancer. The co-primary endpoints of pathological complete response (pCR) and serum trough concentration at predose cycle 8 demonstrated noninferiority between H SC and H IV. Efficacy analyses of event-free survival (EFS) and overall survival (OS) at a median follow-up of 40 months supported this noninferiority. Safety analyses also confirmed the consistency of the safety profile across both arms. In this final follow-up analysis, we report the long-term efficacy and safety outcomes at 5 years of treatment-free follow-up (TFFU; 6 years in total). The correlation between total pCR (tpCR; absence of invasive neoplastic cells in ipsilateral nodes and the breast) and EFS was also explored. Methods Enrolled patients (n=596; pts) were randomized to receive 4 cycles of docetaxel, then 4 cycles of 5-fluorouracil/epirubicin/cyclophosphamide concurrently with 3-weekly fixed-dose 600mg H SC or H IV (loading: 8mg/kg; maintenance: 6mg/kg) in the neoadjuvant setting. Post-surgery, pts received an additional 10 cycles of H SC or H IV in the adjuvant setting to complete 1 year of anti-HER2 therapy. EFS (time from randomization to local, regional, or distant recurrence, contralateral breast cancer, or death) and OS were calculated using the Kaplan-Meier method. Adverse events (AEs) and serious AEs were recorded and graded per standard criteria. Results In total, 297 pts were randomized to the H SC arm and 299 to the H IV arm; 294 and 297 pts were included in the respective efficacy analysis populations. Median duration of follow-up (including TFFU) was 70.8 and 71.4 months in the H SC and H IV arms, respectively. EFS and OS were similar across both study arms (Table 1). Pts who achieved tpCR had longer EFS and OS vs. those who did not (Table 1). Table 1 H SCH IVHazard Ratio (95% CI)6-year EFS, % (95% CI)n=294n=297 Overall65 (59;70)65 (60;71)0.98 (0.74;1.29)tpCR status*tpCRn=102n=90 80 (73;88)83 (75;91) no tpCRn=158n=173 57 (49;65)61 (54;69) 6-year OS, % (95% CI)n=294n=297 Overall84 (79;88)84 (79;88)0.94 (0.61;1.45)* Efficacy per protocol population Cardiac AE incidence was low and consistent across study arms (Table 2). Table 2Pts, n (%)H SC (n=297)H IV (n=298)Any AE290 (98)282 (95)≥ Grade 3 AE158 (53)160 (54)Serious AE65 (22)45 (15)Cardiac AE44 (15)42 (14)LVEF decline (≥10%-points from baseline to &amp;lt;50%)11 (3.8)12 (4.2)LVEF, left ventricular ejection fraction Conclusion Long-term efficacy EFS and OS results confirmed the noninferiority of H SC compared with H IV, as demonstrated by pCR and pharmacokinetic endpoints. tpCR was associated with longer EFS and OS. The overall safety profile of H SC was consistent with that of H IV. Citation Format: Jackisch C, Stroyakovskiy D, Pivot X, Ahn J-S, Melichar B, Chen S-C, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Efficacy and safety of subcutaneous or intravenous trastuzumab in patients with HER2-positive early breast cancer after 5 years' treatment-free follow-up: Final analysis from the phase III, open-label, randomized HannaH study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-11.