Endpoint Of Disease-free Survival Research Articles

PL02.05 IMpower010: Characterization of Stage IB-IIIA NSCLC Patients by Type and Extent of Therapy Prior to Adjuvant Atezolizumab

Surgical resection followed by adjuvant chemotherapy is a standard of care in stage II-III NSCLC. Time from surgery to adjuvant treatment as well as the type and extent of mediastinal staging remain topics of interest. At this interim analysis, the Phase III IMpower010 trial met its primary endpoint, showing significant disease-free survival (DFS) improvement with atezolizumab vs best supportive care (BSC) after adjuvant chemotherapy in patients with PD-L1 TC≥1% stage II-IIIA NSCLC and all randomized patients with stage II-IIIA NSCLC; the significance boundary for DFS was not crossed in the ITT population (stage IB-IIIA NSCLC). We investigated therapies prior to adjuvant atezolizumab, including surgery type, and their potential impact on DFS. IMpower010 enrolled patients with completely resected stage IB (tumors ≥4 cm)-IIIA NSCLC (AJCC/UICC v7) and ECOG PS 0/1. Complete resection must have been performed 4-12 weeks prior to enrollment. Patients (N=1280) received up to four 21-day cycles of cisplatin-based chemotherapy, and 1005 were subsequently randomized 1:1 to atezolizumab 1200 mg Q3W (16 cycles or until disease recurrence or unacceptable toxicity) or BSC. The primary endpoint of investigator-assessed DFS was tested hierarchically in the PD-L1 TC≥1% (SP263) stage II-IIIA population, all-randomized stage II-IIIA population, and ITT population (stage IB-IIIA). Exploratory analyses of the types and frequency of thoracic surgery in patients from this global registration trial will be reported. The type of surgery, time from surgery to adjuvant treatment, including initiation of both chemotherapy and atezolizumab, and type and extent of mediastinal staging will be examined for any impact on the DFS endpoint. DFS by disease stage and nodal status (N0 vs N1 vs N2) will be presented. The ITT population included 507 (atezolizumab) and 498 (BSC) patients; median follow-up was 32.2 months (data cutoff: 21 Jan 2021). The most common surgery was lobectomy (78.1%); 15.9% had pneumonectomy and 5.0% had bilobectomy. Mediastinal lymph node dissection or sampling was performed in 80.7% and 18.0% of patients, respectively. Median (range) time from surgery to first chemotherapy treatment was 1.8 mo (0.9-5.3) and 1.7 mo (0.8-5.2) in the atezolizumab and BSC arms, respectively. A median of 4 (range, 1-4) adjuvant chemotherapy cycles were received for all regimens; 152 patients received cisplatin-docetaxel, 165 received cisplatin-gemcitabine, 303 received cisplatin-vinorelbine and 385 received cisplatin-pemetrexed. Median (range) time from surgery to first atezolizumab treatment or BSC was 5.2 mo (2.4-7.7) and 5.1 mo (2.3-8.0), respectively. DFS by disease and prior treatment characteristics in the PD-L1 TC≥1% stage II-IIIA, all-randomized stage II-IIIA and ITT populations is shown in the Table. In these exploratory analyses, most patients had lobectomy, lymph node dissection and 4 cycles of adjuvant chemotherapy. Median time from surgery to start of randomized treatment was similar between arms. Benefit was seen across disease stages (stage II-IIIA sub-populations), including patients with nodal involvement (N1 and N2). Additional details will be presented.Tabled 1SubgroupPD-L1 TC≥1% stage II-IIIAAll randomized stage II-IIIAITT (stage IB-IIIA)NmDFS (atezo vs BSC), moHRa (95% CI)NmDFS (atezo vs BSC), moHRa (95% CI)NmDFS (atezo vs BSC), moHRa (95% CI)All patients476NE vs 35.30.66 (0.50, 0.88)88242.3 vs 35.30.79 (0.64, 0.96)1005NE vs 37.20.81 (0.67, 0.99)bDisease stageStage IB––––––123NE vs NE1.01 (0.48, 2.13)Stage IIA161NE vs NE0.73 (0.43, 1.24)295NE vs NE0.68 (0.46, 1.00)295NE vs NE0.68 (0.46, 1.00)Stage IIB83NE vs NE0.77 (0.35, 1.69)17437.1 vs 46.40.88 (0.54, 1.42)17437.1 vs 46.40.88 (0.54, 1.42)Stage IIIA23242.3 vs 26.70.62 (0.42, 0.90)41332.3 vs 29.70.81 (0.61, 1.06)41332.3 vs 29.70.81 (0.61, 1.06)Regional lymph node status (pN)N010636.7 vs NE0.88 (0.45, 1.74)229NE vs 46.40.88 (0.57, 1.35)352NE vs NE0.93 (0.64, 1.36)N+370NE vs 31.40.62 (0.46, 0.85)65342.3 vs 31.40.76 (0.60, 0.96)65342.3 vs 31.40.76 (0.60, 0.96)N1194NE vs NE0.59 (0.36, 0.97)348NE vs 36.00.67 (0.47, 0.95)348NE vs 36.00.67 (0.47, 0.95)N217632.3 vs 21.30.66 (0.44, 0.99)30530.2 vs 24.10.83 (0.61, 1.13)30530.2 vs 24.10.83 (0.61, 1.13)Type of surgerycLobectomy359NE vs 33.40.63 (0.45, 0.87)67542.3 vs 32.00.77 (0.61, 0.97)785NE vs 36.00.78 (0.62, 0.97)Bilobectomy2436.7 vs NE0.78 (0.18, 3.33)4736.7 vs NE1.02 (0.35, 2.98)5036.7 vs NE1.14 (0.39, 3.34)Pneumonectomy8536.1 vs NE0.83 (0.43, 1.58)15036.1 vs 42.10.91 (0.56, 1.47)16036.1 vs 42.10.98 (0.61, 1.57)Chemotherapy regimenCisplatin-docetaxel7136.1 vs 18.00.60 (0.30, 1.23)12436.1 vs 37.30.72 (0.42, 1.23)15236.1 vs 42.10.74 (0.45, 1.23)Cisplatin-gemcitabine7536.1 vs NE1.14 (0.50, 2.61)13836.1 vs 46.40.94 (0.56, 1.57)16536.7 vs 46.41.03 (0.62, 1.70)Cisplatin-vinorelbine161NE vs 34.20.55 (0.33, 0.92)271NE vs 37.00.67 (0.46, 0.99)303NE vs 37.00.63 (0.43, 0.91)Cisplatin-pemetrexed169NE vs 31.40.66 (0.42, 1.06)34942.3 vs 31.40.84 (0.61, 1.16)38542.3 vs 36.00.91 (0.67, 1.24)NCT02486718. mDFS, median disease-free survival; NE, not estimable.a Stratified for all patients; unstratified for all other subgroups.b At the time of this analysis (data cutoff 21 Jan 2021), DFS did not cross the significance boundary in the ITT population.c Subgroups with <10 patients are not shown. 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653O Pembrolizumab (pembro) vs placebo as adjuvant therapy for patients (pts) with renal cell carcinoma (RCC): Patient-reported outcomes (PRO) in KEYNOTE-564

The randomized, double-blind, phase III KEYNOTE-564 (NCT03142334) study met its primary endpoint of disease-free survival with adjuvant pembro vs placebo following surgery in pts with RCC. We present PRO findings for adjuvant pembro vs placebo in KEYNOTE-564.

PLLBA-01 PEMBROLIZUMAB (PEMBRO) VS PLACEBO AS POST NEPHRECTOMY ADJUVANT THERAPY FOR PATIENTS (pts) WITH RENAL CELL CARCINOMA (RCC): RANDOMIZED, DOUBLE-BLIND, PHASE 3 KEYNOTE-564 STUDY

PLLBA-01 PEMBROLIZUMAB (PEMBRO) VS PLACEBO AS POST NEPHRECTOMY ADJUVANT THERAPY FOR PATIENTS (pts) WITH RENAL CELL CARCINOMA (RCC): RANDOMIZED, DOUBLE-BLIND, PHASE 3 KEYNOTE-564 STUDY

Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study.

LBA5 Background: Relapse after surgery for high-risk clear cell RCC (ccRCC) is associated with shortened life expectancy. Effective perioperative therapy to reduce this risk remains an unmet need. Adjuvant immune therapy is an attractive potential strategy for these pts. We conducted the KEYNOTE-564 trial to evaluate pembro vs placebo as adjuvant therapy for pts with RCC. Methods: KEYNOTE-564 is a phase III multicenter trial of pembro vs placebo in pts with histologically confirmed ccRCC, with intermediate-high risk (pT2, Gr 4 or sarcomatoid, N0 M0; or pT3, any Gr, N0 M0), high risk (pT4, any Gr, N0 M0; or pT any stage, any Gr, N+ M0), or M1 NED (no evidence of disease after primary tumor + soft tissue metastases completely resected ≤1 year from nephrectomy) (Leibovich et al, 2003; Fuhrman et al, 1982). Pts had undergone surgery ≤12 wks prior to randomization; had no prior systemic therapy; had ECOG PS 0 or 1. Study treatment was given for up to 17 cycles (≈1 yr). The primary endpoint was disease-free survival (DFS) per investigator assessment in all randomized pts (ITT population). Overall survival (OS) was a key secondary endpoint. Safety/tolerability were secondary endpoints, assessed in all treated pts. Results: Between Jun 30, 2017 and Sept 20, 2019, 994 pts were randomized 1:1 to pembro (n=496) or placebo (n=498). As of data cutoff date of Dec 14, 2020, median (range) follow-up, defined as time from randomization to data cutoff, was 24.1 (14.9−41.5) mo. No pts remain on study treatment. Baseline characteristics were generally balanced between arms. At first prespecified interim analysis, the primary endpoint of DFS was met (median not reached [NR] for both arms, HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided]). The estimated DFS rate at 24 mo was 77.3% with pembro vs 68.1% with placebo. Overall, DFS benefit was consistent across subgroups. A total of 51 OS events were observed (18 in the pembro arm, 33 in the placebo arm). Median OS was NR for both arms (HR 0.54, 95% CI 0.30−0.96; P=0.0164 [one-sided]); the p-value did not cross the statistical hypothesis testing boundary. The estimated OS rate at 24 mo was 96.6% with pembro vs 93.5% with placebo. 470 pts (96.3%) and 452 pts (91.1%) experienced ≥1 all-cause adverse events (AEs) with pembro vs placebo, respectively. Grade 3-5 all-cause AEs occurred in 158 pts (32.4%) with pembro and 88 pts (17.7%) with placebo. No deaths related to pembro occurred. Conclusions: Pembro demonstrated a statistically significant and clinically meaningful improvement in DFS vs placebo in pts with intermediate-high, high risk or M1 NED RCC. Additional follow-up is planned for the key secondary endpoint of OS. KEYNOTE-564 is the first positive phase III study with a checkpoint inhibitor in adjuvant RCC, and these results support pembro as a potential new standard of care for pts with RCC in the adjuvant setting. Clinical trial information: NCT03142334.

First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).

391 Background: The standard of care (SOC) for patients (pts) with MIUC is radical surgery ± cisplatin-based neoadjuvant chemotherapy (chemo), but many pts are cisplatin-ineligible. There is no conclusive evidence supporting adjuvant chemo in pts who did not receive neoadjuvant chemo and in those with residual disease after neoadjuvant cisplatin. This phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in pts with MIUC after radical surgery ± neoadjuvant cisplatin (CheckMate 274) aims to address an unmet need in these pts. We report the initial results. Methods: This is a phase 3, randomized, double-blind, multicenter trial of NIVO vs PBO in pts with high-risk MIUC (bladder, ureter, or renal pelvis) after radical surgery. Pts were randomized 1:1 to NIVO 240 mg Q2W or PBO for ≤ 1 year of adjuvant treatment. Pts had radical surgery within 120 days ± neoadjuvant cisplatin or were ineligible/declined cisplatin-based chemo, evidence of UC at high risk of recurrence per pathologic staging, were disease-free by imaging, and ECOG PS ≤ 1. Primary endpoints: disease-free survival (DFS) in all randomized pts (ITT population) and in pts with tumor PD-L1 expression ≥ 1%. DFS was stratified by nodal status, prior neoadjuvant cisplatin, and PD-L1 status. Non–urothelial tract recurrence-free survival (NUTRFS) in ITT pts and in pts with PD-L ≥ 1% is a secondary endpoint. Safety is an exploratory endpoint. Results: In total, 353 pts were randomized to NIVO (PD-L1 ≥ 1%, n = 140) and 356 pts to PBO (PD-L1 ≥ 1%, n = 142). The primary endpoint of DFS was met in ITT pts (median follow-up, 20.9 mo for NIVO; 19.5 mo for PBO) and in pts with PD-L1 ≥ 1%. DFS and NUTRFS were improved with NIVO vs PBO in both populations (Table). DFS improvement with NIVO was generally consistent across subgroups. Grade 3–4 treatment-related adverse events (TRAEs) occurred in 17.9% and 7.2% of pts in the NIVO and PBO arms, respectively. Conclusions: NIVO demonstrated a statistically significant and clinically meaningful improvement in DFS vs PBO for MIUC after radical surgery, both in ITT pts and pts with PD-L1 ≥ 1%. AEs were manageable and consistent with previous reports. These results support adjuvant NIVO as a new SOC for pts with MIUC with high risk for recurrence despite neoadjuvant chemo or those ineligible for and/or declining cisplatin-based chemo. Clinical trial information: NCT02632409 . Research Sponsor: Bristol Myers Squibb[Table: see text]

The effect of using long-acting octreotide as adjuvant therapy for patients with grade 2 pancreatic neuroendocrine tumors after radical resection

Abstract Objective: To investigate the effect of long-acting octreotide as adjuvant therapy in the prevention of tumor recurrence in patients with grade 2 pancreatic neuroendocrine tumors (pNETs) after radical resection. Methods: The postoperative follow-up data of 130 patients with resectable G2 pNET treated in the Changhai Hospital from 2008 to 2018 were retrospectively analyzed: 59 patients received long-acting octreotide as adjuvant therapy for 6 to 12 months (Oct group) and 71 patients received active follow-up (control group), both of which began after the radical resection, with the primary observation endpoint of disease-free survival (DFS) and the secondary study endpoint of overall survival. Results: The median age of the patients in the Oct group and control group was 52 and 54 years, respectively. There were 28 male cases (47.5%) and 33 male cases (46.5%) in the 2 groups. The median maximum tumor diameter was 3.5 and 3.0 cm, respectively; lymph node metastasis was positive in 13 cases (22.0%) and 9 cases (12.7%); there was peripancreatic nerve invasion in 11 cases (18.6%) and 6 cases (8.5%). Survival analysis revealed that there were significant differences in 2-year DFS% (98.3% vs 88.7%, P = .0371) and 3-year DFS% (96.6% vs 85.9%, P = .0498) between the Oct group and control group. Long-acting octreotide treatment was found to reduce the risk of 3-year recurrence of G2 pNET after radical resection (HR = 0.2, P = .044) with the application of inverse-probability-of-treatment weighted to balance the limited data bias. Conclusion: Using long-acting octreotide as adjuvant therapy for G2 pNET patients after radical surgery may improve the rate of 3y-DFS, but the benefit needs to be confirmed in a well-designed random control clinical trial.

Usefulness of Restaging Pelvis Magnetic Resonance Imaging After Neoadjuvant Concurrent Chemoradiotherapy in Patients With Locally Advanced Rectal Cancer

IntroductionIn patients with locally advanced rectal cancer, restaging pelvis magnetic resonance imaging (MRI) after neoadjuvant concurrent chemoradiotherapy is recommended despite its limited accuracy in predicting pathologic T (ypT) and N (ypN) stage. Neoadjuvant rectal (NAR) score is a novel short-term surrogate endpoint for disease-free survival (DFS) and overall survival (OS). We tested the agreement between restaging MRI T (yT) and N (yN) with ypT and ypN stages, respectively, and explored the prognostic significance of restaging MRI NAR (mNAR) score. Patients and MethodsBetween 2014 and 2018, 43 patients with locally advanced rectal cancer completed neoadjuvant concurrent chemoradiotherapy, had a restaging MRI, and underwent surgery. Weighted kappa was used to test the agreement between yT and yN with ypT and ypN, respectively. A kappa value of less than 0.5 was deemed unacceptable. Paired t test was used to compare NAR and mNAR mean scores. Survival was estimated by Kaplan-Meier curves. ResultsRestaging MRI could not predict ypT stage (slight agreement, κ = 0.111) or ypN stage (fair agreement, κ = 0.278). The mean mNAR score was higher than the mean NAR score (20 vs. 16, P = .0079). The median DFS for patients with low-intermediate NAR and high NAR was not reached vs. 30 months (P = .0063). The median OS for patients with low-intermediate NAR and high NAR was not reached vs. 40 months (P = .0056). There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores (not reached in both groups, P = .058) compared to patients with high mNAR scores (not reached in both groups, P = .15). ConclusionRestaging MRI could not predict ypT and ypN stage. The mean mNAR score was higher than the mean NAR score. There was a trend for longer DFS and OS in patients with low-intermediate mNAR scores compared to patients with high mNAR scores.

Evaluation of the change of outcomes over a 10-year period in patients with stage III colon cancer: pooled analysis of 6501 patients treated with fluorouracil, leucovorin, and oxaliplatin in the ACCENT database

Since 2004, adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX or FLOX) have been the standard of care for patients with resected colon cancer. Herein we examine the change of outcomes over a 10-year period in patients with stage III colon cancer who received this regimen. Individual patient data from the ACCENT database was used to compare the outcomes in older (1998-2003) and newer (2004-2009) treatment eras for patients with stage III colon cancer who received adjuvant FOLFOX or FLOX. The outcomes were compared between the two groups by the multivariate Cox proportional-hazards model adjusting for age, sex, performance score, T stage, N stage, tumor sidedness, and histological grade. A total of 6501 patients with stage III colon cancer who received adjuvant FOLFOX or FLOX in six randomized trials were included in the analysis. Patients enrolled in the new era group experienced statistically significant improvement in time to recurrence [3-year rate, 76.1% versus 73.0%; adjusted hazard ratio (HRadj)= 0.83 (95% CI, 0.74-0.92), P= 0.0008], disease-free survival (DFS) [3-year rate, 74.7% versus 72.3%; HRadj= 0.88 (0.79-0.98), P= 0.024], survival after recurrence (SAR) [median time, 27.0 versus 17.7 months; HRadj= 0.65 (0.57-0.74), P<0.0001], and overall survival (OS) [5-year rate, 80.9% versus 75.7%; HRadj= 0.78 (0.69-0.88), P < 0.0001]. The improved outcomes remained in patients diagnosed at 45 years of age or older, low-risk patients (T1-3 and N1), left colon, mismatch repair proficient (pMMR), BRAF, and KRAS wild-type tumors. Improved outcomes were observed in patients with stage III colon cancer enrolled in clinical trials who received adjuvant FOLFOX/FLOX therapy in 2004 or later compared with patients in the older era. Prolonged SAR calls for revalidation of 3-year DFS as the surrogate endpoint of OS in adjuvant clinical trials and reevaluation of optimal follow-up of OS to confirm the trial findings based on the DFS endpoints. NCT00079274; NCT00096278; NCT00004931; NCT00275210; NCT00265811; NCT00112918.

Abstract A43: Spatial organization of pancreatic ductal adenocarcinoma (PDAC)–associated immune cells from the Adjuvant Pancreatic Adenocarcinoma Clinical Trial (APACT) study

Abstract Introduction: It is strikingly difficult to develop successful treatments for PDAC; even with curative resection, most patients die from early occult metastases. Prior studies identified the presence of tumor-infiltrating lymphocytes (TILs) in primary PDAC tumors as having prognostic significance in the PDAC adjuvant setting, sharpening the questions of what fraction of patients have immune-infiltrated tumors and what therapeutic strategies should be pursued in these patients vs. the non-infiltrated group. The phase 3 APACT trial evaluated the use of adjuvant nab-paclitaxel plus gemcitabine vs. gemcitabine in 866 patients with PDAC who had undergone primary tumor resection, with the primary endpoint of disease-free survival evaluated by independent review. We extended studies of the tumor microenvironment of PDAC to a large set of resected APACT primary tumors in an effort to further refine features of tumor or immune infiltrate that influence disease progression and to determine if chemotherapy regimen–specific predictive signatures are identifiable. Tissue analyses for a large subset of APACT samples included RNA-seq, DNA-seq, multiplexed immunohistochemistry (IHC), and proteomics. Methods: We imaged and quantified markers for tumor cells, 7 different immune cells, and 2 immune checkpoint markers using bright-field chromogenic multiplexed IHC from pretreatment samples for more than 500 APACT primary tumor samples. We computationally defined the tumor, tumor margin, and distal stromal (&amp;gt; 150 μm from tumor boundary) regions, and quantified densities and distributions of immune cells in these regions. As part of an initial analysis of more than 400 samples, we applied both unsupervised clustering and supervised classification to these IHC measurements to identify patient subgroups with similar spatial arrangements of immune cells relative to tumor regions. Results: The preliminary analysis of normalized cell densities across all 3 tissue regions revealed 3 patient subgroups: one in which immune cells are mixed within the tumor regions; a second where immune cells approach the tumor boundary but are depleted within the tumor; and a third in which immune cells are depleted in both tumor and its margin, remaining at high densities only in the distal stromal regions. Within these latter subgroups, CD20+, CD4+, and CD8+ cells were more prevalently depleted from tumor and/or margin, whereas CD163+ and CD163+CMAF+ cells showed less of this arrangement. Nearly 85% of patients fell in the second or third patient group. Conclusions: We are pursuing analyses of these data in conjunction with upcoming molecular and genetic profiling data to further elucidate the association of the immune cell populations and these subgroups with clinical outcomes. These data will provide an unprecedented opportunity for exploratory analysis and discovery of immune, molecular, and genetic biomarkers for PDAC patient stratification. Citation Format: David J. Reiss, Thomas Lila, Suzana Couto, Sitharthan Kamalakaran, Yan Ren, Doug Bowman, Amber Ortiz, Maria Wang, Clifton Drew, Kao-Tai Tsai, Mathieu Marella, Brian Fox, Garth McGrath, Matthew Trotter, Fadi Towfic, Ian Cushman, Alexander Ratushny, Brian Lu, Daniel Pierce, Jim Cassidy. Spatial organization of pancreatic ductal adenocarcinoma (PDAC)–associated immune cells from the Adjuvant Pancreatic Adenocarcinoma Clinical Trial (APACT) study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A43.

1O - Trastuzumab emtansine (T-DM1) vs trastuzumab (H) in Chinese patients (pts) with residual invasive disease after neoadjuvant chemotherapy for HER2-positive breast cancer (BC) in the phase III KATHERINE study

BackgroundPts with HER2+ early BC and residual invasive disease after neoadjuvant chemotherapy plus HER2-targeted therapy have a higher risk of recurrence and death than those with a pCR. The KATHERINE (NCT01772472) study showed significantly improved invasive disease-free survival (IDFS) with adjuvant T-DM1 vs H in this population. Here, we compare Chinese pts in KATHERINE to the overall population. MethodsPts with HER2+ BC and residual invasive disease after taxane- and H-containing neoadjuvant chemotherapy followed by surgery were randomized 1:1 to 14 cycles of adjuvant T-DM1 (3.6 mg/kg IV q3w) or H (6 mg/kg IV q3w). IDFS and the secondary endpoints of disease-free survival including non-invasive breast cancers, overall survival, distant recurrence-free interval, and safety were compared between Chinese pts (mainland China, Taiwan, Hong Kong) and the overall population. ResultsThere were 101 (6.8%) Chinese pts in KATHERINE. IDFS was greater in the T-DM1 vs the H group (HR = 0.57; 95% CI: 0.25–1.31), with similar results for secondary endpoints (Table). As in the overall population, Chinese pts receiving T-DM1 vs H had more grade ≥3 adverse events (AEs; 39% vs 4%), serious AEs (SAEs; 20% vs 2%); and AEs leading to treatment discontinuation (28% vs 0). The most common grade ≥3 AE in the T-DM1 arm was thrombocytopenia (22%), a frequency higher than in the overall population (6%). Grade ≥3 hemorrhage was reported in 1 pt (T-DM1 arm). All grade ≥3 thrombocytopenia was resolved or resolving at data cutoff.Table1OTableChineseOverallHT-DM1HT-DM1(N = 50)(N = 51)(N = 743)(N = 743)IDFSPts with event, n (%)14 (28.0)9 (17.6)165 (22.2)91 (12.2)3-yr EF rate, %70.483.877.088.3HRa (95% CI)0.57 (0.25–1.31)0.50 (0.39–0.64); P < 0.001DFSPts with event, n (%)14 (28.0)9 (17.6)167 (22.5)98 (13.2)3-yr EF rate, %70.483.876.987.4HRa (95% CI)0.57 (0.25–1.31)0.53 (0.41–0.68)OSPts with event, n (%)4 (8.0)3 (5.9)56 (7.5)42 (5.7)5-yr EF rate, %90.293.686.892.1HRa (95% CI)0.68 (0.15–3.04)0.70 (0.47–1.05)DRFIPts with event, n (%)8 (16.0)6 (11.8)121 (16.3)78 (10.5)3-yr EF rate, %82.389.583.089.7HRa (95% CI)0.68 (0.24–1.97)0.60 (0.45–0.79)aunstratified hazard ratio Abbreviations: EF, event-free; IDFS, invasive disease-free survival; DFS, disease-free survival (including noninvasive breast cancers); OS, overall survival; DRFI, distant recurrence-free interval. ConclusionsConsistent with the overall study population, T-DM1 was associated with increased efficacy compared to H in Chinese pts. Compared to all pts, increases in SAEs, grade ≥3 AEs, and AEs leading to discontinuation were observed in Chinese pts and were driven by an increase in thrombocytopenia, consistent with previous data in Asian pts. Clinical trial identificationNCT01772472. Editorial acknowledgementMedical writing assistance was provided by Twist Medical and was funded by F. Hoffmann–La Roche. Legal entity responsible for the studyF. Hoffmann-La Roche. FundingF. Hoffmann-La Roche. DisclosureC. Huang: Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy, Research grant / Funding (institution): Eli Lilly; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): EirGenix; Research grant / Funding (institution): MSD; Research grant / Funding (institution): OBI Pharma. Y. Yang: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Ono; Research grant / Funding (institution): Astellas; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Mundipharma; Research grant / Funding (institution): Orient Europharma; Full / Part-time employment: Taichung Veterans General Hospital. A. Kwong: Honoraria (self), ICG Fluorescence in Breast Surgery speaker: Stryker; Honoraria (self), Chairing Meeting: AstraZeneca; Honoraria (self), Chairing Meeting: Pfizer; Honoraria (self), Honoraria (institution), Chairing Meeting, Support on trial to HKU: Roche; Honoraria (institution), Suppprt on trial to HKU: Merck; Honoraria (institution), Support on trial to HKU: Novartis; Honoraria (institution), Supporting device & consumables for Prospective Study on Cryosurgery for treatment of Early Breast Cancer.: WKK Medical Equipment company limited; Leadership role, Chairman: Hong Kong Hereditary Breast Cancer Family Registry; Leadership role, Founding member: Asian BRCA (ABRCA); Leadership role, Council Member: Hong Kong Society of Breast Surgeons. L-M. Tseng: Advisory / Consultancy, Travel / Accommodation / Expenses: Amgen; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Travel / Accommodation / Expenses: AstraZeneca. M-C. Liu: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche. Y. Feng: Full / Part-time employment: Roche (China) Holding Ltd. G. Sun: Full / Part-time employment: Roche (China) Holding Ltd. I.R. Yan: Full / Part-time employment: Roche (China) Holding Ltd. All other authors have declared no conflicts of interest.

Validation of neoadjuvant rectal cancer(NAR) score as a surrogate endpoint for disease free survival in Chinese FOWARC study.

e15162 Background: NAR score is considered as a surrogate endpoint for survival in patients with locally advanced rectal cancer who received neoadjuvant treatment. Here we validate it in Chinese FOWARC study, especially in the chemotherapy alone arm. Methods: NAR score is calculated based on cT, ypT, ypN as reported for patients who received surgery in FOWARC study. NAR score is correlated to DFS with COX regression and Kaplan-Meier analysis. Results: 451 patients had surgery, 147 in FU-RT group, 152 in FOLFOX-RT arm and 152 in FOLFOX arm. NAR score is a significant prognostic factor in COX regression (P=0.000, HR 1.034, 95% CI 1.024-1.045) and in FOLFOX alone group (p=0.001, HR 1.030, 95% CI 1.013-1.047). When NAR score is quartile to &lt;5, 5-10, 10-15,&gt;15, the survival of patients is listed below, and similar to pathological staging. Conclusions: NAR score can be used as a surrogate endpoint for disease free survival Chinese patients. But it is not superior to pathological stage, especially in patients who received chemotherapy alone. [Table: see text]

The prognostic significance of magnetic resonance imaging (MRI) following neoadjuvant concurrent chemoradiation (NCCR) in patients with locally advanced rectal adenocarcinoma (LARA).

e15166 Background: In patients with locally advanced rectal adenocarcinoma (LARA), the response to neoadjuvant concurrent chemoradiation (NCCR) correlates with long-term outcomes. Neoadjuvant rectal (NAR) score ([5 ypN - 3 (cT - ypT) + 12]2/9.61) is a novel short-term surrogate endpoint for disease free survival (DFS) and Overall survival (OS). The prognostic significance of magnetic resonance imaging (MRI) findings following NCCR is yet to be explored. Here, we evaluated the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. In addition, we calculated the post NCCR MRI NAR (mNAR) score using the MRI yT and yN ([5 yN - 3 (cT - yT) + 12]2/9.61) and explored its prognostic significance. Methods: Between 2014 and 2018, all patients with LARA were identified. Among those, 43 patients received NCCR, had post NCCR MRI and underwent surgical resection. Weighted Kappa was used to measure the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. Paired t-test was used to compare the means between NAR and mNAR scores. NAR and mNAR scores were classified as low ( &lt; 8), intermediate (8-16) and high ( &gt; 16). DFS and OS were analyzed using Kaplan-Meier curves. Results: In our cohort, the agreement was slight between post NCCR MRI yT and Pathological ypT (p = 0.111), and fair between post NCCR MRI yN and pathological ypN (0.278). The mean NAR score was 16 and the mean mNAR score was 20 (p = 0.0079). Low-intermediate and high NAR scores were seen in 31 (72%) and 12 (28%) patients respectively. However, low-intermediate and high mNAR scores were seen in 20 (47%) and 23 (53%) patients respectively. The median DFS in patients with low-intermediate and high NAR scores was not reached and 30 months (p = 0.00063) respectively. The median OS in patients with low-intermediate and high NAR scores was not reached and 40 months (p = 0.00056) respectively. The median DFS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.058). The median OS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.15). Conclusions: Post NCCR MRI yT and yN had slight and fair agreements with ypT and ypN respectively. In our cohort, there was a difference between NAR and mNAR. NAR demonstrated prognostic significance for DFS and OS, while mNAR did not at the time of analysis.

Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III colon cancer and deficient mismatch repair (ATOMIC, Alliance A021502).

e15169 Background: In metastatic colorectal cancer with deficient DNA mismatch repair (dMMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for cancers with proficient MMR. In an ongoing phase III randomized trial, we will determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR. By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that could serve as ‘immune priming'. Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR are randomized to modified FOLFOX6 for 6 months (12 cycles) alone (control arm) or combined with atezolizumab (840 mg IV q2 wk) with continuation of the antibody as monotherapy for an additional 6 months (total duration of 12 months) [experimental arm]. Patients will be stratified by T, N stage and tumor sidedness. Local testing for MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. One cycle of FOLFOX is allowed pre-registration. The targeted accrual goal of 700 patients and 165 disease-free survival (DFS) events will provide 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint of DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. Results: This study is being conducted by the Alliance for Clinical Trials in Oncology, was approved by NCI CTEP and activated in 09/2017. The study is actively accruing and, as of 02/11/2019, 152 patients are enrolled. We are actively exploring an international collaboration. Conclusions: This is a current clinical trial in progress. Clinical trial information: NCT02912559.

Adjuvant vemurafenib in resected, BRAFV600 mutation-positive melanoma (BRIM8): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Systemic adjuvant treatment might mitigate the high risk of disease recurrence in patients with resected stage IIC-III melanoma. The BRIM8 study evaluated adjuvant vemurafenib monotherapy in patients with resected, BRAFV600 mutation-positive melanoma. BRIM8 was a phase 3, international, double-blind, randomised, placebo-controlled study that enrolled 498 adults (aged ≥18 years) with histologically confirmed stage IIC-IIIA-IIIB (cohort 1) or stage IIIC (cohort 2) BRAFV600 mutation-positive melanoma that was fully resected. Patients were randomly assigned (1:1) by an interactive voice or web response system to receive twice-daily adjuvant oral vemurafenib 960 mg tablets or matching placebo for 52 weeks (13 × 28-day cycles). Randomisation was done by permuted blocks (block size 6) and was stratified by pathological stage and region in cohort 1 and by region in cohort 2. The investigators, patients, and sponsor were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population, evaluated separately in each cohort. Hierarchical analysis of cohort 2 before cohort 1 was prespecified. This trial is registered with ClinicalTrials.gov, number NCT01667419. The study enrolled 184 patients in cohort 2 (93 were assigned to vemurafenib and 91 to placebo) and 314 patients in cohort 1 (157 were assigned to vemurafenib and 157 to placebo). At the time of data cutoff (April 17, 2017), median study follow-up was 33·5 months (IQR 25·9-41·6) in cohort 2 and 30·8 months (25·5-40·7) in cohort 1. In cohort 2 (patients with stage IIIC disease), median disease-free survival was 23·1 months (95% CI 18·6-26·5) in the vemurafenib group versus 15·4 months (11·1-35·9) in the placebo group (hazard ratio [HR] 0·80, 95% CI 0·54-1·18; log-rank p=0·26). In cohort 1 (patients with stage IIC-IIIA-IIIB disease) median disease-free survival was not reached (95% CI not estimable) in the vemurafenib group versus 36·9 months (21·4-not estimable) in the placebo group (HR 0·54 [95% CI 0·37-0·78]; log-rank p=0·0010); however, the result was not significant because of the prespecified hierarchical prerequisite for the primary disease-free survival analysis of cohort 2 to show a significant disease-free survival benefit. Grade 3-4 adverse events occurred in 141 (57%) of 247 patients in the vemurafenib group and 37 (15%) of 247 patients in the placebo group. The most common grade 3-4 adverse events in the vemurafenib group were keratoacanthoma (24 [10%] of 247 patients), arthralgia (17 [7%]), squamous cell carcinoma (17 [7%]), rash (14 [6%]), and elevated alanine aminotransferase (14 [6%]), although all keratoacanthoma events and most squamous cell carcinoma events were by default graded as grade 3. In the placebo group, grade 3-4 adverse events did not exceed 2% for any of the reported terms. Serious adverse events were reported in 40 (16%) of 247 patients in the vemurafenib group and 25 (10%) of 247 patients in the placebo group. The most common serious adverse event was basal cell carcinoma, which was reported in eight (3%) patients in each group. One patient in the vemurafenib group of cohort 2 died 2 months after admission to hospital for grade 3 hypertension; however, this death was not considered to be related to the study drug. The primary endpoint of disease-free survival was not met in cohort 2, and therefore the analysis of cohort 1 showing a numerical benefit in disease-free survival with vemurafenib versus placebo in patients with resected stage IIC-IIIA-IIIB BRAFV600 mutation-positive melanoma must be considered exploratory only. 1 year of adjuvant vemurafenib was well tolerated, but might not be an optimal treatment regimen in this patient population. F Hoffman-La Roche Ltd.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

TNM stage at diagnosis is more predictive of prognosis than pathological complete response in young breast cancer treated with neoadjuvant chemotherapy.

Survival outcomes of neoadjuvant chemotherapy with zoledronic acid for HER2-negative breast cancer

BackgroundA randomized phase 2 trial in women with HER2-negative breast cancer has shown that adding zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) has potential anticancer benefits in postmenopausal and triple-negative (TN) breast cancer patients. We report the data for the secondary end point of disease-free survival (DFS). MethodsPatients were randomly assigned to receive CT or CT + ZOL (CT-Z). All patients received four cycles of FEC100 followed by 12 cycles of paclitaxel weekly. ZOL (4 mg) was administered 3-4 times weekly for 7 wk to the CT-Z group patients. The primary end point was pathologic complete response (pCR). The secondary end points were the clinical response rates, rate of breast-conserving surgery, safety, and DFS. ResultsOf the 188 patients enrolled, 95 were assigned to the CT group and 93 to the CT-Z group. DFS and overall survival were analyzed in 92 and 88 patients with the mean times of 5.15 y and 5.38 y, respectively. The 3-y DFS rate was 84.6% in the CT group and 90.8% in the CT-Z group (P = 0.188). The particular benefit from ZOL for the neoadjuvant CT seen as improvement of the pCR rate was indicated in the 3-y DFS period for TN cancer cases (CT versus CT-Z: 70.6% versus 94.1%) but not for postmenopausal cases. ConclusionsZOL did not improve DFS when combined with CT. However, the improvement of the pCR rate translated to survival outcomes in TN breast cancer. The short-term application of ZOL may not be sufficient to improve the outcome in postmenopausal patients.

Randomized phase III trial of adjuvant pazopanib versus placebo after nephrectomy in patients with locally advanced renal cell carcinoma (RCC) (PROTECT).

4507 Background: PROTECT (NCT01235962) evaluated the efficacy and safety of pazopanib (PAZ) versus placebo in patients (pts) with locally advanced renal cell carcinoma (RCC) post nephrectomy. Methods: 1538 pts with resected pT2 (high grade), pT3 or greater clear cell RCC were randomly assigned to PAZ or placebo for 1 year. The starting dose (800 mg) following treatment of 403 pts was lowered to 600 mg to improve tolerability and primary endpoint was changed to disease-free survival (DFS) with PAZ 600 (N = 1135). Primary analysis was performed after 350 DFS events in intent-to-treat (ITT) PAZ 600, and DFS follow-up analysis was performed after an additional 12 months. Secondary endpoints included DFS with ITT PAZ 800 and ITT ALL, and safety. Results: Disease characteristics were similar between arms. The primary analysis results of DFS ITT 600 were not significant [HR: 0.862; 95% CI, 0.699, 1.063; p = 0.165] (Table). The secondary endpoint of DFS in ITT PAZ 800 and ITT ALL yielded 31% and 20% risk reduction, respectively. Updated DFS analysis in ITT 600 showed a higher HR with longer follow up. Increased ALT and AST were the most common adverse events leading to treatment discontinuation in the PAZ 600 (ALT 16% and AST 5%) and PAZ 800 (ALT 18% and AST 7%) groups. Conclusions: The study did not meet the primary DFS endpoint in ITT 600; however, a 31% decrease in the risk of recurrence was observed in ITT 800. The safety profiles in the 600 mg and 800 mg groups were similar and consistent with PAZ prior experience. Clinical trial information: NCT01235962. [Table: see text]

Abstract P5-16-10: Zoledronic acid combined with neoadjuvant chemotherapy for HER2-negative early breast cancer (JONIE 1 trial): Survival outcomes of a randomized multicenter phase 2 trial

Abstract BACKGROUND and AIM: Findings from a randomized phase 2 JONIE1 trial in women with HER2-negative early breast cancer have shown that the addition of zoledronic acid (ZOL) to neoadjuvant chemotherapy (CT) has potential anticancer benefits in postmenopausal and triple-negative breast cancer patients. We report the data for the prespecified secondary endpoint of disease-free survival (DFS). METHODS: We enrolled women with HER2-negative early breast cancer and randomly assigned them to receive CT or CT+ZOL (CTZ). All patients received 4 cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered 3-4 times weekly for 7 weeks to the CTZ group patients. Definitive surgery was performed 3-4 weeks after the last paclitaxel dose. The primary endpoint was pathological complete response (pCR). The secondary endpoints were the clinical response rates, rate of breast-conserving surgery, safety, and DFS (defined as the time from randomization to disease occurrence or death). The trial is registered as UMIN000003261 (www.umin.ac.jp/english/) with ongoing follow-up. FINDINGS: Of the 188 patients enrolled, 95 were assigned to the CT group and 93 to the CTZ group. The mean (95% CI) DFS time of the CT group was 5.15 years (4.83-5.47) and that of the CTZ group was 5.38 years (5.11-5.66). The 3-year DFS rate was 84.6% (95% CI 77.2-92.0) in the CT group and 90.7% (84.6-96.8) in the CTZ group with no significant difference (p = 0.120). The particular benefit from ZOL for the neoadjuvant CT seen as improvement of the pCR rate was indicated in the 3-year DFS period for triple-negative cancer cases (CT vs CTZ: 70.6% vs 94.1%), but not for postmenopausal cases. CONCLUSIONS: ZOL slightly improved DFS when combined with CT. Although a significant difference was not found in this study, plans are underway for conducting a combined analysis of 3 neoadjuvant CT trials together with ZOL. The improvement of the pCR rate may be associated with DFS in triple-negative cases. Previous studies have shown that ZOL was more efficacious in an estrogen-suppressed condition. However, the short-term application of ZOL in this study may not be sufficient to improve the outcome in postmenopausal patients. Citation Format: Ishikawa T, Akazawa K, Hasegawa Y, Tanino H, Horiguchi J, Miura D, Hayashi M, Takao S, Kim SJ, Yamagami K, Miyashita M, Konishi M, Shigeoka Y, Suzuki M, Taguchi T, Kubota T, Kohno N. Zoledronic acid combined with neoadjuvant chemotherapy for HER2-negative early breast cancer (JONIE 1 trial): Survival outcomes of a randomized multicenter phase 2 trial [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 P5-16-10.

Family history of colorectal cancer and its impact on survival in patients with resected stage III colon cancer: results from NCCTG Trial N0147 (Alliance).

Family history of colon cancer often portends increased risk of disease development; however, the prognostic significance of family history related to disease and survival outcomes is unclear. To investigate the relationship between family history of colorectal cancer and survival outcomes in stage III colon cancer patients, a prospective cohort of 1,935 patients with resected stage III colon cancer enrolled in a randomized controlled trial (N0147), comparing the standard of care FOLFOX to FOLFOX with cetuximab, was studied. Patients completed a baseline questionnaire on family history and were followed every 6 months until death or 5 years after randomization. We examined the endpoints of disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS), comparing patients with a positive versus negative family history of colorectal cancer. The adjusted hazard ratios (HRs) for patients with a positive family history were 0.95 [95% confidence interval (CI), 0.78-1.16] for DFS, 0.94 (95% CI, 0.76-1.16) for TTR, and 0.92 (95% CI, 0.74-1.15) for OS (all adjusted P>0.47). A non-significant trend toward improved DFS (P=0.17; adjusted P=0.34) was observed when 2 or more relatives were affected as compared to 0 relatives (multivariate HR: 0.72; 95% CI, 0.45-1.15), whereas subjects with histories of 0 or 1 affected relatives had similar DFS (multivariate HR for 1 vs. 0: 1.00; 95% CI, 0.81-1.24). Interactions of the molecular factors KRAS, BRAF, and MMR with family history were also explored. The only significant interaction was for deficient MMR (dMMR) and first-degree relatives with a family history of colorectal cancer (0 vs. 1 vs. 2+ relatives) for a benefit on OS (univariate P=0.001), which remained significant after adjusting for other factors (P=0.029). Among patients with stage III resected colon cancer treated with adjuvant FOLFOX, a family history of colorectal cancer did not significantly impact DFS, TTR, or OS outcomes, with the exception of patients with dMMR-expressing tumors.

Pathological complete response in invasive breast cancer treated by skin sparing mastectomy and immediate reconstruction following neoadjuvant chemotherapy and radiation therapy: Comparison between immunohistochemical subtypes

ContextEven if neoadjuvant chemotherapy (NACT) and oncoplastic techniques have increased the breast conserving surgery rate, mastectomy is still a standard for multifocal or extensive breast cancers (BC). In the prospect of increasing breast reconstruction, an alternative therapeutic protocol was developed combining NACT with neoadjuvant radiation therapy (NART), followed by mastectomy with immediate breast reconstruction (IBR). The oncological safety of this therapeutic plan still needs further exploration. We assessed pathological complete response (pCR) as a surrogate endpoint for disease free survival. MethodsBetween 2010 and 2016, 103 patients undergoing mastectomy after NACT and NART were recruited. After CT and RT were administrated, a completion mastectomy with IBR by latissimus dorsi flap was achieved 6 to 8 weeks later. pCR was defined by the absence of residual invasive disease in both nodes and breast. Histologic response was analyzed for each immunohistochemical subset. ResultspCR was obtained for 53.4% of the patients. This pCR rate was higher in hormonal receptor negative (HER2 and triple negative) patients when compared to luminal tumours (69.7% vs 45.7%, p=0.023). DiscussionThe pCR rate found in this study is higher than those published in studies analyzing NACT (12.5%-27.1%). This can be explained by the combination of anthracycline and taxane, the use of trastuzumab when HER2 was overexpressed but also by RT associated to NACT. ConclusionInverting the sequence protocol for BC, requiring both CT and RT, allows more IBR without diminishing pCR and should therefore be considered as an acceptable therapeutic option.