Neoadjuvant Arm Research Articles

Pathologic complete response (pCR) rates for patients with HR+/HER2− high-risk, early-stage breast cancer (EBC) by clinical and molecular features in the phase II I-SPY2 clinical trial

Hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer (EBC) is a heterogenous disease. Identification of better clinical and molecular biomarkers is essential to guide optimal therapy for each patient. We analyzed rates of pathologic complete response (pCR) and distant recurrence-free survival (DRFS) for patients with HR+/HER2-negative EBC in eight neoadjuvant arms in the I-SPY2 trial by clinical/molecular features: age, stage, histology, percentage estrogen receptor (ER) positivity, ER/progesterone receptor status, MammaPrint (MP)-High1 (0 to-0.57) versus MP-High2 (<-0.57), BluePrint (BP)-Luminal-type versus BP-Basal-type, and ImPrint immune signature. We quantified the clinical/molecular heterogeneity, assessed overlap among these biomarkers, and evaluated associations with pCR and DRFS. Three hundred and seventy-nine patients with HR+/HER2-negative EBC were included in this analysis, with an observed pCR rate of 17% across treatment arms. pCR rates were higher in patients with stage II versus III disease (21% versus 9%, P= 0.0013), ductal versus lobular histology (19% versus 11%, P= 0.049), lower %ER positivity (≤66% versus >66%) (35% versus 9%, P= 3.4E-09), MP-High2 versus MP-High1 disease (31% versus 11%, P= 1.1E-05), BP-Basal-type versus BP-Luminal-type disease (34% versus 10%, P= 1.62E-07), and ImPrint-positive versus -negative disease (38% versus 10%, P= 1.64E-09). Patients with lower %ER were more likely to have MP-High2 and BP-Basal-type disease. At a median follow-up of 4.8 years, patients who achieved pCR had excellent outcomes irrespective of clinical/molecular features. Among patients who did not achieve pCR, DRFS events were more frequent in patients with MP-High2 and BP-Basal-type disease than those with MP-High1 and BP-Luminal-type disease. Among patients with high molecular-risk HR+/HER2-negative EBC, the MP-High2, BP-Basal-type, and ImPrint-positive signatures identified a partially overlapping subset of patients who were more likely to achieve pCR in response to neoadjuvant chemotherapy ± targeted agents or immunotherapy compared to patients with MP-High1, BP-Luminal-type, and ImPrint-negative disease. I-SPY2.2 is incorporating the use of these biomarkers to molecularly define specific patient populations and optimize treatment selection.

Survival Outcomes of Neoadjuvant Therapy Followed by Sleeve Lobectomy in Non-Small Cell Lung Cancer

BackgroundThis study was carried out to evaluate the impact of neoadjuvant therapy on long-term survival of patients with non-small cell lung cancer undergoing sleeve lobectomy. MethodsA total of 613 patients were retrospectively analyzed, including 124 who received neoadjuvant therapy. A 1:2 propensity score matching method was adopted to create a balanced cohort including 110 with neoadjuvant therapy and 169 without neoadjuvant therapy. Survival was estimated by the Kaplan-Meier method and compared with the log-rank test and Cox proportional hazards models. ResultsNeoadjuvant therapy was associated with improved 3-year disease-free survival (DFS; 73.6% vs 54.4%; P < .001) and overall survival (OS; 80.9% vs 63.9%; P = .002) compared with patients without neoadjuvant therapy. Moreover, neoadjuvant chemoimmunotherapy significantly improved 3-year DFS (85.3% vs 54.4%; P = .001) and OS (88.2% vs 63.9%; P = .006), whereas chemotherapy alone did not show a significant effect. Multivariable Cox regression analysis revealed neoadjuvant therapy to be an independent predictor of improved DFS and OS, whereas pathologic N2 stage was independently associated with poorer DFS and OS. Furthermore, subgroup analysis in the neoadjuvant arm revealed that pathologic N2 stage is an independent risk factor for DFS (hazard ratio, 3.830; 95% CI, 1.687-8.694; P = .001), and achieving major pathologic response is an independent predictor for better OS (hazard ratio, 0.120; 95% CI, 0.015-0.933; P = .043). ConclusionsNeoadjuvant therapy before sleeve lobectomy significantly increased DFS and OS in locally advanced non-small cell lung cancer. Sleeve lobectomy is advisable after neoadjuvant therapy, especially following chemoimmunotherapy.

Implementing Standard Diagnosis and Treatment for Locally Advanced Breast Cancer Through Global Research in Latin America: Results From a Multicountry Pragmatic Trial.

Breast cancer mortality rates in Latin America (LA) are higher than those in the United States, possibly because of advanced disease presentation, health care disparities, or unfavorable molecular subtypes. The Latin American Cancer Research Network was established to address these challenges and to promote collaborative clinical research. The Molecular Profiling of Breast Cancer Study (MPBCS) aimed to evaluate the clinical characteristics and treatment outcomes of LA participants with locally advanced breast cancer (LABC). The MPBCS enrolled 1,449 participants from Argentina, Brazil, Chile, Mexico, and Uruguay. Through harmonized procedures and quality assurance measures, this study evaluated clinicopathologic characteristics, neoadjuvant chemotherapy response, and survival outcomes according to residual cancer burden (RCB) and the type of surgery. Overall, 711 and 480 participants in the primary surgery and neoadjuvant arms, respectively, completed the 5-year follow-up period. Overall survival was independently associated with RCB (worse survival for RCBIII-adjusted hazard ratio, 8.19, P < .001, and RCBII [adjusted hazard ratio, 3.69, P < .008] compared with RCB0 [pathologic complete response or pCR]) and type of surgery (worse survival in mastectomy than in breast-conserving surgery [BCS], adjusted hazard ratio, 2.97, P = .001). The hormone receptor-negative-human epidermal growth factor receptor 2-positive group had the highest proportion of pCR (48.9%). The analysis of the ASCO Quality Oncology Practice Initiative breast module revealed high compliance with pathologic standards but lower adherence to treatment administration standards. Notably, compliance with trastuzumab administration varied widely among countries (33.3%-88.7%). In LABC, we demonstrated the survival benefit of BCS and the prognostic effect of the response to available neoadjuvant treatments despite an important variability in access to key treatments. The MPBCS represents a significant step forward in understanding the real-world implementation of oncologic procedures in LA.

Evaluation of Major Pathologic Response and Pathologic Complete Response as Surrogate End Points for Survival in Randomized Controlled Trials of Neoadjuvant Immune Checkpoint Blockade in Resectable in NSCLC

IntroductionControversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC. MethodsA search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were analyzed using a linear regression model weighted by sample size. The regression coefficient and R2 with 95% confidence interval were calculated by the bootstrapping approach. ResultsSeven randomized clinical trials were identified for a total of 2385 patients. At the patient level, the R2 of pCR and MPR with 2-year EFS were 0.82 (0.66–0.94) and 0.81 (0.63–0.93), respectively. The OR of 2-year EFS rates by response status was 0.12 (0.07–0.19) and 0.11 (0.05–0.22), respectively. For the 2-year OS, the R2 of pCR and MPR were 0.55 (0.09–0.98) and 0.52 (0.10–0.96), respectively. At the trial level, the R2 for the association of OR for response and HR for EFS was 0.58 (0.00–0.97) and 0.61 (0.00–0.97), respectively. ConclusionsOur analyses reveal a robust correlation between pCR and MPR with 2-year EFS but not OS. Trial-level surrogacy was moderate but imprecise. More mature follow-up and data to assess the impact of study crossover are needed.

The current state and future of neoadjuvants in resectable melanoma: Review of phase II/III studies conducted between 2018-2022.

e21568 Background: Adjuvant therapy with single agent anti-PD1 and BRAF/MEK-inhibitors (BRAF/MEKi) is approved for patients diagnosed with high-risk stage III melanoma. The goal of adjuvant therapy is to prevent the growth of the occult metastasis to distant organs. The premise of neoadjuvant therapy in clinical stage III melanoma is to allow for a better antigen exposure when checkpoint inhibitors are administered. We aimed to get an overview of the current state of neoadjuvant therapy in resectable melanoma. Methods: A systematic literature search was conducted in November 2022, using PubMed, American Society of Clinical Oncology (ASCO) Journal of Clinical Oncology and European Society for Medical Oncology (ESMO) abstract databases. Eligible studies included Phase 2 and 3 randomized controlled trials (RCT), single-arm trials, pooled analyses, and planned future trials published between 2018-2022 looking at the efficacy of neoadjuvants in resectable melanoma. Two individuals (CL and MM) screened all the studies, and 3 individuals (CM, MM, MW) went over the list of Abstracts. Primary outcomes and secondary outcomes, as well as median duration of follow up and Grade 3 or above adverse effects (AEs) were recorded. Abstracts with more recent findings or final publications were excluded in the final analysis. Results: A total of 14 published studies (4 RTCs, 5 single-arm, 2 OpACIN-neo and 3 related sub-analysis studies) and 16 abstracts (5 ESMO, 11 ASCO) were identified, representing 34 unique Neoadjuvant arms and a total of 1,496 patients. Thirteen of 27 trials making 71% of patients (n = 1061) tested immune checkpoint inhibitors (ICIs). Four of 27 trials of total n = 112 tested BRAF/MEKi. All ongoing or future studies (7 trials) tested combination of ICI with BRAF/MEKi or other molecules such as MDM2 inhibitors, interferon-α, or oncolytic viruses. Most of studies (54% of ICI studies, 50% of BRAF/MEK inhibitor trials, and 80% of other studies) used pathological response as their primary outcome. Other primary end points included event-free survival (EFS) and relapse-free survival (RFS), and 13/14 published studies and 13/16 abstracts met the primary end point. A pooled analysis of complete pathologic response (pCR) revealed an estimate of 38.3% ± 19.7 (mean ± SD) from 16 unique ICI neoadjuvant arms, 51.9% ± 5.3 for BRAF/MEKi (from 3 data points), and 21.0% ± 7.2 for other agents/combinations (from 3 data points). Rate of ≥ Grade 3 AEs was 28.7% ± 31.0 (from 11 data points) for studies testing ICI, 32.5% ± 14.1 (from 6 data points) for BRAF/MEKi, and 23.6% ± 20.2 (from 3 data points) from studies testing other agents/combinations. Conclusions: Recent studies have shown that neoadjuvant in resectable melanoma can offer increased therapeutic efficacy. While past studies have focused on PD-1 and CTLA-4 inhibitors, ongoing and future studies are beginning to test newer agents and novel molecular targets.

Survival update of neoadjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma in the OpACIN and OpACIN-neo trials

Neoadjuvant ipilimumab plus nivolumab has yielded high response rates in patients with macroscopic stage III melanoma. These response rates translated to high short-term survival rates. However, data on long-term survival and disease recurrence are lacking. In OpACIN, 20 patients with macroscopic stage III melanoma were randomized to ipilimumab 3mg/kg plus nivolumab 1 mg/kg q3w four cycles of adjuvant or split two cycles of neoadjuvant and two adjuvant. In OpACIN-neo, 86 patients with macroscopic stage III melanoma were randomized to arm A (2×ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3w; n= 30), arm B (2× ipilimumab 1 mg/kg plus nivolumab 3mg/kg q3w; n= 30), or arm C (2× ipilimumab 3 mg/kg q3w plus 2× nivolumab 3 mg/kg q2w; n= 26) followed by surgery. The median recurrence-free survival (RFS) and overall survival (OS) were not reached in either trial. After a median follow-up of 69 months for OpACIN, 1/7 patients with a pathologic response to neoadjuvant therapy had disease recurrence. The estimated 5-year RFS and OS rates for the neoadjuvant arm were 70% and 90% versus 60% and 70% for the adjuvant arm. After a median follow-up of 47 months for OpACIN-neo, the estimated 3-year RFS and OS rates were 82% and 92%, respectively. The estimated 3-year RFS rate for OpACIN-neo was 95% for patients with a pathologic response versus 37% for patients without a pathologic response (P < 0.001). In multiple regression analyses, pathologic response was the strongest predictor of disease recurrence. Of the 12 patients with distant disease recurrence after neoadjuvant therapy, 5 responded to subsequent anti-PD-1 and 8 to targeted therapy, although 7 patients showed progression after the initial response. Updated data confirm the high survival rates after neoadjuvant combination checkpoint inhibition in macroscopic stage III melanoma, especially for patients with a pathologic response. Pathologic response is the strongest surrogate marker for long-term outcome.

Dynamic Change in Patient Reported Quality of Life is a Predictor for Survival in Localized Prostate Cancer: Exploratory Analysis from a Phase III Randomized Controlled Trial

<h3>Purpose/Objective(s)</h3> Patient reported quality of life (QOL) outcomes are pivotal endpoints to determine treatment efficacy and safety. However, it remains unknown if treatment induced change in patient reported QOL outcomes correlate with survival in localized prostate cancer (LPCa). We performed an exploratory analysis of a phase III randomized controlled study to determine the association of treatment induced dynamic change in patient reported global QOL with long-term overall survival (OS) and disease-free survival (DFS) in LPCa treated with radiotherapy (RT) and androgen deprivation therapy (ADT). <h3>Materials/Methods</h3> LPCa patients with Gleason score ≤7, clinical stage T1b-T3a, and PSA <30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 mos starting 4 mos before prostate RT or concomitant and adjuvant ADT for 6 mos starting concurrently with RT. Patient reported QOL outcomes were collected using EORTC QOL questionnaires. We used the global QOL (G-QOL) score from C30 questionnaire. Increase in G-QOL score indicated improvement in global QOL. To capture the association between the dynamic change in the G-QOL of each patient and the hazard of outcome, we utilized the framework of multivariate joint modeling for longitudinal and survival outcomes. For the time-to-event submodel, a Cox proportional hazard regression model was built with covariables including treatment arm, baseline PSA, tumor stage, Gleason score, and age. For the longitudinal submodel, a linear mixed effect model was built with an interaction term for treatment arm and time of evaluation in addition to fixed covariables - treatment arm, time of evaluation, baseline G-QOL score and age. Time of assessment was included as a random slope while patients were included as random intercepts in the mixed models. The two submodels were linked through a random effect. Baseline hazard was modeled using penalized splines. A two-sided p-value <0.025 was chosen to be the threshold for statistical significance. <h3>Results</h3> A total of 388 patients were eligible for this study – 191 belonged to the neoadjuvant arm while 197 to the adjuvant arm. At a median follow-up of 148 mos, a total of 133 deaths were recorded. On joint modelling, an increase in G-QOL score by 10 units (the threshold for clinically meaningful change) was associated with a 11.2% decrease in the hazard of death (hazard ratio [HR] per 1 unit increase G-QOL: 0.988, 95% CI: 0.980-0.996; p=0.007). An increase in G-QOL score by 10 units was associated with 10% decrease in the hazard of progression or death (HR per 1 unit increase in G-QOL: 0.990; 95% CI: 0.984-0.999; p=0.023). <h3>Conclusion</h3> Treatment induced improvement in global QOL is a predictor for improved DFS and OS in LPCa. This suggests a significant interplay of patient-reported quality of life and quantity of life in LPCa which could mainly be driven by the non-cancer specific mortality in this patient population. Judicious use of these QOL metrics could guide risk stratification and potentially inform treatment decision in these patients

Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)—a randomized phase II trial of the AIO pancreatic cancer group

Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

A study of neo-adjuvant and adjuvant ofra-vec (VB-111) for treatment of surgically accessible recurrent GBM.

TPS2075 Background: Ofranergene obadenovec (ofra-vec, VB-111) is an anti-cancer gene based immune activator and targeted vascular disruptor. The dual mechanism of action triggers a broad antiangiogenic effect and induces of a tumor directed immune response. A previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with ofra-vec monotherapy, that was continued after progression in combination with bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of ofra-vec will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses. Methods: Study NCT04406272 is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy ofra-vec in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous ofra-vec prior to resection, and ofra-vec every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and ofra-vec every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care; however, ofra-vec will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is to evaluate the influence of neoadjuvant ofra-vec on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, 6mPFS and OS. Study is open for enrolment. Clinical trial information: NCT04406272.

Survival update of neoadjuvant ipilimumab + nivolumab in macroscopic stage III melanoma: The OpACIN and OpACIN-neo trials.

9572 Background: OpACIN was the first trial testing neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) versus the same combination given adjuvant. An unexpected high pathologic responses of 78% was observed in the neoadjuvant arm with a 2-year relapse-free survival (RFS) rate of 80%. The subsequent OpACIN-neo trial tested 3 different dosing schedules of neoadjuvant IPI + NIVO and identified 2 cycles IPI 1 mg/kg + NIVO 3 mg/kg q3w as most favorable schedule with a pathologic response rate of 77% and 20% grade 3-4 immune-related adverse events. Long-term data on the durability of the pathologic (path) responses upon neoadjuvant checkpoint inhibition are lacking so far. Therefore, we present here the updated RFS and overall survival (OS) data of both trials. Methods: In OpACIN 20 macroscopic stage III melanoma pts were randomized to receive either IPI 3 mg/kg + NIVO 1 mg/kg q3w 4 cycles adjuvant after lymph node dissection or split 2 cycles neoadjuvant and 2 adjuvant. In OpACIN-neo 86 macroscopic stage III melanoma pts were randomized to arm A (2x IPI 3 mg/kg + NIVO 1 mg/kg q3w, n=30), arm B (2x IPI 1 mg/kg + NIVO 3 mg/kg q3w, n=30), or arm C (2x IPI 3 mg/kg q3w followed by 2x NIVO 3 mg/kg q2w, n=26) followed by lymph node dissection in week 6. RFS and OS were estimated using Kaplan Meier method. All comparative efficacy endpoints are descriptive for OpACIN, since the trial was not powered for comparison of the arms. Results: After a median follow-up (FU) of 68.6 months for OpACIN (minimum FU of 59.8 months), median RFS and OS were not reached. Only 1/7 patients (pts) with a pathologic response on neoadjuvant therapy has relapsed. Estimated 5-year RFS and OS rates for the neoadjuvant arm were 70.0% (95%CI: 46.7-100.0) and 90.0% (95%CI: 73.2-100.0) versus 60.0% (95%CI 36.2-99.5) and 70.0% (95%CI: 46.7-100.0) for the adjuvant arm. After a median FU of 46.8 months for OpACIN-neo (minimum FU of 38.2 months), median RFS and OS were not reached. Of pts with path response on neoadjuvant therapy, 3/64 (4.7%) had an event (2 pts relapsed, 1 pt died due to toxicity), versus 14/21 (66.7%) without path response. This resulted in a 3-year RFS rate of 95.3% (95%CI: 90.3-100.0) for responding versus 36.8% (95%CI: 20.4-66.4) for non-responding pts (p&lt;0.001). Of the pts who relapsed after response, 1 had major path response (&lt;10% vital tumor) and 1 a partial response (10-15% vital tumor). Estimated 3-year RFS and OS rates are presented in the Table. Conclusions: Updated data from OpACIN and OpaCIN-neo trials confirm the durability of responses upon neoadjuvant combination checkpoint inhibition in high risk stage III melanoma. Pathologic response remains a reliable surrogate marker for RFS and OS. Clinical trial information: NCT02437279, NCT02977052. [Table: see text]

The quality of life in neoadjuvant versus adjuvant therapy of esophageal cancer treatment trial (QUINTETT): Randomized parallel clinical superiority trial.

BackgroundWe compared the health‐related quality of life (HRQOL) in patients undergoing trimodality therapy for resectable stage I‐III esophageal cancer.MethodsA total of 96 patients were randomized to standard neoadjuvant cisplatin and 5‐fluorouracil chemotherapy plus radiotherapy (neoadjuvant) followed by surgical resection or adjuvant cisplatin, 5‐fluorouracil, and epirubicin chemotherapy with concurrent extended volume radiotherapy (adjuvant) following surgical resection.ResultsThere was no significant difference in the functional assessment of cancer therapy‐esophageal (FACT‐E) total scores between arms at 1 year (p = 0.759) with 36% versus 41% (neoadjuvant vs. adjuvant), respectively, showing an increase of ≥15 points compared to pre‐treatment (p = 0.638). The HRQOL was significantly inferior at 2 months in the neoadjuvant arm for FACT‐E, European Organization for Research and Treatment of Cancer quality of life questionnaire (EORTC QLQ‐OG25), and EuroQol 5‐D‐3 L in the dysphagia, reflux, pain, taste, and coughing domains (p < 0.05). Half of patients were able to complete the prescribed neoadjuvant arm chemotherapy without modification compared to only 14% in the adjuvant arm (p < 0.001). Chemotherapy related adverse events of grade ≥2 occurred significantly more frequently in the neoadjuvant arm (100% vs. 69%, p < 0.001). Surgery related adverse events of grade ≥2 were similar in both arms (72% vs. 86%, p = 0.107). There were no 30‐day mortalities and 2% vs. 10% 90‐day mortalities (p = 0.204). There were no significant differences in either overall survival (OS) (5‐year: 35% vs. 32%, p = 0.409) or disease‐free survival (DFS) (5‐year: 31% vs. 30%, p = 0.710).ConclusionTrimodality therapy is challenging for patients with resectable esophageal cancer regardless of whether it is given before or after surgery. Newer and less toxic protocols are needed.

Abstract PO-046: The effect of neoadjuvant therapy on immune profiling of pancreatic ductal adenocarcinoma: A prospective study of the PREOPANC-1 randomized controlled trial

Abstract The randomized phase III trial (PREOPANC-1) that was performed in 16 centers in the Netherlands compared the effects of preoperative chemoradiotherapy (Gemcitabine and 2.4 Gy radiation) versus immediate surgery for resectable and borderline resectable pancreatic cancer. The outcomes of the secondary endpoints and predefined subgroup analyses suggest an advantage of the neoadjuvant approach. The aim of the present study was to investigate the changes in the immune microenvironment and infiltration caused by the neoadjuvant treatment. To that aim, we collected formalin-fixed, paraffin-embedded pancreatic cancer samples from all centers that participated in the PREOPANC -1 trial. We performed targeted gene expression using the PanCancer Immune Profiling panel of NanoString. Comparing 50 samples of the patient who were subjected to neoadjuvant treatment to 46 treatment-naïve samples showed a distinct genetic profile induced by the neoadjuvant therapy. More than 250 immune-related genes were significantly differentially expressed between the two groups of samples. The results indicate that neoadjuvant therapy resets the innate immune activation in the tissue samples. A significantly higher infiltration of CD14+, CD33+, CSF1R+, and CD163+, MRC1+ cells were found in samples of the neoadjuvant arm. In contrast, B cells and various subtypes of T cells like CD8+ and FOXP3+ showed a significant decrease in the same samples. Pathway analysis revealed that the neoadjuvant treatment stimulated the expression of genes related to the complement activation, chemotaxis, and wound repair, while genes related to lymphocyte activation and adaptive immune responses were dominant in the treatment-naïve arm. In conclusion, this is the first comprehensive study to describe the immune-molecular changes as a result of neoadjuvant therapy in a randomized clinical trial. The results reveal the enrichment of the myeloid compartment following neoadjuvant therapy which was significantly associated with a survival benefit for the patients. Studying the personalized effect of neoadjuvant therapy will guide choosing the appropriate combined therapy for pancreatic cancer. Citation Format: Diba Latifi, Willem de Koning, Sai ping Lau, Frederiek Grevers, Coen van Dam, Casper H. J. van Eijck, Dana A. M. Mustafa. The effect of neoadjuvant therapy on immune profiling of pancreatic ductal adenocarcinoma: A prospective study of the PREOPANC-1 randomized controlled trial [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-046.

Association of Baseline Patient-reported Health-related Quality of Life Metrics with Outcome in Localised Prostate Cancer

AimsAlthough health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localised prostate cancer. We report the association of baseline HR-QoL metrics with overall survival and toxicity in localised prostate cancer. Materials and methodsThis was a secondary analysis of a phase III randomised controlled study conducted in a single-payer health system. Patients with Gleason score ≤7, clinical stage T1b–T3a and prostate-specific antigen <30 ng/ml were randomised to neoadjuvant and concurrent androgen deprivation therapy (ADT) for 6 months starting 4 months before prostate radiotherapy or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate radiotherapy. HR-QoL scores were estimated using the European Organisation for Research and Treatment of Cancer QoL questionnaire. A multistate Markov model was used to determine the association of baseline HR-QoL metrics with overall survival and a multilevel multivariable Cox regression was used to determine the association with the incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P < 0.025 was considered as statistically significant. ResultsOverall, 393 patients with baseline HR-QoL data were included in this analysis: 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio 1.020, 95% confidence interval 1.010–1.030, P = 0.02) and dyspnoea (hazard ratio 1.020, 95% confidence interval 1.003–1.030, P = 0.01) were associated with inferior overall survival. Baseline dyspnoea was associated with a higher incidence of grade ≥3 toxicity (hazard ratio 1.020, 95% confidence interval 1.010–1.030, P = 0.023). ConclusionIn a cohort of localised prostate cancer patients treated with radiotherapy and short-term ADT, a 10-point higher baseline financial difficulty or dyspnoea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnoea, we noted a 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity.

Association of Baseline Health-Related Quality of Life Metrics With Outcome in Localized Prostate Cancer

While health-related quality of life (HR-QoL) outcomes are pivotal in oncology, the prognostic significance of patient-reported HR-QoL metrics is largely undefined in localized prostate cancer (LPCa). In this exploratory analysis, we report the association of baseline HR-QoL metrics with overall survival (OS) and risk of late radiation-induced toxicity in men with LPCa treated with combination of radiotherapy (RT) and androgen deprivation therapy (ADT).This is a secondary analysis of a phase III randomized controlled study conducted in two tertiary cancer centers. LPCa patients with Gleason score ≤7, clinical stage T1b to T3a, and prostate-specific antigen < 30 ng/mL were randomized to neoadjuvant and concurrent ADT for 6 months starting 4 months before prostate RT or concurrent and adjuvant ADT for 6 months starting simultaneously with prostate RT. HR-QoL scores were estimated using European Organization for Research and Treatment of Cancer QoL questionnaire. A multi-state Markov model was used to determine the association of baseline HR-QoL metrics with OS and a multilevel multivariable Cox regression to determine the association with incidence of delayed-onset grade ≥3 radiotherapy-related toxicities. To adjust for multiple analyses, P-value < 0.025 was considered as statistically significant. Conditional approach was used to calculate 15-year adjusted OS for patients with and without financial difficulty and patients with and without dyspnea at baseline.Overall, 393 patients with baseline HR-QoL data were included in this analysis - 194 in the neoadjuvant arm and 199 in the adjuvant arm. Baseline financial difficulty (hazard ratio [HR]: 1.020, 95% confidence intervals [CI]:1.010-1.030, P = 0.02), and dyspnea (HR: 1.020, 95% CI:1.003-1.030, P = 0.01) were associated with inferior OS. Adjusted OS for patients with and without financial difficulty at baseline was 15.5% and 45.7%, respectively (P < 0.01). Adjusted OS for patients with and without baseline dyspnea was 21.2% and 46.6%, respectively. Baseline dyspnea was associated with higher incidence of grade ≥3 toxicity (HR: 1.020, 95% CI: 1.010-1.030, P = 0.023).In a cohort of LPCa patients treated with RT and short-term ADT, a 10-point increase in baseline financial difficulty or a 10-point increase in baseline dyspnea was associated with a 20% increased risk of death. With each 10-point increase in baseline dyspnea, we noted an 20% increase in the associated risk of grade ≥3 delayed-onset radiotherapy-related toxicity. These findings underscore the importance of integrating these baseline patient-reported metrics in selecting patients, making informed treatment-decisions, and optimizing overall outcome in men with localized prostate cancer.

Preoperative or Perioperative Docetaxel, Oxaliplatin, and Capecitabine (GASTRODOC Regimen) in Patients with Locally-Advanced Resectable Gastric Cancer: A Randomized Phase-II Trial.

Docetaxel associated with oxaliplatin and 5-fluorouracil (FLOT) has been reported as the best perioperative treatment for gastric cancer. However, there is still some debate about the most appropriate number and timing of chemotherapy cycles. In this randomized multicenter phase II study, patients with resectable gastric cancer were staged through laparoscopy and peritoneal lavage cytology, and randomly assigned (1:1) to either four cycles of neoadjuvant chemotherapy (arm A) or two preoperative + two postoperative cycles of docetaxel, oxaliplatin, and capecitabine (DOC) chemotherapy (arm B). The primary endpoint was to assess the percentage of patients receiving all the planned preoperative or perioperative chemotherapeutic cycles. Ninety-one patients were enrolled between September 2010 and August 2016. The treatment was well tolerated in both arms. Thirty-three (71.7%) and 24 (53.3%) patients completed the planned cycles in arms A and B, respectively (p = 0.066), reporting an odds ratio for early interruption of treatment of 0.45 (95% confidence interval (CI): 0.18–1.07). Resection was curative in 39 (88.6%) arm A patients and 35 (83.3%) arm B patients. Five-year progression-free survival (PFS) was 51.2% (95% CI: 34.2–65.8) in arm A and 40.3% (95% CI: 28.9–55.2) in arm B (p = 0.300). Five-year survival was 58.5% (95% CI: 41.3–72.2) and 53.9% (95% CI: 35.5–69.3) (p = 0.883) in arms A and B, respectively. The planned treatment was more frequently completed and was more active, albeit not significantly, in the neoadjuvant arm than in the perioperative group.

Abstract 3412: 36-months and 18-months relapse-free survival after (neo)adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma patients - update of the OpACIN and OpACIN-neo trials

Abstract Introduction The outcome of high-risk stage III melanoma patients was poor with a 5-year overall survival (OS) rate of &amp;lt;50%. Adjuvant ipilimumab (IPI) improved the relapse-free survival (RFS) and OS, and adjuvant anti-PD-1 improved the RFS further. Preclinical data suggested that neoadjuvant therapy may be more effective than adjuvant therapy due to broader immune activation. The OpACIN trial compared neoadjuvant IPI plus nivolumab (NIVO) versus adjuvant IPI plus NIVO, while the subsequent OpACIN-neo trial tested three different dosing schedules of neoadjuvant IPI plus NIVO only. Neoadjuvant IPI plus NIVO induced high pathologic response rates of 74-78%. Here, we present the 36- and 18-months RFS update of the OpACIN and OpACIN-neo trial, respectively. Methods The phase 1b OpACIN trial randomized 20 stage IIIB/IIIC melanoma patients to receive either 4 cycles of adjuvant IPI 3 mg/kg plus NIVO 1 mg/kg or 2 cycles of neoadjuvant IPI plus NIVO at the same dose followed by 2 cycles adjuvant IPI plus NIVO. In the OpACIN-neo trial, 86 patients were randomized to 2 cycles neoadjuvant in arm A: 2x IPI 3 mg/kg plus NIVO 1 mg/kg q3w (n=30), arm B: 2x IPI 1 mg/kg plus NIVO 3 mg/kg q3w (n=30), and arm C: 2x IPI 3 mg/kg q3w followed immediately by 2x NIVO 3 mg/kg q3w (n=26). Pathologic response was defined as &amp;lt;50% viable tumor cells and centrally reviewed by a blinded pathologist. RFS rates were estimated using the Kaplan-Meier method. Results After a median follow-up of 36 months for the OpACIN and 18 months for the OpACIN-neo trial, only 1 of 71 patients (1.4%) with a pathologic response on neoadjuvant therapy had relapsed, versus 15 of 23 patients (65.2%) without a pathologic response. The estimated 3-year RFS rate for the neoadjuvant arm was 80% (95% CI: 59%-100%) versus 60% (95% CI: 36%-100%) for the adjuvant arm in the OpACIN trial. The median RFS was not reached in any of the arms within the OpACIN-neo trial. Estimated 18-months RFS rate was 85% (95% CI: 78%-93%) for all patients; for arm A 90% (95% CI: 80%-100%), for arm B 82% (95% CI: 70%-98%) and for arm C 83% (95% CI: 70%-100%). Translational analyses showed that tumor mutational burden and interferon-γ gene expression score at baseline, both separate and combined, can function as predictors of response. Conclusions OpACIN showed for the first time a potential benefit of neoadjuvant versus adjuvant immunotherapy, while OpACIN-neo confirmed the high pathologic response rates which can be achieved by neoadjuvant IPI plus NIVO. Both trials argue for pathologic response as a surrogate markers for RFS. Clinical trial information: NCT02437279, NCT02977052 Citation Format: Christian U. Blank, Judith M. Versluis, Elisa A. Rozeman, Alexander M. Menzies, Irene L. Reijers, Oscar Krijgsman, Esmée P. Hoefsmit, Bart A. van de Wiel, Karolina Sikorska, Carolien Bierman, Petros Dimitriadis, Maria Gonzalez, Annegien Broeks, Ron M. Kerkhoven, Andrew J. Spillane, John B. Haanen, Winan J. van Houdt, Robyn P. Saw, Hanna Eriksson, Alexander C. van Akkooi, Richard A. Scolyer, Ton N. Schumacher, Georgina V. Long. 36-months and 18-months relapse-free survival after (neo)adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma patients - update of the OpACIN and OpACIN-neo trials [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3412.

Diagnostic accuracy of CT-staging of advanced gastric cancer following neoadjuvant chemotherapy.

4551 Background: Neoadjuvant or perioperative chemotherapy has been accepted as a standard treatment globally in patients (pts) with locally advanced gastric cancer (LAGC). In PRODIGY phase III study (n = 530), we have demonstrated that neoadjuvant chemotherapy with DOS regimen (docetaxel, oxaliplatin, S-1) led to significant tumor downstaging and improved PFS in Korean LAGC pts (Kang, et al. ESMO 2019). Although CT has been performed to re-stage the tumor after neoadjuvant chemotherapy, there has been a relative paucity of diagnostic accuracy data. This study is to evaluate the diagnostic performance of restaging of LAGC after neoadjuvant chemotherapy using CT in PRODIGY study population. Methods: Of 266 pts, who had been diagnosed LAGC of T2-4 or N+ stage as assessed with CT and randomized to neoadjuvant chemotherapy arm (CSC) in PRODIGY study, 214 pts underwent gastrectomy were included in this analysis. The post-chemotherapy T- and N- stage was determined based on CT scan taken just prior to surgery and compared with the pathologic stage (AJCC 7th edition). Two experienced radiologists independently evaluated depth of primary tumor and reached consensus if any discrepancy between two readers. Diameter of short axis of the largest regional lymph node was measured to predict metastatic lymph node. Result of histopathologic T- and N-staging using surgical specimen was used as reference standard. Results: The study cohort consisted of pathologic T0 (n = 22), T1(n = 39), T2(n = 31), T3(n = 79), and T4(n = 43). The overall diagnostic accuracy of CT was 45%. For each T-stage, accuracy of T0,T1,T2,T3, and T4 was 0%, 26%, 29%, 55% and 79%, respectively. Rate of over- and under- staging was 47% and 8%, respectively. Accuracy for prediction of downstaging to early gastric cancer (T0-T1) was 83%. Interobserver agreement of T-staging was moderate (k = 0.41). There were 98 patients of N+ and 116 patients of N- at histopathology. Area under the curve of receiver operating characteristics to differentiate lymph node metastasis was 0.63. Sensitivity and specificity of size criteria of the largest lymph node (cut off value: &gt; 6mm, &gt; 7mm, and &gt; 8mm) to predict pathologic N+ were 90% and 17%, 78% and 34%, and 68% and 51%, respectively. Conclusions: Re-staging using CT after neoadjuvant chemotherapy showed suboptimal accuracy and over-staged residual tumor. However, it predicted downstaging of gastric cancer with high accuracy.

Analysis of Carcinoma of the Esophagus Patients Between Upfront Surgery vs. Neoadjuvant Therapy Followed by Surgery

In the management of carcinoma of the esophagus, neoadjuvant chemoradiation has shown to improve survival in many Western studies. It has still not become the standard of care in many centers due to perioperative morbidity/mortality or non-availability of infrastructure. We carried out a retrospective comparative study of patients undergoing upfront surgery (group A) versus patients undergoing radical esophagectomy after neoadjuvant therapy (group B) during the period 2015 to 2019 by a single surgical team in our hospital. A total of 55 cases were recorded. Baseline demographic parameters were similar between the groups. Perioperative outcomes like duration of surgery, blood loss, anastomotic leak, hospital stay, and postoperative complications were similar in both groups. There were no significant differences in radicality of resection, nodal harvest, and margin status. Pathologic complete response was observed in 20% who received neoadjuvant therapy. After a median follow-up of 28 months, 72% were alive in the upfront surgery arm and 50% in the neoadjuvant therapy arm. The mean overall survival was 10.9 ?????8.9 months in group A and 12.8????????10.8 months in group B. There was no statistically significant difference in survival between the groups (p value 0.503). Radical esophagectomy after neoadjuvant therapy is a feasible and safe oncologic procedure. Careful case selection and surgical expertise are important determinants in perioperative outcome. Prospective randomized controlled trials with long-term follow-up will establish the standard of care in this subset of population.

ATIM-09. CLINICAL TRIAL IN PROGRESS: A STUDY OF NEOADJUVANT AND ADJUVANT VB-111 FOR TREATMENT OF RECURRENT GBM

Abstract BACKGOUND Ofranergene obadenovec (VB-111) is a targeted anti-cancer viral based gene therapy with a dual mechanism: a broad antiangiogenic effect and induction of a tumor directed immune response. Previous study demonstrated a survival benefit for patients with recurrent glioblastoma (rGBM) treated with VB-111 monotherapy that was continued upon progression with combination treatment of VB-111 and bevacizumab. Glioblastoma is an immunologically “cold” microenvironment which fosters immunosuppression and antagonizes anti-tumor immune responses. The role of T-cell infiltration in combating cancer has been increasingly recognized and associated with improved participant outcomes. Based on these observations, this study will assess the hypothesis that neoadjuvant use of VB-111 will lead to a statistically significant increase in tumor infiltrating T lymphocyte (TIL) density within the tumor and enhanced systemic tumor-specific T cell responses. METHODS This is a multicenter, randomized, blinded, placebo-controlled, phase 2 surgical trial to evaluate early immunologic pharmacodynamic parameters for the viral cancer therapy VB-111 in rGBM. 45 participants with rGBM indicated for resection will randomized to one of three treatment arms: Neoadjuvant Arm: intravenous VB-111 prior to resection, and VB-111 every 6 weeks after resection. Adjuvant Arm: placebo prior to resection, and VB-111 every 6 weeks afterwards. The control arm will receive placebo prior to resection followed by standard of care. Upon evidence of contrast-enhancing progression, bevacizumab may be initiated as needed for supportive care and VB-111 will continue until progression is supported at two consecutive time points. Tumor samples will be obtained and archived at the time of surgery, and blood samples will be obtained as pharmacodynamic markers throughout the study to allow DNA sequencing of T cells. The primary endpoint is influence of neoadjuvant VB-111 on TIL density. Other endpoints include safety and tolerability, peripheral T cell response, tumor/microenvironment transcriptomic alteration, and PFS/OS. Study will open for enrolment in 2019.

ATIM-16. VALIDATION OF RESPONSE TO NEOADJUVANT ANTI-PD-1 IMMUNOTHERAPY IN RECURRENT GLIOBLASTOMA

Abstract BACKGROUND Recurrent glioblastoma has a poor median overall survival despite multimodal treatment. The use of pembrolizumab, an anti-PD-1 monoclonal antibody, demonstrates promise, including improved overall survival and increased immune response, when used in the neoadjuvant setting. METHODS We evaluated 13 patients with surgically accessible recurrent glioblastoma who were treated at the University of California, Los Angeles with neoadjuvant checkpoint inhibition prior to tumor resection. Combining data with our previously published multi-center study, we followed this cohort prospectively, performing tumor gene expression to validate the immune response and improved survival following neoadjuvant therapy with pembrolizumab. RESULTS When combined with findings from our prior study, patients in the neoadjuvant group (n = 27) had an overall survival of 400 days, whereas those in the adjuvant-only group (n = 19) had a median overall survival of 228 days by Kaplan-Meier estimator (P = 0.029, log-rank test). Progression-free survival in the neoadjuvant group was 108 days, whereas in the adjuvant-only group it was 72.5 days (P = 0.017, log-rank test). In elastic net penalized Cox proportional hazards regression, neoadjuvant anti-PD-1 blockade continued to be associated with improved overall survival, with a hazard ratio of 0.11 (P=0.003, log-rank test). Bulk tumor gene expression corroborates our previously described pattern of increased T-cell- and IFN-g-related gene expression, decreased cell-cycle-related signatures and their association with clinical response. Additionally, epigenetic regulation inversely correlated with clinical response. CONCLUSIONS Our findings support the neoadjuvant timing of PD-1 blockade in enhancing local immune responses and prolonging overall- and progression-free-survival. Correlative biological studies suggest a potential role for cell-cycle-related gene expression as a biomarker to predict response to therapy. Continued data collection and the addition of patients to the neoadjuvant arm of the trial, will be crucial to determine the potential role of checkpoint inhibition in the treatment of this deadly disease.