Neoadjuvant Multiagent Chemotherapy Research Articles

Adjuvant Chemotherapy With or Without Radiotherapy for Resected Pancreatic Cancer After Multiagent Neoadjuvant Chemotherapy.

Adjuvant therapy is associated with improved pancreatic cancer survival after neoadjuvant chemotherapy and surgery. However, whether adjuvant treatment should include radiotherapy is unclear in this setting. This study queried the National Cancer Database for pancreatic adenocarcinoma patients who underwent curative resection after multiagent neoadjuvant chemotherapy between 2010 and 2019 and received adjuvant treatment. Adjuvant chemotherapy plus radiotherapy (external beam, 45-50.4 gray) was compared with adjuvant chemotherapy alone. Uni- and multivariable Cox regression was used to assess survival associations. Analyses were repeated in a propensity score-matched subgroup. Of 1983 patients who received adjuvant treatment after multiagent neoadjuvant chemotherapy and resection, 1502 (75.7%) received adjuvant chemotherapy alone and 481 (24.3%) received concomitant adjuvant radiotherapy (chemoradiotherapy). The patients treated with adjuvant chemoradiotherapy were younger, were treated at non-academic facilities more often, and had higher rates of lymph node metastasis (ypN1-2), positive resection margins (R1), and lymphovascular invasion (LVI+). The median survival was shorter for the chemoradiotherapy-treated patients according to the unadjusted analysis (26.8 vs 33.2 months; p = 0.0017). After adjustment for confounders, chemoradiotherapy was associated with better outcomes in the multivariable model (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.61-0.93; p = 0.008). The association between chemoradiotherapy and improved outcomes was stronger for the patients with grade III tumors (HR, 0.53; 95% CI, 0.37-0.74) or LVI+ tumors (HR, 0.58; 95% CI, 0.44-0.75). In a subgroup of 396 propensity-matched patients, chemoradiotherapy was associated with a survival benefit only for the patients with LVI+ or grade III tumors. After multiagent neoadjuvant chemotherapy and resection for pancreatic cancer, additional adjuvant chemoradiotherapy versus adjuvant chemotherapy alone is associated with improved survival for patients with LVI+ or grade III tumors.

Radiologic Occult Metastases in Pancreatic Cancer: Analysis of Risk Factors and Survival Outcomes in the Age of Contemporary Neoadjuvant Multi-agent Chemotherapy.

Radiologic occult metastatic disease (ROMD) in patients with pancreatic ductal adenocarcinoma (PDAC) who undergo contemporary neoadjuvant chemotherapy (NAC) has not been well studied. This study sought to analyze the incidence, risk factors, and oncologic outcomes for patients who underwent the NAC approach for PDAC. A retrospective review analyzed a prospectively maintained database of patients who had potentially resectable PDAC treated with NAC and were offered pancreatectomy at our institution from 2011 to 2022. Multivariable regression analysis was performed to assess risk factors associated with ROMD. Kaplan-Meier curves with log-rank analyses were generated to estimate time-to-event end points. The study enrolled 366 patients. Upfront and borderline resectable anatomic staging comprised 80% of the cohort, whereas 20% had locally advanced disease. The most common NAC regimen was FOLFIRINOX (n = 274, 75%). For 55 patients (15%) who harbored ROMD, the most common site was liver-only metastases (n = 33, 60%). The independent risk factors for ROMD were increasing CA19-9 levels during NAC (odds ratio [OR], 7.01; confidence interval [CI], 1.97-24.96; p = 0.008), indeterminate liver lesions (OR, 2.19; CI, 1.09-4.39; p = 0.028), and enlarged para-aortic lymph nodes (OR, 6.87; CI, 2.07-22.74; p = 0.002) on preoperative cross-sectional imaging. Receipt of palliative chemotherapy (p < 0.001) and eventual formal pancreatectomy (p = 0.04) were associated with survival benefit in the log-rank analysis. The median overall survival (OS) of the patients with ROMD was nearly 15 months from the initial diagnosis, with radiologic evidence of metastases occurring after a median of 2 months. Radiologic occult metastatic disease remains a clinical challenge associated with poor outcomes for patients who have PDAC treated with multi-agent NAC.

REDISCOVER guidelines for borderline-resectable and locally advanced pancreatic cancer: management algorithm, unanswered questions, and future perspectives.

The REDISCOVER guidelines present 34 recommendations for the selection and perioperative care of borderline-resectable (BR-PDAC) and locally advanced ductal adenocarcinoma of the pancreas (LA-PDAC). These guidelines represent a significant shift from previous approaches, prioritizing tumor biology over anatomical features as the primary indication for resection. Condensed herein, they provide a practical management algorithm for clinical practice. However, the guidelines also highlight the need to redefine LA-PDAC to align with modern treatment strategies and to solve some contradictions within the current definition, such as grouping "difficult" and "impossible" to resect tumors together. Furthermore, the REDISCOVER guidelines highlight several areas requiring urgent research. These include the resection of the superior mesenteric artery, the management strategies for patients with LA-PDAC who are fit for surgery but unable to receive multi-agent neoadjuvant chemotherapy, the approach to patients with LA-PDAC who are fit for surgery but demonstrate high serum Ca 19.9 levels even after neoadjuvant treatment, and the optimal timing and number of chemotherapy cycles prior to surgery. Additionally, the role of primary chemoradiotherapy versus chemotherapy alone in LA-PDAC, the timing of surgical resection post-neoadjuvant/primary chemoradiotherapy, the efficacy of ablation therapies, and the management of oligometastasis in patients with LA-PDAC warrant investigation. Given the limited evidence for many issues, refining existing management strategies is imperative. The establishment of the REDISCOVER registry ( https://rediscover.unipi.it/ ) offers promise of a unified research platform to advance understanding and improve the management of BR-PDAC and LA-PDAC.

Effect of Neoadjuvant Chemotherapy on Tumor-Infiltrating Lymphocytes in Resectable Gastric Cancer: Analysis from a Western Academic Center.

Tumor-infiltrating lymphocytes (TILs) are an emerging biomarker predictive of response to immunotherapy across a spectrum of solid organ malignancies. The characterization of TILs in gastric cancer (GC) treated with contemporary, multiagent neoadjuvant chemotherapy (NAC) is understudied. In this retrospective investigation, we analyzed the degree of infiltration, phenotype, and spatial distribution of TILs via immunohistochemistry within resected GC specimens treated with or without NAC at a Western center. We hypothesized that NAC executes immunostimulatory roles, as evidenced by an increased number of anti-tumor TILs in the tumor microenvironment. We found significantly elevated levels of conventional and memory CD8+ T cells, as well as total TILs (CD4+, CD8+, Treg, B cells), within chemotherapy-treated tumors compared with chemotherapy-naïve specimens. We also revealed important associations between survival and pathologic responses with enhanced TIL infiltration. Taken together, our findings advocate for an immunostimulatory role of chemotherapy and underscore the potential synergistic effect of combining chemotherapy with immunotherapy in resectable gastric cancer.

AIRPanc: A phase 2, open-label, multicenter, randomized study evaluating neoadjuvant therapy targeting the adenosine immunosuppressive pathway in combination with immune checkpoint blockade and radiation therapy in patients with advanced pancreatic ductal adenocarcinoma who are candidates for surgical resection.

TPS714 Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which immune checkpoint blockade (ICB) has not provided benefit, hypothesized to be due to the presence of an immunosuppressive tumor microenvironment (TME). Neoadjuvant multi-agent chemotherapy and stereotactic body radiation therapy (SBRT) may increase immunosuppression by elevating intratumoral levels of adenosine, an immunosuppressive metabolite. Adenosine, produced from adenosine triphosphate by enzymes CD39 and CD73, binds the adenosine 2a and 2b receptors (A2aR and A2bR) expressed on immune cells and inhibits critical components of the antitumor immune response. Human PDAC expresses high levels of CD73, which is strongly associated with worse progression-free survival. Preclinical investigation has demonstrated CD73 and A2aR inhibition enhances antitumor immune responses, including increasing activity of ICB. The goal of this study is to test inhibition of the adenosine immunosuppressive pathway in combination with ICB and SBRT in patients with advanced PDAC who are candidates for surgical resection after receiving neoadjuvant chemotherapy. Methods: This investigator-initiated, open-label, multicenter, phase 2 clinical trial will randomize patients with borderline resectable or locally advanced PDAC who have completed 8 cycles of neoadjuvant mFOLFIRINOX and are eligible for SBRT to one of three treatment arms: zimberelimab (anti-PD-1) alone (Arm A), zimberelimab plus quemliclustat (anti-CD73) (Arm B), or zimberelimab plus quemliclustat and etrumadenant (A2aR/A2bR inhibitor)(Arm C) for a period of 7 weeks prior to undergoing surgical resection. 40 Gy SBRT in 5 fractions, totaling a biologically effective dose (BED) of 72 Gy, will be delivered concurrently to all randomized patients starting week 2 of study treatment. Part I will comprise a six-patient safety run-in with a dose-de-escalation design in which patients will be treated according to Arm C with a plan for subsequent enrollment of 14 additional patients per arm (N=42) in Part II. The primary endpoint is CD8+ T-cell infiltration at the time of surgery compared between combination arms and Arm A. Group sample sizes of 14 achieve at least 80% power to detect an effect size of 1.23 with a significance level (alpha) of 0.05 using a two-sided two-sample t-test and adjustment for 2 comparisons. Secondary objectives include estimation of median OS, 18-month survival rate, R0 resection rate, safety profile and CA 19-9 biomarker response. Exploratory studies interrogating the tumor immune microenvironment will be performed on surgical resection specimens. The trial was opened for enrollment on May 19th, 2023. Clinical trial information: NCT06048484 .

FLOT compared to FOLFOX/XELOX as a neoadjuvant chemotherapy in locally advanced gastric cancer: Experience of two clinics.

361 Background: The optimal regimen of neoadjuvant chemotherapy (NCT) in locally advanced gastric cancer (GC) remains controversial, especially whether triplet (FLOT) or duplet (FOLFOX/XELOX) regimen is superior since escalation does not always lead to significant clinical improvement. The aim of this study is to assess efficacy of triplet and duplet chemotherapy regimens as a neoadjuvant approach in locally advanced GC via retrospective data. Methods: We queried the data for 334 patients with locally advanced GC (cT2-4 or cN+) diagnosed in 2016–2023 yy administered with multi-agent NCT: FLOT or XELOX/FOLFOX. The primary endpoints were the ratio of patients with disease progression on NCT, rates of ypN0, and rates of pathological complete response (pCR). Secondary endpoints included progression free survival (PFS) and overall survival (OS). Results: 156 patients (out of total 334 included in the study) received doublet NCT (FOLFOX/XELOX, 8/6 cycles respectively), 61.5% were males, median age was 67.4 (range 21.3-85.4) years, 88.2% had cT3-4. and 22.4% had locally advanced gastroesophageal junction (GEJ) adenocarcinoma. 177 patients were treated with triple NCT (FLOT, 8 cycles), 62.1% were males, median age was 59.9 years, 89.2% had cT3-4, and locally advanced GEJ adenocarcinoma was diagnosed in 21.0%. At a median follow up of 34.7 months (mth) using FLOT regimen as NCT was associated with better clinical outcomes. The ratio of patients who have progressed on NCT was 21.5% and 31% in triplet and doublet arms, respectively (p=0.098). Rates of ypN0 were 50.5% in FLOT arm and 43.7% in XELOX/FOLFOX arm (p=0.36). pCR was achieved in 8.2% and 6.3% in FLOT and XELOX/FOLFOX arms, respectively (p=0.59). Median PFS was 20.3 mth in FLOT arm in comparison to 15.7 mth in FOLFOX/XELOX arm (p=0.012). Median OS was not reached (NR) for triplet arm and was 25.1 mth for doublet arm (p= 0.003). Patients who conversed resectable disease had median PFS of 34.5 and 23.1 months for FLOT and FOLFOX/XELOX arms, respectively (p=0.024). Median OS in these subgroups was NR and 37.0 mth (p=0.003). Conclusions: We report that triplet regimen (FLOT) in comparison with doublet (FOLFOX/XELOX) regimen is the more favorable option as a neoadjuvant setting in locally advanced gastric cancer. FLOT NCT is associated with increased ypN0, pCR and shows statistically significant difference in PFS and OS.

Predictors and benefits of multiagent chemotherapy for pancreatic adenocarcinoma: Timing matters.

Adjuvant (A) multiagent chemotherapy (MC) is the standard of care for patients with pancreatic adenocarcinoma (PDAC). Tolerating MC following a morbid operation may be difficult, thus neoadjuvant (NA) treatment is preferable. This study examined how the timing of chemotherapy was related to the regimen given and ultimately the overall survival (OS). The National Cancer Databasewas queried from 2006 to 2017 for nonmetastatic PDAC patients who underwent surgical resection and received MC or single-agent chemotherapy (SC) pre- or postresection. Predictors of receiving MC were determined using multivariable logistic regression. Five-year OS was evaluated using the Kaplan-Meier and Cox proportional hazards model. A total of 12,440 patients (NA SC, n = 663; NA MC, n = 2313; A SC, n = 6152; A MC, n = 3312) were included. MC utilization increased from 2006-2010 to 2011-2017 (33.1%-49.7%;odds ratio [OR]: 0.59;p < 0.001). Younger age, fewer comorbidities, higher clinical stage, and larger tumor size were all associated with receipt of MC (all p < 0.001), but NA treatment was the greatest predictor (OR 5.18;95% confidence interval [CI]: 4.63-5.80; p < 0.001). MC was associated with increased median 5-year OS (26.0 vs. 23.9 months; hazard ratio [HR]: 0.92; 95%CI: 0.88-0.96) and NA MC was associated with the highest survival (28.2 months) compared to NA SC (23.3 months), A SC (24.0 months), and A MC (24.6 months; p < 0.001). Use and timing of MC contribute to OS in PDAC with an improved 5-year OS compared to SC. The greatest predictor of receiving MC was being given as NA therapy and the greatest survival benefit was the NA MC subgroup. Randomized studies evaluating the timing of effective MC in PDAC are needed.

Social determinants of health and utilization of neoadjuvant chemotherapy in patients with triple negative breast cancer (TNBC) in the community oncology setting.

610 Background: TNBC has a higher incidence in African American women compared to European American, often presents at a younger age or more advanced stage, and is associated with worse outcomes. The use of multi-agent neoadjuvant chemotherapy (NC) improves event-free survival and overall survival in patients with early-stage TNBC and is considered standard of care. Race and other social determinants of health (SDOH) have been shown to affect outcomes in patients with TNBC. Differences in use of NC associated with SDOH may be a contributing factor to inferior outcomes. The aim of this study is to determine if SDOH measures affect utilization of NC in patients with early-stage TNBC. Methods: This retrospective observational cross-sectional study examined patient profiles, treatment patterns and SDOH indicators among patients newly diagnosed with early-stage breast cancer in The US Oncology Network. Using iKnowMed EHR data, patients diagnosed with TNBC between 03/31/2017 and 09/30/2021 with stages II-IIIB disease or tumor size ≥2cm (T2 or higher) were included. The initial TNBC diagnosis date was used as the index date for each patient and records were assessed from 6 months pre- to 6 months post-diagnosis for NC initiation, baseline characteristics, and social determinants, including Area Deprivation Index (ADI), a validated measure of socioeconomic status. Results: 3321 patients with TNBC were identified, with a mean age of 58 years; 59% were White, 15% Black, 3% Asian, and 23% other/unknown; and 2139 (64%) received NC. Patients who received NC relative to those who did not were younger (mean 55.9 vs 61.8; p=0.001), had higher BMIs (70% with BMI&gt;25 vs ≤25, p=0.045), and had commercial or Medicaid insurance (67.5% with commercial insurance or Medicaid vs. 52.5% with Medicare; p=0.001). Regional differences were observed, with proportionally fewer patients receiving neoadjuvant chemotherapy in the south US census regions and more in the west. There was no difference in NC use in Black vs White patients (66% vs 64%). No significant differences in receipt of NC were found for race, ethnicity, or ADI. Conclusions: In the community oncology setting, we did not observe inequities in the use of NC based on social determinants analyzed in this study, such as race, ethnicity, and ADI. Poorer outcomes observed in Black patients with TNBC may not be a result of underutilization of NC.

Neoadjuvant Chemotherapy Versus Upfront Surgery for Resectable Pancreatic Adenocarcinoma: An Updated Nationwide Study.

The objective of this study was to assess the association of survival with neoadjuvant chemotherapy (NAC) in resectable pancreatic adenocarcinoma (PDAC). The early control of potential micrometastases and patient selection using NAC has been advocated for patients with PDAC. However, the role of NAC for resectable PDAC remains unclear. Patients with clinical T1 and T2 PDAC were identified in the National Cancer Database from 2010 to 2017. Kaplan-Meier estimates, and Cox regression models were used to compare survival. To address immortal time bias, landmark analysis was performed. Interactions between preoperative factors and NAC were investigated in subgroup analyses. A propensity score analysis was performed to compare survival between multiagent NAC and upfront surgery. In total, 4041 patients were treated with upfront surgery and 1,175 patients were treated with NAC (79.4% multiagent NAC, 20.6% single-agent NAC). Using a landmark time of 6 months after diagnosis, patients treated with multiagent NAC had longer median overall survival compared with upfront surgery and single-agent NAC. (35.8 vs 27.1 vs 27.4mo). Multiagent NAC was associated with lower mortality rates compared with upfront surgery (adjusted hazard ratio, 0.77; 95% CI, 0.70-0.85), whereas single-agent NAC was not. The association of survival with multiagent NAC were consistent in analyses using the matched data sets. Interaction analysis revealed that the association between multiagent NAC and a lower mortality rate did not significantly differ across age, facility type, tumor location, CA 19-9 levels, and clinical T/N stages. The findings suggest that multiagent NAC followed by resection is associated with improved survival compared with upfront surgery.

Pathologic Tumor Regression is Associated With Improved Survival in Pancreatic Cancer.

The advent of effective chemotherapy regimens has increased the use of neoadjuvant multiagent chemotherapy in pancreatic cancer. However, the effect of tumor downstaging with neoadjuvant treatment on survival is unclear. Retrospective study included all resected patients with pancreatic adenocarcinoma who underwent neoadjuvant chemotherapy with FOLFIRINOX or gemcitabine/Abraxane. Downstaging was quantified using (1) difference between presenting AJCC clinical and final pathologic stage and (2) College of American Pathologists (CAP) Tumor Regression Grading Schema. Eighty-seven patients met inclusion criteria. FOLFIRINOX was the most common regimen, 63.2% vs 21.8%. Change in regimen occurred in 15% of patients. Downstaging based on a difference in AJCC stage group occurred in only 4.6%. In contrast, 45.2% were classified as downstaged by the CAP Tumor Regression of 0-2. Downstaging was similar for FOLFIRINOX gemcitabine/Abraxane (64.7 vs 53.6, P = .12) using the CAP criteria. On univariate analysis, treatment regimen (gemcitabine/Abraxane vs FOLFIRINOX, median survival 27 vs 29 mo; HR 1.57, P = .2) had similar survival. Downstaging by the AJCC stage was not associated with improved survival (HR 1.51, P = .4). However, there was a survival benefit for those downstaged by the CAP Tumor Regression Grading Schema, the median survival of 41 mo vs 25 mo; HR 3.05, P = .009. Improved survival 3.32 (1.35-8.16), P = .009) was maintained on multivariate analysis. Survival is significantly improved in those downstaged, as assessed by the CAP Tumor Regression Schema. Downstaging is an important prognostic variable that can help with joint decision making for clinicians and patients.

155TiP A randomised phase II trial of neoadjuvant multi-agent chemotherapy (CHT) OR patritumab deruxtecan (HER3-DXd; U3-1402) +/- endocrine therapy (ET) for high-risk hormone receptor-positive (HR+/HER2-) early breast cancer (EBC): SOLTI-2103 VALENTINE trial

The decision of neoadjuvant treatment for high-risk HR+/HER2- EBC remains a challenge. Despite the availability of both CHT and ET, the risk of recurrence persists over time, highlighting the need for additional therapeutic strategies. In the TOT-HER3 trial, we have shown that a single dose of HER3-DXd, a first-in-class HER3 directed antibody drug conjugate, is associated with clinical response, increased immune infiltration and proliferation suppression, as well as a consistent and manageable safety profile in patients (pts) with HR+/HER2-negative early breast cancer (Prat et al. ESMO Breast 2022). These data have informed the design of the VALENTINE trial of HER3-DXd in the neoadjuvant setting. VALENTINE is a parallel, exploratory, three-arm, randomised, open-label, exploratory study in pts with primary operable HR+/HER2-negative breast cancer with Ki67 IHC ≥ 20% and/or high genomic risk (defined by gene signature), aiming to evaluate the clinical benefit and biological effects of HER3-DXd (with/without letrozole (LET)) as a neoadjuvant treatment. A total of 120 treatment naïve pts will be randomly assigned in a 2:2:1 ratio to receive (1) HER3-DXd (5.6 mg/kg) every 21 days for 6 cycles; (2) HER3-DXd plus daily LET +/- LHRH analogs every 21 days for 6 cycles; (3) standard of care CHT consisting of 4 cycles of EC/AC (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 14/21 days) followed by weekly 80mg/m2 paclitaxel during 12 weeks. The primary endpoint is the rate of pathological complete response (ypT0/is ypN0) at surgery. Baseline, on-treatment (C2D1), and surgical specimens will be collected for molecular characterization and evaluation of response (ERBB3 gene expression, HER3 IHC; CelTIL change, research-based PAM50 subtypes). Additional samples for pharmacokinetic, genomic and circulating biomarkers will also be collected. Secondary endpoints include rate of residual cancer burden, overall response rate, invasive disease-free survival at 3 and 5 years and safety. An interim and final analysis are pre-planned. EudraCT 2022-001181-36. NCT05569811, First Posted: February 18, 2021. SOLTI Cancer Research Group.

Urothelial carcinoma of the bladder with isolated lymph node metastasis: Natural history and outcomes following surgical resection.

Although pathologic lymph node involvement carries a poor prognosis in patients with urothelial carcinoma of the bladder (UCB), a subset of patients may demonstrate durable survival following surgical resection. To this end, there are limited contemporary data describing the natural history of UCB in patients with isolated lymph node involvement (cN0pN+) following radical cystectomy (RC) with pelvic lymph node dissection (PLND). We therefore utilized a large, nationwide oncology dataset to examine the natural history and outcomes of cN0 pN+ UCB after surgical resection. We identified patients in the National Cancer Database (NCDB) with cN0 pN+ cM0 UCB from 2006 to 2015 treated with RC and PLND. The associations of baseline characteristics with all-cause mortality (ACM) were evaluated using Cox regression. A total of 2,884 patients formed the study cohort, including 42% with pN1 and 58% with pN2-3 disease. Of these, 606 (21%) received multiagent neoadjuvant chemotherapy, while 1,172 (41%) received postoperative adjuvant chemotherapy. A median of 15 (IQR 9-23) LNs were removed during PLND. The 5- and 7-year OS for the entire cohort were 20% and 17%, respectively. Compared to the overall cohort, patients surviving ≤5 years had lower pN stage (59% vs. 42% pN1) and lower pT stage (41% vs. 22% ≤pT2). On multivariable analysis, higher pT stage (HR 2.85, 95% CI 1.52-5.36 for pT3, HR 3.27, 95% CI 1.73-6.18 for pT4 vs. pT0), higher pN stage (HR 1.17, 95% CI 1.05-1.31 for pN2-3 vs. pN1), and increasing LN density (HR 2.37, 95% CI 1.88-2.99) were most strongly associated with increased ACM, while receipt of adjuvant chemotherapy (HR 0.61, 95% CI 0.55-0.68) was associated with reduced ACM. Although OS for patients with cN0 pN+ M0 UCB is poor, a subset of patients demonstrates durable long-term survival with 5- and 7-year OS of 20% and 17%, respectively. pT and pN stage represent important prognostic characteristics, while administration of adjuvant chemotherapy represents a potential therapeutic intervention associated with improved ACM.

Preoperative downstaging of pancreatic cancer is associated with improved survival after multi-agent chemotherapy, but not after radiation

BackgroundDownstaging has been associated with improved survival for many cancers. However, the implications of downstaging are unclear for pancreatic cancer in an era of effective neoadjuvant systemic chemotherapy. MethodsNCDB retrospective cohort study of resected pancreatic carcinoma treated with neoadjuvant therapy. ResultsThe study included 73,985 patients: 66,589 with no neoadjuvant therapy, 2,102 neoadjuvant radiation therapy (N-RT), 3,195 neoadjuvant multiagent chemotherapy (N-MAC) and 2.099 with both neoadjuvant radiation and multiagent chemotherapy. There was increased use of N-MAC over the period of this study. Patients selected for treatment with N-MAC had longer survival from surgery on univariate (23.1 vs. 18.7 months, p = < 0.01) and multivariate analyses HR 0.81 (0.76–0.87, p < 0.001) compared to those selected with N-RT. Downstaging was similar in N-RT and N-MAC groups (25.1 vs. 24.1%, p = 0.43). Downstaging following N-MAC was associated with a survival benefit, HR 0.85 (0.74–0.98). However, downstaging following N-RT was not associated with a survival advantage, HR 1.12 (0.99–0.99). ConclusionClinicians have rapidly adopted N-MAC for treatment of pancreatic cancer. Although the rates of downstaging are similar between treatment groups, response translates into increased survival only with N-MAC and not with N-RT.

Abstract PD11-04: PD11-04 Primary results of SOLTI-1503 PROMETEO phase 2 trial of Combination of Talimogene Laherparepvec (T-VEC) with Atezolizumab in patients with residual breast cancer after standard neoadjuvant multi-agent chemotherapy

Abstract Background: Residual disease (RD) following neoadjuvant chemotherapy (NAC) in early HER2-negative breast cancer (BC) remains an unmet medical need. However, no therapies to date have tested their activity directly in chemo-resistant RD. Here, we hypothesized that combining an oncolytic virus such as T-VEC with atezolizumab may offer clinical benefit in patients (pts) with RD after standard NAC. To our knowledge, PROMETEO is the first trial that examines the activity of immunotherapy in pts with RD prior to surgery. Methods: PROMETEO (NCT03802604) is a single-arm, open-label, multicenter phase II trial. Women with triple-negative BC (TNBC) or hormone receptor-positive/HER2-negative (HR+/HER2-) BC with baseline (i.e., before NAC) ki67 ≥ 20% were eligible. RD was confirmed with a magnetic resonance imaging (MRI) showing a tumor diameter ≥ 10 mm and a core-biopsy detecting the presence of invasive cells. Before surgery, T-VEC was administered intratumorally on week 1 (106 pfu/mL), then in week 4 and every 2 weeks thereafter (108 pfu/mL) for 4 injections. Atezolizumab (840 mg) was administered intravenously every 2 weeks for 4 infusions, starting at week 4. Surgery was performed in &amp;lt; 3 weeks after completing the treatment. The primary objective was to evaluate the efficacy of the combination, measured by the rate of residual cancer burden (RCB) class 0/1 at surgery. Tumor samples collected at 5 timepoints (before NAC, during screening period, after first dose of T-VEC, after first dose of T-VEC and atezolizumab and at surgery) were mandatory to assess gene expression, tumor-infiltrating lymphocytes (TILs), immune cells PD-L1 IHC (SP142), tumor mutational burden (TMB) by FoundationOne and other translational endpoints. Results: Between Dec 2018 to Feb 2022, 28 pts were enrolled: 20 pts with HR+/HER2- disease and 8 pts with TNBC. Median age was 47 (range 31-71) and 71% of pts were premenopausal. At diagnosis before NAC, clinical stage II disease represented 60.7%, cN+ 60.7%, median Ki-67 was 37.5% (range 20%-95%), high TILs (≥10%) 37%, median TMB was 3 (0-19) and only 1 of 27 pts (3.7%) had a PD-L1-positive tumor. After NAC, mean tumor size by MRI was 28.3 mm (10-93). Two pts discontinued from the trial (1 withdrawal of consent and 1 COVID infection). The completion of 5 cycles of treatment was achieved by 73% of pts. The overall RCB-0/1 rate was 25% (7 of 28, 95% IC 10.7 – 44.9%), all with RCB 0 (pathologic complete response [pCR]). The pCR rate was 30% in HR+/HER2- disease and 12.5 % in TNBC. Radiological response by MRI was achieved by 3 of 28 pts (10.7%). Interestingly, none of the 7 pts with a pCR had radiological response (stable disease n=5, progressive disease [PD] n=2). Six pts (21.4%) had radiological PD and had RCB 2/3. Overall, 27 (96%) patients had at least one treatment-emergent adverse event (TEAE) of any grade. Most common grade 1 or 2 AEs were fever (11 pts, 39.3%), ALT increased (9 pts, 32.1%), AST increased (8 pts, 28.6%), arthralgia (6 pts, 21.4%) and anemia (6 pts, 21.4%). Grade 3 reversible neutropenia occurred in 1 patient. Across all pts, significant increases (p&amp;lt; 0.001) in TILs, immune genes and immune PDL1+ cells were observed after 1 dose of TVEC, 1 dose of the combination and at surgery. Intrinsic subtype changes at surgery occurred in 73.1% of cases, mostly (46.1%) Luminal A/B converting to Normal-like. At surgery, 19 of 26 (73.1%) of tumors were PDL1+. Conclusions: Two months of T-VEC in combination with atezolizumab induced a pCR in a subgroup of pts with chemoresistant HER2- breast cancer. This effect is probably related to the immune activation provoked by the combined treatment. Interestingly, a high discrepancy was observed between the pre-surgical radiological imaging and the actual surgical pathological report. Pre-operative window-of-opportunity trials in this context might provide important clues regarding the activity of novel treatment strategies. Citation Format: Tomás Pascual, Maria Vidal, Juan Miguel Cejalvo, Estela Vega, Esther Sanfeliu, Sergi Ganau, Ana Julve, Esther Zamora, Ignacio Miranda, Ana Delgado, Begoña Bermejo, Luis de la Cruz-Merino, Manel Juan, Patricia Galván, Xavier Gonzalez-Farré, Juan Manuel Ferrero-Cafiero, Patricia Villagrasa, Mafalda Oliveira, Aleix Prat. PD11-04 Primary results of SOLTI-1503 PROMETEO phase 2 trial of Combination of Talimogene Laherparepvec (T-VEC) with Atezolizumab in patients with residual breast cancer after standard neoadjuvant multi-agent chemotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-04.

Pancreatic Cancer with Vascular Involvement: Adherence to Current Standard-of-Care Associated with Improved Survival.

This study is a retrospective cohort study of National Cancer Data Base (NCDB) data for pancreatic cancer with vascular involvement. A total of 23903 patients with vascular involvement were included and divided into 3 groups; no treatment (40.6%), medical treatment (36.6%), and resection (22.8%). Of the patients undergoing resection, 31.3% received neoadjuvant multiagent chemotherapy (N-MAC). The remainder were treated with postoperative adjuvant treatment (33.8%), surgery alone (24.9%), preoperative radiotherapy (8.3%), or single-agent preoperative chemotherapy (1.7%). Median survival for N-MAC was superior (28.42 months) when compared to neoadjuvant radiotherapy (20.73 months), neoadjuvant single-agent chemotherapy (20.8 months), postoperative adjuvant therapy (17.87 months), and surgery alone (10.12 months). N-MAC was associated with improved survival compared to postoperative multiagent chemotherapy (P-MAC) (28.4 vs 16.95, HR 1.82; CI 1.64-2.02, P < .0010) (Figure 1). The addition of radiation therapy to N-MAC did not improve survival (27.4 vs 29.8, HR .93; CI .83-1.05, P = .3). Clinical downstaging occurred in 40% of patients treated with N-MAC, and downstaging was associated with improved survival (HR .74; CI .64-.85, P < .001). N-MAC patients were more likely to undergo an R0 resection than P-MAC (74% v. 48, P < .001). Most resected pancreatic cancer patients in this study with vascular involvement receive either postoperative or no adjuvant therapy. N-MAC increases downstaging, R0 resection rates, and survival.

Multiagent neoadjuvant chemotherapy compared to upfront surgery in pancreatic cancer of the body and tail using the National Cancer Database.

722 Background: While neoadjuvant chemotherapy is increasingly being using in pancreatic cancer treatment, it is unclear whether it is beneficial in treatment of body and tail tumors. Randomized controlled trials are lacking and previous observational studies have not demonstrated any benefit. We aimed to assess survival associations, trends over time and patient selection associations for multiagent neoadjuvant chemotherapy treated pancreatic cancer of the body and tail using data from the National Cancer Database (NCDB). Methods: We queried the NCDB for pancreatic adenocarcinoma in the body or tail diagnosed between 2010 – 2018 that received multiagent neoadjuvant chemotherapy and/or a distal pancreatectomy. Patients with clinical M1, clinical T4 and surgery other than partial pancreatectomy were excluded. Survival was compared with Kaplan-Meier estimates and multivariable Cox Proportional Hazard Estimates. Results: Between 2010 – 2018, the use of multiagent neoadjuvant chemotherapy increased from 5.7% to 31.8%. In total, 1951 patients were included with n = 384 receiving multiagent neoadjuvant chemotherapy (cases) and n = 1567 undergoing upfront surgery (controls). Neoadjuvant chemotherapy was associated with younger age, tumor in the pancreatic body, clinical N1-2 and with Ca 19-9 ≥98 U/mL. Neoadjuvant chemotherapy was associated with a decreased mortality rate in multivariable Cox regression models adjusting for preoperatively assessed variables (HR 0.65, 95% CI 0.53 – 0.81, p &lt; 0.001) and results were significant in both clinical T1-2 and T3 tumors. Patients treated with upfront surgery had higher rates of adjuvant chemotherapy receipt after resection (41.4% vs 70.6%) but there was no difference in R1 resection rates or 90-day postoperative mortality between the groups. The addition of neoadjuvant radiotherapy was not associated with improved survival in patients receiving neoadjuvant chemotherapy. Conclusions: Multiagent neoadjuvant chemotherapy is increasingly being used in the treatment of pancreatic cancer of the body and tail, especially in younger patients and patients with more aggressive tumor characteristics. Multiagent neoadjuvant chemotherapy is associated with improved survival but randomized trials are needed to establish causal relationships.

Association of Adjuvant Chemotherapy in Patients With Resected Pancreatic Adenocarcinoma After Multiagent Neoadjuvant Chemotherapy

The total number of patients with pancreatic ductal adenocarcinoma (PDAC) who receive neoadjuvant chemotherapy (NAC) is increasing. However, the added role of adjuvant chemotherapy (AC) in these patients remains unknown. To evaluate the association of AC with overall survival (OS) in patients with PDAC who received multiagent NAC followed by curative-intent surgery. This retrospective, matched-cohort study used data from the National Cancer Database and included patients with PDAC diagnosed between 2010 and 2018. The study included patients at least 18 years of age who received multiagent NAC followed by surgical resection and had available records of the pathological findings. Patients were excluded if they had clinical or pathological stage IV disease or died within 90 days of their operation. All included patients received NAC and underwent resection for primary PDAC. Some patients received adjuvant chemotherapy. The main outcome was the OS of patients who received AC (AC group) vs those who did not (non-AC group). Interactions between pathological findings and AC were investigated in separate multivariable Cox regression models. In total, 1132 patients (mean [SD] age, 63.5 [9.4] years; 577 [50.1%] male; 970 [85.7%] White) were included, 640 patients in the non-AC group and 492 patients in the AC group. After being matched by propensity score according to demographic and pathological characteristics, 444 patients remained in each group. The multivariable Cox regression model adjusted for all covariates revealed an association between AC and improved survival (hazard ratio, 0.71; 95% CI, 0.59-0.85; P < .001). Subgroup interaction analysis revealed that AC was significantly associated with better OS (26.6 vs 21.2 months; P = .002), but the benefit varied by age, pathological T category, and tumor differentiation. Of note, AC was associated with better survival in patients with any pathological N category and positive margin status. In this cohort study, AC following multiagent NAC and resection in patients with PDAC was associated with significant survival benefit compared with that in patients who did not receive AC. These findings suggest that patients with aggressive tumors may benefit from AC to achieve prolonged survival, even after multiagent NAC and curative-intent resection.

A safety study of intraoperative radiation therapy following stereotactic body radiation therapy and multi-agent chemotherapy in the treatment of localized pancreatic adenocarcinoma: study protocol of a phase I trial

BackgroundLocalized pancreatic adenocarcinoma carries a poor prognosis even after aggressive therapy. Up to 40% of patients may develop locoregional disease as the first site of failure. As such, there may be a role for intensification of local therapy such as radiation therapy. Radiation dose escalation for pancreatic cancer is limited by proximity of the tumor to the duodenum. However, the duodenum is removed during Whipple procedure, allowing the opportunity to dose escalate with intraoperative radiation therapy (IORT). Although prior studies have shown potential benefit of IORT in pancreatic cancer, these studies did not utilize ablative doses (biologically effective dose [BED10] > 100 Gy). Furthermore, the optimal radiation target volume in this setting is unclear. There has been increased interest in a “Triangle Volume” (TV), bordered by the celiac axis, superior mesenteric artery, common hepatic artery, portal vein, and superior mesenteric vein. Dissection of this area, has been advocated for by surgeons from Heidelberg as it contains extra-pancreatic perineural and lymphatic tracts, which may harbor microscopic disease at risk of mediating local failure. Interestingly, a recent analysis from our institution indicated that nearly all local failures occur in the TV. Therefore, the purpose of this protocol is to evaluate the safety of delivering an ablative radiation dose to the TV with IORT following neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT).MethodsPatients with non-metastatic pancreatic adenocarcinoma centered in the head or neck of the pancreas will be enrolled. Following treatment with multi-agent neoadjuvant chemotherapy, patients will undergo SBRT (40 Gy/5 fractions) followed by IORT (15 Gy/1 fraction) to the TV during the Whipple procedure. The primary objective is acute (< 90 days) toxicity after IORT measured by Clavien-Dindo classification. Secondary objectives include late (> 90 days) toxicity after IORT measured by Clavien-Dindo classification, overall survival, local progression-free survival, distant metastasis-free survival, and progression-free survival.DiscussionIf the results show that delivering an ablative radiation dose to the TV with IORT after neoadjuvant chemotherapy and SBRT is safe and feasible, it warrants further investigation in a phase II trial to evaluate efficacy of this approach.Trial Registration This study was registered at ClinicalTrials.gov on 12/2/2021 (NCT05141513). https://clinicaltrials.gov/ct2/show/NCT05141513

The Optimal Timing of Surgery Following Stereotactic Body Radiation Therapy for Borderline Resectable or Locally Advanced Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> In patients undergoing pre-operative stereotactic body radiotherapy (SBRT) for borderline resectable or locally advanced pancreatic adenocarcinoma (BRPC/LAPC), the optimal timing of surgery following SBRT is unknown. We aimed to assess the impact of time from SBRT to surgery on outcomes in this setting. <h3>Materials/Methods</h3> Patients treated at a single institution with BRPC/LAPC, who underwent neoadjuvant multi-agent chemotherapy followed by SBRT, and then surgical resection, were included in this analysis. Covariates were stratified by time from SBRT to surgery. Pearson's Chi-squared test was used to compare cohorts by time from SBRT to surgery with respect to baseline and treatment characteristics. A Cox regression model was used to identify variables associated with survival outcomes, with statistically significant covariates in univariable analysis included in multivariable modeling. <h3>Results</h3> One hundred seventy-one patients were ultimately included for analysis. The median time from SBRT to surgery was 6.4 weeks (range: 2.7 – 25.3, IQR 2.7 weeks). There was no statistically significant difference in age, sex, tumor location, neoadjuvant chemotherapy type (FOLFIRINOX vs gemcitabine/nab-paclitaxel) or chemotherapy duration >4 months, pathologic complete response (pCR) rates, or R0 resection rates by time from SBRT to surgery, using a 6-week cutoff. Local progression-free survival (LPFS) was higher in patients for whom time from SBRT to surgery was >6 weeks (1-yr LPFS 81.5% vs 70.2%, median LPFS 12.1 vs 10.8 months, log-rank P=.039). No difference in distant metastases-free survival or overall survival was detected. In univariable Cox regression, age, SBRT dose, neoadjuvant chemotherapy duration/type, tumor location, presence of pCR, and surgical margin status were not associated with LPFS, but time from SBRT to surgery less than 6 weeks (P=.042; HR 1.84 95% CI 1.02 – 3.30) and baseline elevated CA19-9 >200 U/mL (P=.018; HR 2.09, 95%CI 1.14 – 3.84) were significantly associated with reduced LPFS. In multivariable analysis, time from SBRT to surgery < 6 weeks (P=.011; HR 2.18, 95% CI 1.19 – 3.97) and baseline elevated CA19-9 (P=.006; HR 2.38, 95% CI 1.28 – 4.42) remained independently associated with reduced LPFS. Sensitivity analysis was performed excluding patients who had surgical resection >15 weeks after completion of SBRT (n=4). Time from SBRT to surgery <6 weeks and elevated baseline CA19-9 remained independently associated with reduced LPFS. <h3>Conclusion</h3> Prolongation of time from SBRT to surgery may be associated with improved local progression free survival. Further study is warranted to understand the factors that may contribute to differential local control rates based on time from SBRT to surgery.

Multiagent Chemotherapy Followed by Stereotactic Body Radiotherapy Versus Conventional Radiotherapy for Resected Pancreas Cancer.

Chemotherapy followed by margin-negative resection (R0) is the treatment of choice for patients with localized pancreatic ductal adenocarcinoma (PDAC). Neoadjuvant multiagent chemotherapy (MAC) or MAC then radiotherapy (RT) may optimize surgical candidacy. The purpose of this study was to compare pathologic outcomes of MAC followed by conventionally fractionated radiotherapy (CRT) versus stereotactic body radiotherapy (SBRT) for patients with resected PDAC. Patients diagnosed with nonmetastatic PDAC between 2012 and 2017 and who received preoperative MAC or MAC+RT were identified in the National Cancer Database. Variables associated with R0 and overall survival were identified with logistic regression and Cox analysis (P<0.05). A total of 5273 patients were identified (MAC: 3900, MAC+CRT: 955, MAC+SBRT: 418). The median RT dose/fraction (fx) in the MAC+CRT and MAC+SBRT cohorts was 50.4Gy/28 fx and 33Gy/5 fx. Patients receiving MAC+CRT versus MAC+SBRT had similar rates of ypT3-T4 disease (54% vs. 58%, P=0.187), R0 (87% vs. 84%, P=0.168), and pathologic complete response (pathologic complete response; 6% vs. 4%, P=0.052), however, MAC+CRT was associated with less regional lymphatic disease (ypN+: 28% vs. 41%, P<0.001). The median overall survival of patients receiving MAC+CRT versus MAC+SBRT was 24.6 versus 29.5 months (P=0.045). For patients with resected PDAC, MAC+CRT, and MAC+SBRT had similar rates of R0 and pathologic complete response, although MAC+CRT was associated with lower ypN+. Prospective evaluation of neoadjuvant RT regimens with attention to radiation therapy design is warranted.