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708 Background: PDAC has a 5-year survival rate of 2) and nab-paclitaxel (125 mg/m2) were given on days 1, 8, and 15 and SEA-CD40 (10 or 30 µg/kg) was given on day 3 of each 28-day cycle. Pembro (400 mg) was given every 6 weeks starting on day 8 for up to 2 years. Results: As of August 16, 2022, 61 pts were treated with 10 µg/kg (N=40) or 30 µg/kg (N=21) SEA-CD40. Median duration of exposure was 25.1 weeks. Confirmed objective responses were observed in 19 pts (48% [95% CI 31.5, 63.9]) at 10 µg/kg and 8 pts (38% [95% CI 18.1, 61.6]) at 30 µg/kg. Median duration of response (months) was 5.7 (95% CI 3.9, 7.4) and 5.7 (95% CI 2.3, 9.2) for the 10 and 30 µg/kg dose groups, respectively. Additional efficacy results are summarized. The most common treatment-emergent adverse events (TEAEs) across dose groups were fatigue (84%), nausea (74%), and neutropenia (67%). The most common grade ≥3 TEAEs across the groups were neutropenia (61%), anemia (33%), and thrombocytopenia (20%). TEAEs leading to treatment discontinuation were reported in 10% of pts, including immune-mediated lung disease (n=3) and septic shock (n=1) in the 10 µg/kg dose group, and colitis (n=1) and portal vein thrombosis (n=1) in the 30 µg/kg dose group. Conclusions: The combination of SEA-CD40 + GnP + pembro has an acceptable safety profile and shows evidence of antitumor activity in pts with PDAC. This regimen may warrant further evaluation. Clinical trial information: NCT02376699 . [Table: see text]

In patients with non–small-cell lung cancer treated with anti–PD-1/PD-L1 agents, no specific radiation parameter was significantly associated with immune-related (IR) pneumonitis. We identify on subset analysis of patients who developed IR pneumonitis and received chest radiation, patients were numerically more likely to have received chest radiation with curative intent than with palliative intent (89% vs. 11 that approached statistical significance. PURPOSE: To investigate the relationship between radiotherapy (RT), in particular chest RT, and development of immune-related (IR) pneumonitis in non–small-cell lung cancer (NSCLC) patients treated with anti–programmed cell death 1 (PD-1)/programmed death ligand 1 (PD-LI). PATIENTS AND METHODS: Between June 2011 and July 2017, NSCLC patients treated with anti–PD-1/PD-L1 at a tertiary-care academic cancer center were identified. Patient, treatment, prior RT (intent, technique, timing, courses), and IR pneumonitis details were collected. Treating investigators diagnosed IR pneumonitis clinically. Diagnostic IR pneumonitis scans were overlaid with available chest RT plans to describe IR pneumonitis in relation to prior chest RT. We evaluated associations between patient, treatment, RT details, and development of IR pneumonitis by Fisher exact and Wilcoxon rank-sum tests. RESULTS: Of the 188 NSCLC patients we identified, median follow-up was 6.78 (range, 0.30–79.3) months and median age 66 (range, 39–91) years; 54% (n = 102) were male; and 42% (n = 79) had stage I-III NSCLC at initial diagnosis. Patients received anti–PD-1/PD-L1 monotherapy (n = 127, 68%) or PD-I/PD-LI -based combinations (n = 61, 32%). In the entire cohort, 70% (132/188) received any RT, 53% (100/188) chest RT, and 37% (70/188) curative-intent chest RT. Any grade IR pneumonitis occurred in 19% (36/188; 95% confidence interval, 13.8–25.6). Of those who developed IR pneumonitis and received chest RT (n = 19), patients were more likely to have received curative-intent versus palliative-intent chest RT (17/19, 89%, vs. 2/19, 11%; P = .051). Predominant IR pneumonitis appearances were ground-glass opacities outside high-dose chest RT regions. CONCLUSION: No RT parameter was significantly associated with IR pneumonitis. On subset analysis of patients who developed IR pneumonitis and who had received prior chest RT, IR pneumonitis was more common in patients who received curative-intent chest RT. Attention should be paid to NSCLC patients receiving curative-intent RT followed by anti –PD-I/PD-LI agents.

559 Background: SEA-CD40 is an investigational nonfucosylated IgG1 monoclonal agonistic antibody targeted to CD40, expressed on antigen-presenting cells. SEA-CD40 binds with increased affinity to FcγRIIIa resulting in enhanced effector function and CD40 agonism, allowing amplification of immune stimulation and antitumor activity. PDAC can be treated with gemcitabine + nab-paclitaxel (GnP), often with poor survival. Combining chemotherapeutic agents with SEA-CD40 could facilitate robust antigen release and amplified presentation to CD8+ T cells. In preclinical models, the combination of SEA-CD40 and chemotherapy resulted in significant antitumor activity which is further enhanced with anti-PD1 treatment. We present data from an ongoing Phase 1 study (SGNS40-001) in a PDAC cohort evaluating the combination of SEA-CD40, GnP, and pembrolizumab (pembro). Methods: Patients (pts) ≥18 years old with untreated metastatic PDAC and Eastern Cooperative Oncology Group performance scores of 0 or 1 were enrolled. GnP were administered on Days 1, 8, and 15 of each 28-day cycle with 10 or 30 μg/kg SEA-CD40 IV on Day 3. Pembro was administered every 42 days starting on Day 8. Results: As of July 9, 2021, 61 pts were treated: 40 and 21 pts at 10 and 30 μg/kg SEA-CD40, respectively. Minimum follow-up was 5 months. The most frequent treatment-emergent adverse events (TEAEs) are shown in Table. 5 (8%) pts experienced an AE leading to treatment (tx) discontinuation (3 and 2 in 10 and 30 μg/kg SEA-CD40 dose, respectively), 35 (57%) pts experienced a serious TEAE (22 and 13 pts in 10 and 30 μg/kg, respectively). Two tx-related deaths occurred: colitis attributed to pembro, and septic shock attributed to GnP. Pts had transient increases in circulating cytokines and chemokines associated with immune activation and trafficking as well as increases in markers of activation on peripheral NK cells and T cells. Conclusions: The combination of SEA-CD40 + GnP + pembro demonstrated a tolerable safety profile. Evidence of immune activation was observed, consistent with the proposed mechanism of action. Follow-up for response and survival are ongoing. Clinical trial information: NCT02376699. [Table: see text]

The recurrence patterns of high-risk, N1 prostate cancer after radiation therapy (RT) including the pelvic lymph nodes have not been fully investigated.We have a prospective clinical study since 2004 that has followed 138 men with locally advanced prostate cancer (T1-T4N0-N1M0) treated with definitive RT encompassing the prostate and pelvic lymph nodes and long-term androgen deprivation therapy (ADT). Forty nine of the 52 patients that developed recurrence were imaged at biochemical failure to detect the site of recurrence.Imaging identified the site of recurrence in 46 patients. Twenty five patients had prostatic recurrence only, none had local lymph node recurrence only, 11 had distant metastases only, 7 had prostatic recurrence and distant metastases, 2 had prostatic recurrence, local nodal recurrence and distant metastases, and 1 had local nodal recurrence with distant metastases. The mean time to recurrence was 62 months for prostate only, 40 months for distant only and 50 months for prostate and distant recurrence. There was a 69% recurrence rate for patients with magnetic resonance imaging -detected N1 disease. There was significantly longer survival for patients with prostate recurrence only compared to patients with distant recurrence (P0.018). Five-year prostate cancer-specific survival were 85% for prostate only, 44% for distant only and 48% for prostate and distant recurrence (prostate only vs. distant only; P = 0.008, prostate only vs. prostate and distant; P = 0.018, distant vs. prostate and distant; P = 0.836).The predominant recurrence pattern for high-risk, N1 prostate cancer was prostatic recurrence and distant spread after pelvic RT and androgen deprivation therapy. Our data argue for further local dose escalation and pelvic nodal radiation to prevent recurrence in these sites. Lymph node metastasis at initial staging with an magnetic resonance imaging was a strong predictor of recurrence and poor survival and may identify patients in need of more aggressive treatment.

BACKGROUND Undetectable End of Radiation PSA (EOR-PSA) has been shown to predict improved survival in prostate cancer (PCa). While validating the unfavorable intermediate-risk (UIR) and favorable intermediate-risk (FIR) stratifications among Johns Hopkins PCa patients treated with radiotherapy, we examined whether EOR-PSA could further risk stratify UIR men for survival. METHODS A total of 302 IR patients were identified in the Johns Hopkins PCa database (178 UIR, 124 FIR). Kaplan-Meier curves and multivariable analysis was performed via Cox regression for biochemical recurrence free survival (bRFS), distant metastasis free survival (DMFS), and overall survival (OS), while a competing risks model was used for PCa specific survival (PCSS). Among the 235 patients with known EOR-PSA values, we then stratified by EOR-PSA and performed the aforementioned analysis. RESULTS The median follow-up time was 11.5 years (138 months). UIR was predictive of worse DMFS and PCSS (P = 0.008 and P = 0.023) on multivariable analysis (MVA). Increased radiation dose was significant for improved DMFS (P = 0.016) on MVA. EOR-PSA was excluded from the models because it did not trend towards significance as a continuous or binary variable due to interaction with UIR, and we were unable to converge a multivariable model with a variable to control for this interaction. However, when stratifying by detectable versus undetectable EOR-PSA, UIR had worse DMFS and PCSS among detectable EOR-PSA patients, but not undetectable patients. UIR was significant on MVA among detectable EOR-PSA patients for DMFS (P = 0.021) and PCSS (P = 0.033), while RT dose also predicted PCSS (P = 0.013). CONCLUSIONS EOR-PSA can assist in predicting DMFS and PCSS among UIR patients, suggesting a clinically meaningful time point for considering intensification of treatment in clinical trials of intermediate-risk men.

301 Background: The aim is to investigate the clinical significance of biochemical response after Androgen Deprivation Therapy (ADT) prior to high-dose-rate brachytherapy (HDR-BT) for early identification of patients at increased risk of recurrence. Measured outcomes included biochemical relapse free survival (bRFS), distant metastasis free survival (DMFS) and overall survival (OS). Methods: A total of 324 patients with high-risk Prostate Cancer (PCa) were identified in the Norwegian Radium Hospital brachytherapy database. Neo-adjuvant ADT was administered for 3-6 months, followed by two 10 Gy HDR-BT treatments to the prostate, each spaced by two weeks, followed by conformal external beam radiation to 50 Gy to the prostate gland and seminal vesicles. Total length of ADT ranged from 12 to 36 months. PSA (ng/mL) and testosterone values (T, nmol/L) after 3-6 months of neo-adjuvant ADT were measured. Kaplan Meier and Cox regression analyses were performed. Results: Median age at diagnosis was 66 years and median follow-up was 10 years. At last follow-up, 277 patients (85,2%) were alive, 10 patients (3.1%) had died of prostate cancer and 37 patients (11.4%) died of other causes. 24 patients (7.4%) had biochemical relapse and 9 patients (2.8%) had distant metastasis within the first 5 years. Patients with PSA > 1 after neo-adjuvant therapy had 4.3 (95%CI 1.7 to 11.1) higher odds of biochemical relapse within 5 years compared to patients with PSA < 1 (p = 0.002). ROC analysis confirmed that PSA < 1 had a prediction accuracy of 0.76 (sensitivity 68% and specificity 67%). T < 0.7 and PSA < 1 after neo-adjuvant therapy were associated with improved bRFS, DMFS and OS (p < 0.001). Neither the length of neo-adjuvant nor total ADT treatment impacted outcomes (p > 0.05). Conclusions: Dose intensification with 2 HDR-BT boosts resulted in excellent survival in our cohort. PSA > 1 after neo-adjuvant ADT may be able to predict patients at increased risk of relapse and worse OS and identify patients in whom increased monitoring and/or intervention is warranted. ADT > 1 year did not improve outcome, indicating that shorter course of ADT may be used.