e20060 Background: Immune checkpoint inhibitor (ICI) therapy has prolonged survival in non-small cell lung cancer (NSCLC), but can also trigger immune-related adverse events (irAEs) requiring therapy discontinuation and re-challenge. Data on morbidity and response outcomes after irAEs, as well as tolerability of re-challenge after irAE, remains limited in these patients. Methods: We conducted a retrospective, single-institution analysis of patients with primary lung malignancy who received immunotherapy at the University of Virginia Emily Couric Cancer Center between 2011-2023. Data on treatment patterns, demographics, survival outcomes, irAEs, and rechallenge after irAE were collected. IrAEs were graded using CTCAE v5. criteria via chart review. Median overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Hazard ratios (HR) were from multivariable Cox regression models, and associated p-values were calculated from Wald tests. Results: Of 598 NSCLC patients who received ICI, 55.7% were male, 81.8% were White, and median age was 65 years. 61.7% had Stage IV disease at diagnosis, and 57.0% of patients had adenocarcinoma on histology. 282 (47.2%) patients experienced an irAE. The most common irAEs experienced were rash (24.8%), pneumonitis (22.7%), and hypothyroidism (11.0%). Of patients who experienced an irAE, 194 (68.8%) underwent ICI re-challenge. Of patients who underwent re-challenge, 59 (30.3%) experienced a subsequent irAE. OS for the whole cohort was 29.1 months (95% CI: 24.8-33.9 months) and PFS was 6.9 months (95% CI: 6.4-8.2 months). Having squamous cell carcinoma histology was associated with decreased OS (HR = 1.47, p = 0.002) compared to adenocarcinoma, as was stage IV disease at diagnosis (HR = 1.83, p = 0.001) vs. stage I. Patients who experienced an irAE had improved OS (HR = 0.55, p < 0.001) and PFS (HR = 0.46, p < 0.001) compared to patients who did not experience one. Conclusions: Occurrence of irAE was associated with improved OS and PFS in NSCLC patients. Additionally, ICI re-challenge is feasible in most patients after irAE. Further studies are needed to evaluate factors associated with successful ICI re-challenge.

All treatment-related adverse events

PURPOSE:This randomized phase I/II clinical trial (NCT03617328) was designed to test whether administration of systemic agonistic anti-CD27 antibody (varlilumab) concurrent with a melanoma vaccine is safe and enhances vaccine immunogenicity. PATIENTS AND METHODS:Adults with definitively treated, high-risk melanoma were randomized to receive a shared antigen vaccine targeting CD4+ T cells (6 melanoma helper peptides; 6MHP) either with (arm A) or without (arm B) systemic varlilumab over 11 weeks. A final vaccine was given at week 25 to assess memory response. RESULTS:Thirty-three participants were treated at two centers. After enrolling 17 participants, the dose-limiting toxicity (DLT) rate with vaccine alone required protocol revision to limit local toxicity. Overall, DLT rates for arms A and B were 6% (1/17) and 31% (5/16), respectively. Twenty (61%) participants had CD4+ T-cell responses ex vivo. Persistent responses were detected in two (2/14, 14%) on arm A and one (1/16, 6%) on arm B. Memory response was detected in two (2/13, 15%) on arm A and four (4/16, 25%) on arm B. On arm A, there was a significant reduction in circulating CD4+ T cells. Four-year disease-free survival rates for arms A and B were 20% [95% confidence interval (CI), 6%-67%] and 69% (95% CI, 49%-96%), respectively. CONCLUSIONS:No synergistic toxicity was observed with combination treatment. Similar durability in immunogenicity was found with or without varlilumab. Depletion of circulating CD4+ T cells with varlilumab may have abrogated benefits of inducing tumor-cognate CD4+ T cells with vaccination. Induction of memory responses supports further work to optimize shared antigen vaccines in combination with other immunotherapies. SIGNIFICANCE:Combination treatment with 6MHP vaccination and varlilumab was safe but did not improve CD4+ T-cell response rates. Circulating CD4+ T cells were reduced with varlilumab, and clinical outcome was improved without varlilumab. This study demonstrates induction of memory responses after shared antigen vaccination; however, CD27 agonism did not enhance durability of response. Depletion of CD4+ T cells after varlilumab may have interfered with the beneficial effects of vaccination.

Representativeness of study participants

Changes in absolute number of circulating Tregs over time

Immune response rates by protocol version

Abstract Background Incidence of solid tumor brain metastasis is on the rise due to improved systemic therapy options and survival of patients with several malignancies. With this in mind, the aim of our study was to explore the pattern of multi-modality treatment options for patients with CNS metastasis and patient outcomes. Methods We conducted a retrospective analysis of patients with CNS metastasis from solid tumors who received multi-disciplinary care at the University of Virginia from 2020-2025. Median overall survival (OS) and CNS progression-free survival (PFS) were estimated using the Kaplan-Meier method. Results Of the 41 patients studied, 43.9% (n = 18) were male, while 56.1% (n = 23) were female. Median age at cancer diagnosis was 59 years. Most common primary cancers were NSCLC (34.1%, n = 14), breast (26.8%, n = 11), and melanoma (17.1%, n = 7). Median time from solid tumor diagnosis to CNS metastasis was 30.4 months. 41.5% (n = 17) had solitary brain metastasis, 31.7% (n = 13) had 1 to 5, 14.6% (n = 6) had 6 to 10, and 12.2% (n = 5) had over 10 brain metastases. Most patients received a combination of systemic and loco-regional therapy (51.2%, n = 21). Six patients (14.6%) received systemic therapy alone, and 13 patients (31.7%) received loco-regional therapy alone. For first line systemic therapy, 39.0% (n = 16) received targeted therapy, 34.1% (n = 14) received chemotherapy, and 19.5% (n = 8) received immunotherapy. For loco-regional therapy, 58.5% (n = 24) patients received SRS (including GKRS), 26.8 % (n = 11) underwent surgical resection, and 4.9% (n = 2) received WBRT. Median OS was 55.4 (95% CI: 31.8-not estimable) months from development of CNS metastasis, and median PFS was 9.0 (95% CI: 6.9-16.1) months. Median time from diagnosis of CNS metastasis to specialist consultation was 3 days. Conclusions Patients with CNS metastasis from solid tumors represent a complex patient population. Provision of multidisciplinary care offers potential for faster access to specialized care and improved survival outcomes.

Changes in circulating Tregs as a percentage of CD4+ T cells over time

6012 Background: A subset of salivary gland cancers (SGCs) express the androgen receptor (AR). A prior AR+ SGC trial with the anti-androgen enzalutamide alone failed to meet its primary endpoint. This is a multicenter, phase II study evaluating the efficacy and safety of the anti-androgen darolutamide (Bayer) in combination with androgen-deprivation therapy (ADT; leuprolide acetate) in hormone-therapy naïve patients with AR+ SGCs. Methods: Patients with locally advanced/unresectable or recurrent/metastatic AR+ SGCs were enrolled. AR status was determined locally by immunohistochemistry (IHC). Prior AR-targeted therapy was not allowed, unless administered in the neoadjuvant and/or adjuvant setting >6 months before disease recurrence. Darolutamide 600 mg orally twice daily was given with leuprolide acetate intramuscular injections (1 cycle= 28 days). The primary endpoint was best overall response (BOR) rate according to RECIST v1.1 within 1 year of initiating treatment. Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity. Exploratory endpoints were evaluating biomarkers in serially obtained research biopsies and exploring efficacy among patients who had not received prior systemic therapy. A two-stage minimax design was used to detect a 50% BOR rate (vs. 25%) (alpha = 9%; beta = 83%). ≥3 responses in the first 9 patients would trigger accrual to 20; ≥8 responses would be considered promising. Results: Study accrual of 20 patients (pts) with AR+ SGCs was completed on 10/30/25. 15 males, 5 females with a median age of 70.5 years were enrolled. Among the 9 pts in the first stage, 6 confirmed partial responses (PRs) were observed, allowing for full study accrual. With a data cutoff of 1/21/26, the best RECIST v1.1 responses among 20 pts were 8 (40% [19.1% 63.9%]) PRs (7 confirmed, 1 unconfirmed with pt still on treatment), 10 (50% [27.2%, 72.8%]) stable disease (SD), 1 (5% [1%, 24.9%]) progression of disease; 1 pt on treatment has not had radiographic assessments yet. 6 (30% [11.9%, 54.3%]) pts came off trial for disease progression, 1 (5% [1%, 24.9%]) withdrew consent after 6 cycles, and 13 (65%, [40.8%, 84.6%]) remain on treatment. Among 5 female pts, best responses were 1 (5% [1%, 24.9%]) PR, 3 (15% [3.2%, 37.9%]) SD, 1 (5% [1%, 24.9%]) PD. With additional follow-up, PFS, OS, and biomarker data (AR IHC %, HER2 status) will be presented. Conclusions: In this molecularly selected cohort of patients with SGC, darolutamide plus ADT possesses significant clinical activity, validating AR as a relevant therapeutic target in a subset of SGCs. Analysis of serial research biopsies will be performed to identify biomarker and/or drug combination strategies to enhance the efficacy of AR-targeting. Clinical trial information: NCT05669664 .

Trial design and protocol amendment for safety. A and B, Trial schema of study interventions (A) before and (B) after protocol amendment for exceeding the DLT threshold. Vaccines included poly-ICLC in the adjuvant at all time points except for week 25, represented by the dashed arrow. Blood draws were obtained prior to vaccination and/or varlilumab therapy. C, CONSORT flow diagram. ID, intradermal; IV, intravenous; SQ, subcutaneous.

Treatment-related adverse events after protocol amendment

BACKGROUND:For patients with high-risk melanoma who are unresponsive or intolerant to immune checkpoint inhibitors, cancer vaccines may provide benefit with a favorable toxicity profile. CD4+ T cells provide essential help to dendritic cells (DCs) for optimal CD8+ T cell priming in the antitumor response, and induction of tumor-cognate CD4+ T cell responses may enhance vaccine efficacy. We report on a first-in-human approach to treat patients with high-risk melanoma using a vaccine composed of six non-mutated melanoma-specific helper peptides (6MHP) and a shared mutated BRAF-V600E neoantigen helper peptide (mBRAF) co-administered locally with a TLR3 agonist (poly-ICLC) and agonistic CD40 antibody (CDX-1140). METHODS:Adults with high-risk melanoma arising from cutaneous, mucosal, or ocular primary sites who were rendered clinically free of disease after definitive treatment were enrolled to this nonrandomized phase I/II trial (NCT04364230) designed to assess safety and immunogenicity. Participants received vaccine (6MHP+mBRAF+poly-ICLC) with a dose-escalation allocation of CDX-1140 into the vaccine mixture at one of four dose levels (50, 200, 800, 3000 μg). Vaccines were administered at 3-week intervals for four doses. Primary endpoints were safety and peripheral CD4+ T cell response. Exploratory analysis to characterize the vaccine site microenvironment was performed. RESULTS:Of 22 eligible participants, 11 (50%) had ocular melanoma. Sixteen (73%) received the maximum CDX-1140 dose. Toxicities were limited to grade 1 or 2 treatment-related adverse events, with no dose-limiting toxicities reported. Peripheral CD4+ T cell responses to 6MHP were found ex vivo in six (27%, 95% CI 11% to 50%), including four with the maximum CDX-1140 dose. One had a durable and persistent T cell response to week 25. T cell responses to mBRAF did not meet criteria for positivity ex vivo, but one participant had a durable response after in vitro stimulation, with expansion of multifunctional Th1-polarized CD4+ T cells. Favorable immune-related changes were observed at the vaccine site, including CDX-1140-mediated increases in mature (DC-LAMP+) DCs. CONCLUSIONS:The vaccine was safe, well-tolerated, and immunogenic. Optimization of vaccines that include agonistic CD40 antibody is needed to enhance immunogenicity. Induction of a multifunctional CD4+ T cell response to mBRAF supports targeting shared mutated neoantigens with melanoma vaccines. TRIAL REGISTRATION NUMBER:NCT04364230.

Changes in absolute number of circulating CD4+ T cells over time

T-cell responses by treatment arm and response type. Response rates are reported as the percentage of responses (n) out of participants (N). The difference in response rates (A − B) is shown with 90% CI.

Participant baseline characteristics by treatment arm.

DLTs. Summary of all DLTs reported in the trial.

Treatment-related adverse events prior to protocol amendment

ABSTRACT Background Mucosal melanoma (MM) is a rare and aggressive subtype of melanoma with a notably worse prognosis than cutaneous melanoma (CM) due to its occult presentation and unique molecular profile. For advanced cases, immunotherapy has improved outcomes in recent years, although more significantly for CM. The recently approved combination of nivolumab and relatlimab has emerged as a promising option for advanced melanoma and a potential alternative to the well‐established nivolumab‐ipilimumab regimen. Due to the rarity of MM often limiting thorough evaluation in trials, there remains a lack of guidance regarding the most appropriate regimen for optimal patient outcomes. Case A 70‐year‐old male with T4aN0M0 sinonasal MM was initiated on neoadjuvant nivolumab‐ipilimumab therapy; however, disease progression soon after rendered the tumor unresectable. Despite undergoing 4 cycles, metastatic progression ensued, necessitating a shift to nivolumab‐relatlimab therapy. Following 8 cycles of nivolumab‐relatlimab alongside radiation to metastatic sites, the patient achieved a complete response, with no signs of active disease. Unfortunately, during a seven‐week treatment interruption due to suspected immune‐related gastrointestinal toxicity requiring corticosteroids, routine PET‐CT monitoring revealed findings suspicious for new metastasis. Despite one additional cycle of immunotherapy, the patient's functional status deteriorated. Although repeat imaging showed stable disease, the patient elected to transition to supportive care without further treatment. Conclusion This case exemplifies the use of nivolumab‐relatlimab in achieving a complete response in a patient with advanced sinonasal MM that progressed after nivolumab‐ipilimumab. While further investigation is needed to clarify the comparative efficacy of existing combination immunotherapy options, this report highlights nivolumab‐relatlimab as a promising option with a potentially favorable safety profile in this rare and aggressive melanoma subtype.