Anti PD-1 Research Articles

Unraveling immune checkpoint inhibitors effects on atherosclerosis: mechanisms and preventive approaches

Abstract Background Immune checkpoint inhibitors (ICIs) represent a novel and rapidly evolving field in cancer treatment. Despite increasing reports of accelerated atherosclerosis and ICI-related atherosclerotic cardiovascular (CV) events in clinical studies and case reports, there is a notable lack of data concerning the underlying mechanisms, appropriate monitoring, and potential interventions. Objectives To explore the role of ICIs in triggering and/or accelerating the atherosclerotic process, with a specific focus on the involvement of CD8+ T-cells. Additionally, we aimed to evaluate and compare the potential beneficial effects of statins and Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors on atherosclerosis under ICIs treatment. Methods Thirty 8-week-old C57BL mice were divided into six groups as follows: (1) Control, normal diet; (2) Control, atherogenic diet; (3) Atherogenic diet + anti PD-1; (4) Atherogenic diet + statins + anti-PD1; (5) Atherogenic diet + PCSK9-i + anti PD-1; (6) Atherogenic diet + PCSK9 inhibitors. At 16 weeks, the carotid arteries and heart were removed for histological examination, and serum was withdrawn for blood work and further analysis. Results Anti-PD1 treatment resulted in extensive lymphocytic infiltration of the carotid intima, primarily constituted of CD8+ T cells. This infiltration was significantly attenuated when statins or PCSK-9 inhibitors were used in conjunction with anti-PD1 treatment. Serum analysis for CD4+ and CD8+ T cells by ELISA revealed no difference in CD4+ abundance between the groups. However, plasma CD8+ T cells were significantly increased with anti-PD1 treatment, and furthermore, when PCSK9 inhibitors were used in combination; but not when statins were used. Conclusion The induction of CD8+ T cell infiltration in the arterial carotid walls by anti-PD-1 was prevented with the use of either statins or PCSK9 inhibitors. In the plasma, while statins reduced the hyper-expression of CD8+ T cells observed under PD-1 treatment, PCSK9 inhibitors enhanced this expression. This may provide a first indication of the potential benefit of PCSK9 inhibitor treatment for both preventing arterial inflammation and enhancing the desired anti-tumor immune response under ICIs treatment. Figure legend: 1A. A cross-section of the carotid artery after 16 weeks of treatment, stained with H&E. Magnification is X100. 1B. A cross-section of the carotid artery after 16 weeks of treatment, stained with anti-CD8 Ab. Magnification is X100. 1C. quantitative CD8+ T cells staining in the carotid arteries. 1D. quantitative results of ELISA for plasma CD8+ T cells.

Efficacy of anti PD-1 therapy in children and adolescent melanoma patients (MELCAYA study)

BackgroundData on the efficacy and safety of anti PD-1 antibodies in children and adolescents (CA) with melanoma are lacking. The aim of this study was to determine outcomes of CA melanoma patients receiving anti PD-1 antibodies. MethodsMelanoma patients ≤18 years treated with anti PD-1 were retrospectively retrieved from 15 academic centers. Information on histopathological diagnosis, surgical treatment, systemic therapy, objective response rate (ORR), safety profile was collected. Progression-free survival (PFS) and overall survival (OS) were assessed by Kaplan-Meier method. ResultsBetween April 2016 and March 2024, 99 patients treated with systemic therapy were retrieved, 81 treated with anti PD-1 therapy. Median age was 14 years (range 2–18 years), 37 pts were ≤12 yrs. Overall, 38 CA patients received anti PD-1 in adjuvant setting, and the 3-year PFS and OS were 70.6 % and 81.1 %, respectively. Two patients received anti-PD-1 based neoadjuvant treatment, both had a pathologic complete response and remain disease free. Fifty-six received a systemic therapy for advanced disease and among them, 43 received anti PD-1-based therapy for advanced disease in 1st line, while 12 and 5 pts received a 2nd and 3rd line, respectively. Among patients receiving a 1st line therapy with anti PD-1 monotherapy the ORR was 25 %, and the 3-year OS was 34 %. Toxicities were consistent with previous studies in adult melanoma patients. ConclusionsOur study provides the first evidence of efficacy of anti PD-1 in CA melanoma patients and supports the use of anti PD-1 therapy in pts ≤18 years, included those <12 years.

1952P Multiomic spatial profiling of whole-slide NSCLC tissues from patients receiving anti PD-1 therapy identifies metabolic phenotypes associated with therapy resistance

1952P Multiomic spatial profiling of whole-slide NSCLC tissues from patients receiving anti PD-1 therapy identifies metabolic phenotypes associated with therapy resistance

1101P Efficacy of anti PD-1 therapy in children and adolescent melanoma patients (MELCAYA study)

1101P Efficacy of anti PD-1 therapy in children and adolescent melanoma patients (MELCAYA study)

LBA46 Primary efficacy, safety, and survival data from the registration-intended cohort of patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial with RP1 combined with nivolumab

LBA46 Primary efficacy, safety, and survival data from the registration-intended cohort of patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial with RP1 combined with nivolumab

Assessment of baseline CCL19+ dendritic cell infiltration for predicting responses to immunotherapy in lung adenocarcinoma patients

To explore the correlation of baseline CCL19+ dendritic cell (CCL19+ DC) infiltration in lung adenocarcinoma microenvironment with immunotherapy efficacy and CD8+ T cell infiltration. We retrospectively analyzed the data of patients with lung adenocarcinoma hospitalized at First Affiliated Hospital of Henan University of Science and Technology from January, 2020 to December, 2023, and collected tissue samples from 96 patients undergoing immunotherapy for assessing CCL19+ DC and CD8+ T cell infiltration using immunofluorescence assay. We evaluated the predictive value of baseline CCL19+ DCs for patient responses to immunotherapy using receiver-operating characteristics (ROC) curves and analyzed the correlations of baseline CCL19+ DC expression with immunotherapy efficacy and CD8+ T cell and cytotoxic T lymphocyte (CTL) infiltrations. In co-culture systems of lung adenocarcinoma PC9 cells, CD8+ T cells and DCs (overexpressing CCL19 with or without anti PD-1 antibody treatment), the expressions of granzyme B, perforin, IFN-γ, and Ki-67 in T cells were analyzed using flow cytometry. The patients with partial or complete remission following immunotherapy had a significantly higher baseline CCL19+ DC infiltration level in lung adenocarcinoma tissues than those with poor responses. CCL19+ DC infiltration had an area under ROC curve of 0.785, a sensitivity of 75.6%, and a specificity of 62.8% for predicting immunotherapy efficacy. The expression of CD8+ T cell surface molecules Granzyme B (P<0.01), Perforin (P<0.01), IFN-γ (P<0.01) and Ki-67 (P<0.001) in patients with high expression of CCL19+ DC were higher than those in patients with low expression of CCL19+ DC. The baseline CCL19+ DC infiltration level was positively correlated with immunotherapy efficacy (P=0.003), CTL infiltration of (r=0.6657, P<0.001) and CD8+ T cell infiltration (P=0.007). In the co-cultured cells, CCL19 overexpression combined with anti-PD1 treatment of the DCs more strongly enhanced cytotoxicity and proliferation of CD8+ T lymphocytes than either of the single treatments (P<0.01 or 0.001). The baseline CCL19+ DC infiltration level in lung adenocarcinoma microenvironment is positively correlated with immunotherapy efficacy and CTL infiltration and can thus predict the response to immunotherapy.

Epigenetic agents plus anti-PD-1 reprogram the tumor microenvironment and restore antitumor efficacy in Hodgkin lymphoma

AbstractDNA methyltransferase inhibitor decitabine plus anti–programmed cell death 1 (DP) therapy was effective in relapsed/refractory classic Hodgkin lymphoma (cHL). However, a subset of patients experienced primary resistance or relapse/progression after DP therapy. In this study, we evaluated the efficacy and safety of a triplet regimen consisting of the histone deacetylase inhibitor chidamide, decitabine, and anti–PD-1 camrelizumab (CDP) in 52 patients who previously received DP therapy. CDP treatment was well tolerated and resulted in an objective response rate of 94% (95% confidence interval [CI], 84-99), with 50% (95% CI, 36-64) of patients achieving complete response (CR). Notably, all patients who were recalcitrant to previous DP treatment exhibited therapeutic responses after CDP therapy, although their CR rate was lower than patients responsive to prior DP. Overall, the median progression-free survival was 29.4 months. Through single-cell RNA sequencing of pretreatment and on-treatment cHL tumor biopsy samples, we observed the heterogeneity of rare malignant Hodgkin Reed/Sternberg (HRS)–like cells. The classical CD30+ HRS-like cells interacted with abundant immunosuppressive IL21+CD4+ T helper cells, forming a positive feedback loop that supported their survival. While the CD30– HRS-like cell population showed potential resistance to anti–PD-1 immunotherapy. CDP treatment promoted the activation of diverse tumor-reactive CD8+ T cells and suppressed the proliferation of IL21+CD4+ T cells by inhibiting STAT1/3 signaling, thereby alleviating their immunosuppressive effects. These findings provide insights into the cHL microenvironment that contributes to anti–PD-1 resistance and highlight the therapeutic effectiveness of dual epi-immunotherapy in overcoming immunotherapy resistance. This trial was registered at www.clinicaltrials.gov as #NCT04233294.

75 WIRE: Window of Opportunity Clinical Trials Platform for Evaluation of Novel Treatments Strategies in Renal Cell Cancer

Abstract Background Despite the success of immunotherapy and VEGFR directed tyrosine kinase inhibitors (TKIs) for the treatment of renal cell carcinoma (RCC), a significant proportion of patients display primary or secondary resistance to systemic therapy. New treatment approaches are needed for these patients. Pre-surgical clinical trials allow us to study the effects of cancer treatment on the tumour microenvironment, comparing baseline biopsy with post-treatment nephrectomy in a ‘window of opportunity’ study. The results may give us insight into the mechanisms of new cancer therapies, that may be advanced into further clinical trials. Methods The WIRE trial (NCT03741426) is a phase II, multi-centre, multi-arm, non-randomised, neoadjuvant clinical trial platform. The overall aim of the trial is proof of mechanism for new RCC therapies. There are five investigational arms: 1. Cediranib (a VEGFR directed TKI), 2. Cediranib + Olaparib (a PARP inhibitor), 3. Olaparib, 4. Volrustomig (anti PD-1/CTLA-4 bispecific) and 5. Rilvegostomig (anti PD-1/TIGIT bispecific). The study uses a Bayesian adaptive design to optimise recruitment, with pre-specified criteria assessed at interim analyses to stop for futility, continue recruitment to that arm, or move to the next investigational arm. Eligible patients have cT1b+, cN0/1, cM0/1 clear cell RCC, planning to undergo surgery, without medical contraindication to trial therapy. Patients undergo baseline biopsy to confirm clear cell RCC and multiparametric dynamic contrast enhanced (DCE) MRI scan of the primary tumour. For tablet arms 1-3, patients receive at least 14 days of investigational medicinal product (IMP). For immunotherapy arms 4 &amp; 5, patients receive one infusion of IMP. The tumour is re-evaluated by DCE-MRI immediately before surgery. At nephrectomy, multi-region tissue sampling from the tumour is performed both pre-arterial ligation and post resection. Serial translational blood and urine samples are collected before, during and after treatment. The primary endpoint for arms 1-3 is a ≥30% reduction in DCE-MRI assessed capillary permeability (Ktrans) compared to baseline. The primary endpoint for arms 4 &amp; 5 is a ≥30% increase in IHC assessed CD8+ T cell density comparing the resected tumour to baseline biopsy. Secondary endpoints include RECIST v1.1 primary tumour response and adverse events. A comprehensive translational science programme accompanies the trial, which will assess the tumour microenvironment and peripheral blood response to therapy, using techniques including imaging mass cytometry and single cell RNA sequencing. This will allow us to gain a deep understanding of mechanisms of response in each investigational arm. To date, arms 1 &amp; 2 have completed recruitment, and arm 3 is actively recruiting. Conclusions WIRE offers a unique opportunity to investigate the mechanisms of new therapies for RCC. Successful completion of these peri-surgical studies depends on co-ordination between many specialties, including surgery, oncology, radiology, and pathology. The adaptive design allows for efficient allocation of patients to treatment arms to generate optimal data for each IMP. WIRE may identify novel biomarkers of response and toxicity, to inform treatment selection for patients. The data generated will be a foundation for further trials of these IMPs in advanced disease.

Predict progression free survival and overall survival using objective response rate for anti—PD1/PDL1 therapy development

In oncology anti—PD1 / PDL1 therapy development for solid tumors, objective response rate (ORR) is commonly used clinical endpoint for early phase study decision making, while progression free survival (PFS) and overall survival (OS) are widely used for late phase study decision making. Developing predictive models to late phase outcomes such as median PFS (mPFS) and median OS (mOS) based on early phase clinical outcome ORR could inform late phase study design optimization and probability of success (POS) evaluation. In existing literature, there are ORR / mPFS / mOS association and surrogacy investigations with limited number of included clinical trials. In this paper, without establishing surrogacy, we attempt to predict late phase survival (mPFS and mOS) based on early efficacy ORR and optimize late phase trial design for anti—PD1 / PDL1 therapy development. In order to include adequate number of eligible clinical trials, we built a comprehensive quantitative clinical trial landscape database (QLD) by combining information from different sources such as clinicaltrial.gov, publications, company press releases for relevant indications and therapies. We developed a generalizable algorithm to systematically extract structured data for scientific accuracy and completeness. Finally, more than 150 late phase clinical trials were identified for ORR / mPFS (ORR / mOS) predictive model development while existing literature included at most 50 trials. A tree-based machine learning regression model has been derived to account for ORR / mPFS (ORR / mOS) relationship heterogeneity across tumor type, stage, line of therapy, treatment class and borrow strength simultaneously when homogeneity persists. The proposed method ensures that the predictive model is robust and have explicit structure for clinical interpretation. Through cross validation, the average predictive mean square error of the proposed model is competitive to random forest and extreme gradient boosting methods and outperforms commonly used additive or interaction linear regression models. An example application of the proposed ORR / mPFS (ORR / mOS) predictive model on late phase trial POS evaluation for anti—PD1 / PDL1 combination therapy was illustrated.

Shortened progression free and overall survival to immune-checkpoint inhibitors in BRAF-, RAS- and NF1- (“Triple”) wild type melanomas

BackgroundMelanomas lacking mutations in BRAF, NRAS and NF1 are frequently referred to as “triple wild-type” (tWT) melanomas. They constitute 5–10 % of all melanomas and remain poorly characterized regarding clinical characteristics and response to therapy. This study investigates the largest multicenter collection of tWT-melanomas to date. MethodsTargeted next-generation sequencing of the TERT promoter and 29 melanoma-associated genes were performed on 3109 melanoma tissue samples of the prospective multicenter study ADOREG/TRIM of the DeCOG revealing 292 patients suffering from tWT-melanomas. Clinical characteristics and mutational patterns were analyzed. As subgroup analysis, we analyzed 141 tWT-melanoma patients receiving either anti-CTLA4 plus anti-PD1 or anti PD1 monotherapy as first line therapy in AJCC stage IV. Results184 patients with cutaneous melanomas, 56 patients with mucosal melanomas, 34 patients with acral melanomas and 18 patients with melanomas of unknown origin (MUP) were included. A TERT promoter mutation could be identified in 33.2 % of all melanomas and 70.5 % of all tWT-melanomas harbored less than three mutations per sample. For the 141 patients with stage IV disease, mPFS independent of melanoma type was 6.2 months (95 % CI: 4–9) and mOS was 24.8 months (95 % CI: 14.2–53.4) after first line anti-CTLA4 plus anti-PD1 therapy. After first-line anti-PD1 monotherapy, mPFS was 4 months (95 %CI: 2.9–8.5) and mOS was 29.18 months (95 % CI: 17.5–46.2). ConclusionsWhile known prognostic factors such as TERT promoter mutations and TMB were equally distributed among patients who received either anti-CTLA4 plus anti-PD1 combination therapy or anti-PD1 monotherapy as first line therapy, we did not find a prolonged mPFS or mOS in either of those. For both therapy concepts, mPFS and mOS were considerably shorter than reported for melanomas with known oncogene mutations.

The World of Immunotherapy Needs More Than PD-1/PD-L1—Two of the New Kids on the Block: LAG-3 and TIGIT

Immunotherapy has paved the way for the development of solid tumor new treatments in the last decade. The approval of immune checkpoint inhibitors such as anti PD-1/PD-L1 provided a revolution with optimal results. However, a considerable proportion of patients experience adverse therapeutic effects, and up to 50% may develop secondary resistance in the first three to five years. This has prompted the need for identifying new targets for immunotherapy that have good tolerance and biosafety and, of course, good tumoral response, either alone or in combination. Two of these new targets are the Lymphocyte-activation gene 3 (LAG-3) and the T cell immunoglobulin and ITIM domain (TIGIT). They are responsible for several interactions with the immune system, prompting an immunosuppressive phenotype in the tumor microenvironment. Both LAG-3 and TIGIT can be druggable, alone or in combination with anti-PD-1/PD-L1, with rather safe profiles making them attractive. In this review, we highlight some of the immune mechanisms of TIGIT and LAG-3 and their detection by immunohistochemistry, providing some insight into their use in the clinical setting.

PD-L1 expression in ovarian clear cell carcinoma using the 22C3 pharmDx assay

BackgroundOvarian clear cell carcinoma (OCCC), well known for its chemoresistance to platinum-based chemotherapy, exhibited a good response in clinical trials of anti–PD-1/PD-L1 inhibitors. By assessing PD-L1 expression, we sought to determine the potential therapeutic benefit of PD-1/PD-L1 inhibitors in OCCC.Methods and resultsThe retrospective study included 152 individuals with OCCC between 2019 and 2022 at Peking Union Medical College Hospital. Paired tumors of primary versus recurrent lesions (17 pairs from 15 patients) or primary versus metastatic lesions (11 pairs from 9 patients) were also included. The 22C3 pharmDx assay and whole sections were used for PD-L1 immunohistochemical staining. Pathologists with experience in premarket clinical trials evaluated PD-L1 expression based on various diagnostic criteria (TPS 1%, CPS 1, or CPS 10). The number and percentage of positive PD-L1 cases were 34 (22.4%, TPS ≥ 1%) and 59 (38.8%, CPS ≥ 1), respectively. Thirty-three (21.7%) of the cases had high PD-L1 expression (CPS ≥ 10). Half of the platinum-resistant patients (11/22) were PD-L1 positive (CPS ≥ 1). In addition, positive PD-L1 expression (CPS ≥ 1) was related to clinicopathological characteristics that represented a worse prognosis, such as advanced stages, lymph node metastasis, and distant metastasis (p = 0.032, p < 0.001 and p = 0.003, separately). PD-L1 was expressed equally or more in the recurrent lesion compared with its matched primary lesion.ConclusionsIn conclusion, anti–PD-1/PD-L1 inhibitors are a promising therapeutic choice for OCCC. For evaluation of PD-L1 expression, CPS is more recommended than TPS. Evaluation of recurrent lesion was still suitable and predictive when the primary tumor tissue was not available. Distant metastatic lesions can serve as alternative samples for PD-L1 evaluation, while usage of lymphatic metastatic lesions is not recommended.

177Lu−SN201 nanoparticle shows superior anti−tumor efficacy over conventional cancer drugs in 4T1 orthotopic model

In the current in-vivo study we demonstrate the potential of the radiolabeled nanoparticle 177Lu-SN201 as an effective anticancer treatment, as evidenced by significantly prolonged survival and reduced tumor burden in the aggressive, triple negative 4T1 murine breast cancer model. We show with high statistical significance that 177Lu-SN201 is superior at suppressing the tumor growth not only compared to vehicle but also to the commonly used cancer drugs paclitaxel, niraparib, carboplatin, and the combination of the immune checkpoint inhibitors anti PD-1 and anti-CTLA-4. The dosing of the standard drugs were based on examples in the literature where good effects have been seen in various mouse models. The treatment is reasonably well-tolerated, as indicated by clinical chemistry of liver and renal function through the measurement of glutamate pyruvate alanine aminotransferase, alanine amino transferase, blood urea nitrogen, and creatinine levels in plasma samples, despite some weight loss. Overall, 177Lu-SN201 presents as a promising therapeutic candidate for cancer treatment.

Membrane-fused and mannose-targeted vesicles as immunoenhanced biomimetic nanovaccines for prevention and therapeutics of melanoma

Melanoma is a tumor sensitive to immune response and its immunotherapy has been a research hotspot in recent years. By fusion of melanoma cell membranes and bacterial exosomes through sequential extrusion, we herein design a three-in-one multi-antigenic nanovaccine, namely TBM, to rapidly target immune system. TBM can induce RAW264.7 macrophage cells to differentiate into M1 type cells to release cytotoxic cytokines. It can also promote the maturation and antigen presentation of bone marrow-derived dendritic cells, thus activating spleen T cells to kill B16F10 melanoma cells in vitro. TBM can significantly inhibit the growth and metastasis of melanoma in vivo, and prolong the lifetime of mice, suggesting the preventive effects of vaccines. Further, we integrate cell membranes from mouse melanoma tissues into a novel personalized therapeutic vaccine, namely autologous TBM (ATBM). ATBM combined with Anti PD1 can activate anti-tumor immune response and increase the survival rate of melanoma allografted mice, as supported by eukaryotic reference mRNA-Seq transcriptome sequencing. Generally, this study demonstrates the preventive and therapeutic effects of biomimetic nanovaccines against melanoma, which may be extended to design personalized tumor vaccines for all tumors with immunogenicity, showing great clinical perspectives.

Tumor-infiltrating T-Lymphocyte immunity-related immune tolerance and anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy for advanced hepatocellular carcinoma

Abstract Systemic therapy has become the standard treatment for patients with advanced hepatocellular carcinoma (HCC) whose treatment options are limited. However, the long-term patient response to drugs and the survival outcomes remain a concern. With increasing exploration of the HCC microenvironment, particularly in terms of T lymphocyte immunity, a new era of immunomolecular targeted therapy, based on molecular signaling, has arrived for advanced HCC. In the study of immune tolerance of the intrinsic HCC microenvironment, we found that multiple immunosuppressive mechanisms and immune checkpoint inhibitors, such as anti–programmed cell death protein 1/ligand of programmed cell death protein 1 therapy, have improved clinical outcomes in some patients with advanced HCC. Furthermore, various combination therapies have been investigated, and HCC types have been categorized into different types based on anti–programmed cell death protein 1 (PD-1)/ligand of programmed cell death protein 1 (PD-L1) treatment. In this paper, we first discuss the tumor-infiltrating T lymphocyte immunity and immune tolerance of HCC. We then clarify the basic mechanism of anti–PD-1/PD-L1 therapy and discuss the types of HCC based on anti–PD-1/PD-L1 therapy. Thereafter, we explain the relevant studies and mechanisms of combination therapy of anti–PD-1/PD-L1 with antiangiogenesis drugs or multikinase kinase inhibitors, anti–T lymphocyte–related signaling pathways in HCC, and other anti-CD8+ T cell immune checkpoints. In this way, this review offers a deeper understanding of anti–PD-1/PD-L1 immunotherapy for advanced HCC, in order to provide better individualized treatments for patients with advanced HCC.

PD1 ligand functionality a biomarker of response to anti PD1 treatment in patients with HNSCC

Therapies targeting the PD-1/PD-L1 pathway have transformed head and neck squamous cell carcinoma (HNSCC) treatment. However, predicting the response to anti-PD-1 therapy remains a clinical challenge. This study evaluated the functional binding of PD-1 ligands in 29 HNSCC patients and compared it to the standard PD-L1 Combined Positive Score (CPS). The assessment of PD-1 ligands’ functionality advances the current ability to predict the response of HNSCC patients to anti-PD-1 therapy.

A randomized, controlled, multicenter, phase 3 study of vusolimogene oderparepvec (VO) combined with nivolumab vs treatment of physician’s choice in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy (IGNYTE-3).

TPS9604 Background: Melanoma is the 5th most common cancer type, with ~100,000 new cases and ~8,000 deaths estimated in the US for 2024. First-line systemic treatment with immune checkpoint inhibitors improved the objective response rate (ORR) and extended progression-free survival (PFS) and overall survival (OS) for patients with advanced disease. The combination of anti–PD-1 nivolumab (nivo) + anti–CTLA-4 ipilimumab (ipi) therapy is associated with the highest ORR and best PFS and OS in this setting. However, only about half of patients respond, and there is no standard of care for patients who progress after anti–PD-1–based therapy. VO (also referred to as RP1) is a selectively replication-competent HSV-1 oncolytic virus that expresses human GM-CSF and a fusogenic glycoprotein (GALV-GP-R–). Preliminary data from the phase 1/2 study (IGNYTE) showed that intratumoral (IT) VO plus intravenous (IV) nivolumab (nivo) was well tolerated and had meaningful antitumor activity (ORR, 31.4%) with durable responses in patients with advanced melanoma who progressed on prior anti–PD-1 therapy. This phase 3 study will evaluate the overall survival and clinical benefit as well as the safety of VO plus nivo for patients with advanced melanoma whose disease has progressed after receiving anti–PD-1 and anti–CTLA-4 therapy (or who are not eligible for anti–CTLA-4 therapy in addition to anti–PD-1) versus physician’s choice. Methods: This is a randomized, controlled, multicenter, phase 3 clinical trial comparing VO in combination with nivo vs physician’s choice of treatment in patients with unresectable or metastatic melanoma. Key eligibility criteria include age ≥12 years, stage IIIb–IV/M1a–M1d cutaneous melanoma, confirmed disease progression on an anti–PD–1 and anti–CTLA-4 treatment (administered in combination or in sequence with anti–PD-1 last), at least 1 measurable tumor (≥1 cm), and adequate hematologic, hepatic, and renal function. Patients who are not candidates for anti–CTLA-4 therapy may enroll if they have confirmed progression on anti–PD-1 therapy. Patients with BRAF V600 mutant melanoma must have received an anti-BRAF + anti-MEK targeted therapy prior to enrollment. Patients (N = ~400) will be randomized 1:1 to receive VO plus nivo or physician’s choice (nivo + relatlimab, anti–PD–1 monotherapy rechallenge [nivo or pembrolizumab], or single-agent chemotherapy [dacarbazine, temozolomide, or paclitaxel/albumin-bound paclitaxel]). VO is given IT Q2W; nivo is administered IV at 240 mg Q2W or 480 mg Q4W starting with the 2nd dose of VO. The primary endpoint of the study is OS; the key secondary endpoints are PFS and ORR. Additional endpoints include complete response rate, duration of response, disease control rate, and safety. Clinical trial information: NCT06264180 .

A phase 1/2 study of favezelimab in combination with pembrolizumab for heavily pretreated anti–PD-1–refractory classical Hodgkin lymphoma (cHL): An updated analysis.

7056 Background: PD-1 inhibitors are standard of care for relapsed or refractory (R/R) cHL, but patients (pts) often progress after anti–PD-1 therapy. The immune checkpoint receptor lymphocyte-activation gene 3 (LAG-3) is proposed to contribute to anti–PD-1 resistance. In a phase 1/2 study (NCT03598608) evaluating favezelimab (anti–LAG-3) plus pembrolizumab (anti–PD-1) for R/R hematologic malignancies, the combination provided antitumor activity and manageable safety in pts with heavily pretreated anti–PD-1–refractory cHL (cohort 2). Updated results after additional follow-up are presented. Methods: Eligible pts were aged ≥18 years with R/R cHL; prior treatment with or ineligibility for autologous stem cell transplantation or no response to salvage chemotherapy; an ECOG performance status of 0 or 1; and disease progression after ≥2 doses of anti–PD-1–based therapy and within 12 weeks of the last dose of anti–PD-1 therapy. The study comprised a safety lead-in (pembrolizumab 200 mg IV Q3W + favezelimab 200-mg starting dose, then dose escalation to 800 mg IV Q3W per a modified toxicity probability interval design) and a dose expansion phase (pembrolizumab + favezelimab at the established recommended phase 2 dose of 800 mg Q3W for ≤35 cycles). Primary end point was safety. ORR per IWG 2007 criteria by investigator review was a secondary end point. DOR and PFS per IWG 2007 criteria by investigator review and OS were exploratory. Results: Cohort 2 enrolled 34 pts. Median time from first dose to data cutoff (August 15, 2023) was 40.7 months (range, 20.4-54.8). Treatment-related AEs occurred in 28 pts (82%); the most common (≥15%) were hypothyroidism (18%), nausea (18%), and fatigue (15%). Grade 3 or 4 treatment-related AEs occurred in 6 pts (18%). Discontinuation due to treatment-related AEs occurred in 6 pts (18%). No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 17 pts (50%); 2 pts (6%) had grade 3 events (encephalitis, hepatitis) and 1 pt (3%) had a grade 4 event (type 1 diabetes mellitus). ORR was 29% (10/34; 95% CI, 15-48), with 3 (9%) complete responses and 7 (21%) partial responses. ORR was 35% (6/17; 95% CI, 14-62) in pts with anti–PD-1 and 24% (4/17; 95% CI, 7-50) in pts with non–anti–PD-1 as most recent therapy. Median DOR was 21.9 months (range, 0.0+ to 26.1+) and an estimated 17% of responders remained in response at 24 months. Median PFS was 9.7 months (95% CI, 5.1-14.7); 24-month PFS rate was 21%. Median OS was 39.0 months (95% CI, 25.7-not reached); 24-month OS rate was 73%. Conclusions: After additional follow-up, favezelimab + pembrolizumab continued to demonstrate manageable safety and antitumor activity in pts with heavily pretreated anti–PD-1–refractory cHL. The phase 3 KEYFORM-008 study (NCT05508867) will evaluate a coformulation of favezelimab and pembrolizumab in pts with anti–PD-1–refractory cHL. Clinical trial information: NCT03598608 .

Efficacy and safety of RP1 combined with nivolumab in patients with anti–PD-1–failed melanoma from the IGNYTE clinical trial.

9517 Background: Patients (pts) with melanoma who progress on anti–PD-1 therapy (anti–PD-1–failed) have limited treatment options. RP1 is an HSV-1–based oncolytic immunotherapy expressing human GM-CSF and a fusogenic protein (GALV-GP-R−). Here, we present data from pts with anti–PD-1–failed melanoma, including the initial cohort and updated data from a registration-directed (R-D) cohort, from the phase 1/2 IGNYTE study (NCT03767348). Methods: Pts had locally advanced or metastatic cutaneous melanoma with ≥1 measurable and injectable tumor (≥1 cm) and confirmed progressive disease (PD) while on therapy and received anti–PD-1 ± anti–CTLA-4 therapy for ≥8 consecutive weeks, with anti–PD-1 being the last treatment received. Pts on prior adjuvant anti–PD-1 therapy had confirmed PD while on adjuvant therapy. RP1 was initially given intratumorally at 1×106 plaque-forming units (PFU)/mL and then every 2 weeks (Q2W) at 1×107 PFU/mL for up to 8 total cycles (≤10 mL/cycle) combined with nivolumab (nivo; cycles 2–8, 240 mg IV); pts then received nivo alone (240 mg Q2W or 480 mg Q4W IV) for up to 2 years, with the option to receive additional courses of RP1 if specified criteria were met. Results: Overall, 156 pts were enrolled (initial melanoma cohort, n = 16; R-D cohort, n = 140); 46.2% of pts had been treated with prior anti–PD-1 combined with anti–CTLA-4, and 51.3% of patients had stage IVM1b-d disease. The overall objective response rate (ORR) was 31.4%, and 12.2% of pts achieved complete response (CR; Table). Responses were observed irrespective of prior anti–PD-1 therapy setting and disease stage (Table). Responses were seen in uninjected lesions and in bulky and visceral disease. The ORR for pts with primary anti–PD-1 resistance was 34.1%. In pts who failed prior ipilimumab + nivo, the ORR was 26.4% (Table). The median duration of response (time from baseline to end of response for responders) was &gt; 24 months, with 100% of responses lasting &gt; 6 months from baseline; 78% of responses were ongoing. Treatment-related adverse events (TRAEs) associated with RP1 + nivo were predominantly grade 1–2; there was 1 grade 5 TRAE (immune-mediated myocarditis attributed to nivo). Conclusions: The updated data from this expanded cohort show that RP1 + nivo provides durable and clinically meaningful antitumor activity in pts with anti–PD-1–failed melanoma. Responses were observed in both injected and uninjected lesions, including visceral lesions. The combination continues to be well tolerated. Clinical trial information: NCT03767348 . [Table: see text]

A phase 1 study of fianlimab (anti–LAG-3) in combination with cemiplimab (anti–PD-1) in patients with advanced HNSCC.

6038 Background: Concurrent blockade of LAG-3 may enhance efficacy of anti–PD-1 therapies. We present safety and clinical activity data from a Phase 1 study in patients (pts) with head and neck squamous cell carcinomas (HNSCC) treated with anti–LAG-3 (fianlimab) + anti–PD-1 (cemiplimab). Methods: Two expansion cohorts of adult pts with recurrent and/or metastatic HNSCC with no curative options who were anti–PD-1/PD-L1-naïve (cohort 11) or anti–PD-1/L1-experienced with most recent dose within 3 months (mos) prior to screening (cohort 12) were enrolled. All pts received fianlimab 1600 mg + cemiplimab 350 mg intravenously every 3 weeks (wks) for up to 24 mos. Tumor measurements were performed every 6 wks for 24 wks, then every 9 wks. Results: 15 pts each in cohort 11 and 12 (total N=30; median age: 69 years) were enrolled and treated with fianlimab + cemiplimab as of 04 Oct 2023 data cutoff.For cohorts 11 and 12 respectively, 80% and 87% of pts were male, and 53% and 80% were White. All pts had prior cancer-related systemic therapy. 33% (5/15) and 87% (13/15) of pts in cohorts 11 and 12 had ≥2 lines of prior therapies, respectively. For cohorts 11 and 12, median treatment duration was 12 wks (mean: 41 wks) and 13 wks (mean: 24 wks), and median follow-up was 12 mos and 10 mos, respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 47% of pts each in cohorts 11 and 12. Serious TEAEs occurred in 13% and 20% of pts in cohorts 11 and 12, respectively. Treatment-related TEAEs (TRAEs) were reported in 67% of pts in cohorts 11 and 53% of pts in cohort 12. The most common TRAEs (any grade) were hypothyroidism (33%) in cohort 11; and fatigue (20%) and pneumonitis (20%) in cohort 12. Grade ≥3 TRAEs occurred in 7% of pts in cohorts 11 and 13% of pts in cohorts 12. Treatment-related immune-related AEs were reported in 47% and 40% of pts in cohorts 11 and 12, respectively. Treatment was discontinued due to any TEAE in 2 pts in cohort 12. In cohort 12, there was one death due to grade 5 respiratory failure attributable to aspiration pneumonia. RECIST 1.1-based investigator-assessed objective response rate (ORR) was 33% (5 partial responses [PRs]) in cohort 11 and 7% (1 PR) in cohort 12. The disease control rate (DCR) was 47% and 67% in cohorts 11 and 12, respectively. Kaplan–Meier estimation of median progression-free survival was 2 mos (95% CI, 1–14) in cohort 11 and 4 mos (95% CI, 1–7) in cohort 12 pts. Duration of responses were 17, 10, 20, 22, and 20 mos in 5 responders in cohort 11; and 32 mos in 1 responder in cohort 12. Estimated event-free probability at 12 month was 33% (95% CI, 12–56) in cohort 11 and 16% (95% CI, 3–40) in cohort 12 pts. Conclusions: Fianlimab + cemiplimab in pts with HNSCC showed signs of clinical activity with durable responses among pts with anti–PD-1/PD-L1-naïve (cohort 11) and anti–PD-1/L1-experienced (cohort 12), with an acceptable safety profile which warrants further investigation. Clinical trial information: NCT03005782 .