Pembrolizumab In Patients Research Articles

Abstract C032: NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study

Abstract Background: 3’-deoxyadenosine (3’-dA) is a natural nucleoside analogue that demonstrated potent anti-cancer activity in vitro but was not successfully developed in the clinic due to rapid breakdown and limited activation to the anti-cancer metabolite (3’-dATP). NUC-7738 is a phosphoramidate modification of 3’-dA designed to overcome these shortcomings and generate higher levels of 3’-dATP. Primarily, 3’-dATP disrupts RNA polyadenylation and can cause metabolic stress, blockade of cell division and apoptosis. Secreted forms of PD-L1, associated with resistance to PD-1 inhibitors, are partially controlled by alternative polyadenylation and were found to be reduced by NUC-7738 in vitro and in some patient (pt) samples. NuTide:701 is a two-part, Phase 1/2 clinical study designed to establish the RP2D of NUC-7738 monotherapy and to investigate NUC-7738 at the RP2D in combination with pembrolizumab. NUC-7738 monotherapy has shown a favourable safety profile and anti-tumour activity (prolonged SD and tumour reductions). Here we focus on the Phase 2 NUC-7738 + pembrolizumab part of the study. Methods: Pts with advanced/metastatic cutaneous melanoma who had progressed on 1- 2 prior lines, one of which may have contained immunotherapy, are included in the ongoing NUC-7738 + pembrolizumab cohort and receive NUC-7738 1125 mg/m2 Q1W (with option to escalate to 1350 mg/m2 beyond C2D8) and pembrolizumab 200 mg/m2 Q3W until progression. In pts with accessible disease, biopsies were taken prior to and 28 days after initiation of treatment to assess tumour levels of NUC-7738 and its metabolites and evaluate changes in the tumour microenvironment. Results: At the time of data cut-off, 4 pts with cutaneous melanoma have received NUC-7738 + pembrolizumab. To date, 1 pt experienced reversable Grade 4 transaminitis, related to pembrolizumab, and 2 pts experienced Grade 3 abdominal pain, diarrhoea and fatigue. At the time of writing, all 4 remain on treatment, 1 pt has SD and 8 additional pts are being recruited. Conclusions: NUC-7738 has a favourable toxicity profile as monotherapy and has been well-tolerated to date in combination with pembrolizumab. Available clinical and translational data for all pts treated with NUC-7738 + pembrolizumab will be presented. Clinical trial information: NCT03428958 Citation Format: Sarah P Blagden, Stefan N Symeonides, Aglaia Skolariki, Noor Md Haris, Zhuang Boh, In Hwa Um, Mustafa Elshani, Alison L Dickson, Ying Zhang, David J Harrison, Fiona G McKissock, Elisabeth Oelmann, Jeffrey D Bloss, Natalie Cook, TR Jeffry Evans, E. Ruth Plummer. NUC-7738 in combination with pembrolizumab in patients with metastatic melanoma: Phase 2 results from the NuTide:701 study [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C032.

110P Outcomes of CUPem: A prospective phase II multicentre clinical trial of pembrolizumab in patients with pre-treated cancer of unknown primary

110P Outcomes of CUPem: A prospective phase II multicentre clinical trial of pembrolizumab in patients with pre-treated cancer of unknown primary

139P Safety and clinical activity of a novel anti-CCR8 antibody (LM-108) as a single agent or in combination with pembrolizumab in patients with advanced solid tumors: Results of phase I study

139P Safety and clinical activity of a novel anti-CCR8 antibody (LM-108) as a single agent or in combination with pembrolizumab in patients with advanced solid tumors: Results of phase I study

EE678 Time and Cost Savings from Adopting an Alternative Dosing Schedule with Pembrolizumab for Patients with Advanced Melanoma in Greece

EE678 Time and Cost Savings from Adopting an Alternative Dosing Schedule with Pembrolizumab for Patients with Advanced Melanoma in Greece

Multicenter randomized controlled trial of neoadjuvant chemoradiotherapy alone or in combination with pembrolizumab in patients with resectable or borderline resectable pancreatic adenocarcinoma

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a challenging target for immunotherapy because it has an immunosuppressive tumor microenvironment. Neoadjuvant chemoradiotherapy can increase tumor-infiltrating lymphocyte (TIL) density, which may predict overall survival...

Favezelimab in Combination with Pembrolizumab in Patients with Heavily Pretreated Anti-PD-1-Refractory Classical Hodgkin Lymphoma: Updated Analysis of an Open-Label Phase 1/2 Study

Background: Programmed cell death protein 1 (PD-1) inhibitors are a standard of care for relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but better treatment options are needed for patients with anti-PD-1-refractory disease. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor with a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 has demonstrated antitumor activity in patients with advanced melanoma. Combination therapy with favezelimab (anti-LAG-3) and pembrolizumab (anti-PD-1) is currently being investigated in a phase 1/2 study (NCT03598608) in patients with R/R hematologic malignancies. Prior analyses showed that the combination had antitumor activity and manageable safety in patients with heavily pretreated anti-PD-1-refractory cHL (cohort 2). Updated results for this cohort are presented. Methods: The study consisted of a safety lead-in (part 1) followed by a dose-expansion phase (part 2). Eligible patients were ≥18 y; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had an ECOG performance status of 0 or 1; and had experienced disease progression after ≥2 doses of anti-PD-1-based therapy and within 12 weeks of the last dose of anti-PD-1 therapy. In part 1, patients received pembrolizumab 200 mg IV Q3W + favezelimab starting at 200 mg and escalating to 800 mg IV Q3W per a modified toxicity probability interval design. In part 2, patients received pembrolizumab + favezelimab at the established RP2D of 800 mg Q3W for ≤35 cycles (~2 y). The 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 end points. Results: 34 patients with anti-PD-1-refractory cHL were enrolled in cohort 2. The median age was 37.5 y (range, 25-79), 16 patients (47%) were male, 21 (62%) had an ECOG performance status of 0, and 94% had received ≥4 prior lines of therapy. Seventeen patients (50%) had received an anti-PD-1-based regimen as their most recent therapy. At database cutoff (March 2, 2023), 8 patients (24%) had completed 35 cycles of treatment and 26 (76%) had discontinued treatment (14 [41%] progressive disease, 7 [21%] AEs, 5 [15%] other reasons). The median time from first dose to data cutoff was 35.3 mo (range, 15.0-49.4). Treatment-related AEs occurred in 28 patients (82%), of which the most common (≥15%) were hypothyroidism (18%), nausea (18%), and fatigue (15%). Grade 3/4 treatment-related AEs occurred in 6 patients (18%). 6 patients (18%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 17 patients (50%); 2 patients (6%) had grade 3 events (encephalitis, hepatitis) and 1 patient (3%) had a grade 4 event (type 1 diabetes mellitus). Of the 2 patients who underwent allogeneic hematopoietic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3 AE (acute graft versus host disease) unrelated to study treatment that resolved. The ORR in cohort 2 was 29% (10/34; 95% CI, 15-48), with 3 (9%) complete responses (CR) and 7 (21%) partial responses (PR). Of the 10 responders, 7 had received ≥5 prior lines of therapy (3 CR/4 PR). The ORR in patients with anti-PD-1 as their most recent therapy was 35% (6/17; 95% CI, 14-62; 1 CR/5 PR); the ORR in patients with non-anti-PD-1 as their most recent therapy was 24% (4/17; 95% CI, 7-50; 2 CR/2 PR). Of 28 patients with a baseline and postbaseline assessment available, 25 (89%) had any reduction in target lesion size from baseline, and 12 (43%) had ≥50% reduction. Median DOR was 21.9 mo (range, 0.0+ to 26.1+) and an estimated 17% of responders remained in response ≥24 mo. Median PFS was 9.7 mo (95% CI, 5.1-14.7); 24-mo PFS rate was 21%. Median OS was 34.3 mo (95% CI, 25.7-NR); 24-mo OS rate was 76%. Conclusion: After additional follow-up, the combination of favezelimab + pembrolizumab continued to demonstrate manageable safety and antitumor activity in patients with heavily pretreated anti-PD-1-refractory cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. The phase 3 KEYFORM-008 study (NCT05508867) is being conducted to evaluate a coformulation of favezelimab and pembrolizumab in patients with anti-PD-1-refractory cHL.

PD-1 Expression in Lymphoma Cells Mediates Cellular Proliferation By Engaging Phosphatase SHP-1/SHP-2

Introduction: Despite the improved clinical outcomes with novel therapies in patients with chronic lymphocytic leukemia (CLL), Richter transformation (RT) of CLL remains a major clinical challenge. Our group showed a selective response (~40%) with the PD-1 blocking antibody pembrolizumab in patients with RT, particularly after prior exposure to ibrutinib (Ding et al, Blood, 2017). It has been established that PD-1 inhibits cytotoxic T-cell functions via the interaction with its ligands, PD-L1 and PD-L2. However, the role of PD-1 in tumor B-cells is understudied. Here we show the expression and functional implications of the PD-1 signaling axis in B-cell pathobiology. Methods: CLL-involved lymph node (LN) (n=26) and RT (with diffuse large B-cell lymphoma [DLBCL] histology) -involved LN (n=20) samples were tested for PD-1 expression by immunohistochemistry (IHC) (mouse clone NAT105, Abcam). Then, PD-1 expression was examined in 10 lymphoma cell lines and 1 CLL-like cell line (MEC-1) by both flow cytometry (FC) and Western blot (WB) analysis. PD-1 overexpression using pLEX-lentiviral packaging system (Thermo Scientific) was evaluated for its impact on in vitro cell cycle regulation and in vivo tumor growth. CRISPR/CAS9 mediated PD-1 knockdown evaluated on cell growth in MEC-1 and Mino cells. Role of PD-1 was further examined on the regulation of cell signaling pathways using human phospho kinase array kit (R&D) and WB analysis. Additionally, gene expression signatures were evaluated by RNA-seq using pLEX-lentiviral-PD-1 transfected DLBCL cell lines OCI-LY7 and OCI-LY19. Results: PD-1 expression was significantly increased in RT-LN compared to CLL-LN (mean ± SEM in RT vs. CLL, 30.6% ± 4.7% vs. 11.5% ± 2.8%, p<0.001) as determined by IHC. PD-1 expression was highest in patients with RT where the last prior CLL therapy was ibrutinib. To test the role of PD-1 in tumor B-cells, its expression was assessed in lymphoma and CLL cell lines. The expression of PD-1 was found to be variable by both FC and WB analysis, but at very low-levels in DLBCL cell lines OCI-LY7 and OCI-LY19. Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in OCI-LY7 and OCI-LY19 cells led to increased cell growth (1.4 and 1.9 fold, respectively, compared to original lines after 4 days of culturing of equal number of cells), which was further confirmed by cell cycle analysis which showed an increase in S phase by 20.4% (p<0.05) and 24.5% (p<0.05) in OCI-LY7 and OCI-LY19 cells, respectively. When the luciferase+ PD-1 overexpressing OCI-LY7 cells (1X10 6) were injected intravenously into NSG mice, increased tumor growth (p<0.01) was observed by bioluminescence imaging after 22 days of follow-up. PD-1 knockdown in MEC-1 and Mino cells (high basal PD-1 expression) led to significant inhibition of cell growth (85% and 79.5%, respectively, p<0.05). Using phospho-kinase array, an overall decrease of phosphorylation was detected on multiple sites of p53 (S392, S15, S46) and Chk-2 (T68) in PD-1 overexpressing OCI-LY7 and OCI-LY19 cell lines. This finding was further confirmed by WB analyses. In addition, decreased total p53 and increased phosphorylation on both SHP-1 and SHP-2 were found in PD-1 overexpressing OCI-LY7 and OCI-LY19 cell lines. SHP-1 (TPI-1) and SHP-1+SHP-2 (TPI-1+TNO155) inhibitor treatment promoted OCI-LY19 cell death and led to recovery of phosphorylation on ATM, Chk-2 and p53 in these cells. RNA sequencing data in PD-1 overexpressing OCI-LY7 and OCI-LY19 cells revealed increased expression of genes that promote cell cycle progression and DNA replication. Conclusion: Our data showed robust PD-1 expression in patients with Richter transformation from CLL to DLBCL. PD-1 overexpression in DLBCL lymphoma cell lines enhanced cell proliferation in vitro and in vivo. Further investigation identified that PD-1 modified the phosphorylation/function of SHP phosphatases and thereby regulated p53 pathways ( Figure 1). These findings indicate that RT with DLBCL cells have the ability to “hijack” the PD-1 pathway which results in downregulation of p53 mediated DNA repair. This novel finding provides for new strategies to further evaluate the interaction of PD-1 signals with DNA repair pathways and suggest potential novel targets for RT.

Pembrolizumab in Relapsed/Refractory Extranodal NK/T Cell Lymphoma and Mature T Cell Lymphoma: A Prospective Phase II Study

Background Pembrolizumab, a monoclonal antibody against programmed death 1 receptor (PD-1) has been shown to be efficacious in relapsed/refractory (R/R) extranodal NK/T cell lymphoma (ENKTL), with an overall response rate (ORR) up to 100% in retrospective case series 1. In R/R mature T cell lymphoma, an overall response rate of 33% has been demonstrated in a phase II study 2. In this prospective phase II study, we aim to evaluate the efficacy of pembrolizumab in patients with R/R mature T- and NK-cell lymphomas. Methods Patients with R/R mature T- and NK-cell lymphomas who failed at least one line of prior therapies were recruited. Pembrolizumab was administered at 200mg intravenously every three weeks for up to two years (35 cycles) unless there was intolerable toxicity or disease progression. PET/CT was performed after at least three cycles of treatment for response evaluation. The primary endpoints were the efficacy and safety of pembrolizumab treatment. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Response assessment was made according to published criteria 3. Survival was analyzed using Kaplan-Meier method. Statistical calculations were performed with SPSS Statistics version 28. Results ENKTL cohort: Ten women and six men at a median age of 57 (range: 41-83 years) were included. Fourteen patients had been treated with L-asparaginase-containing regimens. Ten patients (62.5%) had relapsed disease while six patients (37.5%) had refractory disease. Other relevant features included staging (I, N=3, 18.8%; II, N=3, 18.8%; IV, N=10, 62.5%). Response assessments were performed in all patients, and their best responses were as below: complete response (CR), N=7, 44%; partial response (PR), N=1, 6%; indeterminate response (IR), N=2, 13%; stable or progressive disease (SD/PD), N=6, 38%. At a median follow-up of 24 months (range 1-51 months), the median PFS was 10 months and the OS was 25 months (Figure 1). Adverse events included immunotherapy-related adverse events (IRAE) in five patients (31%), including two endocrine (one grade 1 and one grade 2 toxicity), two hepatic (both grade 2) and one gastrointestinal (grade 2). Haematological toxicity was mild with one patient having grade 1 anaemia. Mature T-cell lymphomas cohort: Four men and four women at a median age of 60 (range: 22-80 years) were included. Underlying diseases were peripheral T cell lymphoma, not otherwise specified (PTCL-NOS) (N=4, 50%), angioimmunoblastic T-cell lymphoma/PTCL with T-follicular helper phenotype (AITL/PTCL-TFH) (N=2, 25%), hepatosplenic T-cell lymphoma (HSTCL) (N=1, 12.5%) and systemic Epstein-Barr Virus (EBV)-positive T cell lymphoma of childhood (N=1, 12.5%). All patients had advanced-stage diseases (stage 3, N=1, 12.5%; stage 4, N=7, 87.5%). The median line of the prior regimens was 2 (range: 1-3). Response assessment was performed in seven patients, and their best responses were as follows: CR, N=1, 14.2%; IR, N=2, 28.4%; SD/PD, N=4, 57.1%. At a median follow-up period of nine months, the progression-free survival was 4 months and overall survival was 7 months. The only patient with a durable response was the one with systemic EBV-positive T-cell lymphoma of childhood. Toxicity included IRAE in two patients (endocrine, N=1, grade 1; pulmonary, N=1, grade 4) and haematological toxicity in three patients (37.5%) (anaemia, N=1, grade 2; neutropenia, N=1, grade 1; thrombocytopenia, N=1, grade 1). Conclusion Pembrolizumab is a safe and efficacious therapy for R/R ENKTL with potentially durable remission. In R/R mature T-cell lymphomas, the benefit of pembrolizumab treatment was limited. With the durable response observed in EBV-positive T-cell lymphoma of childhood, the use of pembrolizumab in EBV-positive T-cell lymphoma warrants further investigation. Reference: 1. Kwong YL, Chan TSY, Tan D, et al. PD1 blockade with pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing l-asparaginase. Blood 2017; 129 (17): 2437-2442 2. Barta SK, Zain J, MacFarlane AW 4 th, et al. Phase II Study of the PD-1 Inhibitor Pembrolizumab for the Treatment of Relapsed or Refractory Mature T-cell Lymphoma. Clin Lymphoma Myeloma Leuk 2019; 19(6): 356-364.e3 3. Cheson BD, Ansell S, Schwartz L, et al. Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. Blood 2016 Nov 24;128(21):2489-2496

Cost-Effectiveness of Neoadjuvant Pembrolizumab plus Chemotherapy Followed by Adjuvant Pembrolizumab in Patients with High-Risk, Early-Stage, Triple-Negative Breast Cancer in Switzerland.

This study assessed the cost-effectiveness of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab versus neoadjuvant chemotherapy plus placebo followed by adjuvant placebo for patients with high-risk, early-stage, triple-negative breast cancer (TNBC) from a Swiss third-party payer perspective over a lifetime horizon (51 years). A transition model with four health states (event-free, locoregional recurrence, distant metastasis, and death) was developed to assess the cost-effectiveness of pembrolizumab plus chemotherapy versus chemotherapy alone for the treatment of high-risk, early-stage TNBC. Data were utilized from the KEYNOTE-522 randomized controlled trial (ClinicalTrials.gov, NCT03036488). The incremental cost-effectiveness ratio (ICER) was calculated, which was reported as cost per life year or quality-adjusted life year (QALY) gained. A one-way deterministic sensitivity analysis, a probabilistic sensitivity analysis (PSA) and scenario analyses were conducted to assess the robustness of the model results. Base-case results estimated an ICER of 14,114 Swiss francs (CHF)/QALY for pembrolizumab plus chemotherapy versus chemotherapy alone. Results were most sensitive to changes in the extrapolation of event-free survival (EFS). All sensitivity and scenario analyses generated ICERs below the willingness-to-pay threshold of CHF100,000/QALY, and the PSA showed a 98.8% probability that the ICER would be below this threshold. Due to the limited follow-up period in the KEYNOTE-522 trial, EFS data were extrapolated over the lifetime horizon to inform transition probabilities. Extensive validation and scenario analyses ensured the results were robust. The model demonstrated that neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was cost-effective versus chemotherapy alone in patients with high-risk, early-stage TNBC in Switzerland.

Pembrolizumab Plus Chemotherapy Followed by Pembrolizumab in Patients With Early Triple-Negative Breast Cancer

In the phase 3 KEYNOTE-522 study, addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab significantly increased pathologic complete response (pCR) and event-free survival (EFS) vs neoadjuvant chemotherapy in patients with early triple-negative breast cancer. To evaluate efficacy and safety outcomes for patients enrolled in East/Southeast Asia (Asia) in KEYNOTE-522. KEYNOTE-522, a multicenter, double-blind, randomized clinical trial, enrolled 1174 patients between March 7, 2017, and September 13, 2018. For interim EFS and overall survival (OS) analyses (data cutoff, March 23, 2021), median follow-up was 39.8 months (range, 30.4-46.9 months) for pembrolizumab plus chemotherapy and 40.8 months (range, 30.1-46.9 months) for placebo plus chemotherapy. Data cutoff for pCR analysis was September 24, 2018. This secondary analysis included adults enrolled in Asia with newly diagnosed, previously untreated, nonmetastatic triple-negative breast cancer (tumor stage T1c and nodal stage N1-2 or tumor stage T2-4 and nodal stage N0-2) and Eastern Cooperative Oncology Group performance status of 0 to 1, regardless of programmed cell death ligand 1 (PD-L1) status. Patients were randomized 2:1 to 4 cycles of pembrolizumab (200 mg every 3 weeks) or placebo plus carboplatin and paclitaxel and another 4 cycles of pembrolizumab or placebo plus doxorubicin or epirubicin and cyclophosphamide before surgery. After definitive surgery, patients received pembrolizumab or placebo every 3 weeks for 9 cycles or until recurrence or unacceptable toxic effects. The main outcome was pCR (no evidence of primary tumor after neoadjuvant therapy or carcinoma in situ after neoadjuvant therapy and no regional lymph node involvement after neoadjuvant therapy) at the time of definitive surgery and EFS. A total of 216 of 1174 randomized patients (all female; median [range] age, 46.0 [24.0-71.0] years) were from Korea, Japan, Taiwan, and Singapore (136 in the pembrolizumab plus chemotherapy group and 80 in the placebo plus chemotherapy group). Of these patients, 104 (76.5%) in the pembrolizumab plus chemotherapy group and 60 (75.0%) in the placebo plus chemotherapy group had a tumor PD-L1 combined positive score of 1 or greater. Pathologic complete response was 58.7% (95% CI, 46.7%-69.9%) with pembrolizumab plus chemotherapy and 40.0% (95% CI, 26.4%-54.8%) with placebo plus chemotherapy; benefit was observed regardless of PD-L1 status. Thirteen patients (9.6%) in the pembrolizumab plus chemotherapy group and 20 patients (25.0%) in the placebo plus chemotherapy group had EFS events (hazard ratio, 0.35; 95% CI, 0.17-0.71). The 36-month EFS rate was 91.2% (95% CI, 85.0%-94.9%) with pembrolizumab plus chemotherapy and 77.2% (95% CI, 66.3%-85.0%) with placebo plus chemotherapy. Grade 3 to 4 treatment-related adverse events occurred in 109 patients (80.1%) receiving pembrolizumab plus chemotherapy and 64 patients (81.0%) receiving placebo plus chemotherapy. In this subgroup analysis of patients enrolled in Asia in KEYNOTE-522, neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab led to clinically meaningful improvements in pCR and EFS vs neoadjuvant chemotherapy alone. These findings support the use of neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab as a standard-of-care therapy for patients in Asian countries with early triple-negative breast cancer. ClinicalTrials.gov Identifier: NCT03036488.

CTIM-31. CLINICAL IMPACT OF ADDING PEMBROLIZUMAB TO STANDARD OF CARE CHEMORADIATION IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA

Abstract BACKGROUND Standard of care (SOC) for newly diagnosed glioblastoma includes radiotherapy plus temozolomide followed by 6 adjuvant cycles monthly temozolomide per the Stupp protocol. We report the secondary objectives of a single arm phase 2 study evaluating the clinical impact of the addition of immune check point inhibitor pembrolizumab to this standard therapy. METHODS Patients with histopathology proven glioblastoma (WHO 4) eligible to receive SOC were prospectively enrolled to received pembrolizumab 200 mg iv every 3 weeks for up to 35 doses, progression, development of dose limiting toxicity or withdrawal of consent. Patients also receive ferumoxytol steady state MRI scans at baseline, 4 weeks after the last day of standard of care stereotactic radiosurgery or chemoradiotherapy, every 9 weeks thereafter until suspected radiographic progression, and then within 4 weeks from suspected radiographic progression. Primary endpoints of the study were to test the sensitivity and specificity of ferumoxytol steady state imaging for response assessment in this cohort. Secondary objective includes Progression free (PFS) and Overall survival (OS) and toxicity. PFS and OS were analyzed using Kaplan-Meier method. RESULTS A total of 52 patients (19 F, 33 M; 43 IHD wt and 9 IDH mu; 25 MGMT gene methylated, 27 unmethylated) were enrolled and included. At a median Follow up of 14.3 months, median PFS was 10.7 m (95% CI:8.1-12.6) and median OS was 14.4 m (95%CI: 12.5-16.9). Two grade 3 or higher toxicities (bullous dermatitis and Steven-Johnson syndrome) were attributed to pembrolizumab. CONCLUSIONS Although, the addition of pembrolizumab to SOC was well tolerated in most patients, this study did not see any meaning clinical benefit in PFS or OS with the addition of pembrolizumab in patients with newly diagnosed glioblastoma. Analysis for the primary imaging endpoint is ongoing.

CTIM-05. RESULTS OF SAFETY LEAD IN OF PHASE II TRIAL OF COMBINATION OLAPARIB, TEMOZOLOMIDE, AND PEMBROLIZUMAB FOR PATIENTS WITH IDH-MUTANT GLIOMA

Abstract BACKGROUND Recurrent gliomas are universally fatal with few adequate treatment options. IDH-mutant gliomas may be susceptible to PARP inhibition, thus combination therapy using alkylating agents and checkpoint inhibition could be synergistic. METHODS This is an open label, phase II study of olaparib, temozolomide, and pembrolizumab for patients with recurrent IDH-mutant glioma, grade 2 or 3, with measurable enhancing disease per RANO. Patients received pembrolizumab 200mg IV on day 1 of each 21-day cycle. Oral olaparib 200mg twice daily and temozolomide 50mg/m2 daily were given days 1-7 of cycles 3-11. Here, we report the results of our safety lead in, consisting of the first 6 patients to complete cycle 3. RESULTS A total of seven patients were enrolled to the safety lead-in: 2 women; 5 patients with astrocytoma, 2 oligodendroglioma. Patients had a median age of 45 (range 29-63) and median KPS 90 (range 80-100). Median number of recurrences was 3.5 (range 1-5). All had received prior alkylating therapy and all but 1 patient had received prior RT. No patients were taking steroids at the time of enrollment. Six patients completed the dose-limiting toxicity (DLT) period without any DLTs. One patient experienced clinical progression on pembrolizumab monotherapy prior to the start of combination therapy and was thus replaced. No grade 3 or 4 toxicities were seen through the DLT period. The most common clinical toxicities at least possibly related to treatment were grade 1 and 2 fatigue (n = 4), nausea (n = 3) and constipation (n = 2). Hematological toxicities include grade 1 anemia (n = 2) and decreased platelet count (n = 1). CONCLUSIONS The combination of olaparib, temozolomide, and pembrolizumab was well tolerated in this cohort. Following completion of the safety lead-in, the trial was redesigned to minimize the length of pembrolizumab monotherapy and introduce combination therapy in cycle 1. Enrollment is ongoing. NCT05188508.

CTIM-24. REPEATED PERIPHERAL INFUSIONS OF ANTI-EGFRVIII CAR T CELLS IN COMBINATION WITH PEMBROLIZUMAB REMODELS THE TUMOR MICROENVIRONMENT IN DE NOVO GLIOBLASTOMA

Abstract Treatment efficacy with chimeric antigen receptor (CAR) T cell therapy in glioblastoma (GBM) is undermined by an immunosuppressive tumor microenvironment (TME). We previously showed that CAR T cell therapy targeting epidermal growth factor receptor variant III (EGFRvIII) produces anti-tumor activity against recurrent GBM and causes upregulation of programmed death-ligand 1 (PD-L1) in the TME. Here, we conducted a phase I trial to study the safety and tolerability of CART-EGFRvIII cells administered concomitantly with the PD-1 inhibitor pembrolizumab in patients with newly diagnosed, EGFRvIII+ GBM (n = 7). Treatment was well tolerated without incidence of dose-limiting toxicity. However, no signal of efficacy was detected with a median progression-free survival of 5.2 months (90% CI, 2.9 – 6.0 months) and overall survival of 11.8 months (90 % CI, 9.2 – 14.2 months). We aimed to elucidate reasons for limited efficacy through correlative analyses. Using BBZ qPCR, we found circulating CAR T cells in 5 out of 7 patients at the time of repeat resection, but only in one patient in the tumor. However, shared TCRs were found between the infusion product and the relapsed tumors, which could indicate an infiltration but lack of persistence of the CART. We further compared the tumor microenvironment of the tumors harvested before and after CAR+aPD1 administration using single cell RNAseq, and observed comparable proportions of the major immune cell subsets. However, the myeloid and T cells infiltrating the tumors significantly evolved, with more exhausted, regulatory and IFN-stimulated T cells at the relapse. At that time, the amount of IFN-stimulated T cells positively correlated with time from relapse to death. Together, these findings suggest that the combination of CAR T cells and PD-1 inhibition in GBM is safe and biologically active but, given the lack of efficacy, also indicate a need to consider alternative immunotherapeutic strategies. ClinicalTrials.gov registration: NCT03726515.

Health-Related Quality of Life with Pembrolizumab in Patients with Locally Advanced or Recurrent or Metastatic Cutaneous Squamous Cell Carcinoma: KEYNOTE-629.

At first interim analysis of KEYNOTE-629, health-related quality of life (HRQoL) with pembrolizumab was stable or improved over 48weeks in recurrent or metastatic (R/M) cutaneous squamous cell carcinoma (cSCC). HRQoL results from the second interim analysis in R/M or locally advanced (LA) cSCC are presented. Patients received pembrolizumab 200mg every 3weeks for ≤ 2years. Change in EORTC Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EQ-5D-5L scores were exploratory end points. Primary analysis was performed at week 12 to ensure adequate completion/compliance. Descriptive analyses were also conducted through weeks 48 and 75 for the LA and R/M cohorts, respectively. At data cutoff (29 July 2020), mean scores in the LA cohort (n = 47) were stable from baseline to week 12 for EORTC QLQ-C30 global health status (GHS)/quality of life (QoL) (-0.27 points [95% confidence interval (CI) -10.93 to 10.39]), physical functioning (-1.29 points [95% CI -8.77 to 6.19]), and EQ-5D-5L visual analog scale (2.06 [95% CI -7.70 to 11.82]). HRQoL remained stable through week 48 in the LA cohort; 76.6% and 74.5% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. HRQoL continued to show stability or improvement through week 75 in the R/M cohort (n = 99); 71.7% and 64.6% of patients had improved or stable GHS/QoL and physical functioning scores, respectively. Pembrolizumab has demonstrated antitumor activity and manageable safety. The current analysis shows pembrolizumab treatment preserved HRQoL. Collectively, these results support pembrolizumab as standard of care for LA or R/M cSCC. ClinicalTrials.gov, NCT03284424-September 15, 2017.

Favezelimab in Combination with Pembrolizumab in Patients with Anti-PD-1-Naive Relapsed or Refractory Classical Hodgkin Lymphoma: Updated Analysis of an Open-Label Phase 1/2 Study

Introduction: Programmed cell death protein 1 (PD-1) inhibitors such as pembrolizumab play an important role in the treatment of patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL), but treatment failure remains a significant challenge. Lymphocyte-activation gene 3 (LAG-3) is an immune checkpoint receptor that downregulates T-cell activity and plays a role in regulating T-cell function. Dual blockade of PD-1 and LAG-3 demonstrated antitumor activity in patients with advanced melanoma in the RELATIVITY-047 trial, which led to FDA approval in this setting. Favezelimab is a humanized IgG4 monoclonal antibody directed against LAG-3 that is being investigated in combination with pembrolizumab in patients with R/R hematologic malignancies in a multicohort phase 1/2 study (NCT03598608). Prior analyses of this study demonstrated that pembrolizumab 200 mg plus favezelimab 800 mg every 3 weeks (Q3W) exhibited sustained antitumor activity and acceptable safety in the cohort of patients with anti-PD-1-naive R/R cHL (cohort 1). We present updated results from this cohort. Methods: A safety lead-in phase to determine the recommended phase 2 dose (RP2D) was followed by a dose-expansion phase. Eligible patients were ≥18 years of age; had R/R cHL after autologous stem cell transplantation (ASCT), were ineligible for ASCT, or did not respond to salvage chemotherapy; had not received prior anti-PD-1 therapy; and had an ECOG performance status of 0 or 1. In the safety lead-in, patients received pembrolizumab 200 mg IV Q3W and favezelimab at a starting dose of 200 mg that was escalated to 800 mg IV Q3W using a modified toxicity probability interval method. In the dose-expansion phase, patients received pembrolizumab 200 mg Q3W plus favezelimab at the established RP2D of 800 mg Q3W for up to 35 cycles (~2 years). CT was performed every 12 weeks and PET at weeks 12 and 24. The primary end point was safety. Objective response rate (ORR) per IWG 2007 criteria by investigator review was a secondary end point. Duration of response (DOR) and progression-free survival (PFS) per IWG 2007 criteria by investigator review and overall survival (OS) were exploratory. Results: Thirty patients with anti-PD-1-naive cHL were enrolled in cohort 1. The median age was 40.5 years (range, 19-82), 17 patients (57%) were male, 16 (53%) had an ECOG performance status of 0, and 24 (80%) had received 3 or fewer prior lines of therapy. At data cutoff (March 2, 2023), 13 patients (43%) had completed 35 cycles of study treatment, 16 (53%) had discontinued treatment (10 [33%] progressive disease, 5 [17%] adverse event [AE], 1 [3%] noncompliance with study drug), and 1 (3%) was ongoing on treatment. The median time from first dose to data cutoff was 31.5 months (range, 24.0-43.2). Treatment-related AEs occurred in 27 patients (90%), of which the most common (≥20%) were hypothyroidism (27%), infusion-related reaction (23%), and fatigue (20%). Grade 3/4 treatment related AEs occurred in 9 patients (30%). Five patients (17%) discontinued treatment because of treatment-related AEs. No deaths due to treatment-related AEs were reported. AEs of clinical interest occurred in 20 patients (67%); 3 patients (10%) had grade 3 events (colitis, pneumonitis, severe skin reaction) and 1 patient (3%) had a grade 4 event (hepatitis). Of 5 patients who received allogeneic stem cell transplantation after discontinuation or completion of study treatment, 1 had a grade 3/4 AE (increased blood bilirubin) that was unrelated to study treatment and resolved. The ORR was 80% (n = 24; 95% CI, 61-92); 10 patients (33%) had a complete response and 14 (47%) had a partial response. Twenty-nine patients (97%) had any reduction in target lesions size from baseline, and 25 (83%) had a reduction of ≥50%. Median DOR was 17.0 months (range, 2.6-30.2), and an estimated 47% of responders remained in response ≥24 months. Median PFS was 19.4 months (95% CI, 9.0-28.5), and the 24-month PFS rate was 46%. Median OS was not reached (NR; 95% CI, NR-NR), and the 24-month OS rate was 93%. Conclusion: With additional follow-up, the combination of favezelimab and pembrolizumab continued to demonstrate sustained antitumor activity and manageable safety in patients with anti-PD-1-naive R/R cHL. Analyses are underway to identify biomarkers predictive of response to the combination of favezelimab and pembrolizumab. Further studies to investigate this combination are warranted.

601P Pembrolizumab in patients of Chinese descent with microsatellite instability-high/mismatch repair deficient advanced solid tumors: KEYNOTE-158

601P Pembrolizumab in patients of Chinese descent with microsatellite instability-high/mismatch repair deficient advanced solid tumors: KEYNOTE-158

Pembrolizumab monotherapy for non-small cell lung cancer (NSCLC): can patient stratification be improved in the UK Tayside population? A retrospective cohort study

ObjectivePembrolizumab is a programmed cell death protein-1 (PD-1) inhibitor used to treat advanced patients with non-small cell lung cancer (NSCLC) with a programmed cell death ligand-1 (PD-L1) tumour proportion score...

Single-dose 177Lu-PSMA-617 followed by maintenance pembrolizumab in patients with metastatic castration-resistant prostate cancer: an open-label, dose-expansion, phase 1 trial

Checkpoint inhibitors have been shown to have limited activity in patients with metastatic castration-resistant prostate cancer. We aimed to determine whether a single dose of lutetium-177 [177Lu]-prostate-specific membrane antigen (PSMA)-617 (177Lu-PSMA-617) followed by maintenance pembrolizumab was safe and could induce durable clinical benefit. We did an open-label, dose-expansion, phase 1 study at the University of California, San Francisco (San Fransisco, CA, USA). Eligible patients were men aged 18 years or older with progressive metastatic castration-resistant prostate cancer who had an Eastern Cooperative Oncology Group performance status of 0 or 1, had progression on one or more androgen signalling inhibitors, and at least three PSMA-avid lesions on 68Ga-PSMA-11 positron emission tomography. In part A, patients were enrolled sequentially to one of three schedules in which a single dose of 177Lu-PSMA-617 (7·4 GBq) was given intravenously 28 days before (schedule 1), concomitant with (schedule 2), or 21 days after (schedule 3) the start of maintenance intravenous pembrolizumab (200 mg every 3 weeks). In part B, 25 patients were enrolled using the recommended phase 2 schedule. The primary endpoint in part A was determination of the recommended phase 2 schedule, and in part B, the objective response rate. The analysis set included all patients who received at least one dose of pembrolizumab or 177Lu-PSMA-617. This study is registered with ClinicalTrials.gov, NCT03805594. Between Aug 8, 2019 and May 7, 2022, 43 male patients were enrolled (n=18 part A [six patients per schedule]; n=25 part B), with a median follow-up of 16·5 months (IQR 12·2-21·9). Schedule 1 was selected as the recommended phase 2 schedule for part B, on the basis of safety and feasibility of administration observed in part A. In part B, 14 (56%; 95% CI 35-76) of 25 patients had a confirmed objective response. Two (5%) of 43 patients had a treatment-related adverse event of grade 3 or worse (grade 3 arthritis in schedule 2, grade 3 pneumonitis in schedule 3). One serious adverse event (one death due to aspiration pneumonia) and no treatment-related deaths were observed. A single priming dose of 177Lu-PSMA-617 followed by pembrolizumab maintenance was safe and had encouraging preliminary activity in patients with metastatic castration-resistant prostate cancer. Prostate Cancer Foundation, National Cancer Institute, Novartis Pharmaceuticals, and Merck.

Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: cohort 2 of the randomized phase III THOR trial

Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved to treat locally advanced/metastatic urothelial carcinoma (mUC) in patients with susceptible FGFR3/2 alterations (FGFRalt) who progressed after platinum-containing chemotherapy. FGFR-altered tumours are enriched in luminal 1 subtype and may have limited clinical benefit from anti-programmed death-(ligand) 1 [PD-(L)1] treatment. This cohort in the randomized, open-label phase III THOR study assessed erdafitinib versus pembrolizumab in anti-PD-(L)1-naive patients with mUC. Patients ≥18 years with unresectable advanced/mUC, with select FGFRalt, disease progression on one prior treatment, and who were anti-PD-(L)1-naive were randomized 1 : 1 to receive erdafitinib 8 mg once daily with pharmacodynamically guided uptitration to 9 mg or pembrolizumab 200 mg every 3 weeks. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. The intent-to-treat population (median follow-up 33 months) comprised 175 and 176 patients in the erdafitinib and pembrolizumab arms, respectively. There was no statistically significant difference in OS between erdafitinib and pembrolizumab [median 10.9 versus 11.1 months, respectively; hazard ratio (HR) 1.18; 95% confidence interval (CI) 0.92-1.51; P= 0.18]. Median PFS for erdafitinib and pembrolizumab was 4.4 and 2.7 months, respectively (HR 0.88; 95% CI 0.70-1.10). ORR was 40.0% and 21.6% (relative risk 1.85; 95% CI 1.32-2.59) and median duration of response was 4.3 and 14.4 months for erdafitinib and pembrolizumab, respectively. 64.7% and 50.9% of patients in the erdafitinib and pembrolizumab arms had ≥1 grade 3-4 adverse events (AEs); 5 (2.9%) and 12 (6.9%) patients, respectively, had AEs that led to death. Erdafitinib and pembrolizumab had similar median OS in this anti-PD-(L)1-naive, FGFR-altered mUC population. Outcomes with pembrolizumab were better than assumed and aligned with previous reports in non- FGFR-altered populations. Safety results were consistent with the known profiles for erdafitinib and pembrolizumab in this patient population.

Effectiveness and safety of atezolizumab, nivolumab and pembrolizumab in metastatic non-small cell lung cancer

ObjectiveTo determine the effectiveness and safety of atezolizumab, nivolumab and pembrolizumab in patients with non-small cell lung cancer. MethodThis is a retrospective observational study including patients treated in second line and beyond. The effectiveness of treatment was assessed by means of overall survival and progression free survival measurements. Toxicity was described according to the Common Criteria for Adverse Event Terminology v5.0. ResultsThe study included 8 patients treated with atezolizumab,19 with nivolumab, and 16 with pembrolizumab. Median progression free survival with atezolizumab was 9.6 months (95%CI 2-17.2), 12.6 months (95%CI 6.9-18.2) for nivolumab, and 8.5 months (95%CI 0-19) for pembrolizumab. Median overall survival was 13.4 months (95%CI 6-20.9) for nivolumab. Both PFS and OS were statistically higher in patients with grade 0-1 metastasis in the case of nivolumab, and in ECOG 0-1 patients for pembrolizumab. Median overall survival was not reached for atezolizumab or pembrolizumab. Around 85% of patients suffered adverse effects of some degree. Two of the patients treated with nivolumab developed vitiligo. Overall survival of both was higher than 2.5 years. ConclusionsFor the patients included in the sample, nivolumab was less effective in those with two or more metastases; the effectiveness of pembrolizumab was lower in ECOG-2 patients. Vitiligo was related to a more durable response to treatment.