Pembrolizumab-treated Patients Research Articles

Efficacy and safety of pembrolizumab in patients with advanced endometrial cancer: a systematic review and meta-analysis.

This meta-analysis evaluated pembrolizumab monotherapy and combination therapy's efficacy and safety in recurrent or advanced endometrial cancer (EC). We utilized PubMed, Embase, Cochrane Library, and Web of Science databases to identify clinical trials that were used to search literature from July 2013 to July 2023 to evaluate the efficacy and safety of pembrolizumab in patients with advanced EC. Eight studies with 2,742 patients were included. Outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), complete remission (CR), and adverse events (AEs); a subgroup analysis was carried out based on combination treatment regimens. Quality assessment of the included studies was conducted using the Cochrane Risk of Bias Tool, the Newcastle-Ottawa Scale (NOS), and the Joanna Briggs Institute (JBI) critical appraisal checklist. Pembrolizumab reduced progression risk [hazard ratio (HR): 0.53; 95% confidence interval (CI): 0.44, 0.63; p < 0.00001] and death risk when combined with lenvatinib (HR: 0.67; 95% CI: 0.59, 0.76; p < 0.00001). Pembrolizumab monotherapy and lenvatinib combination achieved higher ORR (OR: 3.61; 95% CI: 2.12, 6.13; p < 0.00001) and CR rates (OR: 2.7; 95% CI: 1.59, 4.57; p < 0.05) than controls. Single-arm studies: 8% CR and 4% PR in pembrolizumab-treated patients. Pooled AE incidence: 86%, with 43% grade 3/4. Two randomized controlled trials (RCTs) found that the pembrolizumab group had a higher incidence of grade 3 or 4 AEs compared to the control group (OR: 2.23; 95% CI: 1.23, 4.04; p = 0.008). Pembrolizumab monotherapy or combination significantly improves survival in recurrent or advanced EC and has manageable toxicity albeit with a relatively high incidence of treatment-related AEs.

Increased PD-1 expression in livers associated with PD-1-antibody-induced hepatotoxicity

Vanishing bile duct syndrome (VBDS) is a serious drug induced liver injury characterized by chronic cholestasis and loss of intrahepatic bile ducts. VBDS has been reported also following checkpoint inhibitor treatment. We compared CD3 + , CD4 + , CD8 + , CD20 + , CD57 + , PD-1 + and PD-L1 + lymphocyte infiltrates in liver biopsies of patients that encountered VBDS (n = 2) or hepatotoxicity (n = 3) after pembrolizumab (n = 4) or nivolumab (n = 1) treatment with samples from normal liver (n = 10), non-alcohol steatohepatitis (NASH, n = 10), primary biliary cholangitis (PBC, n = 10) or pembrolizumab-treated patients without adverse events (n = 2). Notably, none of the cancer patients had primary nor metastatic liver tumors. We also studied direct growth effects of pembrolizumab on primary human intrahepatic biliary epithelial cells (HIBEpiC) in vitro. Liver sections of all checkpoint inhibitor- treated patients exhibited significantly higher CD3 + infiltration than normal livers, and significantly higher PD-L1 + , CD4 + and CD8 + infiltration, than other groups. PD-1 + infiltration was significantly increased in livers of patients with severe hepatic adverse event. CD57 + infiltration was similar in normal livers, NASH- and PBC groups, but highly increased in the checkpoint inhibitor-treated patients. Immune cell infiltrates were similar between NASH and normal livers. PBC samples had significantly higher CD3 + , CD4 + , CD8 + and CD20 + infiltrates than normal livers. HIBEpiC express PD-L1 but pembrolizumab did not affect their viability in vitro. Our findings suggest that VBDS is not due to direct cytotoxicity of checkpoint inhibitors and that the immunological attack against livers induced by these drugs is different from other cholestatic liver conditions.Biological insight: Checkpoint inhibitors upregulate PD-1 and PD-L1, as well as cytotoxic CD57 + cells in the non-cancerous liver tissues and this may be associated with checkpoint inhibitor-induced hepatotoxicity.

Cost-effectiveness analysis of PD-L1 testing associated with pembrolizumab for first-line treatment of advanced non-small cell lung cancer in China.

Lung cancer is the leading cause of cancer-related deaths in China, and pembrolizumab shows differential efficacy in advanced non-small cell lung cancer (NSCLC) with different PD-L1 expression levels. To assess the cost-effectiveness of PD-L1 testing associated with pembrolizumab for first-line treatment of NSCLC from the perspective of Chinese healthcare system. Over a lifetime horizon, a three-state partitioned survival model was developed to assess the cost-effectiveness of PD-L1 testing and no PD-L1 testing. In the PD-L1 testing group, patients were stratified by PD-L1 tumor proportion score ≥ 50%, 1-49%, or < 1% and received pembrolizumab monotherapy, pembrolizumab plus chemotherapy, or chemotherapy alone, respectively. In the non-PD-L1 testing group, all patients received pembrolizumab plus chemotherapy. Model inputs were obtained from published literature and a healthcare price database, and clinical outcomes from two randomized clinical trials were used. The net monetary benefit (NMB) was estimated for the PD-L1 testing group versus the non-PD-L1 testing group. Deterministic and probabilistic sensitivity analyses, and scenario analyses were conducted to assess robustness of results. Using PD-L1 testing to guide treatment led to cost savings of $49,392.7 and a reduction in quality-adjusted life years (QALYs) of 0.234, resulting in a positive NMB of $46,421.7 at a willingness-to-pay (WTP) threshold of $12,680.8/QALY (GDP per capita in China, 2023). Findings were robust across sensitivity and scenario analyses. Using PD-L1 testing to guide first-line pembrolizumab treatment in patients with advanced NSCLC is a cost-effective strategy at a WTP threshold of $12,680.8/QALY for China.

Hepatobiliary Adverse Events Associated with Pembrolizumab: A Pharmacovigilance Study from the FDA Adverse Event Reporting System (FAERS) Database

Background: Immuno-oncology has transformed cancer treatment, with immune checkpoint inhibitors (ICIs) like pembrolizumab playing a key role. While highly effective, these therapies can also cause immune-related adverse events. This study examines the incidence and characteristics of hepatobiliary adverse events (AEs) linked to pembrolizumab, using data from the FDA Adverse Event Reporting System (FAERS). Objective: To investigate the rates of hepatobiliary AEs linked to pembrolizumab, providing insights into the risks of liver and biliary system damage in patients prescribed pembrolizumab. Methods: This study utilized the FAERS database via OpenVigil 2.1. Adverse events (AEs) related to pembrolizumab were identified and compared to those associated with other drugs. Reporting odds ratios (RORs) were calculated to assess the likelihood of hepatobiliary AEs in pembrolizumab-treated patients. Results: In total, 594 hepatic AEs and 181 biliary AEs were identified. Significant hepatic AEs included elevated ALT (ROR 3.00, 95% CI: 2.685–3.351), hepatotoxicity (ROR 6.436, 95% CI: 5.72–7.242), and hepatic cytolysis (ROR 15.721, 95% CI: 13.854–17.84). Immune-mediated hepatitis exhibited the highest ROR of 346.716 (95% CI: 303.568–395.997). For biliary AEs, cholangitis (ROR 19.597, 95% CI: 16.852–22.791) and sclerosing cholangitis (ROR 24.735, 95% CI: 19.888–30.763) were the most prominent. Conclusions: Pembrolizumab is associated with a significant risk of hepatobiliary adverse events, particularly immune-mediated hepatitis and cholangitis. The elevated RORs for these conditions highlight the importance of close monitoring and managing liver and biliary functions in patients undergoing pembrolizumab checkpoint blockade. These findings emphasize the need for personalized treatment strategies to mitigate risks and optimize outcomes in cancer immunotherapy, especially for those with preexisting hepatobiliary conditions.

Neoadjuvant and adjuvant pembrolizumab in advanced high-grade serous carcinoma: the randomized phase II NeoPembrOV clinical trial

This open-label, non-comparative, 2:1 randomized, phase II trial (NCT03275506) in women with stage IIIC/IV high-grade serous carcinoma (HGSC) for whom upfront complete resection was unachievable assessed whether adding pembrolizumab (200 mg every 3 weeks) to standard-of-care carboplatin plus paclitaxel yielded a complete resection rate (CRR) of at least 50%. Postoperatively patients continued assigned treatment for a maximum of 2 years. Postoperative bevacizumab was optional. The primary endpoint was independently assessed CRR at interval debulking surgery. Secondary endpoints were Completeness of Cytoreduction Index (CCI) and peritoneal cancer index (PCI) scores, objective and best response rates, progression-free survival, overall survival, safety, postoperative morbidity, and pathological complete response. The CRR in 61 pembrolizumab-treated patients was 74% (one-sided 95% CI = 63%), exceeding the prespecified ≥50% threshold and meeting the primary objective. The CRR without pembrolizumab was 70% (one-sided 95% CI = 54%). In the remaining patients CCI scores were ≥3 in 27% of the standard-of-care group and 18% of the investigational group and CC1 in 3% of the investigational group. PCI score decreased by a mean of 9.6 in the standard-of-care group and 10.2 in the investigational group. Objective response rates were 60% and 72%, respectively, and best overall response rates were 83% and 90%, respectively. Progression-free survival was similar with the two regimens (median 20.8 versus 19.4 months in the standard-of-care versus investigational arms, respectively) but overall survival favored pembrolizumab-containing therapy (median 35.3 versus 49.8 months, respectively). The most common grade ≥3 adverse events with pembrolizumab-containing therapy were anemia during neoadjuvant therapy and infection/fever postoperatively. Pembrolizumab was discontinued prematurely because of adverse events in 23% of pembrolizumab-treated patients. Combining pembrolizumab with neoadjuvant chemotherapy is feasible for HGSC considered not completely resectable; observed activity in some subgroups justifies further evaluation to improve understanding of the role of immunotherapy in HGSC.

Difference of oncological efficacy between two immune checkpoint inhibitors following first-line platinum-based chemotherapy in patients with unresectable, metastatic, advanced urothelial carcinoma: a multicenter real-world Japanese cohort.

Maintenance avelumab is currently recommended for patients with unresectable and/or metastatic (mUC) achieving at least stable disease (SD) on first-line platinum-based chemotherapy (1L-CT). Pembrolizumab is an alternative therapeutic avenue for this patient cohort in clinical practice. We investigated real-world data, focusing on the correlation between response to 1L-CT and oncological efficacy of subsequent immune checkpoint inhibitor (ICI) therapy with avelumab or pembrolizumab. A multicenter database registered 626 patients with mUC diagnosed from 2008-2023; among these, 175 receiving 2-6 cycles of 1L-CT followed by ICI therapy. Patients were categorized based on response to 1L-CT using the Response Evaluation Criteria in Solid Tumors (v1.1). Objective response rateonICI, progression to ICI-free survival (ICI-PFS), and overall survival from start of 1L-CT were compared between avelumab-treated and pembrolizumab-treated patients in each response subgroup. ICI-PFS was significantly longer in patients achieving partial response on 1L-CT and subsequently receiving pembrolizumab compared to those receiving avelumab. Notably, patients achieving SD on 1L-CT and subsequently receiving pembrolizumab manifested significantly higher objective response rate (14% and 41%, respectively) and prolonged ICI-PFS relative to those receiving avelumab. In contrast, overall survival did not delineate difference between patients treated with avelumab versus pembrolizumab. Similar findings were discerned in the subanalysis of patients having favorable SD (tumor shrinkage, from -29 to 0%) and unfavorable SD (tumor enlargement, from + 1 to + 19%) on 1L-CT. Our study provides real-world evidence regarding difference of oncological efficacy between maintenanceavelumab and subsequentpembrolizumab in patients with mUC who achieved partial response or SD on 1L-CT.

FDA Approval Summary: Enfortumab Vedotin plus Pembrolizumab for Cisplatin-Ineligible Locally Advanced or Metastatic Urothelial Carcinoma.

On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59-76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.

Prognostic impact of radiological tumor burden in patients with metastatic urothelial carcinoma treated with pembrolizumab

Prognostic impact of radiological tumor burden in patients with metastatic urothelial carcinoma treated with pembrolizumab

Efficacy of perioperative pembrolizumab treatment in patients with resectable metastases from kidney cancer: The PE-PE study.

TPS495 Background: Radical metastasectomy and other local treatment strategies (including definitive radiotherapy, RT) can be carried out instead of systemic therapies for selected metastatic renal cell carcinoma (mRCC) patients (pts) with the aim of healing the patient even in an advanced disease stage. Recent data suggests a potential benefit from perioperative immunotherapy with immune checkpoint inhibitors (ICIs), as shown by the significant efficacy of adjuvant pembrolizumab in the M1 NED subgroup of the KEYNOTE-564 trial. Moreover, important activity of a short course of pembrolizumab has been demonstrated also in oligometastatic mRCC pts in combination with stereotactic ablative RT in the RAPPORT study. To date, no randomized trial has evaluated the concomitant use of pembrolizumab with surgery or definitive RT in mRCC compared to local therapy alone, which is the aim of our study. Methods: PE-PE study (NCT05578664) is a randomized, open-label, multicenter, phase 2 study evaluating the efficacy of pembrolizumab in delaying tumor progression in pts with oligometastatic mRCC who are candidates for radical surgery and/or definitive RT of the metastases. Eligible pts should have undergone previous nephrectomy and have maximum three metastases considered eligible for radical metastasis directed therapy (MDT; either metastasectomy or RT) and new disease must have appeared within 5 years from prior nephrectomy or metastasectomy. Pts will be randomized 2:1 to receive pembrolizumab at flat dose of 400 mg every six weeks for a total of 9 cycles (one year of therapy) and MDT from day 21 to day 42 of the cycle 1 (ARM A); or MDT alone within 42 days from randomization (ARM B). The primary endpoint is to assess the relapse free survival (RFS) defined as the length of time from randomization to the appearance of radiological progression in pts who receive pembrolizumab compared to those who do not. Secondary endpoints include: distant RFS (defined as the time from randomization to the appearance of distant metastases other those treated with surgery or RT), overall survival, and safety. Exploratory biomarkers analysis will be performed. The trial is actively recruiting. Clinical trial information: NCT05578664 .

Comparative Effectiveness of Neoadjuvant Pembrolizumab Versus Cisplatin-based Chemotherapy or Upfront Radical Cystectomy in Patients with Muscle-invasive Urothelial Bladder Cancer

Comparative Effectiveness of Neoadjuvant Pembrolizumab Versus Cisplatin-based Chemotherapy or Upfront Radical Cystectomy in Patients with Muscle-invasive Urothelial Bladder Cancer

Comprehensive molecular characterization to predict immunotherapy response in advanced biliary tract cancer: a phase II trial of pembrolizumab.

Immune checkpoint inhibitors (ICIs) are effective in a subset of patients with metastatic solid tumors. However, the patients who would benefit most from ICIs in biliary tract cancer (BTC) are still controversial. We molecularly characterized tissues and blood from 32 patients with metastatic BTC treated with the ICI pembrolizumab as second-line therapy. All patients had microsatellite stable (MSS) type tumors. Three of the 32 patients achieved partial response (PR), with an objective response rate (ORR) of 9.4% (95% confidence interval [CI], 2.0-25.2) and nine showed stable disease (SD), exhibiting a disease control rate (DCR) of 37.5% (95% CI, 21.1-56.3). For the 31 patients who had access to PD-1 ligand 1 (PD-L1) combined positive score (CPS) testing (cut-off value ≥1%), the ORR was not different between those who had PD-L1-positive (PD-L1+; 1/11, 9.1%) and PDL1-(2/20, 10.0%) tumors (p = 1.000). The tumor mutational burden (TMB) of PD-L1+ BTC was comparable to that of PD-L1-BTC (p = 0.630). TMB and any exonic somatic mutations were also not predictive of pembrolizumab response. Molecular analysis of blood and tumor samples demonstrated a relatively high natural killer (NK) cell proportion in the peripheral blood before pembrolizumab treatment in patients who achieved tumor response. Moreover, the tumors of these patients presented high enrichment scores for NK cells, antitumor cytokines, and Th1 signatures, and a low enrichment score for cancer-associated fibroblasts. This study shows the molecular characteristics associated with the efficacy of pembrolizumab in BTC of the MSS type.

PD-L1 expression guidance on sintilimab versus pembrolizumab with or without platinum-doublet chemotherapy in untreated patients with advanced non-small cell lung cancer (CTONG1901): A phase 2, randomized, controlled trial

No direct comparison has been performed between different programmed cell death-1 (PD-1) inhibitors for first-line treatment in patients with advanced non-small cell lung cancer (NSCLC). The feasibility of using PD-L1-expression-guided immunotherapy remains unknown. In this open-label, phase 2 study (NCT04252365), patients with advanced NSCLC without EGFR or ALK alterations were randomized (1:1) to receive sintilimab or pembrolizumab monotherapy (PD-L1 expression ≥ 50%), or sintilimab or pembrolizumab plus platinum-based chemotherapy (PD-L1 expression < 50%). The sample size was calculated by optimal two-stage design. The primary endpoint was the objective response rate (ORR). The study included 71 patients (sintilimab arms, n = 35; pembrolizumab arms, n = 36) and met its primary endpoint, with a confirmed ORR of 51.4% (18/35) in the sintilimab arms. The confirmed ORR (95% confidence interval) was 46.2% (19.2%, 74.9%) and 42.9% (17.7%, 71.1%) for patients treated with sintilimab and pembrolizumab monotherapy; and 54.5% (32.2%, 75.6%) and 45.4% (24.4%, 67.8%) for those treated with sintilimab- and pembrolizumab-based combination therapies. The median progression-free survival was 6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies. The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients, respectively, in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies. Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies. However, the incidence of rash was higher with sintilimab than pembrolizumab monotherapy. This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC. Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

Immunologic Signatures of Peripheral Blood T Cells Reveal the Outcome of p53MVA Vaccine and Pembrolizumab Treatment in Patients with Advanced Ovarian Cancer.

Our previous studies indicated that p53-reactive T cells were associated with clinical benefit in patients with advanced ovarian cancer who were treated with p53-expressing modified vaccinia Ankara (p53MVA) vaccine and gemcitabine chemotherapy. To replace chemotherapy with an approach that will enhance vaccine efficacy and antitumor immunity, we treated patients with p53MVA in combination with PD-1 checkpoint blocker, pembrolizumab. We also attempted to further characterize the activation status of T cells prior to vaccination and during treatment. Patients received up to three triweekly vaccinations concurrent with pembrolizumab, followed by pembrolizumab monotherapy at 3-week intervals. Correlative studies analyzed peripheral blood T-cell phenotypes and profiles of immune function gene expression. We observed 6/28 (21%) patients with a clinical benefit to therapy, including 3 partial responses (PR) and 3 patients with stable disease (SD) for 6+ months. The median progression-free survival was 1.8 months (95% confidence interval: 1.7-3.8) and median overall survival was 15.1 months (9.4-30.4). Two patients remain progression-free at 28 and 33 months. Of the 18 patients evaluable in correlative studies, 6 were immunologic responders of whom 5 had clinical benefit (3 PR, 2 SD). Immunologic non-responders expressed in pretreatment peripheral blood mononuclear cell samples high levels of mRNA for multiple molecules associated with terminally differentiated T cells. p53MVA/pembrolizumab immunotherapy showed promising antitumor activity in patients who demonstrated functionally competent peripheral blood T cells. Detection of markers of terminally differentiated T cells before treatment may identify patients unlikely to respond to p53MVA/pembrolizumab. The activity of a combination immunotherapy of p53 vaccine and PD-1 checkpoint blockade in patients with platinum-resistant ovarian cancer was evaluated in a phase II trial. Clinical benefit was correlated with the responsive immune status of patients before and during the treatment, defining potential predictive markers for immune therapy.

Plasma Immune Proteins and Circulating Tumor DNA Predict the Clinical Outcome for Non-Small-Cell Lung Cancer Treated with an Immune Checkpoint Inhibitor

Immunotherapy has altered the therapeutic landscape for patients with non-small-cell lung cancer (NSCLC). The immune checkpoint inhibitor pembrolizumab targets the PD-1/PD-L1 signaling axis and produces durable clinical responses, but reliable biomarkers are lacking. Using 115 plasma samples from 42 pembrolizumab-treated patients with NSCLC, we were able to identify predictive biomarkers. In the plasma samples, we quantified the level of 92 proteins using the Olink proximity extension assay and circulating tumor DNA (ctDNA) using targeted next-generation sequencing. Patients with an above-median progression-free survival (PFS) had significantly higher expressions of Fas ligand (FASLG) and inducible T-cell co-stimulator ligand (ICOSLG) at baseline than patients with a PFS below the median. A Kaplan–Meier analysis demonstrated that high levels of FASLG and ICOSLG were predictive of longer PFS and overall survival (OS) (PFS: 10.83 vs. 4.49 months, OS: 27.13 vs. 18.0 months). Furthermore, we identified a subgroup with high expressions of FASLG and ICOSLG who also had no detectable ctDNA mutations after treatment initiation. This subgroup had significantly longer PFS and OS rates compared to the rest of the patients (PFS: 25.71 vs. 4.52 months, OS: 34.62 vs. 18.0 months). These findings suggest that the expressions of FASLG and ICOSLG at baseline and the absence of ctDNA mutations after the start of treatment have the potential to predict clinical outcomes.

Immune-related adverse events of anti-PD-1 immune checkpoint inhibitors: a single center experience.

Immune checkpoint inhibitors (ICIs) stimulate antitumor immune responses and, in parallel, they might trigger autoimmune and other immunopathological mechanisms eventually leading to immune-related adverse events (irAE). In our study, we assessed patients with malignancies who underwent anti-PD-1 treatment at the University of Debrecen, Clinical Center. Between June 2017 and May 2021, 207 patients started ICI treatment at our university. A total of 157 patients received nivolumab and 50 were treated with pembrolizumab. We looked for factors associated with the development of irAEs. In addition to correlation studies, we performed binary logistic regression analysis to determine, which factors were associated with irAEs. We also performed Forward Likelihood Ratio (LR) analysis to determine independent prognostic factors. At the time of data analysis, the mean duration of treatment was 2.03 ± 0.69 years. ROC analysis determined that 9 or more treatment cycles were associated with a significantly higher risk of irAEs. A total of 125 patients received ≥9 treatment cycles. Three times more patients were treated with nivolumab than pembrolizumab. Of the 207 patients, 66 (32%) developed irAEs. Among the 66 patients who developed irAEs, 36 patients (55%) developed one, 23 (35%) developed two, while 7 (10%) developed three irAEs in the same patient. The most common irAEs were thyroid (33 cases), dermatological (25 cases), pneumonia (14 cases) and gastrointestinal complications (13 cases). Patients who developed irAEs received significantly more treatment cycles (21.8 ± 18.7 versus 15.8 ± 17.4; p=0.002) and were younger at the start of treatment (60.7 ± 10.8 versus 63.4 ± 10.1 years; p=0.042) compared to patients without irAEs. Pembrolizumab-treated patients developed more but less severe irAEs compared to those receiving nivolumab. ICI treatment is very effective, however, irAEs may develop. These irAEs might be related to the number of treatment cycles and the type of treated malignancy.

Stress Keratin 17 Is a Predictive Biomarker Inversely Associated with Response to Immune Check-Point Blockade in Head and Neck Squamous Cell Carcinomas and Beyond.

Low response rates in immune check-point blockade (ICB)-treated head and neck squamous cell carcinoma (HNSCC) drive a critical need for robust, clinically validated predictive biomarkers. Our group previously showed that stress keratin 17 (CK17) suppresses macrophage-mediated CXCL9/CXCL10 chemokine signaling involved in attracting activated CD8+ T cells into tumors, correlating with decreased response rate to pembrolizumab-based therapy in a pilot cohort of ICB-treated HNSCC (n = 26). Here, we performed an expanded analysis of the predictive value of CK17 in ICB-treated HNSCC according to the REMARK criteria and investigated the gene expression profiles associated with high CK17 expression. Pretreatment samples from pembrolizumab-treated HNSCC patients were stained via immunohistochemistry using a CK17 monoclonal antibody (n = 48) and subjected to spatial transcriptomic profiling (n = 8). Our findings were validated in an independent retrospective cohort (n = 22). CK17 RNA expression in pembrolizumab-treated patients with various cancer types was investigated for predictive significance. Of the 48 patients (60% male, median age of 61.5 years), 21 (44%) were CK17 high, and 27 (56%) were CK17 low. A total of 17 patients (35%, 77% CK17 low) had disease control, while 31 patients (65%, 45% CK17 low) had progressive disease. High CK17 expression was associated with a lack of disease control (p = 0.037), shorter time to treatment failure (p = 0.025), and progression-free survival (PFS, p = 0.004), but not overall survival (OS, p = 0.06). A high CK17 expression was associated with lack of disease control in an independent validation cohort (p = 0.011). PD-L1 expression did not correlate with CK17 expression or clinical outcome. CK17 RNA expression was predictive of PFS and OS in 552 pembrolizumab-treated cancer patients. Our findings indicate that high CK17 expression may predict resistance to ICB in HNSCC patients and beyond.

A phase 2 study of alrizomadlin, a novel MDM2/p53 inhibitor, in combination with pembrolizumab for treatment of patients with malignant peripheral nerve sheath tumor (MPNST).

e14627 Background: MPNST is a rare and aggressive soft tissue malignancy accounting for 10% of all soft tissue sarcomas. This disease is characterized by high risk of local recurrence and distant metastasis, and there is no current effective standard of care treatment option for patients with MPNST, with the only curative option of complete resection. Therefore, further treatment options are warranted. Investigational mouse double minute 2 (MDM2) inhibitor alrizomadlin restores TP53 function, activating p53-mediated apoptosis in tumor cells. Alrizomadlin also functions as a host immunomodulator and may restore antitumor activity in patients with MPNST that progressed on PD-1/PD-L1 inhibitors. Methods: This US/Australian multicenter trial evaluated alrizomadlin combined with PD-1 inhibitor pembrolizumab in patients with MPNST that progressed on available therapy or in those for whom therapy was unavailable. ECOG performance status was between 0-2 for eligible patients. Alrizomadlin 150 mg was administered orally every other day for 2 consecutive weeks, with 1 week off, and pembrolizumab 200 mg intravenously for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 12, 2022, preliminary clinical results are reported for 24 patients with MPNST, of whom 16 were male, with a median (range) age of 35 (14-73) years. Treatment (alrizomadlin or pembrolizumab)-related adverse events of any grade (&gt;10%) were reported in 18 patients. They included nausea (41.7%), vomiting and anemia (37.5% each), fatigue and diarrhea (33.3% each), thrombocytopenia (25.0%), and decreased leukocyte and lymphocyte counts (12.5% each). A total of 12.5% of patients reported treatment-related serious adverse events, including colitis, abdominal pain, diarrhea, and pericardial effusion. Among17 efficacy evaluable patients, the clinical benefit rate, as defined by the combination of overall response rate and stable disease for ≥ 4 cycles, was 53% per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v.1.1) and iRECIST. The median (range) treatment duration was 10 (4-20) cycles. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and demonstrates meaningful clinical benefit in patients with MPNST for whom standard of care therapy is unavailable. Internal study identifiers: APG-115-US-002. Clinical trial information: NCT03611868 .

Patterns of weight change and overall survival (OS) during first-line pembrolizumab treatment in patients with non-small cell lung cancer (NSCLC).

e21094 Background: Cancer-associated cachexia and weight change from treatment-related side effects profoundly influence treatment outcomes for patients with NSCLC. Limited data are available to compare the association between weight change and OS for patients with NSCLC treated with pembrolizumab alone or combined with chemotherapy. Therefore, we evaluated the change in weight after the first cycle of pembrolizumab-based treatments and its association with OS in patients with metastatic NSCLC. Methods: This retrospective study included 306 patients with NSCLC treated with a first line pembrolizumab-based regimen at Ohio State University from 2018-2021. Baseline characteristics were collected within seven days before cycle one treatment. Percent of weight change (PWC) was calculated as (cycle two weight – baseline weight)/baseline weight x 100%. Severe weight loss was defined as ≥75th percentile (PWC ≤-3.5%). Kruskal Wallis test was used to compare the significance of median PWC between treatment groups. Cox proportional-hazards models were used to test associations with survival. Results: The median age was 64.0 (IQR 56.7-72.6) years. The median baseline BMI was 26.1 (IQR 22.4-30.7). There was no difference between the median PWCs of patients treated with pembrolizumab monotherapy (-1.2%, IQR -3.7-0.8%) vs. pembrolizumab with chemotherapy (-1.0%, IQR -3.4-0.6%), p = 0.587. The patients whose weight remained stable (PWC -1% to 1%, n = 87 (28.4%)) had the highest median OS at 45.6 months (95% CI 27.6 – not reached); while those with severe weight loss (PWC ≤-3.5%, n = 78 (25.5%)) and weight gain (PWC ≥1%, n = 65 (21.2%)) had significantly decreased survival with median OS 15.6 (95% CI 9.3-20.9) and 16.3 (95% CI 10.1-25.6) months respectively, overall model p-value &lt; 0.001. The PWC remained significantly associated with OS after adjusting for performance status, PD-L1, and treatment with p &lt; 0.001 (Table 1). Conclusions: For patients with metastatic NSCLC treated with first line pembrolizumab-based regimen, similar PWCs were seen between patients treated with pembrolizumab alone or combined with chemotherapy. Regardless of treatment, weight gain and severe weight loss after the first cycle of treatment were associated with reduced OS. Further in-depth analysis is warranted to investigate the potential causes of weight changes, especially for patients with positive PWC. [Table: see text]

Correlation between immune-related adverse events and long-term outcomes in pembrolizumab-treated patients with unresectable hepatocellular carcinoma: A retrospective study.

Although immune checkpoint inhibitor (ICI) therapy has improved the prognosis of unresectable hepatocellular carcinoma (HCC), it has also resulted in unique immune-related adverse events (irAEs). The relationship between irAE and treatment outcomes in ICI-treated unresectable HCC patients remains unknown. To elucidate the correlation between immune-related toxic effects and prognosis in patients with unresectable HCC treated with pembrolizumab. From March 2019 to February 2021, a total of 190 unresectable HCC (Barcelona Clinic Liver Cancer C) patients receiving pembrolizumab treatment were retrospectively reviewed. Overall survival (OS) was the primary endpoint, while objective response rate (ORR), disease control rate (DCR), and time to progression (TTP) were secondary evaluation indexes. We assessed demographics, irAEs, and outcomes by retrospective review. One hundred and forty-three males and 47 females were included in the study. The ORR and DCR were 12.1% (23/190) and 52.1% (99/190), respectively. The median OS was 376 d [95% confidence interval (CI): 340-411 d] and the median TTP was 98 d (95%CI: 75-124 d). The overall incidence of treatment-related adverse events was 72.6% (138/190) and 10.0% of them were severe irAEs (grade ≥ 3). Child-Pugh B class, portal vein tumor thrombus, extrahepatic metastasis, and hypothyroidism were the independent risk factors for survival. Patients with hypothyroidism showed a longer OS [517 d (95%CI: 423-562) vs 431 d (95%CI: 412-485), P = 0.011] and TTP [125 d (95%CI: 89-154) vs 87 d (95%CI: 61-98), P = 0.004] than those without irAEs. Pembrolizumab-treated patients with unresectable HCC who experienced hypothyroidism have promising ORR and durable response. Hypothyroidism, an irAE, may be used as a clinical evaluation parameter of response to ICIs in unresectable HCC.

Biomarkers predictive of response to pembrolizumab in head and neck cancer.

We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored. We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcellinf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). Two hundred and fifty-seven patients (KEYNOTE-012, n=106; KEYNOTE-055, n=151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcellinf GEP. TMB, PD-L1, and Tcellinf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcellinf GEP (Spearman ρ=-0.03 and ρ=-0.13, respectively); PD-L1 and Tcellinf GEP were moderately correlated (Spearman ρ=0.47). In multivariate models, TMB, PD-L1, and Tcellinf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcellinf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcellinf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method. TMB and the inflammatory biomarkers PD-L1 and Tcellinf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.