Efficacy Of Pembrolizumab In Patients Research Articles

The clinical outcome of pembrolizumab for patients with recurrent or metastatic squamous cell carcinoma of the head and neck: a single center, real world study in China.

The KEYNOTE-048 and KEYNOTE-040 study have demonstrated the efficacy of pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC), we conducted this real-world study to investigate the efficacy of pembrolizumab in patients with R/M HNSCC. This is a single-center retrospective study conducted in the Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine (Shanghai, China). Between December 2020 and December 2022, a total of 77 patients with R/M HNSCC were included into analysis. The primary endpoint of the study was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), overall response rate (ORR)and toxicity.Efficacy was assessed according to RECIST version 1.1.SPSS 27.0 and GraphPad Prism 8.0 software were utilized to perform the statistical analysis. By the cut-off date (February 28, 2023), the median OS,PFS and ORR were 15.97 months,8.53 months and 48.9% in patients treated with the pembrolizumab regimen in the first line therapy. Among these patients, 17 patients received pembrolizumab with cetuximab,and 18 received pembrolizumab with chemotherapy.We observed no significant differences between two groups neither in median OS (13.9 vs 19.4 months, P=0.3582) nor PFS (unreached vs 8.233 months, P= 0.2807). In the ≥2nd line therapy (n=30), the median OS, PFS and ORR were 5.7 months, 2.58 months and 20% respectively. Combined positive score (CPS) was eligible from 54 patients. For first line therapy, the median OS and PFS were 14.6 and 8.53 months in patients with CPS ≥1, and median OS and PFS were 14.6 and 12.33 months in patients with CPS ≥20. The immune-related adverse events (irAEs) were occurred in the 31 patients (31/77, 40.26%), and the most common potential irAEs were hypothyroidism (25.97%), and pneumonitis (7.79%). Our real-world results indicated that pembrolizumab regimen is a promising treatment in patients with R/M HNSCC.

A study of blood myeloid-derived suppressor cells for predicting pembrolizumab efficacy in patients with metastatic urothelial carcinoma.

658 Background: Immune checkpoint inhibitors (ICIs) are crucial for treating metastatic urothelial carcinoma (mUC) patients, yet current prognostic biomarkers fail to predict ICI efficacy. Previous preclinical models have suggested myeloid-derived suppressor cells (MDSCs) as a potential therapeutic target in bladder cancer. This study aims to evaluate the predictive value of blood MDSCs in mUC patients undergoing pembrolizumab treatment. Methods: Ninety-eight mUC patients who progressed with platinum-based chemotherapy at Osaka Metropolitan University received pembrolizumab. Among them, 30 patients were assessed for blood MDSCs. Peripheral blood samples were collected from healthy individuals (n = 6) and mUC patients (n = 30) before pembrolizumab initiation. The mononuclear cell layer was isolated using density gradient centrifugation for MDSC analysis through flow cytometry. Monocytic and polymorphonuclear MDSCs were defined as CD11b+ HLADR – CD33 high CD14 + CD15 – and CD11b+ HLADR – CD33 low CD14 – CD15 +, respectively. The neutrophil-lymphocyte ratio (NLR) in blood served as a control. Treatment response was assessed via CT images using RECICT v1.1. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, with log-rank test for between-group comparison. Results: First, blood MDSCs were significantly elevated in mUC patients compared to healthy controls (p = 0.0024, Mann Whitney test). Secondly, patients with MDSClow (≤ median, n = 15) had significantly longer PFS than those with MDSChigh (> median, n = 15) (17.6 vs. 1.9 months, p = 0.0126). However, no significant difference was observed in OS. In contrast, when the NLR cutoff was set at 3.5, no significant association was found for PFS and OS. Conclusions: Blood MDSCs show promise as a predictive marker for pembrolizumab therapy efficacy.

Proton pump inhibitors and potassium competitive acid blockers decrease pembrolizumab efficacy in patients with metastatic urothelial carcinoma

We elucidated the efficacy of gut microbiome–altering drugs on pembrolizumab efficacy in patients with metastatic urothelial carcinoma (mUC). Clinical data were analyzed retrospectively from 133 patients with mUC who received second-line pembrolizumab therapy between January 2018 and January 2021, following failed platinum-based chemotherapy. We evaluated the effects of gut microbiome–altering drugs (proton pump inhibitors [PPI]/potassium-competitive acid blockers [P-CAB], H2 blockers, antibiotics, non-steroidal anti-inflammatory drugs [NSAIDs], metformin, antipsychotics, steroids, and opioids), taken by patients within 30 days before/after pembrolizumab treatment, on progression-free survival (PFS) and overall survival (OS). Fifty-one patients received PPI/P-CAB (37/14, respectively); H2 blockers, 7; antibiotics, 35; NSAIDs, 22; antipsychotics, 8; metformin, 3; steroids, 11; and opioids, 29. Kaplan–Meier curves revealed PPI or P-CAB users showed shorter PFS than non-PPI-P-CAB users (p = 0.001, p = 0.005, respectively). Multivariate analysis highlighted PPI/P-CAB use as the only independent prognostic factor for disease progression (hazards ratio: 1.71, 95% confidence interval: 1.14–2.07, p = 0.010) but not death (p = 0.177). Proton pump inhibitors/potassium-competitive acid blockers may decrease the efficacy of pembrolizumab therapy for mUC, possibly via gut microbiome modulation.

Unveiling pembrolizumab effectiveness in diverse subtypes of MSI-high endometrial cancers.

The efficacy of pembrolizumab in patients with microsatellite instability (MSI)-high cancers has been reported; however, the differences in efficacy according to the subtypes of MSI-high endometrial cancers (ECs) remain unclear. MSI-high ECs are classified into at least 3 groups based on their molecular characteristics: MLH1 hypermethylated, Lynch-like syndrome (LLS)-associated, and Lynch syndrome (LS)-associated cancers. This study aimed to investigate whether the efficacy of pembrolizumab differs among these 3 groups, and if so, whether EPM2AIP1 immunohistochemistry (IHC), which correlates with MLH1 promoter methylation, can be used to rule out MLH1 methylation cases. This study included 12 patients with MSI-high EC who received pembrolizumab treatment. Patients were categorized into 3 groups based on MLH1 methylation analysis and the Amsterdam Criteria: MLH1 hypermethylated (sporadic [SP]), LLS-associated, and LS-associated. Patients' medical records were retrospectively reviewed, and the efficacy of treatment was evaluated based on the response rate using the Response Evaluation Criteria in Solid Tumors version 1.1. The overall response rate was 75% (3/4) in the SP group, while it was 100% including one complete response patient in the LLS-associated and the LS-associated group, respectively. The sensitivity and positive predictive value of EPM2AIP1 IHC for MLH1 methylation were 100% and 66.7%, respectively. Pembrolizumab may be more effective in LLS and LS-associated groups. EPM2AIP1 IHC was less predictive than MLH1 methylation analysis; however, it may be useful for ruling out MLH1 methylation cases due to its high sensitivity. Further studies are needed to determine whether EPM2AIP1 IHC can predict pembrolizumab efficacy.

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

Pembrolizumab for the treatment of disease relapse after allogeneic hematopoietic stem cell transplantation.

A failed graft-versus-tumor (GVT) effect is a common mechanism of relapse after allogeneic hematopoietic cell transplantation (alloHCT). Although targeting the PD-1/PD-L1 axis may restore GVT effects, PD-1 blockade exacerbates graft-versus-host disease (GVHD) in murine models, and severe GVHD can occur in patients treated with anti-PD-1 therapy after alloHCT. Therefore, we developed a prospective study to assess the safety and efficacy of pembrolizumab in patients relapsing after alloHCT. Eligible patients received pembrolizumab (200 mg every 3 weeks) for up to 2 years. Twelve patients were enrolled (8patients with acute myeloid leukemia, 1 patient with myelodysplastic syndrome, 1 patient with classical Hodgkin lymphoma, and 2 patients with diffuse large B-cell lymphoma [DLBCL]). All participants received reduced-intensity preparative regimens with invivo T-cell depletion. The median time from alloHCT to enrollment was 587 days (range, 101-4211). Three participants (25%) experienced grade 3 to 4 immune-related adverse events (irAE) (pneumonitis, 2 patients; hyperthyroidism, 1 patient), all occurring after 1 to 2 cycles, and resolving after pembrolizumab discontinuation and corticosteroid treatment. irAEs of any grade occurred in 5 patients (42%). No treatment-emergent GVHD was observed. Overall and complete response (CR) rates were 22% (2/9). Both patients achieving CRs hadPD-L1 gene-amplified lymphomas and diffuse PD-L1 expression on pretreatment biopsies. An acquired EZH2 mutation was identified at relapse in a patient with DLBCL who achieved an initial CR to pembrolizumab, which was associated with downregulated HLAexpression on malignant B cells, implicating EZH2 mutations as a potential immune escape mechanism after PD-1-blockade therapy. In conclusion, after alloHCT, treatment with pembrolizumab is feasible and associated with objective responses in relapsed lymphoid malignancies but can induce severe irAEs, requiring vigilant monitoring. Thistrial was registered at www.clinicaltrials.gov as #NCT02981914.

Pembrolizumab for patients with non-Hodgkin lymphoma: phase 1b KEYNOTE-013 study

The multicohort phase 1b KEYNOTE-013 study (NCT01953692) evaluated the safety and efficacy of pembrolizumab in patients with relapsed or refractory NHL who were ineligible for or failed hematopoietic cell transplantation (HCT). Patients received pembrolizumab (cohort 4) or pembrolizumab plus lenalidomide (cohort 5). Primary end points were safety and objective response rate (ORR) per IWG 2007 criteria. Cohort 4 included 89 patients. ORR was 22% (19/86; 90% CI 15–31; 10 CR, nine PR); ORRs by disease type were 48% (10/21), 10% (2/20), 12% (5/41), and 50% (2/4), for PMBCL, FL, DLBCL, and ‘other’ NHL, respectively. Toxicity was as predicted. Cohort 5 included 19 patients. ORR was 39% (90% CI 20–61; four CR, three PR). Hematologic toxicities were the most common treatment-related AEs. In conclusion, pembrolizumab following HCT ineligibility/failure confirms prior experience in PMBCL but not with NHL subtypes in this study. Additional analyses in DLBCL may not be warranted.

Mass Cytometry Reveals Classical Monocytes, NK Cells, and ICOS+ CD4+ T Cells Associated with Pembrolizumab Efficacy in Patients with Lung Cancer.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non-small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12-0.51; P < 0.0001). As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Immune-related adverse events in urothelial cancer patients: Adjustment for immortal time bias.

To investigate the association between the onset, severity, and type of immune-related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum-pretreated advanced urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade≥3 irAEs. Propensity score matching extracted 198 patients with and without grade≥2 irAEs. The onset of grade≥2 irAEs was associated with longer median progression-free survival (PFS) (8.3 months vs. 4.5 months, p=0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p=0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p=0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade≤1 and≥3 irAEs. Patients with grade≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low-grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum-pretreated advanced UC.

Pancreatic cancer: still a cold case?

Little advancement has happened in the therapeutic management of metastatic pancreatic ductal adenocarcinoma. Among countless attempts to improve the outcome, studies of immunomodulation have been abundant with disappointing results. 1 Tempero M Oh DY Tabernero J et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021; 32: 600-608 Summary Full Text Full Text PDF PubMed Scopus (36) Google Scholar , 2 Henriksen A Dyhl-Polk A Chen I Nielsen D Checkpoint inhibitors in pancreatic cancer. Cancer Treat Rev. 2019; 78: 17-30 Summary Full Text Full Text PDF PubMed Scopus (85) Google Scholar Even in the more favourable context of high microsatellite instability or mismatch repair-deficient pancreatic ductal adenocarcinoma, pembrolizumab yielded a poor median progression-free survival of 2·1 months and a median overall survival of only 4·0 months. 3 Marabelle A Le DT Ascierto PA et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020; 38: 1-10 Crossref PubMed Scopus (1001) Google Scholar Some progress came from the identification of the small subset of patients bearing germline pathogenic variants of BRCA1 and BRCA2 and other DNA damage repair genes, whose disease is remarkably sensitive to platinum-based chemotherapy. 4 Orsi G Di Marco M Cavaliere A et al. Chemotherapy toxicity and activity in patients with pancreatic ductal adenocarcinoma and germline BRCA1-2 pathogenic variants (gBRCA1-2pv): a multicenter survey. ESMO Open. 2021; 6100238 Summary Full Text Full Text PDF Scopus (6) Google Scholar Niraparib plus nivolumab or niraparib plus ipilimumab in patients with platinum-sensitive advanced pancreatic cancer: a randomised, phase 1b/2 trialThe primary endpoint of 6-month progression-free survival was met in the niraparib plus ipilimumab maintenance group, whereas niraparib plus nivolumab yielded inferior progression-free survival. These findings highlight the potential for non-cytotoxic maintenance therapies in patients with advanced pancreatic cancer. Full-Text PDF

Efficacy of pembrolizumab in patients with advanced cancer of unknown primary (CUP): a phase 2 non-randomized clinical trial

BackgroundCancer of unknown primary (CUP) is an aggressive rare malignancy with limited treatment options. Data regarding clinical activity of immune checkpoint inhibitors in CUP is lacking. Therefore, we evaluated the...

A0909 - Impact of non-muscle invasive bladder cancer treatment history on the efficacy of pembrolizumab for patients with metastatic urothelial carcinoma

A0909 - Impact of non-muscle invasive bladder cancer treatment history on the efficacy of pembrolizumab for patients with metastatic urothelial carcinoma

Platelet-to-Lymphocyte Ratio Predicts the Efficacy of Pembrolizumab in Patients With Urothelial Carcinoma.

This study aimed to determine useful predictive factors for selecting patients with advanced urothelial carcinoma (UC) who might benefit clinically from treatment with pembrolizumab. We retrospectively analyzed 54 patients who underwent pembrolizumab treatment for UC. The hemoglobin, albumin, lymphocyte and platelet (HALP) score, neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were calculated as indices of systemic inflammatory response, and the relationships between these scores and the initial tumor response or overall survival, as well as other clinicopathological factors, were assessed. High NLR and PLR were associated with a poor initial tumor response to pembrolizumab. A HALP score <30.05 and a PLR ≥173.73 were associated with worse overall survival. In the multivariate Cox regression analysis, a high PLR was a significant independent prognostic factor for unfavorable outcomes. A high pretreatment PLR may be a valuable indicator for choosing therapy other than pembrolizumab in patients with advanced UC.

Efficacy of pembrolizumab and comprehensive CD274/PD-L1 profiles in patients previously treated with chemoradiation therapy as radical treatment in bladder cancer

BackgroundChemoradiation therapy (CRT) has been increasingly reported as a possible alternative to total cystectomy (TC) for localized bladder cancer (BC). Pembrolizumab is the standard of care for platinum-refractory metastatic urothelial...

MO10-4 The efficacy of pembrolizumab in patients with high-frequency microsatellite instability (MSI-H) solid tumors

MO10-4 The efficacy of pembrolizumab in patients with high-frequency microsatellite instability (MSI-H) solid tumors

Pembrolizumab for treating advanced urothelial carcinoma in patients with impaired performance status: Analysis of a Japanese nationwide cohort.

BackgroundThe benefits of pembrolizumab in patients with advanced urothelial carcinoma (UC) and impaired performance status (PS) remain unknown. This study assessed the safety and efficacy of pembrolizumab in patients with platinum‐refractory UC and Eastern Cooperative Oncology Group PS ≥2 to identify which subgroups may benefit from this drug.MethodsThis retrospective nationwide cohort study collected clinicopathological information for 755 patients from 59 institutions. The overall response rate (ORR) and overall survival (OS) were compared among the patients with PS 0–1, 2, and 3–4. Multivariate analysis was conducted to identify factors predicting OS in patients with PS ≥2.ResultsThe numbers of patients with PS 0–1, 2, and 3–4 were 602, 98, and 55, respectively; the ORRs in these groups were 29.5, 15.3, and 9.1%, respectively, and the median OS times were 14.3, 3.1, and 2.4 months, respectively. In multivariate Cox regression analysis, a neutrophil–lymphocyte ratio (NLR) ≥3.5 (hazard ratio [HR] = 1.897) and liver metastasis (HR = 2.072) were associated with OS in the PS ≥2 subgroup. The median OS of patients with PS ≥2 without either risk factor was 6.8 months, compared with 3.1 months for patients with one risk factor and 2.3 months for patients with both risk factors.ConclusionsPS ≥2 portended worse ORR and OS than PS ≤1 despite a comparable safety profile. Among the patients with impaired PS, patients with NLR <3.5 and no liver metastasis may most greatly benefit from pembrolizumab therapy.

48-Year-Old Woman With Dyspnea and Chest Pain

48-Year-Old Woman With Dyspnea and Chest Pain

Efficacy of Pembrolizumab Monotherapy for Advanced Gastric/Gastroesophageal Junction Cancer with Programmed Death Ligand 1 Combined Positive Score ≥10.

Pembrolizumab demonstrated efficacy in PD-L1-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (G/GEJ) cancer in the first-, second-, and third-line setting in KEYNOTE-062, KEYNOTE-061, and KEYNOTE-059, respectively. To better delineate the specificity of CPS as a predictor of clinical outcomes, we analyzed pembrolizumab efficacy in patients with CPS ≥ 10 in these trials. Included were patients with CPS ≥ 10 tumors from KEYNOTE-059 cohort 1 (pembrolizumab, n = 46; post hoc), KEYNOTE-061 (pembrolizumab, n = 53; chemotherapy, n = 55; post hoc), and KEYNOTE-062 (pembrolizumab, n = 92; chemotherapy, n = 90; primary). Efficacy outcomes were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR). In KEYNOTE-059, median follow-up was 6 months, median OS was 8 months [95% confidence interval (CI), 5.8-11.1], ORR was 17%, and median (range) DOR was 21 months (3+ to 35+). In KEYNOTE-061, median follow-up was 9 months, median OS (pembrolizumab vs. chemotherapy) was 10 versus 8 months (HR, 0.64; 95% CI, 0.41-1.02), median PFS was 3 months versus 3 months (HR, 0.86; 95% CI, 0.56-1.33), ORR was 25% versus 9%, and median (range) DOR was not reached (4 to 26+ months) versus 7 months (3-7). In KEYNOTE-062, median follow-up was 11 months, median OS (pembrolizumab vs. chemotherapy) was 17 months versus 11 months (HR, 0.69; 95% CI, 0.49-0.97), median PFS was 3 months versus 6 months (HR, 1.09, 95% CI; 0.79-1.49), ORR was 25% versus 38%, and median (range) DOR was 19 months (1+ to 34+) versus 7 months (2+ to 30+). This comprehensive analysis showed consistent improvements toward more favorable clinical outcomes with pembrolizumab across lines of therapy in patients with CPS ≥ 10 G/GEJ cancer.

Keytruda and PD-L1: a Real-World Example of Co-development of a Drug with a Predictive Biomarker.

Pembrolizumab, an anti-programmed death 1 monoclonal antibody, underwent a rapid clinical development program for the treatment of patients with malignancies in parallel to the development of a companion diagnostic for detecting programmed death ligand 1 (PD-L1) expression, which was considered to be a likely biomarker for response and cancer outcome. When investigating outcomes in patients with non-small cell lung cancer (NSCLC) treated with pembrolizumab, PD-L1 tumor proportion score (TPS) was initially identified as a marker of clinical efficacy, with a cutoff of ≥ 50%. This threshold was later reduced to TPS ≥ 1%, which demonstrated that pembrolizumab offered a clinical benefit in a broader population of patients with PD-L1-expressing tumors. As new evidence emerged, it also became clear that immune cell PD-L1 expression has an important role in predicting tumor response in patients treated with pembrolizumab; the combined positive score (CPS), which accounts for both tumor and immune cell PD-L1 expression, was then applied in clinical studies for indications outside of NSCLC. This review summarizes the outcomes of landmark studies in the KEYNOTE clinical development program that investigated the efficacy of pembrolizumab in patients with a variety of malignancies, the relative outcomes when patients were stratified by PD-L1 status, and how these observations have influenced the approved indications for pembrolizumab.

Efficacy of pembrolizumab in patients with brain metastasis caused by previously untreated non-small cell lung cancer with high tumor PD-L1 expression

ObjectivesPembrolizumab is recommended for patients with previously untreated non-small cell lung cancer (NSCLC) with a programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of ≥1%. The KEYNOTE-024 study described the efficacy of pembrolizumab in patients with previously untreated NSCLC who had a PD-L1 TPS of at least 50 %. However, patients with untreated brain metastasis (BM) were excluded from many clinical trials. Therefore, we assessed the efficacy of pembrolizumab against BM of NSCLC with high tumor PD-L1 expression. Materials and MethodsWe retrospectively reviewed patients who received pembrolizumab as first-line treatment against NSCLC with PD-L1 TPS ≥ 50 % between March 2017 and September 2019. Treatment efficacy was compared between patients with (BM group) and without BM (non-BM group). In addition, the BM group was divided into patients who previously received treatment for BM before pembrolizumab (BM-T group) and those with no prior treatment for BM (BM-not T group). ResultsEighty-seven patients (23 BM group and 64 non-BM group) were assessable for efficacy. No significant differences in patient characteristics were found between the BM and non-BM groups, but proportion of patients with stage IV at diagnosis was significantly higher in the BM group. Median progression-free survival (PFS) (6.5 months vs. 7.0 months) and overall survival (OS) (21.6 months vs. 24.6 months) did not significantly differ between the two groups. The response rate of BM was 70 %. The BM group was subdivided into 13 patients in the BM-T group and 10 patients in the BM-not T group. No significant differences in patient characteristics were found between the two groups, but maximum diameter of BM and proportion of patients with symptomatic BM were significantly greater in the BM-T group. PFS and OS did not significantly differ between the two groups. The median PFS of BM was 13.6 months in the BM-T group and 18.6 months in the BM-not T group. ConclusionPembrolizumab may be effective for BM caused by previously untreated NSCLC with high PD-L1 tumor expression.