Second-line Pembrolizumab Research Articles

Survival Outcomes of Metastatic or Recurrent Cervical Cancer Patients Treated with Palliative Intent Chemotherapy: Real-World Data

ObjectiveTo analyse the outcomes of metastatic or recurrent cervical cancer patients treated with palliative intent chemotherapy, as data on their outcomes are scant from LMIC.MethodsIn this retrospective analysis, 302 upfront metastatic or recurrent cervical cancer patients were treated with palliative intent from 1 January 2015 till 31 March 2020. The demographics, palliative therapy details, progression-free survival (PFS) and overall—survival (OS) were analysed for those receiving chemotherapy.ResultsThe median age was 53 (IQR 48-61) years and 248, (82.0 %) patients belonged to low-socioeconomic strata. Most common histology was squamous cell carcinoma (SCC) in 263 (87.1%) patients. De novo metastatic disease was seen in 119 (39.4 %) and recurrence post-treatment was seen in 183 (60.6 %) patients. Among the 302 patients, 149 (49.3%) patients received palliative chemotherapy, 70 (23.2 %) received palliative radiotherapy and 83 (27.5%) patients were considered for palliative care alone. The most common regimen was paclitaxel and carboplatin in 124 (83.2 %) patients. Eighty (53.7 %) patients completed 6 cycles. Four (2.7 %) received bevacizumab with chemotherapy in the first line and 3 (2.0%) patients received pembrolizumab in second line. The median PFS was 8.5 months (95% CI: 7.12–9.89 months) and median OS was 13.0 months (95% CI: 11.10–14.98 months) with median duration of follow-up of 33.4 months (range 27.9–38.9 months).ConclusionsIn real-world scenario, only half of the metastatic or recurrent cervical patients received any palliative chemotherapy. Paclitaxel and carboplatin are an effective regimen, and there was limited access to targeted therapy and immunotherapy.

Pembrolizumab in Patients with Advanced Urothelial Carcinoma with ECOG Performance Status 2: A Real-World Study from the ARON-2 Project.

The benefit of immune checkpoint inhibitors (ICIs) for poor performance status patients with advanced urothelial carcinoma (UC) remains unknown. In the present sub-analysis of the ARON-2 study, we investigated the role of pembrolizumab for advanced UC patients with ECOG (Eastern Cooperative Oncology Group) performance status (ECOG-PS) 2. Patients aged ≥18 years with a cytologically and/or histologically confirmed diagnosis of advanced UC progressing or recurring after platinum-based therapy and treated with pembrolizumab between 1 January 2016 to 1 April 2024 were included. In this sub-analysis we focused on patients with ECOG-PS 2. We included 1,040 patients from the ARON-2 dataset; of these, 167 patients (16%) presented an ECOG-PS 2. The median overall survival (OS) was 14.8 months (95% confidence interval (CI) 12.5-16.1) in the overall study population, 18.2 months (95% CI 15.8-22.2) in patients with ECOG-PS 0-1, and 3.7 months (95% CI 3.2-5.2) in subjects with ECOG-PS 2 (p<0.001). The median progression-free survival (PFS) in the overall study population was 5.3 months (95% CI 4.3-97.1), 6.2 months (95% CI 5.5-97.1) in patients with ECOG-PS 0-1, and 2.8 months (95% CI 2.1-3.4) in patients with ECOG-PS 2. Among the latter, liver metastases and progressive disease during first-line therapy were significant predictors of OS at both univariate and multivariate analyses. For PFS, univariate and multivariate analyses showed a prognostic role for lung metastases, liver metastases, and progressive disease during first-line therapy. This large real-world evidence study suggests the effectiveness of second-line pembrolizumab for mUC patients with poor performance status. The presence of liver metastases and progressive disease during first-line therapy is associated with worse clinical outcomes and, thus, should be taken into account when making treatment decisions in clinical practice.

Randomized phase III study comparing suspension or continuation of PD-1 pathway blockade for patients with advanced non-small-cell lung cancer (SAVE study: JCOG1701).

TPS8659 Background: The advent of immune checkpoint inhibitors (ICIs) targeting the PD-1 pathway, including nivolumab, pembrolizumab, and atezolizumab, has significantly improved the efficacy outcomes, namely progression-free survival (PFS) and overall survival (OS), in the treatment of advanced non-small cell lung cancer (NSCLC). This improvement is underscored by the observation that some patients (pts) who responded to ICIs continued to show a response even after discontinuing the treatment. Consequently, cessation of ICIs may not adversely impact OS, while potentially reducing immune-related toxicity and financial burden. Methods: The JCOG1701 is a multi-institutional, two-armed, open-label, randomized phase III trial. The objective of this study is to confirm the non-inferiority of suspension of ICIs to their continuation in patients with advanced or recurrent NSCLC who have shown a positive response to ICIs for 12 months or longer. For patients in the suspension arm who experience disease progression, re-initiation of immune checkpoint inhibitors (ICIs) is conducted. The patients were randomized in a 1:1 ratio to either the continuation or discontinuation arms. Randomization was performed by the minimization method using the institution, histology (squamous vs. non-squamous), and drug/timing parameters (first-line pembrolizumab/atezolizumab vs. second-line atezolizumab vs. second-line nivolumab vs. second-line pembrolizumab vs. combined therapy with chemotherapy) as adjustment factors. The primary endpoint of the trial is OS, while secondary endpoints include PFS, time to treatment failure of strategy, response rate, PFS post resumption of ICIs, and safety. In the periodical blinded monitoring, the pooled Kaplan-Meier curve for OS seemed significantly better than planned. This motivated to change the primary analysis method from hazard ratio to a difference in 6-year restricted mean survival time with a non-inferiority margin of 5.6 months. With one-sided alpha of 5% and power of 70%, the study aimed to enroll 172 patients assuming that 2-year OS is 94% in both arms. As of Jan 2024, 162 patients have been randomized, with full enrollment projected by Nov 2024. The trial is registered in the Japan Registry for Clinical Trials as jRCT1031190032. An ancillary study exploring the predictive and prognostic role of circulating tumor DNA is also planned. The findings of the JCOG1701 will provide data for making more informed treatment decisions in advanced NSCLC, specifically related to the continuation or suspension of ICIs. Clinical trial information: CRB3180009 .

Association between comorbidities and survival in patients with metastatic urothelial carcinoma treated with pembrolizumab.

This study aims to investigate the relationship between comorbidities and survival in patients with mUC treated with pembrolizumab as a second-line treatment. From February 2018 to October 2021, we analyzed the data of 185 consecutive patients with metastatic UC who received pembrolizumab as second-line therapy at The Jikei University Hospital and five affiliated hospitals. We used the Charlson Comorbidity Index (CCI) to assess the comorbidities. The outcomes of interest were progression-free survival (PFS) and overall survival (OS). To compare the survival differences, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier curves and the IPTW-adjusted Cox regression hazards model were used. After IPTW adjustment, patient characteristics were well-balanced between patients with high CCI and those with low CCI. The IPTW-adjusted Kaplan-Meier curves of PFS and OS based on CCI revealed that the patients with high CCI (2 or more) had a shorter PFS (median, 1.6 vs. 2.8months) and a shorter OS (median, 12.4 vs. 18.8months) (0-1). Similarly, in the IPTW-adjusted Cox regression hazards model, patients with high CCI had significantly shorter PFS [HR, 1.84 (95% CI 1.26-2.68; p = 0.002)] and OS [HR, 1.98 (95% CI 1.20-3.27; p = 0.008)] than those with lower CCI. High CCI was associated with a higher risk of disease progression as well as overall mortality in mUC patients treated with second-line pembrolizumab.

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

PurposeRadiological tumor burden has been reported to be prognostic in many malignancies in the immunotherapy era, yet whether it is prognostic in patients with metastatic urothelial carcinoma (mUC) treated with pembrolizumab remains uninvestigated. We sought to assess the predictive and prognostic value of radiological tumor burden in patients with mUC. MethodsWe performed a retrospective analysis of 308 patients with mUC treated with pembrolizumab. Radiological tumor burden was represented by baseline tumor size (BTS) and baseline tumor number (BTN). Optimal cut-off value of BTS was determined as 50 mm using the Youden index (small BTS: n = 194, large BTS: n = 114). Overall (OS), cancer-specific (CSS), progression-free survival (PFS), and objective response rate (ORR) were compared. Non-linear associations between BTS and OS and CSS were evaluated using restricted cubic splines. ResultsPatients with large BTS were less likely to have undergone the surgical resection of the primary tumor (P = 0.01), and more likely to have liver metastasis (P < 0.001) and more metastatic lesions (P < 0.001). On multivariable analyses controlling for the effects of confounders (resection of primary tumor, metastatic site, number of metastases and lactate dehydrogenase level), large BTS and high BTN were independently associated with worse OS (HR 1.52; P = 0.015, and HR 1.69; P = 0.018, respectively) and CSS (HR 1.59; P = 0.01, and HR 1.66; P = 0.031, respectively), but not PFS. Restricted cubic splines revealed BTS was correlated with OS and CSS in linear relationships. Additionally, large BTS was significantly predictive of lower ORR and complete response rate on univariable analyses (P = 0.041 and P = 0.032, respectively), but its association disappeared on multivariable analyses. ConclusionRadiological tumor burden has independent prognostic value with a linear relationship in pembrolizumab-treated patients with mUC and might help drive the earlier introduction of second-line pembrolizumab and/or switching to subsequent therapies.

New phase 1 SURPASS trial cohort: Early-line ADP-A2M4CD8 T-cell receptor T-cell therapy plus pembrolizumab in urothelial carcinoma.

TPS708 Background: ADP-A2M4CD8 T-cell receptor (TCR) T-cell therapy consists of autologous CD4+ and CD8+ T-cells genetically modified to target melanoma-associated antigen A4 (MAGE-A4) in patients (pts) with advanced cancers who are human leukocyte antigen A*02 eligible. In the late-line setting, ADP-A2M4CD8 monotherapy has demonstrated an acceptable benefit-to-risk profile and clinical responses across multiple tumor types in the ongoing Phase 1 SURPASS trial (NCT04044859). As of November 23, 2022, there were encouraging signs of antitumor activity in the 7 pts with advanced urothelial carcinoma (UC) treated in SURPASS, with best overall responses of 1 complete response, 3 partial responses, and 3 stable disease, giving an overall response rate of 57.1% and a disease control rate of 100% (Aggen DH. et al., Poster 517, ASCO-GU 2023; San Francisco, CA, USA). Furthermore, inhibiting immunosuppressive pathways may enhance antitumor activity. Thus, a new SURPASS cohort consisting of early-line ADP-A2M4CD8 TCR T-cell therapy combined with pembrolizumab in participants with UC has been opened. Methods: A dedicated UC cohort will enroll ≤15 pts with unresectable locally advanced or metastatic UC who have received first-line cisplatin-based standard-of-care (SOC) chemotherapy and are either currently receiving second-line SOC pembrolizumab or have received avelumab maintenance therapy and no second-line therapy. Key eligibility criteria include &gt;30% of tumor cells expressing MAGE-A4 (≥2+ by immunohistochemistry); positivity for HLA-A*02:01, 02:02, 02:03, or 02:06 alleles; measurable disease per RECIST v1.1 prior to lymphodepletion; and ECOG performance status of 0 or 1. T-cells are collected by leukapheresis, transduced with a lentiviral vector expressing the MAGE-A4-specific TCR and an additional CD8α co-receptor designed to increase functionality of CD4+ T-cells, and expanded ex vivo. Pts receive lymphodepletion chemotherapy consisting of cyclophosphamide 600 mg/m2/day for 3 days and fludarabine 30 mg/m2/day for 4 days followed by ADP-A2M4CD8 infusion (1x109 to 10x109 transduced T-cells) and subsequent pembrolizumab 400 mg (administered every six weeks for ≤2 years, until unacceptable toxicity or disease progression). Primary and secondary endpoints include evaluation of adverse events (AEs), serious AEs, AEs of special interest, and overall response rate per RECIST v1.1 by investigator review, respectively. Trial registration number: NCT04044859. Editorial acknowledgement:This study is sponsored by Adaptimmune (Philadelphia, PA, USA). Writing and editorial support was from Excel Scientific Solutions (Fairfield, CT, USA); funding was provided by Adaptimmune. Clinical trial information: NCT04044859 .

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.

TERT promoter mutations and the outcome of patients with advanced urothelial carcinoma treated by platinum-based chemotherapy or pembrolizumab.

BackgroundTERT promoter mutation is one of the most common genomic alterations in urothelial carcinoma (UC). Its prognostic role on patients' outcomes is still not clear. MethodsWe performed a single-center retrospective analysis on patients with advanced UC treated with platinum-based chemotherapy or immunotherapy to assess the presence of somatic TERT−124[C>T] and TERT−146[C>T] mutations and their association with clinicopathologic factors and survival outcomes. Patients were assessed for Overall Survival (OS), Progression-Free Survival (PFS), and Overall Response Rate (ORR). ResultsWe analyzed 45 UC tumors; 38 of them received first-line chemotherapy and 21 second-line pembrolizumab; 6 patients (13%) harbored −146 C > T TERTp mutation and 25 patients (56%)−124 C > T. The presence of TERT promoter mutations was associated with a higher rate of lower tract UC and a lower rate of synchronous or lymph node metastases. TERT wild-type patients showed higher 12- and 24-months OS-rates in the chemotherapy subgroup and 6-, 12- and 24-months OS rates in the pembrolizumab subgroup. The presence of TERT promoter mutations was also associated with a lower 6 months-PFS rate in patients receiving chemotherapy and in all the three time points in those treated by pembrolizumab. The ORRs of pembrolizumab were 21% and 71% in patients with or without TERT promoter mutations, respectively (p < 0.001). ConclusionsOur analysis suggests that the presence of TERT promoter mutations could negatively affect the outcome of UC patients treated by chemotherapy or pembrolizumab. This hypothesis should be further evaluated in wider cohorts.

Second-line Pembrolizumab for Metastatic Urothelial Carcinoma: Differences in Treatment Outcomes According to the Primary Site.

To evaluate the difference in the clinical efficacy and safety of pembrolizumab between patients with metastatic upper tract urothelial carcinoma (UTUC), which includes renal pelvic urothelial carcinoma (UC) and ureteral UC, and those with metastatic lower tract urothelial carcinoma (LTUC). A total of 752 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. We compared progression-free survival (PFS), overall survival (OS) and adverse events (AEs) in patients with renal pelvic UC, ureteral UC, and LTUC. The median follow-up period was 42.5 [interquartile range (IQR)=35.1-47.4] months. The primary tumor site was in the upper tract in 362 (48.1%) patients [renal pelvis, n=219 (60.5%); ureter, n=143 (39.5%)] and in the lower tract in 390 (51.9%) patients. The estimated glomerular filtration rate before pembrolizumab treatment in the UTUC group was significantly lower than that in the LTUC group (p<0.001). The median PFS in the UTUC and LTUC groups was 3.4 months, respectively (p=0.271). The median OS in the UTUC and LTUC groups was 10.1 months and 11.7 months, respectively (p=0.195). In an analysis of UTUC divided into renal pelvic UC, ureteral UC, and LTUC, patients with renal pelvic UC had a significantly poorer prognosis in comparison to the other two groups (p=0.041). The incidence of any-grade AEs (51.7% vs. 47.9%, p=0.343) and grade ≥3 AEs (12.2% vs. 12.8%, p=0.826) in the two groups was not statistically significantly different. No significant differences were found between the UTUC and LTUC groups with regard to the oncological outcomes and safety of pembrolizumab. Patients with renal pelvic UC had a significantly poorer prognosis than those with other ureteral UCs and LTUCs.

Pembrolizumab plus lenvatinib in second-line and third-line patients with pleural mesothelioma (PEMMELA): a single-arm phase 2 study

The combination of pembrolizumab, an anti-PD-1 antibody, and lenvatinib, an antiangiogenic multikinase inhibitor, shows synergistic activity in preclinical and clinical studies in solid tumours. We assessed the clinical activity of this combination therapy in patients with pleural mesothelioma who progressed after platinum-pemetrexed chemotherapy. In this single-arm, single-centre, phase 2 study, done at the Netherlands Cancer Institute in Amsterdam, The Netherlands, eligible patients (aged ≥18 years) with pleural mesothelioma with an Eastern Cooperative Oncology Group performance status of 0-1, progression after chemotherapy (no previous immunotherapy), and measurable disease according to the modified Response Evaluation Criteria In Solid Tumours (mRECIST) for mesothelioma version 1.1. Patients received 200 mg intravenous pembrolizumab once every 3 weeks plus 20 mg oral lenvatinib once per day for up to 2 years or until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate identified by a local investigator according to mRECIST version 1.1. This trial is registered with ClinicalTrials.gov, NCT04287829, and is recruiting for the second cohort. Between March 5, 2021, and Jan 31, 2022, 42 patients were screened, of whom 38 were included in the primary endpoint and safety analyses (median age 71 years [IQR 65-75], 33 [87%] male and five [13%] female) . At data cutoff (Jan 31, 2023), with a median follow-up of 17·7 months (IQR 13·8-19·4), 22 (58%; 95% CI 41-74) of 38 patients had an objective response. The independent review showed an objective response in 17 (45%; 95% CI 29-62) of 38 patients. Serious treatment-related adverse events occurred in ten (26%) patients, including one treatment-related death due to myocardial infarction. The most common treatment-related grade 3 or worse adverse events were hypertension (eight patients [21%]) and anorexia and lymphopenia (both four patients [11%]). In 29 (76%) of 38 patients, at least one dose reduction or discontinuation of lenvatinib was required. Pembrolizumab plus lenvatinib showed promising anti-tumour activity in patients with pleural mesothelioma with considerable toxicity, similar to that in previous studies. Available evidence from the literature suggests a high starting dose of lenvatinib for optimal anti-tumour activity. This, however, demands a high standard of supportive care. The combination therapy of pembrolizumab and lenvatinib warrants further investigation in pleural mesothelioma. Merck Sharp & Dohme.

1109P Second-line pembrolizumab (pembro) in Chinese patients (pts) with advanced melanoma: Long-term follow-up of the phase I KEYNOTE-151 study

1109P Second-line pembrolizumab (pembro) in Chinese patients (pts) with advanced melanoma: Long-term follow-up of the phase I KEYNOTE-151 study

Use of concomitant proton pump inhibitors, statins or metformin in patients treated with pembrolizumab for metastatic urothelial carcinoma: data from the ARON-2 retrospective study.

Concomitant medications may potentially affect the outcome of cancer patients. In this sub-analysis of the ARON-2 real-world study (NCT05290038), we aimed to assess the impact of concomitant use of proton pump inhibitors (PPI), statins, or metformin on outcome of patients with metastatic urothelial cancer (mUC) receiving second-line pembrolizumab. We collected data from the hospital medical records of patients with mUC treated with pembrolizumab as second-line therapy at 87 institutions from 22 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate. We carried out a survival analysis by a Cox regression model. A total of 802 patients were eligible for this retrospective study; the median follow-up time was 15.3months. PPI users compared to non-users showed inferior PFS (4.5 vs. 7.2months, p = 0.002) and OS (8.7 vs. 14.1months, p < 0.001). Concomitant PPI use remained a significant predictor of PFS and OS after multivariate Cox analysis. The use of statins or metformin was not associated with response or survival. Our study results suggest a significant prognostic impact of concomitant PPI use in mUC patients receiving pembrolizumab in the real-world context. The mechanism of this interaction warrants further elucidation.

Immunotherapy in Urothelial Cancer: Stop When Achieving a Response, Restart upon Disease Progression.

Since there is no clear consensus on optimal treatment duration of PD-(L)1 targeting checkpoint inhibitors in the setting of urothelial cancer (UC) patients, even patients with durable responses are often treated up to 2 years. It is questionable whether this is necessary and whether quality of life improves when treatment is discontinued earlier and restarted when necessary. We collected available data from locally advanced or metastatic UC patients within the Netherlands between September 2017 and December 2019 treated with first or second-line pembrolizumab, to evaluate treatment duration, reasons for discontinuation, subsequent treatments and survival outcomes. Data were available from 74 patients: 85% (63/74) of patients had a treatment duration of 12 months or shorter, and in seven out of them, treatment was discontinued for another reason than progressive disease. Two patients (3%) had a treatment duration between 12 and 24 months, and eight patients (11%) completed 24 months of treatment. Survival at data cut-off (1 July 2020) with a median follow-up of 35 months was 100% in patients with partial or complete response (6/7 patients) and treatment duration ≤ 12 months, and 100% in patients treated for 24 months. In total, three patients were re-treated with pembrolizumab upon progressive disease during follow-up. In patients who reach partial or complete response during treatment with a PD-(L)1 targeting checkpoint inhibitor, early discontinuation of treatment with pembrolizumab and restart if necessary seems to be reasonable with preserved favorable outcomes. This article should drive further efforts to optimize the treatment duration for patients who respond to treatment with pembrolizumab.

Association between gene expression signatures and clinical outcomes of pembrolizumab versus paclitaxel in advanced gastric cancer: exploratory analysis from the randomized, controlled, phase III KEYNOTE-061 trial

BackgroundIn the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction...

Association of tertiary lymphoid structures with outcomes from PD-1 inhibition in advanced malignant pleural mesothelioma.

e20545 Background: Predictive biomarkers of benefit form immunotherapy in malignant mesothelioma patients remain poorly defined. The 9-15 PROMISE-MESO study (NCT02991482) of the European Thoracic Oncology Platform (ETOP) evaluated second-line pembrolizumab against chemotherapy. Pembrolizumab led to an increased response rate compared to chemotherapy, which did not translate to survival benefits. We evaluated if the presence of tertiary lymphoid structures (TLSs) with different compositions or LRRC15+ immune suppressive fibroblasts could predict the clinical benefit from pembrolizumab. Methods: We performed multiplex immune histochemistry analysis on tumor tissues. 144 patients were included in the clinical trial, from whom, 112 had available tumor tissue for analysis: 55 patients in the chemotherapy arm, and 57 patients in the immune therapy arm. We performed the following panel: calretinin or WT1 (mesothelioma cells), CD20, CD23, CD11c, LRRC15, aSMA, and DAPI. We used the Akoya Vectra Polaris platform for analysis. The IFQuant analytical pipeline developed at the Swiss Institute for Bioinformatics (SIB) was used for analyses. Results: We defined three categories of TLSs: general CD20+ TLSs independent of other markers. CD20/CD23 double-positive as mature TLSs (mTLS), and TLSs with dendritic cells (CD11c+, cTLS). Immune suppressive CAFs were defined as LRRC15+ cells/mm2. CD20+ TLSs were identified in 84% of patients' stroma, with a median of 21 TLSs/tumor tissue and 2 TLSs/mm2. mTLSs were rare, only detected in 10 of the 112 patients (9%). cTLSs with dendritic cells were more frequent and present in 45% of all patients (50/112), and roughly half of the TLS+ patients (53%) had CD11c+ cells detected in TLSs. LRRC15+ cancer-associated fibroblasts (CAFs) were detected in 85% of patients, with a median density of 61 cells/mm2. LRRC15- tumors also contained TLSs but had significantly fewer than LRRC15+ tumors (p = 0.0079). We did not find any significant association between the responses or PFS with TLS, mTLS, and LRRC15+ CAFs. We found inverse association between cTLS levels and response to immune therapy (p = 0.037) but not for PFS. Conclusions: Our data shows that advanced malignant mesotheliomas frequently harbor TLSs, but these TLSs are mostly not activated/mature. The absence of antigen-presenting cells in TLSs, like CD11c dendritic cells, is unexpectedly associated with increased response to pembrolizumab. The high prevalence of immune suppressive LRRC15+ CAFs might explain the low response rate to pembrolizumab and could be linked to the absence of maturation of TLSs. Clinical trial information: EudraCT number: 2016-002062-31 .

Abstract 4528: Evaluation of plasma circulating tumor DNA (ctDNA)-based whole genome sequencing (pWGS) and whole exome sequencing (pWES) and concordance with tumor tissue whole exome sequencing (tWES): a pilot study in patients with recurrent or metastatic head and neck squamous cell carcinoma or metastatic urothelial carcinoma

Abstract Background: The genetic heterogeneity and clonal evolution of tumors is hypothesized to influence disease response and acquisition of resistance during treatment. However, comprehensive analysis of the changing tumor molecular landscape to support evaluation of such a hypothesis is often difficult to quantify due to the lack of accessibility to longitudinal biopsy samples in a large number of patients (pts). Longitudinal analyses using pWGS or pWES may allow the delineation of the genetic evolution of tumors and its impact on treatment outcomes. We conducted a pilot study to evaluate the feasibility of obtaining pWGS and pWES data from ctDNA in pretreatment samples from pts enrolled in 2 phase 3 trials that evaluated second-line pembrolizumab versus chemotherapy/standard-of-care therapy: KEYNOTE-040 (recurrent or metastatic head and neck squamous cell carcinoma; NCT02252042) and KEYNOTE-045 (metastatic urothelial carcinoma, NCT02256436). Concordance between pWES and tWES was also evaluated. Methods: Cell-free DNA was isolated from 1-3 mL of plasma; pWGS (via low-pass WGS) and pWES were performed on samples from pts with available tWES data generated as part of planned tissue biomarker analyses for the respective studies. Tumor burden in ctDNA was estimated from pWES data using single nucleotide variant (SNV)-based maximum somatic allele frequency (MSAF) and from pWGS data using a copy number variation-based measure of mutational burden in the tumor fraction. Concordance between the pWES and tWES mutational spectrum was determined using the Jaccard index. Concordance of key driver somatic events (FGFR3, TP53, and HPV status) was evaluated. Results: Plasma samples from 47 pts (KEYNOTE-040, n = 24; KEYNOTE-045, n = 23) were analyzed. Tumor burden estimates from pWGS (median coverage, 5.84; range, 4.28-8.18) and pWES (median coverage, 1806; range, 1038-2413) data were highly correlated (Spearman ρ = 0.94). A range of 0 to 956 nonsynonymous SNVs (median, 50) per pt was identified in ctDNA. When the ctDNA tumor burden was high (MSAF ≥5%, observed in two-thirds of pts), a relatively high concordance was observed for individual alterations in TP53, FGFR3, and HPV status (overall agreement: 0.87, 0.97, and 0.96, respectively); between tissue- and plasma-based tumor mutational burden (R = 0.49); and in overall mutational landscape overlap (Jaccard index: median, 0.30; range, 0.002-0.53). Conclusions: These data show that pWES exhibits reasonably high concordance with tWES when the tumor burden in ctDNA is relatively high and may be informative regarding tumor genomic characteristics. Extensive longitudinal studies are still needed to understand tumor genetic evolution using plasma ctDNA. Citation Format: Razvan Cristescu, Andrew Albright, Steven Townson, Cai Chen, Blanca Homet Moreno, Nati Lerman, Z. Alexander Cao, Carol Peña. Evaluation of plasma circulating tumor DNA (ctDNA)-based whole genome sequencing (pWGS) and whole exome sequencing (pWES) and concordance with tumor tissue whole exome sequencing (tWES): a pilot study in patients with recurrent or metastatic head and neck squamous cell carcinoma or metastatic urothelial carcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4528.

MP32-01 ONCOLOGICAL OUTCOMES IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA AFTER DISCONTINUING PEMBROLIZUMAB AS A SECOND-LINE TREATMENT: A RETROSPECTIVE MULTICENTER REAL-WORLD COHORT STUDY

You have accessJournal of UrologyCME1 Apr 2023MP32-01 ONCOLOGICAL OUTCOMES IN PATIENTS WITH METASTATIC UROTHELIAL CARCINOMA AFTER DISCONTINUING PEMBROLIZUMAB AS A SECOND-LINE TREATMENT: A RETROSPECTIVE MULTICENTER REAL-WORLD COHORT STUDY Toyohiro Yamada, Risa Tomioka, Tomohiro Yokoyama, Fumiya Sugino, Naoya Kumada, Shinichi Takeuchi, Makoto Kawase, Manabu Takai, Daiki Kato, Koji Iinuma, Keita Nakane, and Takuya Koie Toyohiro YamadaToyohiro Yamada More articles by this author , Risa TomiokaRisa Tomioka More articles by this author , Tomohiro YokoyamaTomohiro Yokoyama More articles by this author , Fumiya SuginoFumiya Sugino More articles by this author , Naoya KumadaNaoya Kumada More articles by this author , Shinichi TakeuchiShinichi Takeuchi More articles by this author , Makoto KawaseMakoto Kawase More articles by this author , Manabu TakaiManabu Takai More articles by this author , Daiki KatoDaiki Kato More articles by this author , Koji IinumaKoji Iinuma More articles by this author , Keita NakaneKeita Nakane More articles by this author , and Takuya KoieTakuya Koie More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003265.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The treatment options are currently limited, and the oncological outcomes remain unclear for patients with metastatic urothelial carcinoma (mUC) with or without third-line systemic therapy. We aimed to evaluate the oncological outcomes in real-world daily clinical practice after platinum-based chemotherapy followed by pembrolizumab for mUC. METHODS: This retrospective, multicenter cohort study included patients with mUC who received second-line pembrolizumab in Japan. The patients were divided into the treatment group (those who received third-line treatment) and BSC group (those who did not receive other treatments). The primary endpoint of this study was to evaluate the oncological outcomes. Of 126 patients enrolled in this study, 40 received third-line therapy. RESULTS: The median follow-up period was 8.0 months. The median overall survival (OS) times were nine months in the BSC group and 17 months in the treatment group (p<0.001). The median progression-free survival (PFS) times were four months in the BSC group and 14 months in the treatment group (p<0.001). In the multivariate analysis, performance status and liver metastasis were significantly associated with OS. CONCLUSIONS: Third-line therapy may have clinical potential advantages to improve the oncological outcomes in patients with mUC.Further prospective studies and long-term evaluations in large patient populations are required to identify the useful predictive markers for determining patients with mUC who should continue pembrolizumab treatment for a relatively long term. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e439 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Toyohiro Yamada More articles by this author Risa Tomioka More articles by this author Tomohiro Yokoyama More articles by this author Fumiya Sugino More articles by this author Naoya Kumada More articles by this author Shinichi Takeuchi More articles by this author Makoto Kawase More articles by this author Manabu Takai More articles by this author Daiki Kato More articles by this author Koji Iinuma More articles by this author Keita Nakane More articles by this author Takuya Koie More articles by this author Expand All Advertisement PDF downloadLoading ...

Immuntherapie in der Hepatogastroenterologie: Wirkung und Nebenwirkung

Immune-checkpoint-inhibitors (ICI) are used for adjuvant therapy of squamous cell carcinoma and adenocarcinoma of the esophagogastric junction after prior radiotherapy. The combination of ICI with chemotherapy (CTx) is approved for first-line therapy in a palliative setting (Nivolumab and Ipilimumab) and as second-line option (Nivolumab). Squamous cell carcinoma probably has a higher response rate to ICI and Nivolumab and Ipilimumab are approved as a single therapy for this entity. ICI combined with CTx is approved for metastatic gastric cancer. MSI-H tumors respond well to ICI and can be treated with Pembrolizumab in second line. ICI are only approved for MSI-H/dMMR CRC. Pembrolizumab is a first-line option and Nivolumab combined with Ipilimumab a second-line therapy. Atezolizumab with Bevacizumab is the new first-line therapy of advanced HCC, with additional ICI combinations with positive Phase III studies expected to be approved in the near future. Durvalumab and CTx achieved promising results in a recent Phase 3 study. Pembrolizumab is already EMA-approved as a second-line therapy of MSI-H/dMMR biliary cancer. ICI have not yet achieved a breakthrough in the therapy of pancreatic cancer. FDA-approval exists only for the small subgroup of MSI-H/dMMR tumors. The disinhibition of the immune response by ICI can cause irAE. IrAE most frequently affect the skin, gastrointestinal tract, liver, and endocrine organs. Starting with grade 2 irAE, ICI should be paused, differential diagnosis excluded and if necessary steroid therapy has to be started. Early high-dose use of steroids negatively affects patient outcome. New therapy strategies for irAE are currently tested, such as extracorporeal photopheresis, but larger prospective trials are lacking.

Pembrolizumab as Second-Line Therapy for Advanced Hepatocellular Carcinoma: Longer Term Follow-Up from the Phase 3 KEYNOTE-240 Trial

Introduction: KEYNOTE-240 showed a favorable benefit/risk profile for pembrolizumab versus placebo in patients with sorafenib-treated advanced hepatocellular carcinoma (HCC); however, prespecified statistical significance criteria for overall survival (OS) and progression-free survival (PFS) superiority were not met at the final analysis. Outcomes based on an additional 18 months of follow-up are reported. Methods: Adults with sorafenib-treated advanced HCC were randomized 2:1 to pembrolizumab 200 mg intravenously every 3 weeks or placebo. Dual primary endpoints were OS and PFS assessed per RECIST v1.1 by blinded independent central review (BICR). Secondary endpoints included objective response rate (ORR), assessed per RECIST v1.1 by BICR, and safety. Results: 413 patients were randomized (pembrolizumab, n = 278; placebo, n = 135). As of July 13, 2020, median (range) time from randomization to data cutoff was 39.6 (31.7–48.8) months for pembrolizumab and 39.8 (31.7–47.8) months for placebo. Estimated OS rates (95% CI) were 17.7% (13.4–22.5%) for pembrolizumab and 11.7% (6.8–17.9%) for placebo at 36 months. The estimated PFS rate (95% CI) for pembrolizumab was 8.9% (5.3–13.6%) and 0% for placebo at 36 months. ORR (95% CI) was 18.3% (14.0–23.4%) for pembrolizumab and 4.4% (1.6–9.4%) for placebo. Immune-mediated hepatitis events did not increase with follow-up. No viral hepatitis flare events were reported. Conclusion: With extended follow-up, pembrolizumab continued to maintain improvement in OS and PFS and was associated with a consistent adverse event profile compared with placebo in patients with sorafenib-treated advanced HCC. Although KEYNOTE-240 did not meet prespecified statistical significance criteria at the final analysis, these results together with the antitumor activity of second-line pembrolizumab observed in KEYNOTE-224 and the statistically significant and clinically meaningful OS and PFS benefits of second-line pembrolizumab in patients from Asia observed in KEYNOTE-394 reinforce the clinical activity of pembrolizumab in previously treated patients with advanced HCC.

Significance of second progression-free survival in patients with advanced urothelial cancer who received platinum-based combination chemotherapy followed by pembrolizumab.

The present study comprehensively investigated the significance of several factors reflecting the therapeutic effects of anticancer treatment on overall survival (OS) in advanced urothelial cancer (UC) patients receiving sequential systemic therapy. This study included 101 consecutive advanced UC patients who received first-line platinum-based combination chemotherapy followed by second-line pembrolizumab. The impacts of the following factors on OS in these patients were analyzed: responses to chemotherapy, responses to pembrolizumab, progression-free survival (PFS) with chemotherapy, PFS with pembrolizumab, and second PFS (PFS2). The median age of patients was 71 years, and 35 and 66 had UC in the upper urinary tract and bladder, respectively. objective response rate to first-line chemotherapy and second-line pembrolizumab were 37.6% and 19.8%, respectively. Median PFS with chemotherapy, pembrolizumab, and PFS2 were 5, 4, and 9months, respectively. Uni- and multivariate analyses of the five factors examined identified PFS with pembrolizumab and PFS2 as independent surrogates for OS, with PFS2 (hazard ratio [HR]=0.23) being more closely associated with OS than PFS with pembrolizumab (HR=0.31). Furthermore, uni- and multivariate analyses of various prognostic parameters showed the independent impacts of baseline performance status (PS) and neutrophil-to-lymphocyte ratio (NLR) on PFS2. The present results suggest the potential of PFS2 as an optimal surrogate for OS in advanced UC patients receiving standard sequential systemic therapy and indicate that intensive treatment needs to be considered for those with poor PS and/or high NLR prior to the introduction of first-line chemotherapy.