PD-L1 Combined Positive Score Research Articles

The optimal threshold of PD-L1 combined positive score to predict the benefit of PD-1 antibody plus chemotherapy for patients with HER2-negative gastric adenocarcinoma: a meta-analysis.

Immune checkpoint inhibitors (ICIs) combined with chemotherapy have become the first-line treatment of metastatic gastric and gastroesophageal adenocarcinomas (GEACs). This study aims to figure out the optimal combined positive score (CPS) cutoff value. We searched for randomized phase III trials to investigate the efficacy of ICIs plus chemotherapy for metastatic GEACs compared with chemotherapy alone. Pooled analyses of hazard ratios (HRs) based on PD-L1 expression were performed. A total of six trials (KEYNOTE-062, KEYNOTE-590, KEYNOTE-859, ATTRACTION-04, CheckMate 649, and ORIENT-16) were included, comprising 5,242 patients. ICIs plus chemotherapy significantly improved OS (HR: 0.79, 95% CI 0.72-0.86 in global patients; HR: 0.75, 95% CI 0.57-0.98 in Asian patients) and PFS (HR: 0.74, 95% CI 0.68-0.82 in global patients; HR: 0.64, 95% CI 0.56-0.73 in Asian patients) compared with chemotherapy alone. The differences in OS (ratio of HR: 1.05, 95% CI 0.79-1.40; predictive value: - 5.1%) and PFS (ratio of HR: 1.16, 95% CI 0.98-1.36; predictive value: - 13.5%) were not statistically significant between the global and Asian patients. Subgroup analyses indicated that the optimal CPS threshold was at ≥ 5 for OS and ≥ 10 for PFS with the highest predictive values. The benefit derived from ICIs plus chemotherapy is similar between Asian and global GEAC patients. However, those with a PD-L1 CPS < 5 or CPS < 10 may not have significant benefits from ICIs therapy. Therefore, it is advisable to routinely assess PD-L1 expression in GEAC patients considered for ICIs treatment.

Claudin-18 status and its correlation with HER2 and PD-L1 expression in gastric cancer with peritoneal dissemination

Abstract Background Gastric cancer with peritoneal dissemination (PD) has a dismal prognosis, and current treatments have shown little efficacy. CLDN18.2-targeted therapies have shown promising efficacy against gastric cancers that express high levels of CLDN18. Because of the limited information regarding CLDN18.2 status in PD, we analyzed PD-positive gastric cancers for CLDN18 status in both primary and PD, along with HER2 and PD-L1 combined positive score (CPS). Methods Immunohistochemical analyses were performed on 84 gastric cancer cases using paired primary and PD tissue samples. Results At 40% cut-off, CLDN18 was positive in 57% (48/84) primary tumors and in 44% (37/84) PDs. At 75% cut-off, 28.6% (24/84) primary tumors and 20.2% (17/84) PDs were CLDN18-positive. The concordance rate between primary tumors and PD was 79.8% at 40% cut-off and 75% at 75% cut-off. When comparing biopsy and surgical specimens, the concordance rates were 87.5% at 40% cut-off and 81.3% at 75% cut-off. Within a tumor, the superficial area tended to have a higher CLDN18-positive rate than the invasive front (P = 0.001). Although HER2 -positivity was only 11.9% in this cohort, CLDN18 positivity in HER2-negative tumors (n = 74) was relatively high: 60.8% at 40% cut-off and 28.4% at 75% cut-off. Among double-negative (HER2 − and PD-L1 CPS &lt; 1) tumors, CLDN18 positivity was 67.6% at 40% cut-off and 26.5% at 75% cut-off. Conclusions CLDN18 expression is generally maintained in PD and is relatively high even in double-negative tumors, making it a promising therapeutic target for PD-positive gastric cancer.

Abstract GS01-05: Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) showed statistically significant improvements in PFS and OS vs placebo + chemo in patients (pts) with previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer (TNBC) whose tumors expressed PD-L1 with a combined positive score (CPS) ≥10 in the phase 3 KEYNOTE-355 study. Tolerable and effective maintenance regimens after induction therapy are needed to sustain clinical benefit. The PARP inhibitor olaparib is an established maintenance therapy for multiple platinum-sensitive tumor types and prior data suggest that PARP inhibitors combined with PD-1/PD-L1 inhibitors could provide an improved therapeutic effect. KEYLYNK-009 (NCT04191135) is a randomized open-label phase 2 study to evaluate the efficacy and safety of maintenance pembro + olaparib vs pembro + chemo in pts with locally recurrent inoperable or metastatic TNBC who had clinical benefit from induction with 1L pembro + platinum-based chemo. Methods: Eligible pts with measurable, locally recurrent inoperable or metastatic TNBC that had not been previously treated with chemo in the metastatic setting received induction therapy for up to 6 cycles of pembro 200 mg + chemo (carboplatin AUC 2 + gemcitabine 1000 mg/m2 on days 1 and 8) every 3 wk (Q3W). Pts with complete response (CR), partial response (PR), or stable disease (SD) after 4-6 treatment cycles were randomized 1:1 to receive pembro 200 mg Q3W + olaparib 300 mg twice daily or pembro + chemo (continued induction regimen). Olaparib or chemo was continued until progression or unacceptable toxicity; pembro was continued for up to 35 cycles (including induction treatment), progression, or unacceptable toxicity. Pts were stratified by induction response (CR or PR vs SD, by RECIST v1.1), tumor PD-L1 status (CPS ≥1 vs CPS &amp;lt; 1), and tumor genomic status (tBRCAm vs tBRCAwt). Dual primary endpoints were PFS per RECIST v1.1 by BICR and OS from randomization in all pts. Secondary endpoints included PFS and OS from randomization in pts with PD-L1 CPS ≥10 tumors and in pts with tBRCAm, and safety. Results: Of the 460 pts who received induction therapy, 271 were randomly assigned to pembro + olaparib (n=135) or pembro + chemo (n=136). At the Dec 15, 2022 data cutoff, median follow-up was 17.2 mo. Maintenance pembro + olaparib did not significantly improve PFS or OS vs pembro + chemo after induction therapy (Table). Median PFS was longer with pembro + olaparib vs pembro + chemo in pts with tBRCAm, but not in pts with PD-L1 CPS ≥10 tumors; a similar trend was observed for OS (Table). In 268 treated pts, treatment-related AEs (TRAEs) occurred in 114 of 135 pts (84.4%) for pembro + olaparib and in 128 of 133 pts (96.2%) for pembro + chemo. Grade ≥3 TRAEs occurred in 44 pts (32.6%) for pembro + olaparib (0 deaths) and in 91 pts (68.4%) for pembro + chemo (2 [1.5%] deaths), with 12 (8.9%) vs 26 (19.5%) discontinuations for TRAEs, respectively. Conclusions: The primary endpoints of PFS and OS were not met in an unselected population of pts with advanced TNBC. However, directionally favorable improvements in PFS and OS were observed in pts with tBRCAm with pembro + olaparib vs pembro + chemo, representing a potential maintenance strategy. Further data are required to confirm this effect. No new safety signals were observed, and there were fewer TRAEs in the pembro + olaparib group vs the pembro + chemo group. PFS and OS were evaluated from the time of randomization. *Based on stratified Cox regression model with Efron’s method of tie-handling with treatment as a covariate. NR = not reached. Citation Format: Hope Rugo, Mark Robson, Seock-Ah Im, Florence Dalenc, Eduardo Yañez Ruiz, Young-Hyuck Im, Sergii Kulyk, Oleksandr Dudnichenko, Néstor Llinás-Quintero, Shigehira Saji, Yasuo Miyoshi, Nadia Harbeck, Li Fan, Jaime Mejia, Vassiliki Karantza, David Cescon. Pembrolizumab + Olaparib vs Pembrolizumab + Chemotherapy After Induction With Pembrolizumab + Chemotherapy for Locally Recurrent Inoperable or Metastatic TNBC: Randomized Open-Label Phase 2 KEYLYNK-009 Study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-05.

Surgical management of gastric cancer in the era of immunotherapy

With the widespread application of immune checkpoint inhibitors, chemotherapy combined with immunotherapy has shown promising efficacy in the treatment of various cancers. Especially gastric cancer, this strategy is gradually expanding from first-line treatment in advanced stages to perioperative management. Compared to neoadjuvant chemotherapy alone, the combined approach not only improves pathological regression but also leads to better downstaging, which is particularly significant in gastric cancer subsets that are HER2-positive, mismatch repair deficient, PD-L1 combined positive score ≥5, or EB virus-positive. This combined treatment has made it possible to reduce the extent of gastrectomy, perform function-preserving surgeries, or even consider non-surgical strategies. Currently, exploring the optimal protocols for combining immune checkpoint inhibitors with chemotherapy, identifying potential indications for function-preserving surgery, improving surgical methods, and developing non-surgical strategies represent key issues in the surgical management of gastric cancer in the era of immunotherapy.

Impacts of tumor microenvironment during neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma.

With the advent of immune checkpoint inhibitors (ICIs), a better understanding of tumor microenvironment (TME) is becoming crucial in managing esophageal squamous cell carcinoma (ESCC) patients. We investigated the survival impact of TME status and changes in patients with ESCC who underwent neoadjuvant chemotherapy (NAC) followed by surgery (n = 264). We examined immunohistochemical status (CD4+, CD8+, CD20+, Foxp3+, HLA class-1+, CD204+, and programmed death ligand-1 [PD-L1+]) on 264 pre-NAC and 204 paired post-NAC specimens. Patients were classified by their pre- and post-NAC immune cell status and their changes following NAC. Our findings showed that pre-NAC TME status was not significantly associated with survival outcomes. In contrast, post-NAC TME status, such as low level of T cells, CD4+ T cells, and high PD-L1 combined positive score (CPS), were significantly associated with poor overall survival (OS). Notably, TME changes through NAC exerted significant survival impacts; patients with consistently low levels of T cells, low levels of CD4+ T cells, or high levels of PD-L1 (CPS) had very poor OS (3-year OS: 35.5%, 40.2%, and 33.3%, respectively). Tumor microenvironment changes of consistently low T cells, low CD4+ T cells, and high PD-L1 were independent predictors of poor OS in multivariate Cox hazards analyses, while factors indicating post-NAC status (T cells, CD4+, and PD-L1 [CPS]) alone were not. Therefore, we suggest that the consistently low T/high PD-L1 group could benefit from additional therapies, such as ICIs, and the importance of stratification by the TME, which has recently been recognized.

Discordant PD-L1 results between 28-8 and 22C3 assays are associated with outcomes of gastric cancer patients treated with nivolumab plus chemotherapy.

We evaluated the concordance/discordance of PD-L1 staining results between the 28-8 and 22C3 assays and its impact on the efficacy outcomes of advanced gastric cancer patients treated with nivolumab plus chemotherapy. This retrospective study involved 143 gastric cancer patients treated with first-line nivolumab plus chemotherapy whose PD-L1 results with both 28-8 and 22C3 assays were available. The concordance/discordance between these assays and the inter-observer variability were evaluated for PD-L1 combined positive score (CPS) positivity. Discordant PD-L1 results were analyzed regarding survival outcomes. The agreement rates and Cohen's kappa values between the 28-8 and 22C3 assays were 78.3% and 0.56 (for CPS ≥ 1), 81.8% and 0.60 (for CPS ≥ 5), and 88.8% and 0.66 (for CPS ≥ 10), respectively. Inter-observer variability, as represented by the intra-class correlation coefficient, was 0.89 and 0.88 for the 28-8 and 22C3 assays, respectively. With PD-L1 CPS ≥ 5 defined as positive, 35 (24.5%) and 82 (57.3%) had concordantly positive and negative results, respectively, between the 28-8 and 22C3 assays, whereas 26 (18.2%) had discordant results. Progression-free survival was shorter for those who exhibited negatively concordant PD-L1 results and discordant PD-L1 positivity between the 28-8 and 22C3 assays relative to those with positively concordant PD-L1 results (P = 0.013). PD-L1 assays by 28-8 and 22C3 showed suboptimal concordance, while inter-observer variability was not critical in advanced gastric cancer. Discordant PD-L1 results between 28-8 and 22C3 assays may be associated with unfavorable efficacy outcomes in patients treated with nivolumab plus chemotherapy.

Cost-utility of sintilimab plus chemotherapy vs chemotherapy as first-line treatment of advanced gastric or gastroesophageal junction cancer in China

ABSTRACT Objectives ORIENT-16, a phase III clinical trial conducted at 62 hospitals in China, reported that add-on sintilimab (Sin) to chemotherapy (Chemo) had favorable efficacy (p < 0.05) for patients with advanced HER2-negative gastric or gastroesophageal junction cancer (GC/GEJC). This study aimed to evaluate the cost-utility of the Sin+Chemo based on results of ORIENT-16 from the perspective of Chinese healthcare payers. Methods A three-state partitioned survival model was developed to simulate the 10-year life expectancy and total healthcare costs for patients with advanced HER2-negative GC/GEJC. Primary measure outcomes were: cost, quality-adjusted life-years (QALYs), and incremental cost-utility ratios (ICURs). Sensitivity/scenario analyses were conducted to assess the model robustness. Results In all patients, Sin+Chemo vs Chemo increased costs by $6,472, additionally providing 0.61 QALYs, resulting in an ICUR of $10,610/QALY. While, in PD-L1 combined positive score ≥ 5 cohort, the ICUR was $9,738/QALYs. The ICUR was most sensitive to the utility of progression-free survival. The probabilistic sensitivity analysis showed that add-on Sin had a 100% probability of being cost-effective at a willingness-to-pay threshold of $18,625/QALY gained. Conclusions Sin+Chemo is a cost-effective first-line treatment option for advanced HER2-negative GC/GEJC in China. Clinical trial registration ORIENT-16, www.clinicaltrials.gov, identifier is NCT03745170.

Gastric Carcinoma in Autoimmune Gastritis: A Histopathologic and Molecular Study

Patients with autoimmune gastritis (AIG) have a 13-fold risk of developing type-1 neuroendocrine tumors, whereas the risk for gastric adenocarcinoma is still uncertain. Here we describe the clinicopathologic and molecular features of a series of gastric carcinomas (GC) arising in the context of AIG. A total of 26 AIG-associated GC specimens were collected from 4 Italian Institutions. Immunohistochemistry for MUC1, MUC2, MUC5AC, MUC6, CDX2, HER2, PD-L1, CLDN18, mismatch repair (MMR) proteins, and p53 and EBV-encoded RNA (EBER) in situ hybridization were performed. Histologic and immunohistochemical features were jointly reviewed by 5 expert gastrointestinal pathologists. Next-generation sequencing analysis (TrueSight Oncology 500, Illumina) of 523 cancer-related genes was performed on 19 cases. Most tumors were diagnosed as pT1 (52%) and they were located in the corpus/fundus (58%) and associated with operative link for gastritis assessment stage II gastritis (80.8%), absence of parietal cells, complete intestinal metaplasia, and enterochromaffin-like-cell micronodular hyperplasia. Only 4 (15.4%) GCs were diagnosed during follow-up for AIG. The following histotypes were identified: 20 (77%) adenocarcinomas; 3 (11%) mixed neuroendocrine–non-neuroendocrine neoplasms, and 2 (8%) high-grade solid adenocarcinomas with focal neuroendocrine component, 1 (4%) adenocarcinoma with an amphicrine component. Overall, 7 cases (27%) showed MMR deficiency, 3 (12%) were positive (score 3+) for HER2, 6 (23%) were CLDN18 positive, and 11 (42%) had PD-L1 combined positive score ≥ 10. EBER was negative in all cases. Molecular analysis revealed 5/19 (26%) microsatellite instability (MSI) cases and 7 (37%) tumor mutational burden (TMB) high. The most frequently altered genes were TP53 (8/19, 42%), RNF43 (7/19, 37%), ERBB2 (7/19, 37% [2 amplified and 5 mutated cases]), ARID1A (6/19, 32%), and PIK3CA (4/19, 21%). In summary, AIG-associated GCs are often diagnosed at low stage in patients with longstanding misrecognized severe AIG; they often display a neuroendocrine component or differentiation, have relatively higher rates of MMR deficiency, and TMB high.

Abstract CT095: Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) &amp;lt;10: Safety, antitumor activity, and association between biomarkers and response

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) is an approved therapy for patients (pts) with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) based on results from KEYNOTE-355. However, there is unmet need for effective treatment options in pts with PD-L1 CPS &amp;lt;10. In a first-in-human, open-label, phase 1 study (NCT03396445), treatment with escalating doses of the humanized anti-CD27 agonist boserolimab (MK-5890) alone and with pembro had acceptable safety and preliminary evidence of antitumor activity in pts with advanced solid tumors. We report results for a dose-expansion cohort of this study in pts with metastatic TNBC and PD-L1 CPS &amp;lt;10 tumors who received first-line triple therapy with boserolimab, pembro, and chemo. Exploratory analyses in this cohort assessed the association of baseline T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) with ORR. Methods: This dose-expansion cohort enrolled pts aged ≥18 y with previously untreated locally recurrent inoperable or metastatic TNBC, measurable disease per RECIST v1.1, ECOG PS of 0/1, and tumors expressing PD-L1 at the cutoff of CPS &amp;lt;10 per PD-L1 IHC 22C3 pharmDx (local or central testing). Pts received boserolimab 30 mg IV Q6W plus pembro 400 mg IV Q6W for 18 cycles plus nab-paclitaxel 100 mg/m2 (3 weeks on [days 1, 8, and 15]/1 week off). Primary objectives were safety/tolerability. A secondary objective was ORR per RECIST v1.1 by investigator assessment. Baseline TcellinfGEP was assessed using the NanoString PCI assay (N=31); TMB was assessed using the Illumina TSO500 mutational panel assay (N=21). Results: 41 pts were enrolled in the dose-expansion cohort. Median study follow-up at data cutoff (Apr 25, 2023) was 11.1 (range, 2.2-20.5) mo. The most common treatment-related AEs were fatigue (51.2%), pruritus (51.2%), and alopecia (46.3%). Grade 3/4 treatment-related AEs occurred in 56.1% of pts (23/41); no grade 5 treatment-related AEs occurred. 9.8% of pts (4/41) discontinued ≥1 study treatment due to treatment-related AEs. Confirmed ORR was 46.3% (95% CI, 30.7%-62.6%), with 2 CRs and 17 PRs; 14 pts had SD, 5 had PD, and 3 had no postbaseline assessment at data cutoff. Median PFS was 10.3 (95% CI, 4.2-not reached) mo. No clear association between TcellinfGEP or TMB and confirmed ORR was observed; responses were observed in pts with non-TcellinfGEP-high (less than −0.318) and non-TMB-high (&amp;lt;10 mut/Mb) tumors. Conclusions: In pts with TNBC and tumors expressing PD-L1 at the cutoff of CPS &amp;lt;10, triple therapy with boserolimab, pembro, and chemo had acceptable safety and showed preliminary evidence of antitumor activity regardless of baseline TcellinfGEP expression or TMB status. Citation Format: Carlos Rojas, Bernard Gaston Doger de Spéville, Seock-Ah Im, Ronnie Shapira-Frommer, María De Miguel, Lucía González Cortijo, Margarita Romeo Marin, Maja de Jonge, Mark Ayers, Yiwei Zhang, Song Zhai, Elliot Chartash, Konstantin Dobrenkov, Joohyuk Sohn. Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) &amp;lt;10: Safety, antitumor activity, and association between biomarkers and response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT095.

Abstract CT114: Phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously untreated advanced head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC)

Abstract Background: ILT4 is an immunosuppressive receptor commonly expressed on myeloid cells. Antagonism of ILT4 may induce a proinflammatory state and stimulate antitumor T-cell response, especially with PD-(L)1 blockade. In the dose escalation phase of a first-in-human phase 1 study (NCT03564691), the anti-ILT4 IgG4 monoclonal antibody, MK-4830, in combination with pembrolizumab (pembro) was well tolerated and demonstrated antitumor activity in advanced solid tumors. Here, we present safety, efficacy, and biomarker analyses for MK-4830 + pembro from the multi-cohort expansion phase of patients (pts) with previously untreated advanced HNSCC or NSCLC. Methods: Pts aged ≥18 y with previously untreated advanced HNSCC and PD-L1 combined positive score (CPS) ≥1 (cohort D) or NSCLC regardless of PD-L1 status (cohorts E and F) were enrolled. Pts in all cohorts received either MK-4830 800 mg (cohorts D and E) or 1600 mg (cohort F) + pembro 200 mg Q3W for ≤35 cycles. Primary end points were safety and ORR per RECIST v1.1 by investigator assessment. Exploratory end points included DOR and PFS per RECIST v1.1 by investigator assessment and evaluating possible biomarkers of response to MK-4830 + pembro. Results: At data cut-off (September 27, 2023), 35, 47, and 11 pts were enrolled and received treatment in cohorts D, E, and F, respectively. Median study follow-up was 34.4 mo (range, 26.5-42.4) in cohort D, 35.9 mo (22.4-39.8) in cohort E, and 38.7 mo (37.6-39.6) in cohort F. Adverse events (AEs) occurred in 33 pts (94%) in cohort D, 43 pts (91%) in cohort E, and 10 pts (91%) in cohort F. Treatment-related AEs (TRAEs) occurred in 20 pts (57%) in cohort D, 26 pts (55%) in cohort E, and 6 pts (55%) in cohort F; grade 3-5 TRAEs occurred in 5 pts (14%), 4 pts (9%), and 1 pt (9%), respectively. One pt in cohort E and 1 pt in cohort F died due to a TRAE (pneumonitis and pneumonia, respectively). ORR was 24% (95% CI, 11-41) in cohort D, 30% (17-45) in cohort E, and 27% (6-61) in cohort F. Median DOR was 16.4 mo (range, 2.2+ to 24.4+) in cohort D, 14.8 mo (4.2+ to 32.9+) in cohort E, and 8.4 mo (3.0-21.5) in cohort F. Median PFS was 5.2 mo (95% CI, 2.0-8.0) in cohort D, 4.3 mo (1.8-8.1) in cohort E, and 3.3 (1.2-7.6) in cohort F. In cohort D, T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) did not enrich for response to MK-4830 + pembro. In cohorts E and F, PD-L1 tumor proportion score (TPS) and TcellinfGEP trended higher in pts with response to MK-4830 + pembro than pts with no response; TMB did not trend with response. Conclusions: In pts with advanced HNSCC or NSCLC, first-line MK-4830 + pembro had a manageable AE profile with modest antitumor activity. Consistent with what was previously observed for pembro alone, a trend was observed between PD-L1 TPS and response to MK-4830 + pembro in pts with NSCLC. Citation Format: Byoung Chul Cho, John Hilton, Cristina P. Rodriguez, Marcelo Bonomi, Lillian L. Siu, Marta Gil-Martin, Shabana Siddiqi, Nicole M. Myer, Leah Suttner, Douglas Wilson, Omobolaji Akala, Rafal Dziadziuszko. Phase 1 study of the anti-immunoglobulin-like transcript 4 (ILT4) monoclonal antibody MK-4830 plus pembrolizumab in patients with previously untreated advanced head and neck squamous cell carcinoma (HNSCC) or non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT114.

Abstract CT061: Pharmacodynamic analysis from a phase 1/2 study of subasumstat (TAK-981) as single agent in patients (pts) with advanced/refractory metastatic solid tumors

Abstract Background Subasumstat (TAK-981, suba) is a first-in-class innate immunity enhancer that unlocks innate/adaptive immune responses to target tumors through SUMOylation inhibition, which may enhance antitumor activity by restoring endogenous type 1 IFN signaling in immune cells. In the phase 1/2 study (NCT03648372), suba showed dose-dependent upregulation of an IFN-1 gene signature in peripheral blood (PB) and plasma levels of several IFN-1-induced cytokines, and an increase in activated NK, CD8, and CD4 T cells in PB. Here, we report pharmacodynamic data from skin and tumor biopsy samples from this study. Methods In phase 1, 84 pts received suba IV at escalating doses (3-120 mg) twice-weekly (BIW) or once-weekly in 21-day cycles. In phase 2, 25 pts with refractory NSCLC, cervical cancer, or CRC received suba 90 mg BIW. Skin and tumor biopsies were collected at screening and on cycle 1, day 8 (C1D8, skin) or C2D8 (+7 days; tumor). Target engagement (TE) and levels of SUMO2/3-conjugates were assessed using IHC. Immune activation in the tumor microenvironment (TME) was measured by IHC and multiplex IF. Results In skin samples collected 1-3 hours after D8 dosing, suba ≥10 mg demonstrated dose-dependent TE as seen by suba-SUMO adduct formation and dose-dependent SUMO2/3 inhibition at ≥60 mg. Assays of paired tumor samples from pts with CPI-naïve MSS-CRC (90 mg BIW, n=3), cervical cancer (90 mg BIW, n=1), CPI-exposed non-squamous NSCLC (90 mg BIW, n=2), and melanoma (25 mg BIW, n=1) showed robust TE in the post-dose sample, along with SUMO2/3 inhibition or stabilization. Suba’s effects on the TME were assessed through PD-L1 IHC. There was an increase in PD-L1 combined positive score in most on-treatment tumors, consistent with suba’s ability to enhance IFN production, leading to induction of an inflammatory landscape in the TME. Multiplex IF analysis revealed significant CD8+ and CD4+ T cell infiltration in samples from CPI-naïve (cervical cancer) and CPI-exposed (melanoma and NSCLC) pts. In contrast, biopsies obtained from MSS-CRC pts did not exhibit an increase in T cell density, suggesting that “cold” tumors may be less susceptible to suba-mediated immune remodeling. Accordingly, biopsies from pts with cervical cancer and melanoma displayed a significant increase in T cell activation and density of activated CD11c+HLA-DR+ myeloid dendritic cells within the TME, as well as a marked increase in HLA-class I expression. Conclusion Suba-mediated inhibition of SUMOylation led to marked changes in the TME across different indications, supporting the hypothesized immune-activating mechanism of action of the drug. Our findings support continued development of suba in solid tumors. Suba is being evaluated in combination with pembrolizumab in NSCLC, cervical cancer, and melanoma (NCT04381650). Citation Format: Dina Stroopinsky, Slawomir Mandzuik, Daniel Anderson, José-Ángel Hernández-Rivas, Hadeel Assad, Allison Berger, Aleksander Chudnovsky, Qi Dong, Afshin Dowlati, Dejan Juric, Razelle Kurzrock, Iwona Lugowska, Kelly Richter, Jordi Rodón, David Schröder, Siddha Kasar, Anthony Olzanski. Pharmacodynamic analysis from a phase 1/2 study of subasumstat (TAK-981) as single agent in patients (pts) with advanced/refractory metastatic solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT061.

FOLFIRI Plus Durvalumab With or Without Tremelimumab in Second-Line Treatment of Advanced Gastric or Gastroesophageal Junction Adenocarcinoma

Efficacy of second-line chemotherapy in advanced gastric or gastrooesphageal junction (GEJ) adenocarcinoma remains limited. To determine the efficacy of 1 or 2 immune checkpoint inhibitors combined with FOLFIRI (leucovorin [folinic acid], fluorouracil, and irinotecan) in the treatment of advanced gastric/GEJ adenocarcinoma. The PRODIGE 59-FFCD 1707-DURIGAST trial is a randomized, multicenter, noncomparative, phase 2 trial, conducted from August 27, 2020, and June 4, 2021, at 37 centers in France that included patients with advanced gastric/GEJ adenocarcinoma who had disease progression after platinum-based first-line chemotherapy. Patients were randomized to receive FOLFIRI plus durvalumab (anti-programmed cell death 1 [PD-L1]) (FD arm) or FOLFIRI plus durvalumab and tremelimumab (anti-cytotoxic T-lymphocyte associated protein 4 [CTLA-4]) (FDT arm). The efficacy analyses used a clinical cutoff date of January 9, 2023. The primary end point was progression-free survival (PFS) at 4 months according to RECIST 1.1 criteria evaluated by investigators. Overall, between August 27, 2020, and June 4, 2021, 96 patients were randomized (48 in each arm). The median age was 59.7 years, 28 patients (30.4%) were women and 49 (53.3%) had GEJ tumors. Four month PFS was 44.7% (90% CI, 32.3-57.7) and 55.6% (90% CI, 42.3-68.3) in the FD and FDT arms, respectively. The primary end point was not met. Median PFS was 3.8 and 5.4 months, objective response rates were 34.7% and 37.7%, and median overall survival was 13.2 and 9.5 months in the FD and FDT arms, respectively. Disease control beyond 1 year was 14.9% in the FD arm and 24.4% in the FDT arm. Grade 3 to 4 treatment-related adverse events were observed in 22 (47.8%) patients in each arm. A combined positive score (CPS) PD-L1 of 5 or higher was observed in 18 tumors (34.0%) and a tumor proportion score (TPS) PD-L1 of 1% or higher in 13 tumors (24.5%). Median PFS according to CPS PD-L1 was similar (3.6 months for PD-L1 CPS ≥5 vs 5.4 months for PD-L1 CPS <5) by contrast for TPS PD-L1 (6.0 months for PD-L1 TPS ≥1% vs 3.8 months for PD-L1 TPS <1%). Combination of immune checkpoint inhibitors with FOLFIRI in second-line treatment for advanced gastric/GEJ adenocarcinoma showed an acceptable safety profile but antitumor activity only in a subgroup of patients. ClinicalTrials.gov Identifier: NCT03959293.

Pembrolizumab Plus mFOLFOX7 or FOLFIRI for Microsatellite Stable/Mismatch Repair–Proficient Metastatic Colorectal Cancer: KEYNOTE-651 Cohorts B and D

BackgroundThe phase 1b KEYNOTE-651 study evaluated pembrolizumab plus chemotherapy in microsatellite stable or mismatch repair-proficient metastatic colorectal cancer. Patients and MethodsPatients with microsatellite stable or mismatch repair-proficient metastatic colorectal cancer received pembrolizumab 200 mg every 3 weeks plus 5-fluorouracil, leucovorin, oxaliplatin (previously untreated; cohort B) or 5-fluorouracil, leucovorin, irinotecan (previously treated with fluoropyrimidine plus oxaliplatin; cohort D) every 2 weeks. Primary end point was safety; investigator-assessed objective response rate per RECIST v1.1 was secondary and biomarker analysis was exploratory. ResultsThirty-one patients were enrolled in cohort B and 32 in cohort D; median follow-up was 30.2 and 33.5 months, respectively. One dose-limiting toxicity (grade 3 small intestine obstruction) occurred in cohort D. In cohort B, grade 3/4 treatment-related adverse events (AEs) occurred in 18 patients (58%), most commonly neutropenia and decreased neutrophil count (n = 5 each). In cohort D, grade 3/4 treatment-related AEs occurred in 17 patients (53%), most commonly neutropenia (n = 7). No grade 5 treatment-related AEs occurred. Objective response rate was 61% in cohort B (KRAS wildtype: 71%; KRAS mutant: 53%) and 25% in cohort D (KRAS wildtype: 47%; KRAS mutant: 6%). In both cohorts, programmed cell death protein 1 combined positive score and T-cell-inflamed gene expression profiles were higher and human epidermal growth factor receptor 2 expression was lower in responders than nonresponders. No association between tumor mutational burden and response was observed. ConclusionPembrolizumab plus 5-fluorouracil, leucovorin, oxaliplatin/5-fluorouracil, leucovorin, irinotecan demonstrated an acceptable AE profile. Efficacy data appeared comparable with current standard of care (including by KRAS mutation status). Biomarker analyses were hypothesis-generating, warranting further exploration. ClinicalTrials.gov IdentifierClinicalTrials.gov; NCT03374254

Atezolizumab plus modified docetaxel, cisplatin, and fluorouracil as first-line treatment for advanced anal cancer (SCARCE C17-02 PRODIGE 60): a randomised, non-comparative, phase 2 study

The modified docetaxel, cisplatin, and fluorouracil (mDCF) regimen has shown efficacy and safety as first-line treatment for advanced squamous cell carcinoma of the anus, making it a standard regimen. Inhibitors of programmed cell death protein 1 and its ligand, such as pembrolizumab, nivolumab, retifanlimab, avelumab, and atezolizumab, have shown some antitumour activity as monotherapy in advanced squamous cell carcinoma of the anus that is refractory to chemotherapy. This phase 2 study evaluated the combination of mDCF and atezolizumab as first-line treatment in advanced squamous cell carcinoma of the anus. In this randomised, open-label, non-comparative, phase 2 study, participants from 21 centres (academic, private, and community hospitals and cancer research centres) across France with chemo-naive, metastatic, or unresectable locally advanced recurrent squamous cell carcinoma of the anus, aged 18 years or older, and with an Eastern Cooperative Oncology Group performance status of 0 or 1, were randomly allocated (2:1) to receive either atezolizumab (800 mg intravenously every 2 weeks up to 1 year) plus mDCF (eight cycles of 40 mg per m2 docetaxel and 40 mg per m2 cisplatin on day 1 and 1200 mg per m2 per day of fluorouracil for 2 days, every 2 weeks intravenously; group A) or mDCF alone (group B). Randomisation was done centrally using a minimisation technique and was stratified by age (<65 years vs ≥65 years) and disease status. The primary endpoint was investigator-assessed 12-month progression-free survival in the modified intention-to-treat population in group A (35% for the null hypothesis and 50% for the alternative hypothesis). This trial is registered with ClinicalTrials.gov, NCT03519295, and is closed to new participants. 97 evaluable participants (64 in group A and 33 in group B) were enrolled between July 3, 2018, and Aug 19, 2020. The median follow-up was 26·5 months (95% CI 24·8-28·4). The median age of participants was 64·1 years (IQR 56·2-71·6), and 71 (73%) were female. 12-month progression-free survival was 45% (90% CI 35-55) in group A and 43% (29-58) in group B. In participants with a PD-L1 combined positive score of 5 or greater, 12-month progression-free survival was 70% (95% CI 47-100) in group A and 40% (19-85) in group B (interaction p=0·051) Both groups showed high compliance. Adverse events of grade 3 or higher were observed in 39 (61%) participants in group A and 14 (42%) in group B. The most common grade 3-4 adverse events were neutropenia (nine [14%] participants in group A vs five [15%] in group B), anaemia (nine [14%] vs one [3%]), fatigue (three [5%] vs four [12%]), and diarrhoea (seven [11%] vs one [3%]). Serious adverse events occurred in 16 (25%) participants in group A and four (12%) in group B, and these were mDCF-related in seven (11%) participants in group A and four (12%) in group B. Atezolizumab-related serious adverse events occurred in nine (14%) participants in group A, including grade 2 infusion-related reaction in three (5%), grade 3 infection in two (3%), and grade 2 colitis, grade 3 acute kidney injury, grade 3 sarcoidosis, and a grade 4 platelet count decrease each in one participant (2%). There were no treatment-related deaths. Despite a higher incidence of adverse events, combining atezolizumab with mDCF is feasible, with similar dose intensity in both groups, although the primary efficacy endpoint was not met. The predictive value of a PD-L1 combined positive score of 5 or greater now needs to be confirmed in future studies. GERCOR, Roche.

Abstract 3629: Prevalence of claudin18.2 expression in gastric/gastroesophageal junction adenocarcinoma among patients in TranStar101 and TranStar102 clinical trials

Abstract Background: Claudin18.2 (CLDN18.2) is a tight junction protein highly specific to gastric mucosa, and a validated target for gastric cancer (GC) treatment. Immune checkpoint therapy targeting PD-1 combined with chemotherapy has been approved as the first line therapy of GC. Understanding the expression profiles of CLDN18.2 and PD-L1 could guide the development of combination therapies to maximize the benefits of these two agents. This study investigated the prevalence of CLDN18.2 expression in gastric/gastroesophageal junction adenocarcinoma (G/GEJC) screening samples from studies Transtar101 (NCT04396821 in US) and TranStar102 (NCT04495296 in China), and its correlation with various clinical characteristics and PD-L1 expression. Methods: CLDN18.2 expression in formalin-fixed, paraffin-embedded (FFPE) G/GEJC tissue samples was prospectively detected by an immunohistochemistry-based LDT using an in-house anti-CLDN18.2 antibody (Clone14G11) on the Leica Bond III stainer. CLDN18.2 expression was assessed by scoring the staining intensity (0, 1+, 2+, 3+) and the percentage of positive tumor cells. Positive CLDN18.2 expression is defined as the cutoff at ≥10% of tumor cell with ≥1+ staining intensity for this evaluation. PD-L1 expression was assessed by combined positive score (CPS) using Agilent’s PD-L1 IHC 28-8 pharmDx. Both assays were conducted in CAP/CLIA certified LabCorp central lab. Results: 547 G/GEJC patient samples had CLDN18.2 results as part of the screening procedures for the clinical trials. Of these patients (454 GC/93 GEJC), 439 (80%) were Asian, 29 (5%) were Caucasian, 2 (0.4%) were other ethnic group, and 77 (14%) were not recorded; 434 (79%) were primary tumors and 113 (21%) were metastasis; 201 (37%) were core needle biopsies (CNB), 108 (20%) were surgical resections (SR) and 238 (44%) had no information. 311 (57%) samples had positive CLDN18.2 expressions (≥10%/≥1+). No significant difference in CLDN18.2 positive rates were found between TranStar101 and TranStar102 studies (p=0.801), Asian and Caucasian (p=0.612), GC and GEJC (p=0.373), primary and metastatic specimens (p=0.055) or CNBs and SRs (p=0.715). Out of 83 TranStar102 specimens that had both CLDN18.2 and PD-L1 results, 15 (18%) had PD-L1 CPS≥5, 59 (71%) had positive CLDN18.2, and 10 (15%) had both positive CLDN18.2 and PD-L1 CPS≥5. No correlation (p=0.393) was observed between PD-L1 scores (CPS&amp;lt;5 or CPS≥5) and CLDN18.2 expression (≥10%/≥1+ or &amp;lt;10%/≥1+). Conclusions: Data suggested CLDN18.2 expression levels were independent of PD-L1 status, and support the use of Transcenta 14G11 antibody for CLDN18.2 detection regardless of sample collection methods, location, and patient demographics. An anti-CLDN18.2 companion diagnostic device based on 14G11 is being developed (CLDN18.2 IHC 14G11 pharmDx, Agilent Technologies, Inc.). Citation Format: Li Shen, Carol Mao, Alan Lin, Ying Gu, Jenny Milata, Lijuan Zhang, Chuan Qi, Jenny Yao, Steven Yu, Changjun Yue, Lin Shen, Yelena Janjigian, Xueming Qian, Wen-I Chang, Caroline Germa. Prevalence of claudin18.2 expression in gastric/gastroesophageal junction adenocarcinoma among patients in TranStar101 and TranStar102 clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3629.

Tislelizumab plus chemotherapy is an optimal option for second-line treatment for advanced gastroesophageal junction adenocarcinoma.

The development of programmed cell death receptor-1 and its ligand (PD-L1) have offered new treatment options for several cancers, but the clinical benefit of tislelizumab in the gastroesophageal junction (GEJ) adenocarcinoma is still murky. Thus, we aim to investigate the efficacy and safety of tislelizumab combined with chemotherapy in patients with GEJ cancer. In this study, 90 GEJ patients were retrospectively enrolled including 45 patients who received chemotherapy plus tislelizumab while 45 underwent chemotherapy only. Overall response rate (ORR), overall survival (OS), and progression-free survival (PFS) were estimated and safety was assessed by treatment-related adverse events between two arms. The ORR was significantly higher in the tislelizumab group than in patients with chemotherapy alone (71.1 vs. 44.4%). The PFS [54.7% (47.2-62.2) vs. 33.3% (26.3-40.3), P = 0.047] and OS [62.1% (54.5-69.7) vs. 40.0% (32.5-47.5), P = 0.031] were also significantly improved in patients with concomitant use of tislelizumab. When stratified by PD-L1 combined positive score (CPS), patients with PD-L1 CPS ≥ 1 also with significantly higher PFS and OS when taking tislelizumab (P = 0.015 and P = 0.038). The incidence of hematologic toxicity was similar in the combination arm compared to the chemotherapy alone arm and the number of adverse events was not significantly increased by adding tislelizumab (all P > 0.05). Concomitant use of tislelizumab and chemotherapy in GEJ patients may be with optimal therapeutic effect and similar incidence of adverse events than chemotherapy alone. Further studies with larger number of patients are warranted to confirm it.

First effectiveness data of lenvatinib and pembrolizumab as first-line therapy in advanced anaplastic thyroid cancer: a retrospective cohort study

BackgroundAnaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC.MethodsIn a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients.ResultsFive patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8–5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%.ConclusionsThe combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients.

First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We report 3-year efficacy and safety results from the phase III CheckMate 649 trial. Patients with previously untreated advanced or metastatic gastroesophageal adenocarcinoma were randomly assigned to nivolumab plus chemotherapy or chemotherapy. Primary end points were overall survival (OS) and progression-free survival (PFS) by blinded independent central review (BICR) in patients whose tumors expressed PD-L1 combined positive score (CPS) ≥5. With 36.2-month minimum follow-up, for patients with PD-L1 CPS ≥5, the OS hazard ratio (HR) for nivolumab plus chemotherapy versus chemotherapy was 0.70 (95% CI, 0.61 to 0.81); 21% versus 10% of patients were alive at 36 months, respectively; the PFS HR was 0.70 (95% CI, 0.60 to 0.81); 36-month PFS rates were 13% versus 8%, respectively. The objective response rate (ORR) per BICR was 60% (95% CI, 55 to 65) with nivolumab plus chemotherapy versus 45% (95% CI, 40 to 50) with chemotherapy; median duration of response was 9.6 months (95% CI, 8.2 to 12.4) versus 7.0 months (95% CI, 5.6 to 7.9), respectively. Nivolumab plus chemotherapy also continued to show improvement in OS, PFS, and ORR versus chemotherapy in the overall population. Adding nivolumab to chemotherapy maintained clinically meaningful long-term survival benefit versus chemotherapy alone, with an acceptable safety profile, supporting the continued use of nivolumab plus chemotherapy as standard first-line treatment for advanced gastroesophageal adenocarcinoma.

Phase 3 KEYNOTE-992 study of pembrolizumab plus chemoradiotherapy versus placebo plus chemoradiotherapy in patients with muscle-invasive bladder cancer (MIBC).

TPS720 Background: Concurrent chemoradiotherapy (CRT) is a recommended treatment option for patients (pts) with MIBC who seek a bladder-preserving alternative to radical cystectomy and/or not candidates for radical cystectomy. The anti–PD-1 antibody pembrolizumab is approved for metastatic bladder cancer and non–muscle-invasive bladder cancer (NMIBC). The randomized, double-blind, phase 3 KEYNOTE-992 study (NCT04241185) is evaluating efficacy and safety of pembrolizumab plus CRT versus placebo plus CRT in pts with MIBC who chose bladder preservation. Methods: Eligibility criteria include adultswho have a histologically confirmed initial diagnosis of MIBC (T2-T4aN0M0) with ≥50% urothelial histology, ECOG PS score of 0 to 2, have received no prior therapy with anti–PD-1/L1 or agents directed to another stimulatory or coinhibitory T-cell receptor, and have planned treatment with one of the specified radiosensitizing chemotherapies. Prior treatment for NMIBC with intravesical instillation therapy such as BCG or intravesical chemotherapy is permitted. Approximately 636 pts will be randomly assigned 1:1 to receive pembrolizumab 400 mg IV or placebo IV every 6 weeks for up to 9 cycles, both with CRT. Investigator’s choice of chemotherapy will be specified before random assignment. Pts will be stratified by ECOG PS (0 and 1 vs 2), PD-L1 combined positive score (&lt;10 vs ≥10), T stage (T2 vs T3 and T4), and geographic region (United States vs European Union vs rest of the world). Radiosensitizing chemotherapy will be cisplatin monotherapy (35 mg/m2 IV weekly on day 1), 5-fluorouracil (500 mg/m2 on days 1-5 and days 22-26) plus mitomycin C (12 mg/m2 on day 1), or gemcitabine monotherapy (27 mg/m2 IV twice weekly on days 1 and 4). Radiation therapy will be conventional radiotherapy consisting of 64 Gy at 2 Gy/fraction over 6.5 weeks (whole bladder with or without pelvic nodes) or hypofractionated radiotherapy consisting of 55 Gy at 2.75 Gy/fraction over 4 weeks (whole bladder only). Imaging via CT and CT urography or magnetic resonance urography will be performed 10 weeks after completion of CRT, every 12 weeks until the end of year 2, then every 24 weeks thereafter. Adverse events (AEs) will be monitored throughout the study and up to 30 days after cessation of treatment (90 days for serious AEs). Primary end point is bladder-intact event-free survival (defined as time from random assignment to first documented occurrence of residual/recurrent MIBC, nodal or distant metastases, radical cystectomy, or death from any cause) as assessed by blinded independent central review and/or central pathology review. Secondary end points are overall survival, metastasis-free survival, time to cystectomy, time to occurrence of NMIBC, safety and tolerability, and patient-reported outcomes. Enrollment is ongoing in Asia, Australia, Europe, North America, and South America. Clinical trial information: NCT04241185 .

Phase 3 KEYNOTE-676 cohort A: Bacillus Calmette-Guérin (BCG) with or without pembrolizumab for high-risk (HR) non–muscle-invasive bladder cancer (NMIBC) that persists/recurs after BCG induction.

TPS722 Background: Intravesical instillation of BCG is a standard-of-care treatment for patients with HR NMIBC, but up to 50% of patients later experience disease recurrence or progression to muscle-invasive bladder cancer (MIBC) despite BCG treatment. In the phase 2 KEYNOTE-057 study (NCT02625961), pembrolizumab monotherapy was shown to have antitumor activity in patients with HR BCG–unresponsive NMIBC who had carcinoma in situ (CIS) with or without papillary tumors and in patients with only papillary tumors. In cohort A of the randomized, phase 3 KEYNOTE-676 trial (NCT03711032), pembrolizumab plus BCG versus BCG alone is being evaluated in patients with persistent/recurrent HR NMIBC after first BCG induction. Methods: Key eligibility criteria include adults with histologically confirmed HR NMIBC (T1, high-grade Ta, and/or CIS) that is persistent/recurrent following 1 adequate course of BCG induction therapy, have no concurrent extravesical disease or history of extravesical disease that recurred within 2 years, have an ECOG PS score of 0 to 2, and have undergone cystoscopy/TURBT ≤12 weeks before randomization. Approximately 430 patients will be randomly assigned 1:1 to receive pembrolizumab 200 mg intravenously every 3 weeks plus BCG or BCG alone. BCG (50 mg) will be administered by intravesical instillation as induction therapy once weekly for 6 weeks and then as maintenance therapy once weekly for 3 weeks at weeks 13 and 25, then every 24 weeks (Q24W) thereafter. Treatment will continue for approximately 2 years (pembrolizumab) or 3 years (BCG), or until confirmed persistent/recurrent HR NMIBC or disease progression to MIBC or metastatic bladder cancer, unacceptable toxicity, or withdrawal. Randomization to treatment will be stratified by PD-L1 combined positive score (≥10 or ˂10), histology (CIS or non-CIS), and NMIBC disease history (persistence/recurrence 0 to ≤6 months or recurrence ˃6 to ≤12 months or recurrence ˃12 to ≤24 months). Response will be assessed by local cystoscopy and blinded independent central review of urine cytology and biopsy (as applicable) every 12 weeks for years 1 to 2 and Q24W for years 3 to 5. Computed tomography urography will occur every 72 weeks through year 5, then every 104 weeks thereafter. The primary end point is complete response rate in patients with CIS. Secondary end points are duration of response in patients with CIS, event-free survival, recurrence-free survival, time to cystectomy, overall survival, disease-specific survival, safety and tolerability, and patient-reported outcomes. Enrollment incohort A of KEYNOTE-676 is ongoing in Asia, Australia, Europe, and North America. Clinical trial information: NCT03711032 .