Administration Of Pembrolizumab Research Articles

CTIM-11. SINGLE-CENTER, OFF-LABEL NEOADJUVANT PEMBROLIZUMAB FOR TREATMENT OF RECURRENT GBM AT UCLA

Abstract Neoadjuvant drug administration provides a window of opportunity for developing novel therapies. Specifically, neoadjuvant pembrolizumab (PD1 checkpoint inhibitor) has the potential for improving understanding of immunomodulatory effects on the tumor microenvironment and for treating recurrent GBM. It is known that a functional immune deficit exists within the tumor T-lymphocyte compartment. As pembrolizumab promotes lymphocyte infiltration, it may contribute to antitumor effects in the neoadjuvant setting. Our previous randomized clinical trial (RCT) suggested that neoadjuvant pembrolizumab improved survival for recurrent GBM patients with 1-2 relapses. Here, we sought to extend our original findings and analyze the role of off-label neoadjuvant pembrolizumab in patients with multiple recurrences. We identified a retrospective 22-patient cohort at UCLA. Every patient had a GBM tissue diagnosis, received standard treatment, and had one to five recurrences. Each received off-label neoadjuvant pembrolizumab and surgical resection within 7-21 days. Progression-free (PFS) and overall survival (OS) for our cohort of neoadjuvant-treated patients were calculated as days from surgical resection and compared to historical control data from the original RCT (n = 15 neoadjuvant, 15 adjuvant). Results show that administration of neoadjuvant pembrolizumab in our cohort significantly increased median PFS compared to our historical adjuvant control (114 vs 75 days, p = 0.03). The OS of our neoadjuvant cohort was 294 days as compared to 192 days in the historical control. Both PFS and OS in our neoadjuvant cohort were not statistically different than the historical neoadjuvant cohort (PFSp = 0.08, OSp = 0.13). Since our cohort was not limited to initial recurrences, this data suggests that patients with more advanced recurrences could also benefit from neo-adjuvant therapy. Ongoing work will evaluate the microenvironmental genetic signature induced by pembrolizumab and assess pre-surgical tumor volume so that adequate comparisons can be made with other trials. We believe this promising finding offers novel therapeutic options for those patients with multiple recurrences.

EP08.01-046 Examination of Long-Term Administration of Pembrolizumab in Patients with Non-small Cell Lung Cancer at Our Institution

There are many reports suggesting the effectiveness of combination therapy of cytotoxic agents and immune checkpoint inhibitors in patients with non-small cell lung cancer. There have been some cases of long-term administration of pembrolizumab because good disease control of the patient can be maintained. We assessed the prognosis of patients who continued to be administer pembrolizumab at our institution for more than one year.

The Impact of Neutrophil-to-Lymphocyte Ratio after Two Courses of Pembrolizumab for Oncological Outcomes in Patients with Metastatic Urothelial Carcinoma.

We focused on the therapeutic effect of pembrolizumab for metastatic urothelial carcinoma (mUC) and evaluated predictive factors for improving clinical outcomes. We conducted a retrospective multicenter cohort study of patients with mUC who received pembrolizumab. The endpoint was to evaluate the association between clinicopathological features and oncological outcomes. A total of 160 patients were enrolled in this study and were divided into two groups: the responder and the non-responder group, according to the best response. They were followed up for a median period of 10 months. The median overall (OS) and progression-free survival (PFS) in this study were 17 and 4 months, respectively. The responder group did not achieve median OS and it was 10 months in the non-responder group (p < 0.001). Similarly, the responder group did not achieve PFS, and it was 2 months in the non-responder group (p < 0.001). Regarding the neutrophil-to-lymphocyte ratio (NLR) after two courses of administration of pembrolizumab, patients with NLR < 3.24 had significantly better oncological outcomes than those with NLR ≥ 3.24. Multivariate analysis showed a significant association between NLR after two courses of pembrolizumab and OS. Therefore, the absolute value of NLR after two courses of pembrolizumab was a significant predictive factor for oncological outcomes.

Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma.

Immune checkpoint inhibitors have been approved as second-line therapy for patients with advanced urothelial carcinoma (UC). However, which patients will obtain clinical benefit remains to be determined. To identify predictive biomarkers for the pembrolizumab (PEM) response early during treatment, the present study investigated 31 patients with chemotherapy-resistant recurrent or metastatic UC who received 200 mg PEM intravenously every 3 weeks. Blood was taken just before the first dose and again before the second dose, and the peripheral blood mononuclear cells of all 31 pairs of blood samples were immune phenotyped by flow cytometry. Data were assessed by principal component analysis (PCA), correlation analysis and Cox proportional hazards modeling in order to comprehensively determine the effects of PEM on peripheral mononuclear immune cells. Absolute counts of CD45RA+CD27-CCR7- terminally differentiated CD8+ T cells and KLRG1+CD57+ senescent CD8+ T cells were significantly increased after PEM administration (P=0.042 and P=0.043, respectively). Senescent and exhausted CD4+ and CD8+ T cell dynamics were strongly associated with each other. By contrast, counts of monocytic myeloid-derived suppressor cells (mMDSCs) were not associated with other immune cell phenotypes. The results of PCA and non-hierarchical clustering of patients suggested that excessive T cell senescence and differentiation early during treatment were not necessarily associated with a survival benefit. However, decreased mMDSC counts after PEM were associated with improved overall survival. In conclusion, early on-treatment peripheral T cell status was associated with response to PEM; however, it was not associated with clinical benefit. By contrast, decreased peripheral mMDSC counts did predict improved overall survival.

Abstract 3527: Novel bacteria strains, CJRS-10671 and CJRS-10672, enhance anti-tumor efficacy in LLC1 syngeneic model and humanized PDX mice model

Abstract Background: Immune checkpoint inhibitor has emerged as remarkable therapeutic that improves the anti-cancer effect of patients. However, response rate is low in a large proportion of patients. The overall efficacy of immune checkpoint inhibitor therapy remains unsatisfactory. Recently, live biotherapeutic products (LBPs) have emerged as potential therapeutics to overcome the limitation of immune checkpoint inhibitor. Here, we demonstrated the efficacy of CJRS-10671 and CJRS-10672 in tumor bearing mice models. Methods: To evaluate anti-tumor effects, 109 CFU/mouse CJRS-10671 was administered via oral gavage twice daily (BID) alone or in combination with anti-PD-1 (10 mg/kg, QOD, i.p.) for 10 days in a Lewis Lung Carcinoma (LLC1) syngeneic tumor model. Tumor growth was measured by calipers 3 times per week. We analyzed immune cell profiles by flow cytometry. In lung squamous cell carcinoma patient derived xenograft (PDX) model,109 CFU/mouse CJRS-10671 and CJRS-10672 were orally administered twice daily (BID) alone or in combination with pembrolizumab (10 mg/kg, Q5D, i.p.) for 35 days. Tumor growth was measured by calipers 3 times per week. We analyzed immune cell profiles and single cell RNA sequencing. Results: In LLC1 syngeneic tumor model, CJRS-10671 alone suppressed tumor growth comparable to that of immune checkpoint inhibitor (anti-PD-1 antibody) only treatment group. Combined administration of CJRS-10671 and immune checkpoint inhibitor significantly suppressed tumor growth (p&amp;lt;0.05). We found that combination of CJRS-10671 with anti-PD-1 antibody increased the population of CD8+IFN-γ+ cells in splenocytes and tumor-infiltrating lymphocytes (TILs).In humanized PDX model, CJRS-10671 alone significantly suppressed tumor growth compared with that of vehicle control and pembrolizumab only treatment (p&amp;lt;0.001). CJRS-10672 alone suppressed tumor growth compared with that of vehicle control (p&amp;lt;0.001) which is comparable with the efficacy of pembrolizumab alone. Combined administration of CJRS-10672 and pembrolizumab further significantly suppressed tumor growth than pembrolizumab alone (p&amp;lt;0.01). None of the mice in pembrolizumab showed more than 75% tumor growth inhibition cut-off (TGI-75%). Fifty percent of the mice in CJRS-10671 single treated group showed over TGI-75%. The groups of pembrolizumab combination with CJRS-10672, pembrolizumab combination with CJRS-10671, CJRS-10672 alone were observed 25%, 20%, and 11.1%, respectively (&amp;gt;TGI-75%).We confirmed that administration of CJRS-10671 increased population of CD8+ central memory T cells in tumor. Also, TGI (%) directly related features were mostly antigen presentation and monocyte origin cells, especially macrophage in immune-profiling analysis. Furthermore, we observed that CJRS-10671 and CJRS-10672 were associated with signaling of damage-associated molecular pattern (DAMP) and especially CJRS-10671 was related to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling by single cell RNA sequencing analysis. Conclusion: CJRS-10671 and CJRS-10672, single administration or combination with anti-PD-1 antibody, have potential anti-tumor effect. Citation Format: Arim Min, Bo-eun Kwon, Hyunjeong Kim, Hyunkyung Park, Jiyoung Lee, Kyoung-Ho Pyo, Byoung Chul Cho. Novel bacteria strains, CJRS-10671 and CJRS-10672, enhance anti-tumor efficacy in LLC1 syngeneic model and humanized PDX mice model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3527.

Adoptive NK Cell Transfer as a Treatment in Colorectal Cancer Patients: Analyses of Tumour Cell Determinants Correlating With Efficacy In Vitro and In Vivo.

BackgroundColorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC.MethodsNK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity.ResultsHLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control.ConclusionsOur results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.

Clinical efficacy and safety of individualized pembrolizumab administration based on pharmacokinetic in advanced non-small cell lung cancer: An open-label, single-arm, exploratory clinical trial.

e21161 Background: Pembrolizumab with or without chemotherapy has become the standard therapy in advanced non-small cell lung cancer (NSCLC), with a fixed dose of 200mg every 3 weeks. We performed this study to explore the clinical efficacy and safety of pharmacokinetic (PK)-guided pembrolizumab administration in advanced NSCLC. Methods: In this prospective, open-label, single-arm exploratory study, we enrolled advanced NSCLC patients without sensitizing EGFR or ALK mutation in Sun Yat-Sen University Cancer Center. Eligible patients received pembrolizumab 200mg every 3 weeks with or without chemotherapy for four cycles, then for patients without progressive disease, pembrolizumab was administrated in new dose-intervals (T) until disease progression. We set the effective concentration (Ce) at 15μg/ml and new dose-intervals (T) was calculated according to steady state plasma-concentration (Css) of pembrolizumab using following equation: Css × 21D = Ce (15μg/ml) ×T. Primary endpoint was the progression-free survival (PFS), secondary endpoints were objective response rate (ORR), and safety. Besides, advanced NSCLC patients who regularly received pembrolizumab 200mg 3-weekly until disease progression and more than four cycles in our center were respectively enrolled as the history-controlled cohort. Patients with Css of pembrolizumab also underwent genetic polymorphism analysis of variable number of tandem repeats region (VNTR) in neonatal Fc receptor (FcRn). This study is registered at Clinicaltrials. gov, NCT05226728. Results: Between Nov 2019 and Dec 2020, total 58 patients were enrolled and received pembrolizumab 200mg every 3 weeks with or without chemotherapy, and 33 patients further received pembrolizumab in new adjusted dose-intervals according to Css after four cycles. The Css of pembrolizumab ranged from 11.01 to 61.21 μg/ml, 30 patients need prolonged intervals (22-80d) and 3 shortened intervals (15-20d). In PK-guided cohort, the median PFS was 15.1 months (95%CI 10.2-20.0 months) and ORR 57.6%, whereas the median PFS in history-controlled cohort was 7.7 months (95% CI 5.1-10.2 months) and ORR 48.2%. The immune-related adverse events occurred in 15.2% of patients in PK-guided cohort and 17.9% of patients in history-controlled cohort. The VNTR3/VNTR3 genotype of FcRn had significantly higher Css of pembrolizumab than VNTR2/VNTR3 ( p= 0.005). Conclusions: PK-guided pembrolizumab administration showed promising clinical efficacy and manageable toxicity, which provided an alternative rational therapeutic strategy of pembrolizumab in advanced NSCLC. Clinical trial information: NCT05226728.

Phase 1 study of OBT076, a first-in-class anti-DEC205 ADC, in patients with advanced/metastatic solid tumors: Safety, efficacy, and PK/PD results.

3028 Background: OBT076, an Antibody Drug Conjugate (ADC) consisting of a fully human IgG1 antibody conjugated via a cleavable linker to the derivative microtubule inhibitor DM4. It has specificity for the CD205/Ly75 target antigen which is an endocytic receptor overexpressed on the cell surface and immunosuppressive dendritic cells. This phase 1 study evaluates safety, tolerability, PK/PD and preliminary efficacy of OBT076 in solid tumor patients with high expression of target protein CD205 (CAP-CLIA validated centralized IHC test). Methods: Open label, two parts trial in patients with metastatic CD205+ve solid tumors who progressed on standard therapy. Part 1 of the study consisted in dose escalation from 1.6 mg/kg to 3.5 mg/kg. An mTPI design is used to guide to determine the maximum tolerated dose (MTD) Treatment was given on day 1 every 3 weeks followed by GCSF on day 8. Blood samples and flow cytometry were used to assess PK/PD. Tumor response was assessed every three cycles. Part 2 of trial is an expansion basket trial enriched in indications where preliminary efficacy has been shown. Results: The study completed Part 1 dose escalation. Part 2 expansion phase is ongoing. Between Dec 2019 and January 2022, 20 patients were enrolled (18 patients in the dose escalation and 2 in the ongoing expansion). The median age 61, 9 patients were males and 9 had ECOG PS 0. All patients had at least one metastatic site and 90% received at least 2 lines of chemotherapy in the metastatic setting. Recommended dose for the expansion phase is 3.0 mg/kg. No other significant side effects have been observed. PK data showed that Cmax of 40.000-90.000 ng/ml was achieved between 2.5 and 3.5mg/kg dose and is comparable to the therapeutic dose in mouse models. In part 1 of the study, 7 patients derived clinical benefit despite being in disease progression at trial entry. One patient with gastric cancer with linitis plastica experienced major improvement with complete disappearance of ascites and metastatic adenopathy after cycle 3. The six other patients had lasting stable disease and received between 5-14+ cycles with median of 5 cycles. Two patients with low PD-L-1 expression received checkpoint inhibitor treatment with pembrolizumab after 2 and 5 cycles of OBT076, both patients experienced near complete response after only one to two cycles. Conclusions: OBT076 at 3.0mg/kg has shown favorable safety profile with manageable neutropenia. The preliminary efficacy has shown preliminary antitumoral single agent activity in gastric, ovarian and lung cancer. The two patients who received a sequential administration of pembrolizumab after OBT076 showed major tumor activity. Sequential administration of OBT076 followed by a PD-1 inhibitor was also supported by PD markers and warrants further evaluation. Clinical trial information: NCT04064359. [Table: see text]

The effect of circadian rhythm on clinical outcome in patients receiving pembrolizumab in the INSPIRE pan-cancer trial.

2589 Background: The molecular networks comprising circadian rhythm are expressed in immune cells where they affect immune-related processes. Within the emerging field of chrono-immunotherapy, it has been proposed that immunotherapies should be applied at certain times of day to optimize efficacy. Two recent reports have suggested that earlier administration of immune checkpoint inhibitors (ICIs) in non-small cell lung cancer and melanoma may offer improved survival outcomes (Karaboué et al. ASCO 2021, PMID 34780711). Whether this observation applies to other tumour types, or occurs in geographic regions with differing seasonality, is not known. Methods: We retrospectively analyzed the time of administration data from the INSPIRE single-centre, phase II, multi-cohort study of pembrolizumab (200 mg IV over 1 hour, q3w to maximum 35 cycles) in patients with advanced solid tumours (NCT02644369). Kaplan-Meier methods were used to estimate PFS and OS. Cox proportional hazards models were fitted to assess the association between time of administration and PFS or OS, adjusting for cohort. Fisher’s exact test was used to test for association with immune-related adverse events (irAEs). Results: A total of 106 patients (19 head and neck squamous cell, 22 triple negative breast, 21 epithelial ovarian, 12 melanoma, 32 other solid tumours) were accrued between March 21, 2016, and May 9, 2018. Median time of follow-up was 11.5 months. Start of infusion times were obtained for 806 total doses. The median time of administration was 15h06 for the first dose and 15h11 for all doses (range 09h19 – 18h34). No differences in PFS or OS were observed between patients who received their first dose before or after noon, or before or after 15h06. Furthermore, no differences in PFS or OS were observed between patients who received ≥ 50% of their doses before or after noon, or before or after 15h11. There was also no difference in PFS or OS between patients who did or did not have a significant proportion of doses (≥ 20%) after 16h30 (“evening” in previous reports). There were no differences in the frequency of grade ≥ 2 irAEs amongst the various groups. No differences in efficacy were found when individual cohorts were evaluated separately. Finally, no differences in PFS or OS were observed when participants were grouped by season of first dose. Conclusions: Despite previous reports of improved survival with earlier ICI dosing, we did not identify any association of time of pembrolizumab administration with clinical outcomes. Our analysis is limited by small sample size and patient heterogeneity which may hinder identification of smaller associations. It is also unclear whether lower response rates in a pan-cancer population (relative to prior reports in lung cancer and melanoma) might impact correlation analysis. Further studies will be necessary to interrogate this phenomenon and ensure that ICI are optimally applied.

Targeting the Axl and mTOR Pathway Synergizes Immunotherapy and Chemotherapy to Butylidenephthalide in a Recurrent GBM.

Background The role of inherent tumor heterogeneity and an immunosuppressive microenvironment in therapeutic resistance has been determined to be of importance for the better management of glioblastoma multiforme (GBM). Some studies have suggested that combined drugs with divergent mechanisms may be promising in treating recurrent GBM. Methods Intracranial sustained (Z)-n-butylidenephthalide [(Z)-BP] delivery through Cerebraca Wafers (CWs) to eliminate unresectable brain tumors was combined with the administration of temozolomide (TMZ), pembrolizumab, and cytokine-induced killer (CIK) cells for treating a patient with recurrent glioblastoma. Neurological adverse events and wound healing delay were monitored for estimating tolerance and efficacy. Response Assessment in Neuro-Oncology criteria were applied to evaluate progression-free survival (PFS); further, the molecular characteristics of GBM tissues were analyzed, and the underlying mechanism was investigated using primary culture. Results Intracerebral (Z)-BP in residual tumors could not only inhibit cancer stem cells but also increase interferon gamma levels in serum, which then led to the regression of GBM and an immune-responsive microenvironment. Targeting receptor tyrosine kinases, including Axl and epidermal growth factor receptor (EGFR), and inhibiting the mechanistic target of rapamycin (mTOR) through (Z)-BP were determined to synergize CIK cells in the presence of pembrolizumab and TMZ in recurrent GBM. Therefore, this well-tolerated regimen could simultaneously block multiple cancer pathways, which allowed extended PFS and improved quality of life for 22 months. Conclusion Given the several unique functions of (Z)-BP, greater sensitivity of chemotherapy and the synergism of pembrolizumab and CIK cells could have affected the excellent prognosis seen in this patient with recurrent GBM.

Alopecia areata following pembrolizumab: A case report and literature review

Since malignancies develop their escape strategy from anti-tumor immunity mediated by PD-1/PD-L1 or CTLA-4, the recent advancement of immune checkpoint inhibitor treatment proves the importance of immune reaction against malignancies. On the other hand, healthy human tissue or organs also need to tolerance mechanism escaping from immune reactions not to cause excessive inflammatory reactions. We report a case of alopecia areata following pembrolizumab administration and also review the previously published cases of alopecia areata following PD-1/PD-L1 targeted therapy further.

Two Cases of Cutaneous Adverse Events After Pembrolizumab Administration

Two Cases of Cutaneous Adverse Events After Pembrolizumab Administration

Abstract P2-08-23: Early intratumoral changes after a single dose of anti-PD-1 treatment in patients with early breast cancer (BC)

Abstract Intro: Despite the growing success of immune checkpoint blockade in BC, the underlying mechanisms of response or resistance to these treatments is still poorly understood. We recently conducted a window-of-opportunity study (BioKey) including 54 patients with early BC (NCT03197389) in which patients were treated with one dose of pembrolizumab 10 ± 4 days before surgery. A tumor biopsy was taken before and after the administration of pembrolizumab. Using single-cell transcriptome profiling, we identified patients with clonotype expansion of PD-1-expressing T-cells after treatment with pembrolizumab (Bassez A, Vos H et al, Nature Medicine 2021). Expansion mainly involved CD8+ T - and CD4+ T cells. We designated these as patients with clonotype expansion or ‘expanders’ (E), whereas patients lacking clonotype expansion were considered ‘non-expanders’ (NE). In this study, we aimed at investigating the association between stromal tumor infiltrating lymphocytes (sTIL) and various immune markers using immunohistochemistry with the E phenotype. Methods: The BioKey trial has 2 cohorts. The first one included 39 treatment-naive patients who were scheduled for upfront surgery. The second cohort included 15 patients with an estimated residual tumor size of at least 1cm on imaging after neo-adjuvant chemotherapy. All molecular subtypes were represented: triple-negative (TN) BC (n= 18, 8 E and 10 NE), HER2-positive BC (n= 5, 1 E and 4 NE) and hormone receptor (HR)-positive/HER2-negative BC (n= 17, 3 E and 14 NE). 7 core biopsies and 5 resection slides were not contributive and were excluded. The expander status of 14 patients was unknown. sTIL were evaluated and immunohistochemical stains (CD3, CD4, CD8, CD68, CD73, FoxP3, Ki67, PD-1 and PD-L1) were performed. Associations between expander status and biomarkers were assessed using firth logistic regressions, adjusting per cohort. Biomarkers were considered as continuous variables and Odds Ratio computed per one unit increase on a non-transformed scale. Given the low number of E in cohort B, subgroup analyses were performed only in cohort A. Results: We observed that 1) higher levels of sTIL, PD-1+ sTIL and FOXP3+ cells in the pre-treatment biopsies, 2) higher levels of sTIL, PD1+ sTIL, PD-L1+, CD3+, CD4+, CD8+, CD68+, FOXP3+ cells and Ki67 in the post-treatment surgical specimen, as well as, 3) higher delta values (surgical specimen - biopsy) of sTIL, CD3+, CD4+, CD8+, CD68+ and Ki67 are associated with the E phenotype (Table 1). With regard to the subgroup analyses, we observed that higher levels of PD-1+ sTIL and CD68+ cells at diagnosis and surgery respectively, as well as higher delta values for CD68+, Ki67 and sTIL were associated with the E phenotype in HR+/HER2- BC, while high levels of FOXP3+ cells and PD-1+ sTILs in the biopsies, high levels of sTIL, CD3+, CD4+, CD8+, CD68+, FOXP3+, PD-1+ sTILs, PD-L1+ and Ki67 as well as higher delta values for PD-L1+ in the resection specimen were associated with the E phenotype in TNBC. Conclusion: We were able to detect associations between various cell populations of the tumor immune microenvironment evaluated before and after a single dose of pembrolizumab and the T-cell expansion phenotype previously defined at the single-cell level. It highlights the possible clinical utility of a biopsy taken early during treatment. Future neo-adjuvant studies will allow the validation of our findings and investigate the association between T-cell expansion and clinical outcomes. Table 1.Association between the various biomarkers and the expanding T-cell phenotypeVariableOdds RatioLower 95% CIUpper 95% CIp-valuePre-treatment. Core biopsyCD31.071.001.160.061CD41.060.981.170.156CD81.130.951.380.161CD681.050.901.230.494CD73.tumor1.070.821.370.609CD73.on sTIL1.010.961.060.713FoxP32.251.394.030.001Ki671.021.001.050.107sTIL1.061.021.140.005PD-1 on sTIL1.731.212.830.001PD-L11.041.011.070.002Post-treatment. Resection specimenCD31.091.031.190.001CD41.151.051.29&amp;lt;0.001CD81.581.192.34&amp;lt;0.001CD681.471.152.15&amp;lt;0.001CD73.tumor1.090.771.520.608CD73.on sTIL1.030.991.080.110FoxP32.051.313.82&amp;lt;0.001Ki671.041.011.070.004sTIL1.081.031.15&amp;lt;0.001PD-1 on sTIL1.641.152.650.004PD-L11.051.021.110.002Delta (resection-biopsy)CD31.071.011.250.029CD41.091.011.280.030CD81.211.021.690.025CD681.221.051.580.007CD73.tumor0.970.731.290.794CD73.on sTIL1.040.991.120.132FoxP31.220.891.810.219Ki671.051.001.130.031sTIL1.071.001.160.046PD-1 on sTIL0.960.701.330.765PD-L11.000.961.040.941 Citation Format: Hanne Vos, Kathleen Lambein, François Richard, Ines Nevelsteen, Ayse Bassez, Diether Lambrechts, Kevin Punie, Hans Wildiers, Giuseppe Floris, Christine Desmedt, Ann Smeets. Early intratumoral changes after a single dose of anti-PD-1 treatment in patients with early breast cancer (BC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-08-23.

Abstract P5-14-04: Changes in management of TNBC during the COVID19 pandemic of 2020

Abstract INTRODUCTION An increasing body of evidence demonstrates that the COVID-19 pandemic of 2020 saw large reductions in the number of US patients being diagnosed with a variety of conditions, including cancer. A previous real world evidence study based upon analysis of CMS claims data showed a large drop in cancer diagnoses across multiple solid tumor diseases and evidence suggesting changes in testing behaviors for these patients over the period of maximal lockdown measures to mitigate spread of infection. Further, the drop in patient numbers had not returned to normal once these measures were relaxed by the end of June. Therefore, we decided to examine CMS data for the entire year of 2020 and focus on a single sub-group in breast cancer, TNBC. These patients have poor prognosis and are relatively intensively managed; it was reasoned that changes in management, especially testing behavior, might be more apparent in this group than in breast cancer patients as a whole. METHODS CMS data for 2019-20 were queried using a proprietary business rule for identifying TNBC cases and then subdivided into 2 groups: those who received a treatment under a “J” HCPCS code and those who had not. Office visits, Level IV surgical pathology (SP) and immunohistochemistry (IHC) were defined by appropriate HCPCS codes. Since all PD-L1 testing is covered by HCPCS code 88360, a claim for 88360 was considered indicative of a PD-L1 test. A decrease in the number of patients during the COVID-19 pandemic was defined as a ≥ 10% drop for the value in a given month in 2020 compared to the same month in 2019, as a percentage of the 2019 median value. This is termed the “COVID-Dip”. RESULTS Data were gathered from a total of 68,018 patients, 8,131 with a J code treatment and 59,887 without. Results of COVID dip analysis are presented in Table 1. Trastuzumab administration showed an overall decline across the entire study period. While IHC for 88360 showed a COVID dip, administration of atezolizumab and pembrolizumab increased across the study period with administration of nivolumab (collectively immuno-oncology, IO, drugs) remaining relatively constant. 47% of patients receiving IO therapy received a presumed PD-L1 test. There was longitudinal variation in the use of chemotherapy agents but no apparent COVID dip in their use. DISCUSSION There were declines both in patient presentation to doctors’ offices, as well as diagnostic testing among TNBC patients during the COVID-19 pandemic of 2020 with differences between those receiving chemotherapy under J codes and those not. There was no evidence of decline in use of chemotherapy under J codes. Increased IO use but declines in IHC testing suggest a greater use of off-label prescribing of these drugs during the pandemic. The decline in presentation to doctors’ offices and in testing of patients not receiving J code drugs suggests that these patients may experience significant delays in management of their condition with concomitant increases in morbidity and mortality. PATIENT GROUPCOVID DIP DURATION(MONTHS)MAXIMUM COVID DIP(% OF 2019 MEDIAN)ESTIMATED MISSING PATIENTSTOTAL PATIENTSALL2235495WITH J CODE000NO J CODE2275162OFFICE VISITSALL34011161WITH J CODE119304NO J CODE3489659SURGICAL PATHOLOGYALL335644WITH J CODE553301NO J CODE549482IMMUNOHISTOCHEMISTRY(88341)ALL247243WITH J CODE26864NO J CODE339209IMMUNOHISTOCHEMISTRY(88360)ALL349508WITH J CODE356143NO J CODE347366 Citation Format: Dave Smart, Wendy L Allen, Raymond H Henderson, Susanne Munksted, Peter Riccelli. Changes in management of TNBC during the COVID19 pandemic of 2020 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-14-04.

Pembrolizumab induces HIV latency reversal in people living with HIV and cancer on antiretroviral therapy

In people living with HIV (PLWH) on antiretroviral therapy (ART), virus persists in a latent form where there is minimal transcription or protein expression. Latently infected cells are a major barrier to curing HIV. Increasing HIV transcription and viral production in latently infected cells could facilitate immune recognition and reduce the pool of infected cells that persist on ART. Given that programmed cell death protein 1 (PD-1) expressing CD4+ T cells are preferentially infected with HIV in PLWH on ART, we aimed to determine whether administration of antibodies targeting PD-1 would reverse HIV latency in vivo. We therefore evaluated the impact of intravenous administration of pembrolizumab every 3 weeks on HIV latency in 32 PLWH and cancer on ART. After the first infusion of anti-PD-1, we observed a median 1.32-fold increase in unspliced HIV RNA and 1.61-fold increase in unspliced RNA:DNA ratio in sorted blood CD4+ T cells compared to baseline. We also observed a 1.65-fold increase in plasma HIV RNA. The frequency of CD4+ T cells with inducible virus evaluated using the tat/rev limiting dilution assay was higher after 6 cycles compared to baseline. Phylogenetic analyses of HIV env sequences in a participant who developed low concentrations of HIV viremia after 6 cycles of pembrolizumab did not demonstrate clonal expansion of HIV-infected cells. These data are consistent with anti-PD-1 being able to reverse HIV latency in vivo and support the rationale for combining anti-PD-1 with other interventions to reduce the HIV reservoir.

Successful management of pelvic recurrence of MSI-High endometrial cancer by total pelvic exenteration followed by administration of pembrolizumab:A case report.

Surgery can be curative treatment for pelvic locoregional recurrence of endometrial cancer; however, a cure is contingent on complete resection. Here, we report the case of a patient in whom recurrent endometrial tumor remained in the pelvis after resection; long-term control was achieved with postoperative administration of pembrolizumab.The patient had recurrent endometrial cancer of stage IA and was treated with chemotherapy and radiation, but tumor persisted in the pelvic cavity. We therefore attempted total pelvic exenteration, but the tumor was adherent to the pelvic wall and complete resection could not be achieved. However, postoperative administration of pembrolizumab controlled the residual tumor for more than two years without regrowth. We believe that since the resected tumor was MSI-High, the residual tumor responded well to pembrolizumab. It is not known whether cytoreductive surgery contributes to a long-term response to pembrolizumab, but at least in our patient, pembrolizumab appeared to be a very effective drug therapy for MSI-High endometrial cancer that was refractory to chemotherapy and radiotherapy.

Efficacy of pembrolizumab combined with anlotinib in 3 patients with advanced non-small cell lung cancer

Non-small-cell lung carcinoma (NSCLC) is any type of epithelial lung cancer and accounts for about 85% of all lung cancers. Pembrolizumab, a PD-1 inhibitor, is approved to treat patients with advanced NSCLC. Anlotinib, a multi-target tyrosine kinase inhibitor, is approved in China for treating patients with advanced NSCLC with progression or recurrence after ≥ 2 lines of systemic chemotherapy. Whether pembrolizumab combined with anlotinib has synergistic effects on treating advanced NSCLC patients remains unclear. Here we reported that three cases of patients with advanced NSCLC had a good response and a long time of PR to pembrolizumab combined with anlotinib treatment, indicating that combined administration of pembrolizumab and anlotinib can be optional management for advanced NSCLC.

Macular‐type cutaneous adverse reaction due to atezolizumab and pembrolizumab

Anti-PD-1/PD-L1 targeted therapy is widely used for the treatment of various intractable malignancies and develops the therapeutic option in the frontier fields of oncology treatment. On the contrary, these immune checkpoint therapies sometimes develop undesirable adverse reaction as the results of activation of immune reaction to various organs. Herein, we report a case of cutaneous adverse reactions during PD-1/PD-L1 targeted treatment in both atezolizumab and pembrolizumab in a patient with lung cancer. Dear Editor, Anti-PD-1-/PD-L1-targeted therapy is widely used for the treatment of various intractable malignancies and develops the therapeutic option in the frontier fields of oncology treatment.1, 2 On the contrary, these immune checkpoint therapies sometimes develop an undesirable adverse reaction as a result of activation of immune reaction to various organs.3, 4 A cutaneous adverse reaction is a representative immune checkpoint treatment-mediated reaction.3 Herein, we report a case of cutaneous adverse reactions during PD-1-/PD-L1-targeted treatment in both atezolizumab and pembrolizumab in a patient with lung cancer. A 68-year-old man noticed erythematous plaques and papules on his trunk and extremities 4 days after first atezolizumab administration for the treatment of his right lung adenocarcinoma clinical stage IV, and his skin eruption gradually developed. On physical examination, erythematous plaques were localized in trunk and extremities without the involvement of the mucosal membrane (Figure 1A). A skin biopsy revealed liquefaction and spongiosis in the epidermis and lymphocyte infiltration in the dermis (Figure 1B). After the treatment with an antihistamine agent, topical application of betamethasone dipropionate, and the discontinuation of additional administration of atezolizumab, his skin eruption was gradually improved without recurrence of skin eruption. As an alternative treatment for his lung cancer, pembrolizumab was next administrated; however, he again recognized erythematous plaques on trunk and extremities after the first administration of pembrolizumab (Figure 1C). The second time cutaneous adverse reaction was more widely spread in his whole body. A skin biopsy again revealed that spongiosis and inflammatory infiltration in the interface of epidermis and dermis (Figure 1D). After the antihistamine agent, topical application of betamethasone dipropionate, and the discontinuation of additional pembrolizumab administration, his skin eruption was improved in several days. One of the unique characteristics of this case was to cause similar cutaneous adverse reactions by the different action point targeted treatment, PD-1 and PD-L1. Although the detailed molecular mechanism remains unclear in our case, we thought 3 possible mechanisms to cause cutaneous adverse reaction by both atezolizumab and pembrolizumab. The first reason is that atezolizumab and pembrolizumab have same additives in the drug, such as L-histidine, white soft sugar, and polysorbate. In particular, polysorbate includes in various drugs and influenza vaccine and is known to cause allergic reaction in some cases.5, 6 Therefore, we speculated that cutaneous allergic reaction to polysorbate might be enhanced by atezolizumab and pembrolizumab. The second reason is another drug contribution to cause adverse reaction. However, he ordinally continued to intake acetaminophen without cutaneous adverse reaction. The third reason is atezolizumab and pembrolizumab might become a trigger to cause a cutaneous autoimmune-like reaction. Because skin eruption is relatively mild form and is improved by topical corticosteroid application and oral antihistamine agent, it seemed to be easy to recover his skin eruption even if his skin eruption is an autoimmunity-related skin eruption. Taken together, clinicians should keep in mind that adverse reaction might occur after switching into another anti-PD-1-/PD-L1-related inhibitor. Approval of the research protocol: No human participant was involved in this study. Informed Consent: N/A. Registry and the Registration No. of the study/trial: N/A. Animal Studies: N/A. The authors declare no conflicts of interest.

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006

Antitumor activity of ipilimumab or BRAF ± MEK inhibitors (BRAFi ± MEKi) following pembrolizumab administration in melanoma is poorly characterized. In the phase III KEYNOTE-006 study, patients with unresectable stage III/IV melanoma received pembrolizumab (10 mg/kg) once every 2 or 3 weeks (Q3W) or ipilimumab (3 mg/kg) Q3W. The current post hoc analysis evaluates outcomes with ipilimumab or BRAFi ± MEKi as first subsequent systemic therapy after pembrolizumab administration and includes patients who completed or discontinued pembrolizumab after one or more dose. Pembrolizumab arms were pooled. At data cut-off (4 December 2017), median follow-up was 46.9 months. Of 555 pembrolizumab-treated patients, first subsequent therapy was ipilimumab for 103 (18.6%) and BRAFi ± MEKi for 59 (10.6%) [33 received BRAFi+ MEKi, 26 BRAFi alone; 37 (62.7%) were BRAFi ± MEKi naïve]. In the subsequent ipilimumab group, ORR with previous pembrolizumab was 17.5% [1 complete response (CR); 17 partial response (PR)]; 79.6% had discontinued pembrolizumab due to progressive disease (PD); median overall survival (OS) was 21.5 months. ORR with subsequent ipilimumab was 15.5%; 11/16 responses (8 CRs; 3 PRs) were ongoing. ORR with subsequent ipilimumab was 9.7% for patients with PD as best response to pembrolizumab. Median OS from ipilimumab initiation was 9.8 months. In the subsequent BRAFi ± MEKi group, ORR with previous pembrolizumab was 13.5% (8PR); 76.3% had discontinued pembrolizumab due to PD; median OS was 17.9 months. ORR with subsequent BRAFi ± MEKi was 30.5%, 7/18 responses (4 CR, 3 PR) were ongoing. Median OS from BRAFi ± MEKi initiation was 12.9 months. ORR for BRAFi ± MEKi-naïve patients who received subsequent BRAFi ± MEKi was 43.2%; 6/16 were ongoing (3 CR, 3 PR). Ipilimumab and BRAFi ± MEKi have antitumor activity as first subsequent therapy after pembrolizumab in patients with advanced melanoma.

Hyperprogression of a mismatch repair-deficient colon cancer in a humanized mouse model following administration of immune checkpoint inhibitor pembrolizumab.

Immunotherapy is an established treatment modality in oncology. However, in addition to primary or acquired therapy resistance with immune checkpoint blockade (ICB), hyperprogressive disease (HPD) or hyperprogression (HP) with acceleration of tumor growth occurs in a subset of patients receiving ICB therapy. A validated and predictive animal model would help investigate HPD/HP to develop new approaches for this challenging clinical entity. Using human cytotoxic T-cell line TALL-104 injected intraperitoneally into immunodeficient NCRU-nude athymic mice bearing mismatch repair-deficient (MMR-d) human colon carcinoma HCT116 p53-null (but not wild-type p53) tumor xenograft, we observed accelerated tumor growth after PD-1 blockade with pembrolizumab administration. There was increased colon tumor cell proliferation as determined by immunohistochemical Ki67 staining of tumor sections. There was no increase in MDM2 or MDM4/MDMX in the p53-null HCT116 cells versus the wild-type p53-expressing isogenic tumor cells, suggesting the effects in this model may be MDM2 or MDM4/MDMX-independent. Human cytokine profiling revealed changes in IFN-γ, TRAIL-R2/TNFRSF10B, TRANCE/TNFSF11/RANK L, CCL2/JE/MCP-1, Chitinase 3-like 1, IL-4 and TNF-α. This represents a novel humanized HPD mouse model with a link to deficiency of the p53 pathway of tumor suppression in the setting of MMR-d. Our novel humanized preclinical TALL-104/p53-null HCT116 mouse model implicates p53-deficiency in an MMR-d tumor as a possible contributor to HPD/HP and may help with evaluating therapeutic strategies in cancer immunotherapy to extend clinical benefits of ICB’s in a broader patient population.