Pembrolizumab Research Articles

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Evolution of systemic therapy for advanced HCC patients: Did we make progress in 2022?

Pembrolizumab immunotherapy in advanced and recurrent/metastatic salivary gland carcinoma (R/M SGC): A systematic review and meta-analysis.

e18101 Background: Treatment options for advanced R/M SGC are a limited and with variable response rates due to their safety/toxicity profile and the heterogenous l histology. Recent clinical trials tested pembrolizumab (PMB), a PD-1 inhibitor, in diverse settings. Methods: We performed a systematic review and single arm meta-analysis of clinical trials of PMB monotherapy or combined therapy in advanced and R/M SGC. PubMed, Scopus, and Cochrane database were searched for clinical trials published up to January 31, 2023. Data were extracted from published reports and quality assessment was performed per Cochrane recommendations. The primary endpoints of interest were complete/partial response (CR,PR) and disease control (DC= SD or better response) per RECIST v1.1, at any period of the trial. Results: Out of 199 database results, 4 clinical trials and 180 patients were included, all were using some form of PMB therapy. Overall, PMB was associated with a CR,PR ratio of 5.6% (95% CI 0.01-0.10, I²=25%, p=0.262) and DC ratio of 58.4% (95% CI 0.50-0.66, I²=13%, p=0.326), somewhat similar to recent evidence of PD-1/CTLA-4 combined therapy (nivolumab + ipilimumab [CR,PR=6-16%) in ongoing phase II clinical trials or PD-1 monotherapy (nivolumab [CR,PR=6%; SD=50%] in a completed clinical trial. Other systemic therapies, in which the current guidelines are based, include TKI (lenvatinib + sorafenib PR=3-15%; SD=50-94%) for adenoid cystic carcinoma (ACC); NTRK (larotrectinib CR,PR=90%, entrectinib CR,PR=86%), HER2 (transtuzumab associations CR,PR=60-90%), and AR (leuprorelin + bicalutamide CR,PR=42%, enzalutamide PR=4-15%; SD=52%) in non-ACC; and cytotoxic chemotherapy associations CR,PR=16-34% in heterogeneous histology tumors. Conclusions: There are marked limitations to the applicability of these findings in clinical practice, therefore a cautionary approach to this data is recommended, given their overall low statistical power, heterogenous histology, and tolerability to adverse effects. New trials with better standardized outcomes and comparative arms for different therapy associations and populations will help clarify the effects PD-1 inhibitors in the treatment of advanced and R/M SGC. [Table: see text]

Phase II basket trial evaluating the efficacy of pembrolizumab (PE) combined with vorinostat (VO) in patients (pts) with recurrent and/or metastatic squamous cell carcinoma (SCC).

2597 Background: Epigenetic modulation plays a major role in escaping tumor immunosurveillance and confers resistance to immune checkpoint inhibitors. Preclinical evidence suggests that modulating the epigenome might improve the efficacy of immunotherapy. Patients and Methods: PEVOsq is an open-label, non-randomized, multi-center, basket phase II trial, evaluating the efficacy of pembrolizumab in combination with vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma of the cervix, head and neck, anus, vulva/vagina, penis, and lung. Patients had to be PD1/PD-L1 antagonist-naïve. There was no selection based on PD-L1 expression nor on HPV status, and no restriction in terms of prior lines of treatments. Pembrolizumab dose was 200 mg Q3W IV, and vorinostat 400 mg QD PO. Sample size was determined for each cohort using an A’Hern design. Primary endpoint was objective response rate (ORR) according to RECISTv1.1. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Results: Among 112 included patients, 111 were evaluable for safety and 107 for efficacy. The lung cohort was closed prematurely because of lack of enrollment. Median age was 61 years old [range: 18-85] and the median number of prior lines of therapies was 1 [range: 0-4]. ORR, PFS, G3/4 treatment related adverse events (TRAE), and OS are reported. 28 patients (26%) had an objective response and median DOR was 9.7 months [95%CI: 3.1-15.2]. Results per PD-L1 status will be presented at the meeting. Pembrolizumab and vorinostat were stopped for toxicity in 9% and 39% of patients, respectively. 60% of patients had a dose-reduced of vorinostat for toxicity. Pembrolizumab safety was as expected. Main vorinostat toxicities included hematological toxicity, gastrointestinal disorders, and asthenia and creatinine increase. Conclusions: Pembrolizumab combined with vorinostat showed encouraging antitumor activity in squamous cell carcinoma with unselected PD1/PD-L1 status, especially in cervical and anal cancer, although vorinostat dose had to be reduced because of toxicity in a substantial proportion of patients. Clinical trial information: NCT04357873 . [Table: see text]

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

LBA03-08 PEMBROLIZUMAB (PEMBRO) FOR PATIENTS (PTS) WITH HIGH-RISK NON-MUSCLE-INVASIVE BLADDER CANCER (HR NMIBC) UNRESPONSIVE TO BACILLUS CALMETTE-GUERIN (BCG): EFFICACY AND EVALUATION OF SUBSEQUENT CYSTECTOMY FROM COHORT B OF THE PHASE 2 KEYNOTE-057 STUDY

MP63-05 OUTCOMES IN PATIENTS (PTS) WITH BACILLUS CALMETTE-GUERIN (BCG)-UNRESPONSIVE HIGH-RISK (HR) NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) WHO UNDERWENT RADICAL CYSTECTOMY (RC) FOLLOWING PEMBROLIZUMAB (PEMBRO) TREATMENT IN KEYNOTE-057 COHORT A

MP63-05 OUTCOMES IN PATIENTS (PTS) WITH BACILLUS CALMETTE-GUERIN (BCG)-UNRESPONSIVE HIGH-RISK (HR) NON-MUSCLE-INVASIVE BLADDER CANCER (NMIBC) WHO UNDERWENT RADICAL CYSTECTOMY (RC) FOLLOWING PEMBROLIZUMAB (PEMBRO) TREATMENT IN KEYNOTE-057 COHORT A

Abstract P3-06-10: Immune-related adverse events (irAEs) and pathological complete response (pCR) rates in patients receiving neoadjuvant chemotherapy (CHT) and pembrolizumab (PEM) for early triple-negative breast cancer (eTNBC)

Abstract Background and Significance: Recently, the addition of the immune checkpoint-inhibitor PEM to CHT was shown to increase pCR rates and invasive event-free survival in the Keynote-522 (KN522) trial. Several irAEs are known to occur during use of PEM in various cancer entities. In our multicenter analysis we aimed to identify real-world occurrence rates of irAES and pCR rates in women receiving PEM and CHT, analogously to KN522, for eTNBC treatment. Methods: All patients receiving CHT + PEM for eTNBC treatment at participating centers were followed prospectively and monitored for occurrence of irAEs and neoadjuvant treatment outcome as defined by pCR from October 2020 until data cut-off on September 15th 2022. Only patients who underwent surgery for their primary tumor before data cut-off were included. Results: A total number of 22 patients with available pCR outcomes were included. All patients were female. Median age was 51 years (range 25-72). Mean tumor size at baseline was 29mm (range 10-75). 41% (9/22) of patients exhibited nodal involvement according to baseline radiological findings. Median MIB-1/Ki67 expression at biopsy was 70%. Patients received a median of 8 (range 1-8) neoadjuvant cycles of PEM and exhibited a median duration of CHT of 24 weeks (range 4-24). Neoadjuvant PEM was discontinued in 32% (7/22) of patients. Discontinuation of neoadjuvant treatment before week 18 occurred in 22,7% (5/22) of patients. We report irAE rates of any kind and all grades of 50% (11/22) and of grade 3-4 in 9% of patients (2/22). Steroids were administered in 7/11 patients experiencing irAEs (64%). 8 irAEs occurred during the neoadjuvant treatment phase, 3 during postneoadjuvant treatment with PEM. No grade 5 toxicity was observed. irAEs observed were hypothyroidism (n=3, all grade 2), arthritis (n=3, all grade 2), myocarditis (n=2, one grade 3/one grade 4), and single cases of hepatitis (grade 2), nephritis (grade 3) and pneumonitis (grade 1). 18% (4/22) of patients underwent mastectomy and 36% (8/22) of patients underwent axillary dissection. Lastly, upon definitive surgery of the primary tumor, we observed pCR in 50% (11/22) of cases. Patients who completed >18 weeks of neoadjuvant therapy exhibited a pCR rate of 59% (10/17), whilst patients who completed ≤18 weeks of neoadjuvant therapy reached pCR in 20% of cases (1/5). Conclusion: We report real-world prospective data about irAE as well as pCR rates during eTNBC treatment with PEM and CHT. irAEs occurred in similar rates as observed in KN522, although numerically higher for irAEs of all grades. The pCR rate within our cohort was numerically lower than reported for KN522, most probably due to a low pCR rate observed for 5 of 22 patients included in this analysis who completed ≤18 weeks of neoadjuvant treatment. Looking at our data, we hypothesize that clinical benefit from combination therapy of PEM and CHT depends on reaching an adequate duration of >18 weeks of neoadjuvant treatment. Citation Format: Maximilian Marhold, Simon Udovica, Kerstin Wimmer, Zsuzsanna Bago-Horvath, Tim Robinson, Florian Fitzal, Kathrin Strasser-Weippl, Rupert Bartsch. Immune-related adverse events (irAEs) and pathological complete response (pCR) rates in patients receiving neoadjuvant chemotherapy (CHT) and pembrolizumab (PEM) for early triple-negative breast cancer (eTNBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-06-10.

MSI exploration in patients with biliary tract cancer from the Spanish RETUD Registry.

602 Background: Biliary tract cancer (BTC) is a resistant tumor better addressed by targeting molecular alterations. Among described biomarkers, Microsatellite Instability (MSI) is rarely found in BTC patients (pts) (~2%) and therefore, it is scarcely described in literature. Pembrolizumab (PBL) has proved beneficial for MSI-H BTC pts who did not respond to previous treatment. Our aim is to describe outcomes of MSI pt in Spanish daily practice. Methods: This is a descriptive analysis of a cohort of pts from the Spanish RETUD registry diagnosed with BTC between 1 January 2017 and 31 December 2020. All patients recruited at the cut-off date (7 July 2021) were considered in the analysis. Data collected included demographic and clinical characteristics, systemic oncologic treatment and effectiveness (best response and survival outcomes). Pts characteristics were recorded in all MSI-H pts. Survival outcomes and best response were calculated for pts who received systemic oncologic treatment. Descriptive statistic was used to analyze sociodemographic data, tumor characterization, molecular analysis, and best response. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: The registry included 778 evaluable pts. Only 206 pts were tested for MSI and 13 (6.3%) had positive results. Median (interquartile range, IQR) age was 74.5 (68.9-80.8) years, and the male sex (84.6%) was predominant. Primary tumor was 92.3% intrahepatic and 7.7% extrahepatic. Metastatic and locally advanced disease were diagnosed in 3 (23.1%) and 7 (53.8%) pts respectively. Only 4 (30.8%) pts underwent previous surgery. Molecular profile analyses reported 2 (20.0%) BRAF mutations, 1 (10.0%) IDH1 mutations, 2 (20.0%) FGFR2 fusions and 1 (10.0%) HER2 amplification (missing data n=3 pts). One pt was positive to BRAF, IDH1, FGFR2 and HER2 mutations. Eleven pts received systemic oncologic treatment, predominantly frontline therapy with gemcitabine-based combinations (n=9, 81.8%). At the database cut-off, 6 pts died due to disease progression (83.3%) or disease-related complications (16.7%). The median PFS to frontline treatment was 2.7 months (95% Confidence Interval [CI]: 1.5–9.9), and the median OS was 21.0 months (95% CI: 6.5-NA). Five (38.3%) pts received PBL as second-line therapy, with 3 pts responding (1 complete response and 2 partial responses). Median PFS after PBL was 2.6 (95% CI 2.1- NA) months and median OS was 21.0 (19.5-NA) months, in contrast to non-MSI population survival outcomes: PFS= 4.7 (95% CI 4.1-5.2) months, OS=9.0 (95% CI 8.1-9.8) months. Conclusions: This study describes clinical outcomes of the MSI-H pts in a sample of Spanish patients with BTC. Molecular characterization was poorly performed at the time of database cut-off; however, we found a higher presence of MSI-H than expected. PBL, as the second-line strategy, showed a good response.

Protective effect of resveratrol against pembrolizumab-induced hepatotoxicity and neurotoxicity in male rats.

The present study investigates the effects of resveratrol (RSV) on brain and liver tissues in rats with pembrolizumab (PEMB)-induced toxicity. Obtained for the study were 28 male Sprague-Dawley rats (3-4 months old) which were divided into four groups: Group 1: Control. Group 2: Administered PEMB at 5 mg/kg/day i.p. for a week. Group 3: Administered RSV orally at the dose of 20 mg/kg/day for 30 days by gavage. Group 4: Administered PEMB and RSV at 20and 5 mg/kg/day RSV, respectively, for 30 days. The results of this study revealed that PEMB leads to a significant increase in thiobarbituric acid reactive substance (TBARS) levels and a significant decrease in glutathione peroxidase (GPx), catalase (CAT), superoxide dismutase (SOD) activities, and glutathione (GSH) levels in the liver and brain tissues. The decreased SOD, CAT, GPx activities, and GSH levels increased significantly following RSV treatment in Group 4. The PEMB treatment showed histopathological alterations associated with strong positive cysteinyl aspartic acid-protease-3 (caspase-3) immunoreactivity, while RSV treatment reduced both the expression of caspase-3 protein and the histopathological changes. RSV administration prevents the biochemical, immunological, and histological alterations induced by PEMB. It can be suggested that the lower caspase-3 immunoreactivity in the PEMB + RSV group than in the PEMB group led to an inhibition of RSV on apoptosis.

LBSUN292 Learning Lesson From A Case of Fulminant Type 1 Diabetes Mellitus Shortly After Pembrolizumab Treatment

Abstract Background Immune checkpoint inhibitors (ICIs) in cancer treatment are considered one of the major breakthroughs in the past decade. Pembrolizumab (PBL) is one of the immune checkpoint inhibitors that targets the programmed cell death protein-1 (PD-1) receptor in order to block its interaction with programmed cell death ligand-1 (PD-L1) and programmed cell death ligand-2 (PD-L2). By inhibition of these molecules, PBL helps increase T-cell activation against cancer cells. Unfortunately, this inhibition also enhances autoimmunity against normal cells, leading to immune-related adverse events (irAEs) including endocrinopathies. Unlike other irAEs, endocrinopathies are usually irreversible upon diagnosis. While hypophysitis, hypo/hyperthyroidism, and adrenal insufficiency are more commonly reported, type 1 diabetes mellitus (T1DM) is also seen around 0.9 to 1.9% of cases. Unfortunately, it can become fatal if not being promptly recognized. To raise awareness about this life-threatening adverse event, we are reporting a case of new onset T1DM, presenting with diabetic ketoacidosis (DKA) only after 22 days of the first PBL infusion. Clinical case A 19-year-old male was recently diagnosed with NUT (nuclear protein in testis) carcinoma of the left floor of mouth with high PD-L1 score. NUT carcinoma is a rare type of squamous cell cancer with chromosomal rearrangement in the nuclear protein in testis gene (NUTM1) that makes the cancer aggressive and resistant to standard therapy, hence requiring a multimodal approach. This patient underwent surgery followed by concurrent cisplatin-radiation and PBL. Two weeks after his first PBL infusion, he suddenly developed polydipsia, polyuria, and nausea. He continued to receive the second PBL dose on day 20 and developed DKA on day 21. His work-up revealed a plasma glucose of 856 mg/dL, anion gap of 20 (H), CO2 of 17 mEq/L (L), and beta-hydroxybutyrate of 3.35 mmol/L (H), while hemoglobin A1C of only 5.5% suggesting his fulminant progression. He was immediately treated with DKA protocol with clinical improvement. The patient was discharged on basal bolus insulin regimen. He had non-detectable C-peptide (<0.10 ng/mL) and high GAD Antibody (>250 IU/mL) levels, which was consistent with PBL induced T1DM. Conclusion PBL use has been linked to multiple endocrinopathies and even though rare, DKA can also be seen in setting of T-cell mediated irreversible damage to pancreas beta cells. Due to life threatening potential of DKA, clinicians should monitor patients receiving immune checkpoint inhibitors closely and should be aware symptoms of hyperglycemia for earlier intervention. | Keywords: pembrolizumab, NUT carcinoma, diabetic ketoacidosis Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

ODP170 Check Point Inhibitor Associated Multi-Endocrine Dysfunction Presenting With Euglycemic Ketoacidosis

Abstract Introduction Immune check point inhibitors have become breakthrough therapy for many types of cancers. They inhibit one of two immune regulatory pathways, the cytotoxic T-lymphocyte antigen 4 (CTLA-4), and 'programmed death-1' (PD-1) and (PD-L1) pathways. Removing immune regulation allows for anti-cancer immune responses. They also cause immune related endocrine dysfunction such as hypophysitis, thyroiditis, diabetes mellitus (DM) and primary adrenal insufficiency (AI). We describe a patient on Pembrolizumab (PEM) (an anti-PD-1 inhibitor) who presented with new onset DM, euglycemic diabetic ketoacidosis (DKA) with simultaneous secondary AI. Case report 54-year-old woman with stage 4 non-small cell carcinoma of the lung (NSCLC) with known brain metastasis, was under therapy with carboplastin, paclitaxel and PEM, presented with headache, blurry vision and altered mental status. She had past history of Graves’ disease s/p radioactive iodine therapy, currently on levothyroxine. For two weeks, she had decreased oral intake, and generalized weakness. Upon presentation, she was cachectic, BP 152/65, pulse 117 and confabulating. Laboratory evaluation showed: serum glucose 72 mg/dL, Na 139 mmol/L, K 3.2 mmol/L, Cl 113 mmol/L, HCO3 11 mmol/L, anion gap 15 mmol/L, beta-hydroxybutyrate 4.8 mmol/L, lactic acid 0.7 mmol/L, venous pH 7.2 and base excess -16.6 mmol/L. The delta-delta gap was 10 mmol/L, compatible with a mixed anion-gap and hyperchloremic acidosis (HCA). Antibodies to GAD-65, and Zinc transporter-8 were negative. To evaluate euglycemia despite DKA, levels were obtained for serum cortisol 1 mcg/dL, and ACTH <1 pg/mL confirming secondary AI. MRI neuroimaging showed several metastatic brain lesions, a small pituitary gland without stalk enhancement or thickening. Management of euglycemic ketoacidosis required high dose glucose infusion (>10 g/hour), stress doses of hydrocortisone (HC), and infusion of low chloride solute for HCA. Conclusion Awareness of the potential for multi-endocrine dysfunction, directed us towards the urgent institution of therapy for DKA with supplementation of stress dose HC for presumed AI, the latter as a cause of relative "hypoglycemia". Central AI was confirmed with undetectable levels of cortisol and ACTH. Although less frequent than with CTLA-4 inhibitors, PD-1 inhibitors are associated with hypophysitis even without abnormalities on pituitary MRI. The DM (associated with PD-1 inhibitors) although autoimmune is nature, is "antibody" positive approximately 50% of the time. Further therapy for both euglycemic DKA and HCA required adjustment of the conventional management for DKA. To our knowledge this is the first reported case of Euglycemic DKA and secondary AI due to PD-1 inhibitors per literature review. Reference: Walters AGB, BraatvedtG G. Endocrine adverse effects of immune check point inhibitors . Intern Med J. 2021Jul;51(7): 1016-1020. doi: 10.111/imj . 14992. PMID: 34278695. Hattersley R, Nana M,Lansdown AJ. Endocrine complications of immunopathies: a review . ClinMed(Lond).2021 Mar;21(2): e212-e222. doi: 10.7861/clinmed.2020-0827. PMID: 33762389;PMCID: PMC8002767 Presentation: No date and time listed

LBA4 CANOPY-N: A phase II study of canakinumab (CAN) or pembrolizumab (PEM), alone or in combination, as neoadjuvant therapy in patients (pts) with resectable stage Ib–IIIa non-small cell lung cancer (NSCLC)

CAN is a monoclonal antibody that inhibits proinflammatory IL-1β–driven pathways that may play a role in tumor growth in early-stage NSCLC. Preclinical data suggest targeting IL-1β could decrease inflammation and immunosuppression in the tumor microenvironment (TME).

1449MO Updated efficacy of lenvatinib (LEN) + pembrolizumab (PEMBRO) vs sunitinib (SUN) in patients (pts) with advanced renal cell carcinoma (aRCC) in the CLEAR study

The phase 3 CLEAR study showed statistically significant PFS (primary endpoint) and OS benefits, and improved ORR with LEN + PEMBRO vs SUN in pts with aRCC in the 1L setting. We report updated efficacy and describe pts who completed 2 years of PEMBRO and continued on LEN monotherapy.

The Combining of Tyrosine Kinase Inhibitors and Immune Checkpoint Inhibitors as First-Line Treatment for Advanced Stage Hepatocellular Carcinoma.

Aim: Hepatocellular carcinoma (HCC) is one of the most common cancers. Tyrosine kinase inhibitors (TKIs), including sorafenib (SOR) and lenvatinib (LEN), as well as immune checkpoint inhibitors (ICIs), including nivolumab (NIVO) and pembrolizumab (PEMBRO), have been approved for the treatment of advanced HCC. The aim of the study is to determine whether advanced-stage HCC patients should receive a combination of TKI and ICI as first-line therapy. Methods: Data for subjects with BCLC stage C HCC, who were receiving combining TKI and ICI as first-line therapy at Taichung Veterans General Hospital from April 2019 to July 2021, were evaluated. The general and therapeutic outcome data were collected and analyzed. Results: A total of 33 patients were enrolled (8 SOR/NIVO, 4 SOR/PEMBRO, 11 LEN/NIVO, and 10 LEN/PEMBRO). All cases belonged to Child-Pugh class A. The objective response rate was 48.5%, and disease control rate was 72.7%. The average progression-free survival (PFS) and overall survival (OS) of all patients was 9.2 and 17.0 months, respectively. The use of PEMBRO, when compared with NIVO, had a significantly positive impact towards achieving an objective response, defined as either complete response or partial response (OR 5.54, p = 0.045). PFS and OS between the different TKIs or ICIs had no differences. The most adverse event was fatigue (36.4%), and most cases were mild and manageable. Conclusion: Combining TKI and ICI provides an acceptable antitumor efficacy in first-line therapy for advanced-stage HCC patients. The survival outcomes between different TKIs or ICIs display no differences.

The effect of aromatase inhibitors against possible testis toxicity in pembrolizumab treated rats.

Pembrolizumab is a monoclonal antibody. Anastrozole is an infertility inhibitor of aromatase. Resveratrol is an antioxidant polyphenol in the reproductive system. This study was planned to demonstrate the protective effects of anastrozole and resveratrol against pembrolizumab-induced reproductive damage. Forty-two Sprague-Dawley rats were used in the study. Groups: The control, Pembrolizumab (PEMB), PEMB + Anastrazol (ANAST), PEMB + Resveratrol (RES), RES, and ANAST groups. At the end of the experiment, rats were euthanased under anaesthesia. Tissue samples were taken from rats for biochemical, histological, and ELISA evaluations. Tissues were subjected to routine tissue follow-up for histological analysis. Biochemically, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) levels were measured. Sperm motility, abnormal sperm rate, and epididymal sperm concentration were examined spermatologically. Serum testosterone and programmed cell death-1 (PD-1) levels were measured using the ELISA. TBARS levels were significantly increased and GSH, SOD, GPx, and CAT levels were mitigated in PEMB-treated rats. Histologically; Control, ANAST, and RES groups testis samples were observed with normal histological appearance. Histological damage was detected in seminiferous tubule structures in testicular tissue in the PEMB group. In treatment groups, this damage was decreased. In addition, PD-1 and testosterone levels were evaluated by the ELISA method. ANAST and RES have therapeutic effects against reproductive damage caused by PEMB.

Cost-effectiveness analysis of tumor molecular testing in stage III endometrial cancer (089)

<b>Objectives:</b> Treatment of advanced and recurrent endometrial cancer (EC) has traditionally been based on factors, such as histology and stage. Recent studies suggest that tumor molecular profiles may predict treatment outcomes and guide treatment choice. For example, pembrolizumab (PMB) use in patients with mismatch repair deficient (MMRd) tumors versus combined pembrolizumab and lenvatinib (PL) in patients with mismatch repair proficient tumors (MMRp). Furthermore, <i>POLE</i> mutated (<i>POLE</i>mut) tumors demonstrate a favorable prognosis even with minimal treatment. Prospective trials using molecular profiling for treatment assignment are ongoing, but tumor molecular testing (TMT) is costly and time-consuming. We, therefore, sought to evaluate the cost-effectiveness of TMT in stage III EC. <b>Methods:</b> A Markov decision model was created to compare two testing strategies in patients with stage III EC: TMT versus no testing (NT). TMT patients had sequential <i>POLE</i> next-generation sequencing (NGS), mismatch repair (MMR) immunohistochemistry (IHC), and p53 IHC. Adjuvant therapies included radiation (RT) alone for <i>POLE</i>mut and chemoradiation (CTRT) for NT, MMRd, p53 mutated (p53mut), and no specific molecular profile (NSMP) using PORTEC-3 data. All patients received six cycles of carboplatin and paclitaxel (CP) for first recurrence using GOG 209 outcomes. MMRd patients received PMB alone for the second recurrence, whereas all other patients received PL. National database and registry values, literature review, and expert input were used for cost and utility values. A healthcare payer perspective, willingness-to-pay (WTP) threshold of $100,000, and 5-year time horizon were used. Data analysis was done with TreeAge Pro Software 2021. Outcomes were reported in quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs). Sensitivity analyses tested model robustness, and a structural sensitivity analysis was performed in which controls underwent MMR IHC alone. <b>Results:</b> Compared to NT, TMT was less costly and more effective. While the model was most sensitive to median overall survival with PL, probability of MMRd status, and cost of lenvatinib, TMT remained cost-saving over all parameters tested. On Monte Carlo analysis, TMT was favored in 79% and 80% of iterations with a WTP of $50,000 and $100,000, respectively. When controls had MMR IHC alone, TMT was no longer cost-effective with an incremental cost of $3100 and incremental effectiveness of 0.017 QALYs, or $184,942/QALY gained. <b>Conclusions:</b> For patients with stage III EC, this model suggests TMT is associated with cost savings compared to NT. However, when compared to MMR IHC alone, a common clinical approach, TMT was no longer a cost-effective strategy at a WTP threshold of $100,000. Further prospective studies are needed to determine the prognostic value of molecular profiles in endometrial cancer. It will be essential to continue assessing the cost-effectiveness of these molecular tests as new data becomes available.

Adverse Events of Axitinib plus Pembrolizumab Versus Lenvatinib plus Pembrolizumab: A Pharmacovigilance Study in Food and Drug Administration Adverse Event Reporting System

No head-to-head postmarket surveillance study has compared the differences in adverse events (AEs) between two combination therapies, axitinib (AXI) + pembrolizumab (PEMBRO) and lenvatinib (LEN) + PEMBRO, against metastatic renal cell carcinoma. This study aims to highlight the comprehensive differences in AEs between these two therapies based on the real-world big data from the Food and Drug Administration Adverse Event Reporting System (FAERS) database. In total, 28 937 records were extracted from the FAERS database, and 139 AEs grouped into the System Organ Class according to the Medical Dictionary for Regulatory Activities were analysed. Logistic regression analyses were performed, and the reporting odds ratio with a 95% confidence interval was determined. We found that the incidences of cardiac and hepatobiliary disorders for AXI + PEMBRO, and blood and lymphatic system, metabolism and nutrition, and vascular disorders for LEN + PEMBRO, all of which were associated with serious AEs, were higher than those for LEN + PEMBRO and AXI + PEMBRO, respectively. The differences in the AEs between AXI + PEMBRO and LEN + PEMBRO were not derived merely from those between AXI and LEN monotherapies. Furthermore, remarkable AE potentiation was observed for AXI + PEMBRO. As FAERS is a spontaneous reporting system comprising partially limited information, analysing more detailed relationships between AEs and patient or treatment characteristics was challenging in this study. The present study is the first to show the overall real-world postmarketing differences in AEs between AXI + PEMBRO and LEN + PEMBRO. Our novel findings will substantially improve clinical practice; we recommend comparing patients’ conditions associated with the above AEs when selecting between these two therapies. Patient summaryHerein, we highlight the differences in adverse events (AEs) between axitinib + pembrolizumab and lenvatinib + pembrolizumab therapies using data from the real-world Food and Drug Administration Adverse Event Reporting System database aimed at patients with metastatic renal cell carcinoma. We identified AEs that needed attention in each combination. We recommend the differences in AEs to be considered when selecting these two therapies.

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 CT135: Preliminary safety and efficacy of DSP-7888 plus nivolumab (NIV) or pembrolizumab (PEM) in patients (pts) with advanced solid tumors (ASTs): A phase (Ph) 1b/2 open-label study

Abstract Background: DSP-7888—an investigational immunotherapeutic cancer vaccine derived from Wilms’ tumor 1 (WT1)—induced WT1-reactive T cells, the activity of which was maintained and enhanced by anti-PD-1 mAbs (preclinical; Goto, et al. ASH 2016). Results from the Ph 1b dose search cohort of a Ph 1b/2 study of DSP-7888 + immune checkpoint inhibitors (ICIs) NIV or PEM in ASTs (NCT03311334) are presented. Methods: Pts (aged ≥18 y; ECOG PS 0-1; locally advanced/metastatic solid tumors; approved for NIV or PEM) received intradermal (ID) DSP-7888 10.5 mg once weekly (wk) (Q1W) + NIV 240 mg IV Q2W for 4 (Arm 1) or PEM 200 mg IV Q3W for 6 (Arm 2) wks (induction), then DSP-7888 + NIV (Q2W; Arm 1) or PEM (Q3W; Arm 2) (maintenance). A DSP-7888 3.5-mg dose cohort would open if dose limiting toxicities (DLTs) occured in &amp;gt;1 of 6 pts. Primary objectives: evaluate safety (including DLTs) and identify the recommended Ph 2 dose of DSP-7888 + NIV or PEM. Results: At data cutoff (March 30, 2021), 13 pts (mean age 63.8 [range 38-82] y; 61.5% male; median 3 (1-5) lines of prior therapy; 84.6% prior ICIs) were enrolled and treated with DSP-7888 10.5 mg + NIV (Arm 1, n=7) or PEM (Arm 2, n=6). Treatment-emergent adverse events (TEAEs) were reported in 100% (any grade) and 76.9% (grade ≥3; most commonly injection site reactions [ISR; 30.8%]) of pts (Table). No DLTs occurred during the evaluation period (NIV, 4 wk; PEM, 6 wk), establishing 10.5 mg as the recommended dose for DSP-7888 + NIV or PEM. Serious AEs were reported in 7 (53.8%) pts (2 [15.4%] related to DSP-7888). At efficacy data cutoff (May 4, 2020), 2 (15.4%) pts with prior ICIs achieved partial response, which lasted 9.5 and 5.5+ months; 6 pts achieved stable disease (n=4 ≥8 months) and 3 had progressive disease. Conclusions: DSP-7888 + NIV or PEM was generally tolerable at 10.5 mg ID (most common TEAE was ISR) and showed evidence of preliminary antitumor activity. An expansion cohort in ovarian cancer is enrolling. Table. Safety and Efficacy (N=13a) DSP-7888 + NIV (n=7) DSP-7888 + PEM (n=6) Overall (N=13) Patient characteristics Prior lines of therapy, n (%) -1 0 1 (16.7) 1 (7.7) -2 2 (28.6) 1 (16.7) 3 (23.1) -≥3 5 (71.4) 4 (66.7) 9 (69.2) Prior ICI, n (%) 7 (100) 4 (66.7) 11 (84.6) Safety All patients with TEAE grade ≥3, n (%)b — — 10 (76.9) TEAEs grade ≥3 (in ≥2 patients), n (%)b -Injection site reaction — — 4 (30.8) Pts with treatment-emergent SAEs, any grade, n (%)b — — 7 (53.8) Efficacy ORR (CR+PR), n (%) [95% CI] 2 (28.6) [3.7, 71.0] 0 2 (15.4) [1.9, 45.5] Best overall response, n (%) -PRc 2 (28.6) 0 2 (16.7) -SD 3 (42.9) 3 (50.0) 6 (46.2) -PD 0 3 (50.0) 3 (23.1) -Non-CR/Non-PD 1 (14.3) 0 1 (7.7) -NE 1 (14.3) 0 1 (7.7) Disease control rate (CR+PR+SD+Non-CR/Non-PD), n (%) [95% CI] 6 (85.7) [42.1, 99.6] 3 (50.0) [11.8, 88.2] 9 (69.2) [38.6, 90.9] aTumor types included non-small cell lung cancer (n=7), urothelial cancer (n=3), gastroesophageal junction adenocarcinoma (n=1), head and neck squamous cell carcinoma (n=1), and renal cell carcinoma (n=1). For inclusion, patients either progressed on their prior treatment or were being treated with NIV or PEM, achieved at least SD, and could benefit from the addition of DSP-7888 (physician’s judgement). bRegardless of causality. cOf the patients that exhibited a PR, 1 had renal cell carcinoma and 1 had urothelial cancer. Both patients were previously treated with an ICI (NIV and atezolizumab, respectively. DOR w as 9.5 and 5.5 (+) months in the patients with renal cell carcinoma and urothelial cancer, respectively (DOR was defined as the time, in months, from the first documentation of CR or PR to the first documentation of PD or death due to any cause. Patients who were alive and progression-free as of the analysis cut-off date were censored (+) at their last date of response assessment. CI, confidence interval; CR, complete response; ICI, immune checkpoint inhibitor; DOR, duration of response; NE, not evaluable; NIV, nivolumab; ORR, overall response rate; PD, progressive disease; PEM, pembrolizumab; PR, partial response; SAE, serious adverse event; SD, stable disease; TEAE, treatment-emergent adverse event. Citation Format: Wael A. Harb, Makoto Origuchi, Patrick W. Cobb, Trisha Wise-Draper, Natsuko Suginobe, Megumi Nakamura, Masashi Goto, Aaron Chen, Jian Li, James Wade III. Preliminary safety and efficacy of DSP-7888 plus nivolumab (NIV) or pembrolizumab (PEM) in patients (pts) with advanced solid tumors (ASTs): A phase (Ph) 1b/2 open-label study [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 CT135.

Abstract 4151: Effect of camidanlumab tesirine (Cami) as monotherapy and in combination with pembrolizumab (PEM) on the immune cell profile in patients with selected advanced solid tumors

Abstract Background: Cami, an investigational anti-CD25, pyrrolobenzodiazepine-based antibody drug conjugate, imparts cytotoxicity on CD25+ regulatory T cells (Tregs), leading to immunomodulatory effects (eg, modifying effector T cell [Teff]:Treg intratumoral balance). Objective: Describe the pharmacokinetics (PK) and circulating immune cell profile of Cami monotherapy and in combination with PEM in patients with advanced solid tumors. Methods: In the dose-escalation phase 1b trial of Cami (NCT03621982) in patients with advanced solid tumors after failure of recommended therapies, we investigated Cami monotherapy (n=44; doses: 20, 30, 45, 60, 80, 100, 125, and 150 µg/kg every 3 weeks [Q3W]) and Cami combination therapy (n=12; doses: 30, 45, and 60 µg/kg with PEM 200 mg Q3W). Serum conjugated antibody (cAb) and total antibody (tAb) were quantified by a validated chemoimmunoluminescence assay. Soluble CD25 was quantified by a qualified enzyme-linked immunoassay. Circulating immune cell absolute counts were assessed by flow cytometry for Tregs (FoxP3+CD25+CD127low) as a fraction of absolute CD4+ cells, Teff (CD8+), and Teff:Treg. Statistical analyses were performed using a linear mixed-effects model (maximum likelihood) for the biomarker effects model with cAb area under the curve (AUC) during cycle 1, therapy (monotherapy vs combination), and treatment cycle as fixed effects and log AUC slope with intercept by subject or visit day as random effects. Results: PK analysis found Cmax and AUC of cAb and tAb increased during cycles 1 and 2 with Cami monotherapy and combination therapy across the range of doses. Variability of AUCinf for cAb in cycle 1 appeared modest to marked across discrete dose groups (CV=14.7-98.1%). The clearance of cAb ranged from 1.34 to 3.52 L/day in cycle 1 with no apparent differences between monotherapy and combination therapy. Biomarker modeling demonstrated that cAb AUC and cycle were associated with a significant Tregs depletion and a significant positive effect on Teff:Treg ratio but with no relevant effect on Teff. Within cycle, treatment-related modulation of Teff and Tregs was observed for all doses and conditions. Soluble CD25 appears to be significantly positively affected by cycle 2 treatment. Conclusions: PK exposure of Cami was dose-related with varying degrees of interpatient variability. Circulating Tregs were significantly decreased and Teff:Treg was significantly increased by Cami exposure, demonstrating the intended immunomodulatory effect of Cami in circulation and suggesting that a combination approach with Cami could address an immune-resistance mechanism. Future analyses will consider discrete PEM effect, correlates to tumor biopsy expression and response, and combined Cami+PEM effect in tumor biopsies. Funding: ADC Therapeutics; medical writing: CiTRUS Health Group. Citation Format: Igor Puzanov, Christopher T. Chen, Patricia LoRusso, Kyriakos P. Papadopoulos, Shivaani Kummar, Erika Hamilton, Yvan LeBruchec, Karin Havenith, Serafino Pantano, Marie Toukam, Jens Wuerthner, Joseph Boni. Effect of camidanlumab tesirine (Cami) as monotherapy and in combination with pembrolizumab (PEM) on the immune cell profile in patients with selected advanced solid tumors [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 4151.

IMPemBra, a phase 2 study comparing pembrolizumab with intermittent/short‐term dual MAPK pathway inhibition plus pembrolizumab in patients with melanoma harboring the BRAFV600 mutation: Three-year survival data and translational analyses.

9552 Background: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-PD-(L)1 showed high response rates, but also high frequency of treatment-related adverse events (TRAE) in BRAFV600-mutated melanoma patients (pts). Short‐time MAPKi already induces T cell infiltration in pts and was synergistic with anti-PD‐1 in a pre-clinical model. This phase 2b trial aimed to identify the optimal duration of MAPKi with dabrafenib + trametinib (D+T) in combination with pembrolizumab (PEM). We have previously shown that no SUSARs were observed, toxicity was related to duration of D+T, and response rates increased after addition of D+T. Here we present 3-year PFS and OS data and results of translational analyses. Methods: In IMPemBra, pts with treatment-naïve BRAFV600E/K mutant advanced melanoma started with PEM 200mg Q3W. After 2 cycles, pts were randomized to continue PEM only (cohort 1) or to receive in addition intermittent dabrafenib 150 mg BID + trametinib 2mg QD for 2 x 1 week (cohort 2), 2 x 2 weeks (cohort 3) or continuous for 6 weeks (cohort 4). All cohorts continued PEM for up to 2 years. Primary endpoints were safety, treatment adherence and immune-activating capacity of the different regimens. Secondary endpoints were objective response rate (ORR) and PFS, OS was an exploratory endpoint. For survival analyses, pts that received D+T (cohort 2-4) were pooled. Results: Thirty-two pts were randomized, 56% were male, 53% had M1c disease and 88% had a LDH level &lt; ULN. No new grade 3-4 TRAE were observed; frequencies were 12%, 12%, 50% and 62% for pts in cohort 1, 2, 3 and 4, respectively. ORRs were 75% in cohort 1 and 2, and 88% in cohort 3 and 4. The frequency of PD1+CD8+ T cells in peripheral blood decreased slightly during treatment and there were no differences between cohorts. In cohort 1 and 2, an increase in IFNγ signature in tumor biopsies was already observed after 6 weeks of PEM, in cohort 3-4 an increase in IFNγ signature was observed in week 9, after addition of D+T. The same pattern was observed for CD8+ T cell infiltration and PD-L1 expression. After a median follow-up of 43.5 months, the median PFS of pts treated with PEM monotherapy was 10.6 months versus 32.3 months for pts treated with PEM plus D+T (p = 0.19). The 3-year PFS rates were 25.0% and 50.0% respectively. Median OS was 40.5 months in the PEM pts and not reached for pts treated with PEM plus D+T (p = 0.32); 3-year OS rates were 62.5% and 70.8% respectively. Conclusions: IMPemBra demonstrated that short-term addition of intermittent D+T to PEM seems a more feasible, tolerable and an effective alternative for the continuous triple combination. In addition, it gives the opportunity to treat with second line targeted therapy after disease progression. Therefore, this regimen should be considered for further investigation in a larger cohort. Clinical trial information: NCT02625337.