Combination Of Tyrosine Kinase Inhibitors Research Articles

Clinical efficacy and safety of immune checkpoint inhibitor in combination with regorafenib therapy as second⁃line regimen for patients with unresectable hepatocellular carcinoma.

e16105 Background: Combined systemic and local therapy is a promising treatment strategy for patients with advanced hepatocellular carcinoma (HCC). Transarterial chemoembolization (TACE), tyrosine kinase inhibitors (TKI) and PD-1 antibodies are all recommended for patients with unresectable HCC (uHCC). This study was aimed to evaluate the efficacy and safety of TACE combined with TKIs and camrelizumab in the treatment of uHCC. Methods: In this multicenter, single-arm phase II trial (ChiCTR2000039508), patients with intermediate-stage uHCC who had a Child-Pugh score ≤ 7 and had not received prior systemic anti-cancer treatment would receive treatment with TACE followed by immunotherapy with camrelizumab 200 mg every 3 weeks plus a TKI agent selected from lenvatinib (12 mg/day for bodyweight ≥60 kg or 8 mg/day for bodyweight <60 kg), sorafenib 400 mg bid or donafenib 200 mg bid until intolerable toxicity or disease progression. During the study treatment, patients assessed as eligible for resection would undergo surgery. The primary endpoint was objective response rate (ORR) per modified RECIST. Secondary endpoints included progression-free survival (PFS), disease control rate (DCR), duration of response (DOR) and overall survival (OS). Results: From September 2020 to November 2021, 87 patients (81 men and 6 women; median age, 56 years) were enrolled. Among them, 43 (49.4%) patients had extrahepatic metastases, and 65 (74.7%) patients had HBV infection. As of September 28, 2022, the median duration of follow-up was 13.6 (0.83-24.9) months. A total of 34 patients (39.1%) died, and the median OS was not reached. The median PFS was 10.5 months (95% CI: 7.8-13.1). The ORR rate was 71.3% (62/87), and the DCR rate was 89.7% (78/87) per mRECIST. According to RECIST version 1.1, the ORR rate was 35.6% (31/87), and the DCR rate was 87.4% (76/87). The ORR and PFS showed consistent benefits in subgroups based on ECOG score, HBV infection, baseline alpha-fetoprotein level, combined TKI, and the number of TACE treatments. Ten patients (11.5%) successfully underwent conversion therapy and all achieved R0 resection. Two patients achieved a complete pathological response (pCR) and four achieved a major pathological response (MPR). The most common AEs were hypoproteinemia (92%), elevated lactate dehydrogenase (80.5%), elevated glutamic oxaloacetic transaminase (79.3%), elevated bilirubin (78.2%), abdominal pain (62.1%), nausea (33.3%), and RCCEP (26.4%). The incidence of grade 3-4 adverse reactions was 67.8%, and no treatment-related deaths occurred. Conclusions: TACE combined with TKI and camrelizumab showed promising clinical benefits. It can effectively control tumor progression and provide opportunities for resection with acceptable safety, which will bring great benefits to uHCC.

Comprehensive plasma genotyping of patients with EGFR positive NSCLC as a monitoring tool for therapy response and disease progression.

e20598 Background: Targeted therapy against molecular drivers has revolutionized the NSCLC standard of care. EGFR activating mutations (mEGFR) are most prominent in Asian NSCLC patients and can benefit from tyrosine kinase inhibitor (TKi) therapy. NCCN guidelines recommend screening lung tumors for detecting mEGFR as a standard of care for TKi inhibitor therapy. However, a significant number of patients with mEGFR do not respond well to TKi due to naturally occurring or therapy-induced TKi blunting mutations. Small gene panels may fail to detect concomitant rare mutations, e.g genomic instability. We longitudinally monitored mEGFR dynamics and the presence of cooccurring clinically important mutations using a comprehensive gene panel in NSCLC patients. Methods: We retrospectively analyzed outcomes from the plasma genotyping of 150 samples from 25 mEGFR-positive NSCLC pts on TKi therapy. For NGS, ctDNA was isolated from longitudinally collected plasma samples (at diagnosis, and during Tx including PD). Libraries prepared using a custom-designed comprehensive gene panel OncoIndx to target 600 cancer-relevant exons, including MSI and HRR pathway genes, were target captured and sequenced in pair-end mode on Illumina platform Nextseq2000. Variant calling was performed using an in-house developed bioinformatics pipeline based on GATK environment. Results: ex 19 deletion variant was the most frequent (35 %) mEGFR followed by L858R (20 %) and T790M (10 %). Rest 10 % had other mutations, including TP53, KRAS, TGFBR1 and PTEN and 25 % of the longitudinal samples did not show any mutations. In 40 % of patients increase in mEGFR vaf correlated with the clinical progression. Surprisingly, these patients had either TP53, RB1 or TGFBR1 variants cooccurring with mEGFR. For the remaining patients, we did not observe a clear temporal correlation with mEGFR vaf. This was corroborated well by the absence of any TKi blunting mutations among these patients. T790M variants were detected only at the progression onset and were absent at earlier time points. MGA, TP53, and RB1 variants were detected along high mEGFR vaf in 10 % of patients around the time of clinical progression. At the genomic scale, TMB scores were low and did not vary longitudinally among the pts. HRD and LOH sores were high and correlated well in patients with mEGFR cooccurrence along variants such as KRAS, TP53, PTEN, and BAP1. Conclusions: Comprehensive plasma genotyping identified cooccurring key drivers that correlated with the clinical progression. Their presence may suggest the blunting effect of TKi and early progression. The patient with high genome instability scores may benefit from HRR inhibitor +TKi combination therapy in EGFR-positive pts. A small patient cohort limits the interpretation of this data and warrants further investigation through clinical trials.

Inhibition of CDCP1 by 8-isopentenylnaringenin synergizes with EGFR inhibitors in lung cancer treatment.

CUB domain-containing protein 1 (CDCP1) contributes to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance by regulating EGFR signaling pathways and is a potential target in lung cancer treatment. This study aims to identify a CDCP1 reducer that synergistically improves TKI treatment. Utilizing a high-throughput drug screening system, a phytoestrogen 8-isopentenylnaringenin (8PN) was identified. Upon 8PN treatment, CDCP1 protein levels and malignant features were reduced. 8PN exposure caused the accumulation of lung cancer cells in G0/G1 phase and increased the proportion of senescent cells. In EGFR TKI-resistant lung cancer cells, the combination of 8PN and TKI synergistically reduced cell malignance, inhibited downstream EGFR pathway signaling and exerted additive effects on cell death. Moreover, combination therapy effectively reduced tumor growth and enhanced tumor necrosis in tumor xenograft mice models. Mechanistically, 8PN increased interleukin (IL)6 and IL8 expression, induced neutrophil infiltration, and enhanced neutrophil-mediated cytotoxicity to attenuate lung cancer cell growth. In conclusion, 8PN enhances the anti-cancer efficacy of EGFR TKI on lung cancer, and triggers neutrophil-dependent necrosis, highlighting the potential to overcome TKI resistance in lung cancer patients who have EGFR mutation.

The toxicity associated with combining immune check point inhibitors with tyrosine kinase inhibitors in patients with non-small cell lung cancer.

Latest advances in non-small cell lung cancer (NSCLC) therapies have revolutionized the treatment regimens utilized for NSCLCs with or without a driver mutation. Molecular targeted treatments such as tyrosine kinase inhibitors (TKIs) are utilized to prevent tumor progression and improve survival. Despite the great benefit of immunotherapy in NSCLC tumors with no driver mutation, the use of immune checkpoint inhibitors (ICIs) in NSCLC tumors harboring a driver mutation has been under debate. Furthermore, several trials have been conducted investigating the use of these therapies with TKIs. A few trials were halted due to growing concerns of increased toxicity with the combination of TKI and immunotherapy. The adverse events ranged from low grade dermatologic complaints to fatal interstitial lung diseases. These toxicities occur with both concurrent and sequential administration of treatment. Thus, recommendations for the safest method of combination treatment have not yet been described. This review paper discusses recent views on combination treatment, previous clinical trials reporting grade 3-4 toxicities, and guidelines for a safe timeline of administration of treatment based on past evidence.

Abstract CT257: First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors

Abstract Background: Protein tyrosine phosphatase non-receptor type 2 and type 1 (PTPN2/1) antagonists inhibit PTPN2/1-mediated negative regulation of immune response pathways. They may promote antitumor activity by increasing function of immune cells such as T cells and dendritic cells, inducing cytokine production, increasing antigen presentation, and amplifying interferon gamma-mediated tumor growth arrest. ABBV-CLS-484 and ABBV-CLS-579 are potent, orally bioavailable, first-in-class PTPN2/1 inhibitors that showed promising antitumor activity and were well tolerated in preclinical models. Preclinical data also indicated that PTPN2/1 inhibitors have improved efficacy when combined with PD-1-targeting agents (eg, pembrolizumab) or vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) in multiple tumor models. Here, we describe 2 first-in-human trials of ABBV-CLS-484 or ABBV-CLS-579 as monotherapy and in combination with pembrolizumab or VEGFR TKI in patients with locally advanced/metastatic tumors. Methods: These phase 1, open-label, multicenter, non-randomized trials (ABBV-CLS-484: NCT04777994; ABBV-CLS-579: NCT04417465) comprise dose-escalation (ESC) and dose-expansion (EXP) phases. ESC is guided by a Bayesian optimal interval design based on dose-limiting toxicities. ESC data are used to inform evaluation of EXP cohorts in select tumor types including relapsed/refractory (R/R) head and neck squamous cell carcinoma, R/R non-small cell lung cancer, advanced renal cell carcinoma, and microsatellite instability-high tumors. In both ESC and EXP phases, the study drug (ABBV-CLS-484 or ABBV-CLS-579) is administered orally either alone or in combination with pembrolizumab (200 mg intravenously once every 3 weeks) and is slated to also be administered in combination with a VEGFR TKI. Eligible patients have locally advanced/metastatic tumors for which no effective standard therapy exists (or has failed), and Eastern Cooperative Oncology Group performance status ≤2. Patients (≥18 years) must have received ≥1 prior systemic anticancer therapy for the indication being considered, have relapsed or be refractory to ≥1 prior anti-PD-1/PD-L1 therapy (EXP monotherapy and pembrolizumab combination), or have relapsed after ≤1 (ABBV-CLS-484) or ≥1 (ABBV-CLS-579) prior VEGFR TKI therapy (EXP VEGFR TKI combination). Primary objectives are to assess safety, tolerability, pharmacokinetics, and to determine the recommended expansion dose and/or maximum tolerated dose of ABBV-CLS-484 or ABBV-CLS-579, both as monotherapy and in combination. Evaluation of objective response rate (RECIST v1.1) is a primary objective in EXP phase and a secondary objective in ESC phase. Both studies are active, and as of 30 Nov 2022, 30 (ABBV-CLS-484) and 45 (ABBV-CLS-579) patients had been enrolled in ESC phase. Citation Format: Patricia M. LoRusso, Emiliano Calvo Aller, Noboru Yamamoto, Chia-Chi Lin, Thaddeus Beck, David Sommerhalder, Do-Youn Oh, John D. Powderly, Talia Golan, Linu Sara Abraham, Joel S. Hayflick, Tamar Uziel, Priya Brunsdon, Wijith Munasinghe, Marcia Paddock, Cathleen Brdlik Hartman, Jonathan Powell, Bruno Medeiros, Martha R. Neagu, Benedito A. Carneiro. First-in-human phase 1 studies of PTPN2/1 inhibitors ABBV-CLS-484 and ABBV-CLS-579 in locally advanced or metastatic tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT257.

Abstract 3999: Combination of T-DXd with the irreversible pan-HER TKI afatinib drives combination benefit in HER2-low gastric and lung tumors

Abstract Background: Trastuzumab deruxtecan (T-DXd) has been approved for advanced or metastatic breast, gastric and lung cancers. It has been postulated that irreversible tyrosine kinase inhibitors (TKIs) increase HER2 internalization, thus enhancing T-DXd efficacy. Here we report studies evaluating the combination of TKIs with T-DXd in preclinical models of HER2-low disease. Methods: Surface HER2 was measured with flow cytometry quantifying fluorescently labelled trastuzumab on the surface of HER2-low cell lines HCC38 and HCC1171 treated with afatinib, neratinib, lapatinib or tucatinib for 12 h. HER2 receptor dynamics on cell surface was also measured in NCI-N87 (HER2 IHC 3+) and HCC38 at 24, 48, 72 and 96 h post-treatment with afatinib, and recovery was measured up to 72 h after drug washout. In vivo efficacy was established with T-DXd alone and in combination with afatinib or tucatinib in two gastric patient-derived xenograft (PDX) models, HD-2 (HER2 IHC 1+) and FU (HER2 IHC 2+), and one lung PDX model, MEDI-NSCLC-04 (HER2 IHC 1+). Results: In both HER2-low cell lines, treatment with irreversible inhibitors neratinib or afatinib led to enhanced internalization with a greater than 50% surface HER2 reduction, while treatment with the reversible inhibitors lapatinib or tucatinib led to 13-35% higher surface HER2 levels. Washout experiments indicated that receptor recovery at the plasma membrane begins between 4-12h post-washout of afatinib, with complete recovery at about 72h. Tumor shrinkage was significant in HER2-low gastric PDXs when T-DXd was combined with afatinib, but not with tucatinib. In HD-2, T-DXd 10mg/kg with afatinib 20mg/kg, and T-DXd 3mg/kg with tucatinib 25mg/kg combinations resulted in 74% and -3% (with respect to T-DXd) tumor growth inhibition (TGI), respectively. In FU, T-DXd 3mg/kg with afatinib 20mg/kg, and T-DXd 3mg/kg with tucatinib 25mg/kg combinations resulted in 80.3% and 24.7% TGI, respectively. Similarly, in MEDI-NSCLC-04 PDX model, benefit was observed in 5mg/kg T-DXd combination with 20mg/kg QD afatinib (95.3% TGI with respect to monotherapy T-DXd), but not with tucatinib (0.37% TGI). Intermittent schedules (QW, MWF) were also tested for afatinib in combination with T-DXd, with the MWF showing 49.2% TGI and QW showing 33.0 %TGI. In tissue samples from MEDI-NSCLC-04 efficacy study, γH2AX was detected by IHC in T-DXd and T-DXd+afatinib combination. In western blots, a decrease in HER2 as well as pHER2 was observed in response to T-DXd and 20mg/kg afatinib treatment, but not with tucatinib. Conclusions: In HER2 low gastric and lung preclinical models, T-DXd combined with irreversible pan-HER inhibitor induced superior antitumor effects compared to single agents or the combination of T-DXd with reversible inhibitors. These data support the rationale to test combination of T-DXd and pan-HER irreversible inhibitors in the clinical setting. Citation Format: Deepa Bhavsar, Laura Kazlauskas, Flavia Michelini, Matt Griffin, Matt Wilson, Fabiola Cecchi, Liz Croydon, Kim Maratea, Elisa de Stanchina, Yelena Y. Janjigian, Maurizio Scaltriti, Theresa Proia, Jerome Mettetal. Combination of T-DXd with the irreversible pan-HER TKI afatinib drives combination benefit in HER2-low gastric and lung tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3999.

MP28-08 OUTCOME CHANGE IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA OUTSIDE OF CLINICAL TRIALS FROM THE TYROSINE-KINASE INHIBITOR ERA TO THE IMMUNE CHECKPOINT INHIBITOR ERA

You have accessJournal of UrologyCME1 Apr 2023MP28-08 OUTCOME CHANGE IN PATIENTS WITH ADVANCED RENAL CELL CARCINOMA OUTSIDE OF CLINICAL TRIALS FROM THE TYROSINE-KINASE INHIBITOR ERA TO THE IMMUNE CHECKPOINT INHIBITOR ERA Hiroki Ishihara, Yuki Nemoto, kazutaka Nakamura, Hidekazu Tachibana, Hironori Fukuda, Kazuhiko Yoshida, Hirohito Kobayashi, Junpei Iizuka, Hiroaki Shimmura, Yasunobu Hashimoto, Tsunenori Kondo, and Toshio Takagi Hiroki IshiharaHiroki Ishihara More articles by this author , Yuki NemotoYuki Nemoto More articles by this author , kazutaka Nakamurakazutaka Nakamura More articles by this author , Hidekazu TachibanaHidekazu Tachibana More articles by this author , Hironori FukudaHironori Fukuda More articles by this author , Kazuhiko YoshidaKazuhiko Yoshida More articles by this author , Hirohito KobayashiHirohito Kobayashi More articles by this author , Junpei IizukaJunpei Iizuka More articles by this author , Hiroaki ShimmuraHiroaki Shimmura More articles by this author , Yasunobu HashimotoYasunobu Hashimoto More articles by this author , Tsunenori KondoTsunenori Kondo More articles by this author , and Toshio TakagiToshio Takagi More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003256.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Clinical trials have demonstrated the superior efficacy of immune checkpoint inhibitor (ICI)-based combination therapy over sunitinib, a multi-target tyrosine kinase inhibitor (TKI), in patients with advanced renal cell carcinoma (RCC). However, such benefit has not been elucidated in populations outside of clinical trials. METHODS: We retrospectively evaluated data of 331 patients with advanced RCC receiving ICI-based combination therapy or TKIs as first-line therapy. Patients were determined as trial-ineligible when at least one of following factors was present: KPS score <70%, hemoglobin level <9.0 g/dL, eGFR <40 mL/min/1.73 m2, platelet count <100,000/µL, neutrophil count <1500/µL, non-clear cell histology, or brain metastasis. The outcome change from the previous TKIs to the current ICI-based combination therapy was analyzed in both trial-eligible and trial-ineligible populations. RESULTS: This study included 48/93 (52%) and 101/238 (42%) patients receiving TKI and ICI-based combination therapy outside of clinical trials, respectively. Among the TKI-treated patients, the trial-ineligible patients had significantly lower progression-free survival (PFS) (p<0.0001) and overall survival (OS) (p<0.0001) than the trial-eligible patients. In contrast, among ICI-based combination therapy-treated patients, no significant difference in PFS (p=0.393) or OS (p=0.634) was found between them. On analyzing each population based on trial eligibility throughout the TKI and ICI-based combination therapy, in the trial-eligible population, no significant difference in PFS (p=0.236) or OS (p=0.333) was found between TKI and ICI-based combination therapy (Figure a and b). However, in the trial-ineligible population, PFS (p=0.0037) and OS (p<0.0001) were significantly higher for the ICI-based combination therapy than for the TKIs (Figure c and d). CONCLUSIONS: Using real-world data, this study indicated the substantial rate of patients with advanced RCC treated with systemic therapy outside of clinical trials. ICI-based combination therapy helped improve outcomes of advanced RCC, and the therapeutic benefit was more prominent in the trial-ineligible population than in the trial-eligible population. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e373 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiroki Ishihara More articles by this author Yuki Nemoto More articles by this author kazutaka Nakamura More articles by this author Hidekazu Tachibana More articles by this author Hironori Fukuda More articles by this author Kazuhiko Yoshida More articles by this author Hirohito Kobayashi More articles by this author Junpei Iizuka More articles by this author Hiroaki Shimmura More articles by this author Yasunobu Hashimoto More articles by this author Tsunenori Kondo More articles by this author Toshio Takagi More articles by this author Expand All Advertisement PDF downloadLoading ...

Efficacy and Safety of Tyrosine Kinase Inhibitors Alone or Combination with Programmed Death-1 Inhibitors in Treating of Hepatitis C-Related Hepatocellular Carcinoma.

Tyrosine kinase inhibitors (TKI) combined with programmed cell death-1 (PD-1) inhibitor is a potential treatment modality for patients with HCV-related unresectable hepatocellular carcinoma (uHCC). The participants of the present work included the patients having HCV-related uHCC who were treated with TKI monotherapy (TKI group) or TKI combined with PD-1 inhibitors therapy (combination group) in our center between June 2018 and June 2021. In addition, the patients were classified into RNA-positive and RNA-negative groups based on whether or not the baseline HCV RNA was detectable. The overall survival (OS) was used as the primary efficacy endpoint, while progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR) were used as secondary endpoints. The adverse events were recorded and evaluated. Among the 67 patients contained this work, 43 patients were classified into the TKI group, while 24 patients formed the combination group. In relative to the TKI group, the combination group presented notably better median OS (21 months vs 13 months, p = 0.043) and median PFS (8 months vs 5 months, p = 0.005). No evident differences were observed between the two groups in terms of the DCR (58.1% vs 79.2%, p = 0.080), ORR (13.9% vs 25.0%, p = 0.425) and the incidence of grade 3-4 adverse events (34.8% vs 33.3%, p = 1.000). In addition, there existed no obvious difference between the RNA-positive group and RNA-negative group in terms of median OS (14 months vs 19 months, p = 0.578) and median PFS (4 months vs 6 months, p = 0.238). The patients having HCV-related uHCC after being treated with the TKI and PD-1 inhibitor combination therapy exhibited a better prognosis and manageable toxicity compared to the patients who underwent TKI monotherapy.

Efficacy and safety of anlotinib plus camrelizumab in treating retroperitoneal soft tissue sarcomas: a single-center retrospective cohort study.

Conventional chemotherapy has limited therapeutic effects in retroperitoneal soft tissue sarcomas (RSTs), while anlotinib emerged as a novel multi-target tyrosine kinase inhibitor (TKI) for sarcomas. TKIs in combination with immunotherapy have demonstrated clinical activity in a variety of solid tumors. This study retrospectively analyzed the efficacy and safety of anlotinib plus camrelizumab for the treatment of RSTs. Patients with RSTs who received anlotinib plus camrelizumab at Peking University Cancer Hospital Sarcoma Center were enrolled. Response assessment was conducted every 3 cycles of treatment according to response evaluation criteria in solid tumors version 1.1 (RECIST v1.1). Treatment-related adverse events (TRAEs) were evaluated by Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Patients who had at least 1 response evaluation were analyzed. In all, 57 RSTs cases including 35 males and 22 females were analyzed, with a median age of 55 years. The pathological subtypes included 38 cases of L-sarcoma (liposarcoma and leiomyosarcoma), and 19 cases of non-L-sarcoma. Two patients (3.5%) had complete response (CR) and 13 patients (22.8%) had partial response (PR), with an objective response rate (ORR) of 26.3%. There were 31 (54.4%) and 11 (19.3%) patients with stable and progressive disease, respectively, with a disease control rate of 80.7%. Patients with non-L-sarcoma had a significantly better response rate than those with L-sarcoma (ORR: 52.6% vs. 13.2%; P=0.0031). After a median follow-up of 15.8 months, the median progression-free survival (PFS) was 9.1 months, with 3- and 6-month PFS rates of 83.6% and 60.8%, respectively. Patients with non-L-sarcoma had a significantly longer median PFS than did those with L-sarcoma (median PFS: 11.1 vs. 6.3 months; P=0.0256). TRAEs occurred in 28 (49.1%) patients, and 13 (22.8%) patients had grade 3-4 TRAEs. Hypertension (24.6%), hypothyroidism (19.3%), and palmar-plantar erythrodysesthesia syndrome (12.3%) were the most common TRAEs. The combination of anlotinib and camrelizumab demonstrated possible therapeutic efficacy and safety in the treatment of RSTs, especially for non-L-sarcomas.

Characterization and survival benefit of drugs approved for advanced renal cell carcinoma.

633 Background: The treatment landscape of advanced renal cell carcinoma (RCC) drastically changed with the approval of tyrosine kinase inhibitors (TKIs). Since then, immunotherapy (IO) and now TKI plus IO combination therapies is considered standard-of-care. Despite multiple drug approvals, it remains unclear how much improvement in survival these therapies have provided. Methods: We reviewed the US Food and Drug Administration (FDA) website to evaluate all approvals for RCC from 2005 to 2022. We collected progression-free survival (PFS) and overall survival (OS) from the approval notification or from the corresponding clinical trial cited for drug approval. Results: Between 2005 and 2022, there were 16 drug (single or combination) approvals for advanced RCC. Most therapy approvals (93.75%) were granted through accelerated approval. Eight approvals were TKIs, 6 approvals were TKI plus IO combination therapies, and 1 approval each were for immunotherapy and a VEGF inhibitor. Average PFS benefit for 1st line approvals was 5.63 months (range 1.9-14.7) and average PFS benefit for 2nd or later line approvals was 2.95 months (range 0.2-9.1). Average OS benefit in the 1st line setting was 3.6 months and average OS benefit in the 2nd or later line setting was 5.4 months. Conclusions: Despite 16 drug (single or combination) approvals for advanced RCC since 2005, the improvements in average PFS and OS were modest. As OS data matures from recent TKI plus IO combination therapies, OS benefit may improve. Nonetheless, continued drug development is urgently warranted in advanced RCC. [Table: see text]

A prospective phase II trial of pembrolizumab plus lenvatinib in advanced adrenal cortical carcinoma after failure of platinum- and mitotane-based chemotherapy (ACCOMPLISH).

TPS3 Background: Adrenal cortical carcinoma (ACC) is a very rare cancer with poor prognosis. For advanced ACC, systemic treatment options are limited. There has been only one randomized phase III clinical trial in which etoposide, doxorubicin, cisplatin, and mitotane (EDP-M) achieved statistically significant improvement in terms of objective response rate (ORR) and progression-free survival (PFS). However, after failure of EDP-M regimen, no universally accepted treatment option exists. In human ACC sample, vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) expression were higher than adrenal adenoma, and 10-20% of tumor cells and 70% of tumor infiltrating monocyte are PD-L1 positive. In retrospective review of cabozantinib in advanced ACC, cabozantinib demonstrated 19% of ORR and 16.2 weeks of median PFS. Also, in phase II clinical trial of pembrolizumab in advanced ACC, ORR of 14-23% were shown. Considering synergism of VEGFR tyrosine kinase inhibitors (TKIs) and immune check point inhibitors (ICIs) in other cancers, combination of VEGFR TKI and ICI is an attractive approach in advanced ACC. Methods: This is an open-label,single-arm,multi-center,investigator-initiated phase II trial of lenvatinib plus pembrolizumab in patients with advanced ACC who failed previous platinum and mitotane therapy (NCT 05036434). Using Simon’s optimal two-stage design, 10 patients will be enrolled initially in the first stage. If at least 2 or more patients achieve complete response or partial response, the trial will continue until enrollment of a total of 30 patients. Patients will receive 200 mg of pembrolizumab every 3 weeks intravenously and 20 mg of daily lenvatinib orally until disease progression, intolerable toxicity, or patients’ withdrawal of consent. Key eligibility criteria are age ≥ 19 years, ECOG PS 0-1, biopsy-proven ACC, disease progression despite cisplatin- and mitotane-based chemotherapy, measurable disease according to RECIST v1.1, no uncontrolled hypertension, adequate kidney, liver, and bone marrow function. Primary endpoint is ORR, and secondary endpoints include PFS, safety profile, overall survival, duration of response. Exploratory evaluation of tumor genomics and immune microenvironment by whole exome sequencing, single-cell RNA sequencing, and T cell receptor sequencing in correlation with response will be performed. Enrollment began in June 2022 and projected enrollment goal is 3 years. Clinical trial information: NCT05036434 .

Financial toxicity from first-line TKI plus IO therapies for advanced renal cell carcinoma.

634 Background: Since the approval of sunitinib for the treatment of advanced renal cell carcinoma (RCC), the first-line treatment landscape has drastically altered with combination tyrosine kinase inhibitor (TKI) plus immunotherapy (IO) regimens. Despite improvements in survival, it remains unclear if these therapies are cost prohibitive for patients or hospitals compared to prior standard of care sunitinib. Methods: Approved TKI plus IO therapies were identified using the US FDA Oncology Announcements website and confirmed with NCCN Guidelines (Version 3.2023). Cost per unit was identified using public data (Lexicomp or manufacturer’s website). We calculated total cost of each treatment regimen using the cost per unit for each therapy and the median duration on treatment as reported in each combination therapy's clinical trial publication. Results: Average PFS benefit from combination TKI plus IO therapies was 8.1 months (range 4-14.7) in comparison with sunitinib. Average cost of TKI plus IO therapy was $443,839.32 compared with $199,541.44 for sunitinib therapy. Conclusions: Average increase in cost of TKI plus IO therapy compared to sunitinib was $244,297.88. For every month of PFS benefit with TKI plus IO combination therapy, there was on average $30,160.23 cost added per month. These increased costs may be prohibitive for many patients and hospitals, particularly in low- and middle-income countries (LMICs). [Table: see text]

Efficacy of treatment based on TKIs in combination with PD-1 inhibitors for unresectable recurrent hepatocellular carcinoma

Background and objectiveThe recurrence occurs within 5 years in up to 70% of hepatocellular carcinoma (HCC) patients who received radical liver resection, and most patients are no longer suitable for repeat surgery. There are limited treatment options for unresectable recurrent HCC. This study aimed to explore the potential efficacy of treatment based on TKIs in combination with PD-1 inhibitors for unresectable recurrent HCC.MethodsForty-four patients with unresectable recurrent HCC after radical surgery between January 2017 and November 2022 were retrospectively collected and screened. All patients received the combination therapy of tyrosine kinase inhibitors (TKIs) and programmed cell death protein 1 (PD-1) inhibitors, and 18 of these patients received trans-arterial chemoembolization (TACE) or TACE combined with radiofrequency ablation (RFA). Two patients who received TKIs in combination with PD-1 inhibitors eventually obtained repeat surgery, with one patient undergoing a repeat hepatectomy and one patient receiving a liver transplant.ResultsThe median survival for these patients was 27.0 months (95% confidence interval [CI] 21.2, 32.8), with a 1-year overall survival (OS) rate of 83.6% (95% CI 77.9%, 89.3%). Median progression-free survival (PFS) was 15.0 months (95.0% CI 12.1, 17.9), with a 1-year PFS rate of 77.0% (95% CI 70.6%, 83.4%). The two patients who underwent repeat surgery had a survival time of 34 and 37 months after the combined treatment with no recurrence, respectively, as of November 2022.ConclusionThe combination of TKIs and PD-1 inhibitors for unresectable recurrent HCC is effective and can prolong the survival of patients in this group.

Clear Cell Renal Cell Carcinoma: From Biology to Treatment.

The majority of kidney cancers are detected incidentally and typically diagnosed at a localized stage, however, the development of regional or distant disease occurs in one-third of patients. Over 90% of kidney tumors are renal cell carcinomas, of which, clear cell is the most predominate histologic subtype. Von Hippel Lindau (VHL) gene alterations result in the overexpression of growth factors that are central to the pathogenesis of clear cell carcinoma. The therapeutic strategies have revolved around this tumor suppressor gene and have led to the approval of tyrosine kinase inhibitors (TKI) targeting the vascular endothelial growth factor (VEGF) axis. The treatment paradigm shifted with the introduction of immune checkpoint inhibitors (ICI) and programed death-1 (PD-1) inhibition, leading to durable response rates and improved survival. Combinations of TKI and/or ICIs have become the standard of care for advanced clear cell renal cell carcinoma (ccRCC), changing the outlook for patients, with several new and promising therapeutic targets under development.

Associated Factors of Spontaneous Hemorrhage in Brain Metastases in Patients with Lung Adenocarcinoma.

Hemorrhage in brain metastases (BMs) from lung cancer is common and associated with a poor prognosis. Research on associated factors of spontaneous hemorrhage in patients with BMs is limited. This study aimed to investigate the predictive risk factors for BM hemorrhage and assess whether hemorrhage affects patient survival. We retrospectively evaluated 159 BMs from 80 patients with lung adenocarcinoma from January 2017 to May 2022. Patients were classified into hemorrhagic and non-hemorrhagic groups. Patient demographics, lung cancer molecular subtype, treatment type, and tumor-node-metastasis stage were compared between the groups. Multivariate generalized estimating equation (GEE) analysis and gradient boosting were performed. To determine whether BM hemorrhage can stratify overall survival after BM (OSBM), univariate survival analysis was performed. In the univariate analysis, hemorrhagic BMs were significantly larger and had a history of receiving combination therapy with tyrosine kinase inhibitor (TKI) and intracranial radiation (p < 0.05). Multivariate GEE showed that tumor size and combination therapy were independent risk factors for BM hemorrhage (p < 0.05). Gradient boosting demonstrated that the strongest predictor of BM hemorrhage was tumor size (variable importance: 49.83), followed by age (16.65) and TKI combined with intracranial radiation (13.81). There was no significant difference in OSBM between the two groups (p = 0.33). Hemorrhage in BMs from lung adenocarcinomas may be associated with BM tumor size and a combination of TKI and intracranial radiotherapy. BM hemorrhage did not affect OSBM.

Loss of MiR-155 Sensitizes FLT3-ITD+AML to Chemotherapy and FLT3 Inhibitors via Glycolysis Blocking by Targeting PIK3R1.

FLT3 tyrosine kinase inhibitors in combination with chemotherapy have shown some success in patients with FLT3 mutations. But a variety of mechanisms have led to the rapid resistance to the treatment. One of the most prominent is the metabolic alteration on aerobic glycolysis. We aim to explore the role of a high expressing microRNA, miR-155, in mediating resistance to chemotherapy and FLT3 inhibitor treatment. The deep sequencing data mining revealed the connection between glycolysis and drug resistance. MV411 cells with miR-155 knockout (KO) not only had increased sensitivity to FLT3 inhibitors but also Adriamycin (ADM) treatment. When combined with glycolysis inhibition the treatment response in MV411 cells further increased. Whereas in miR-155 KO cells, a lower glucose consumption level and lactic acid level were observed, and western blotting showed a decreased expression of key enzymes in glycolysis pathways. A negative correlation between PIK3R1 and miR-155 level can be observed in the sequencing data from FLT3-ITD+ AML patients. Moreover, luciferase reporter assay revealed that the 3'UTR of PIK3R1 mRNA can interact with the seed sequence of miR-155-5p. In conclusion, the loss of miR-155 increased treatment sensitivity to both chemotherapy and FLT3 inhibitors in FLT3-ITD+ AML cells via glycolysis blocking by targeting PIK3R1.

A rapidly evolving landscape: immune checkpoint inhibitors in pretreated metastatic endometrial cancer.

Endometrial cancer is a common malignancy and recurrences can be fatal. Although platinum-pretreated endometrial tumors are commonly treated with anthracyclines and taxanes, there is no current standard of care. Both immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) have been extensively assessed in this setting, including tumors selected for DNA mismatch repair (MMR)/microsatellite instability (MSI) and programmed death-ligand 1 expression status. This review will provide evidence-based guidance on use of ICIs alone or in combination with TKIs in patients with pretreated advanced, persistent, or recurrent metastatic endometrial cancer. Randomized phase II-III trials in unselected populations pretreated, recurrent, or metastatic endometrial cancer and phase I-II trials in biomarker selected populations were identified from PubMed as well as conference proceedings using the key search terms 'immune checkpoint inhibitors', 'endometrial cancer', and 'advanced'. A total of nine eligible studies were identified assessing ICI monotherapy for biomarker-selected or ICI plus TKI combinations and a dual ICI regimen for biomarker-unselected patients with pretreated recurrent or metastatic endometrial cancer. In MMR/MSI-selected tumors, five phase I/II studies evaluated ICI monotherapy indicating benefit in these patients. Only the phase III KEYNOTE-775 trial reported a statistically significant overall survival improvement for the combination of pembrolizumab plus lenvatinib compared with docetaxel or paclitaxel regardless of MMR/MSI status. Pembrolizumab plus lenvatinib is indicated for patients with unselected pretreated metastatic endometrial cancer and pembrolizumab monotherapy is a preferred option for patients with MMRd/MSI-H tumors.

Therapeutic Management of Metastatic Clear Cell Renal Cell Carcinoma: A Revolution in Every Decade.

Clear cell renal cell carcinoma (RCC) oncogenesis is mainly driven by VHL gene inactivation, leading to overexpression of vascular endothelial growth factor (VEGF). The use of tyrosine-kinase inhibitors (TKIs) directed against VEGF and its receptor (VEGFR) revolutionised the management of metastatic renal cancer in the 2000s. The more recent development of next-generation TKIs such as cabozantinib or lenvatinib has made it possible to bypass some of the mechanisms of resistance to first-generation anti-VEGFR TKIs. During the decade 2010-2020, the development of immune checkpoint blockade (ICB) therapies revolutionised the management of many solid cancers, including RCC, in first- and subsequent-line settings. Dual ICB or ICB plus anti-VEGFR TKI combinations are now the standard of care for patients with advanced clear cell RCC. To optimise these combination therapies while preserving patient quality of life, escalation and de-escalation strategies are being evaluated in prospective randomised trials, based on patient selection according to their prognosis risk. Finally, new therapeutic approaches, such as targeting hypoxia-inducible factor (HIF) and the development of innovative treatments using antibody-drug conjugates (ADCs), CAR-T cells, or radiopharmaceuticals, are all potential candidates to improve further patient survival.

Prognostic model of immune checkpoint inhibitors combined with anti-angiogenic agents in unresectable hepatocellular carcinoma.

The combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic agents has shown promising efficacy in unresectable hepatocellular carcinoma (HCC), but until now no clinical prognostic models or predictive biomarkers have been established. From 2016 to 2021, a total of 258 HCCs treated with ICIs and tyrosine kinase inhibitors (TKIs) were retrospectively enrolled, as the study cohort. Patients' baseline data was extracted by least absolute and shrinkage selection operator (LASSO) and Cox regression. Finally, a prognostic model in the form of nomogram was developed. Model performance was assessed in terms of discrimination, calibration, and clinical utility. A 5-fold cross-validation was used to evaluate the internal repeatability of the model. In addition, the patient cohort was divided into three subgroups according to nomogram scores. Their survivals were estimated by Kaplan-Meier methods and the differences were analyzed using log-rank tests. Seven clinical parameters were selected: Eastern Cooperative Oncology Group performance status (ECOG PS), combination of transarterial chemoembolization (TACE), extrahepatic metastasis (EHM), platelet to lymphocyte ratio (PLR), alanine aminotransferase (ALT), alpha-fetoprotein (AFP), and Child-Pugh score. The model had an area under the curve (AUC) of 0.777 at 1 year and 0.772 at 2 years. Receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA) showed that the discrimination, consistency and applicability of the model were good. In addition, cross-validation validated the discrimination of the model, and the C index value of the model is 0.7405. The median overall survival (OS) of the high-, medium- and low-risk subgroups was 7.58, 17.50 and 53.17 months, respectively, with a significant difference between the groups (P < 0.0001). We developed a comprehensive and simple prognostic model for the combination of ICIs plus TKIs. And it may predict the efficacy of the combination regimen for unresectable HCC.

Nivolumab plus cabozantinib for advanced renal cell carcinoma.

Advanced renal cell carcinoma (RCC) remains a challenging oncologic disease to treat despite advancements in therapeutics. Nonetheless, the development of tyrosine kinase inhibitors (TKIs) and immunotherapy has drastically altered the treatment landscape for advanced RCC over the past decade. The current standard-of-care treatment for advanced RCC involves combination TKI and immunotherapy regimens including cabozantinib and nivolumab as studied in the CheckMate 9ER trial. This review summarizes the preclinical and clinical evidence that led to the CheckMate 9ER study, as well as pertinent study aspects such as treatment efficacy, adverse events and patient-related outcomes.