Tyrosine Kinase Inhibitor Monotherapy Research Articles

Research trends and hotspots of radioiodine-refractory thyroid cancer treatment in the twenty-first century: a bibliometric analysis.

The treatment of radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) has made significant advancements in the twenty-first century. This study aimed to assess the current state of research and identify potential new directions by conducting a bibliometric analysis of scientific publications on RAIR-DTC treatment. Publications relevant to RAIR-DTC, published from January 1, 2000, to December 31, 2023, were retrieved from the Web of Science Core Collection. Bibliometric analyses of major keywords, authors, countries, institutions, publications, and journals were conducted using CiteSpace and VOSviewer. A total of 859 papers were included in the analysis. The results demonstrated a rising trend in the number of publications over time. The United States was identified as the leading contributor in terms of publication output, citations, and international collaborations. Gustave Roussy emerged as the top organization in publication productivity, while the journal Thyroid had the highest number of related publications. The research on RAIR treatment was categorized into three key hotspots: clinical trials of targeted therapies, novel therapeutic strategies, and debates surrounding the RAIR-DTC management. RAIR-DTC research is expanding from the clinical trial phase of tyrosine kinase inhibitor monotherapy to a more complex combination therapy strategy, in particular, the synergistic effect of immune checkpoint inhibitors and other therapeutic agents, requiring more high-quality prospective studies to validate the clinical benefits. Moreover, the timely identification of RAIR-DTC patients holds the potential to enable early disease intervention, constituting a pivotal novel research direction in the future.

Efficacy of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor in Treating Choroidal Metastasis from Non-small Cell Lung Cancer: A 10-Year Review.

To describe the clinical characteristics of choroidal metastasis (CM) in non-small cell lung carcinoma (NSCLC) patients and report treatment outcomes following targeted therapy versus conventional radiotherapy and/or chemotherapy. A retrospective review was conducted in two hospitals in Hong Kong between 2013-2023. Outcomes included tumor response and visual function following treatment. A total of 25 eyes of 21 Chinese patients with CM secondary to metastatic NSCLC were identified. The majority of patients were non-smokers. At the time of diagnosis, 88% of eyes were visually symptomatic with a mean visual acuity of 20/100. There were 52% of tumors locating within the macula. TKI monotherapy, TKI with radiotherapy and radiotherapy and/or chemotherapy groups were observed to demonstrate similar tumor response from 1 month, and comparable ocular progression-free indices. Untreated patients had deteriorated vision without any tumor response. Tyrosine kinase inhibitor (TKI) monotherapy group achieved the most rapid and differential vision gain than other groups. TKI achieved durable disease control in epidermal growth factor receptor mutation positive NSCLC patients with CM, while improving visual function. TKI can be considered as an alternative to conventional orbital radiotherapy or chemotherapy for these patients in view of the rapid visual recovery.

First-line treatment of EGFR-mutated non-small cell lung cancer with brain metastases: a systematic review and meta-analysis

This systematic review and network meta-analysis evaluates first-line treatment options for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and brain metastases. We analyzed 24 randomized controlled trials (RCTs) involving 2,682 patients, comparing various EGFR tyrosine kinase inhibitors (TKIs) and combination therapies. Direct comparisons showed that the addition of bevacizumab or chemotherapy to first-generation (1G) EGFR-TKIs improved overall survival (OS) compared to 1G TKIs alone, with HRs of 0.704 (95% CI: 0.433–0.973) and 0.682 (95% CI: 0.464–0.899), respectively. However, third-generation (3G) TKI monotherapy did not significantly improve OS compared with 1G TKIs, with an HR of 0.855 (95% CI: 0.511–1.198). Indirect comparisons suggested that the combination of 3G TKIs with chemotherapy provided the most significant improvements in OS and progression-free survival (PFS), significantly outperforming 3G TKIs, with HRs of OS 1.69 (95% CI: 1.14–3.4) and PFS 2.13 (95% CI: 1.28–3.54). Intracranial PFS was best with 1G TKIs plus bevacizumab. Our findings suggest that 3G EGFR-TKIs in combination with chemotherapy may be the most effective strategy for patients with EGFR-mutant NSCLC and brain metastases, though further head-to-head trials are needed for validation.

Slipping Away: Slippage in Hazard Ratios Over Datacuts and Its Impact on Immuno-oncology Combination Economic Evaluations

ObjectivesThis study examines the impact of slippage in hazard ratios (tending toward the null over subsequent datacuts) for overall survival for combination treatment with a PD-(L)-1 inhibitor and a tyrosine kinase inhibitor in advanced renal cell carcinoma. MethodsFour trials’ Kaplan-Meier curves were digitized over several datacuts and fitted with standard parametric curves. Accuracy and consistency of early data projections were calculated versus observed restricted mean survival time and fitted lifetime survival from the longest follow-up datacut. The change in economically justifiable price (eJP) was calculated fitting the same curve to both arms, using an assumed average utility of 0.7 and willingness-to-pay threshold of £30 000 per quality-adjusted life-year. The eJP represents the lifetime justifiable price increment for the new treatment, including differences in drug-, administration-, and disease-related costs. ResultsSlippage in hazard ratios was observed in trials with longer follow-up, potentially influenced by subsequent PD-(L)-1 use after tyrosine kinase inhibitor monotherapy, early stoppage of PD-(L)-1, and development of resistance. Lognormal and log-logistic curves were more likely to overpredict the observed result; Gompertz and gamma underpredicted. Statistical measures for goodness of fit did not reliably predict the restricted mean survival time. Large differences in incremental mean life-years were observed between even the penultimate and final datacuts for most of the fitted curves, meaningfully affecting the eJP. ConclusionsThis work demonstrates the challenge in predicting treatment benefits with novel therapies using immature data. Incorporating information on the impact of subsequent treatment is likely to play a key role in improving predictions.

Epidermal growth factor receptor-mutated lung carcinomas with insufficient response to epidermal growth factor receptor inhibitors.

Administration of single-agent epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a standard treatment option for metastatic non-small cell lung carcinomas with EGFR exon 19 deletions (ex19del) and L858R substitutions. However, there is a significant interpatient heterogeneity with regard to the degree of the response and its duration. Patients with EGFR ex19del mutation, TP53 wild-type, good performance status, low tumor burden and no circulating tumor DNA (ctDNA) at baseline have the best chances to derive pronounced benefit from TKI therapy. In contrast, subjects with EGFR L858R substitution, mutated TP53, poor overall condition, high tumor volume and detectable ctDNA are generally poor responders to EGFR inhibitors. ctDNA dynamics in the first days or weeks of treatment allows reliable identification of patients, who are very unlikely to derive clinically meaningful benefit from single-agent TKIs. These patients are candidates for clinical trials, which may involve the addition of chemotherapy and antiangiogenic drugs to patients, who failed to achieve immediate benefit from TKI monotherapy.

Changes in outcome of patients with advanced non-clear cell renal cell carcinoma from the tyrosine kinase inhibitor era to the immuno-oncology era.

The therapeutic benefit of immuno-oncology (IO) therapy for patients with advanced non-clear-cell renal cell carcinoma (nccRCC) remains unclear. We reviewed clinical data from 93 patients with advanced nccRCC who received first-line systemic therapy including IO combination therapy and tyrosine kinase inhibitor (TKI) monotherapy at our affiliated institutions. Patients were divided based on the period when the treatment was implemented as the standard of care into the IO and TKI eras. Survival and tumor response outcomes were compared between the IO and TKI eras. Of the 93 patients, 50 (54%) and 43 (46%) were categorized as IO era and TKI era groups, respectively. Progression-free survival (PFS) and overall survival (OS) were significantly longer in the IO era than in the TKI era (median PFS: 8.97 vs. 4.96months, p = 0.0152; median OS: 38.4 vs. 13.5months, p = 0.0001). After the adjustment using other covariates, the treatment era was an independent factor for PFS (hazard ratio: 0.59, p = 0.0235) and OS (hazard ratio: 0.27, p < 0.0001). Objective response and disease control rates was not significantly different between the treatment eras (26% vs. 16.3%, p = 0.268; 62% vs. 62.8%, p = 0.594). The implementation of IO therapy was significantly associated with longer survival in the nccRCC population. Further studies are needed to establish a more effective treatment strategy in this population using multiple regimens of IO combination therapy.

35 Efficacy of treatments post-lenvatinib in patients with advanced renal cell carcinoma (aRCC)

Abstract Background Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of therapies post-lenvatinib in patients with aRCC. Methods We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Patients having received treatment post-lenvatinib exposure were eligible and divided into two cohort: patients post-1st line lenvatinib (2nd line cohort) and patients post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results Overall, 84 patients received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. The median duration of prior lenvatinib was 9.7 months. All patients received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 19.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most patients were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The median follow up from 2nd-line treatment initiation was 4.9 months. The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed patients (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. The median duration of prior lenvatinib was 5.9 months. Most patients received 2nd line everolimus + lenvatinib (97%) (ORR 31%, median TTF 9.2 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most patients were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The median follow up from 3rd-line treatment initiation was 14.9 months. The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for patients progressing on lenvatinib-based therapies.

Immunomodulatory effects of antiangiogenic tyrosine kinase inhibitors in renal cell carcinoma models: Impact on following anti-PD-1 treatments

The approval of immune checkpoint inhibitors (ICIs) has revolutionized the management of metastatic renal cell carcinoma (RCC), introducing several ICI-based combinations as the new standard of care for affected patients. Nonetheless, monotherapy with antiangiogenic tyrosine kinase inhibitors (TKIs), such as pazopanib or sunitinib, still represents a first-line treatment option for selected patients belonging to the favorable risk group according to the International mRCC Database Consortium (IMDC) model. After TKI monotherapy, the main second-line option is represented by ICI monotherapy with the anti-Programmed Death Receptor 1(PD-1) nivolumab.To date, the expected clinical outcomes are similar with pazopanib or sunitinib and there is no clear indication for selecting one TKI over the other. Moreover, their impact on subsequent ICI treatment outcomes is not well defined, yet.Based on these premises, we investigated the immunomodulatory activity of these drugs in vitro and in vivo.Both TKIs induced Programmed Cell Death Ligand-1 (PD-L1) expression and soluble PD-L1 release in RCC cells, and hampered T cell activation, reducing cytokine production and the proportion of activated T cells. Nevertheless, in a syngeneic co-culture system with peripheral blood mononuclear cells (PBMCs) and tumor cells, incubation with anti-PD-1 antibody following TKIs treatment significantly restored T cell function, potentiating the cytotoxic effects against tumor cells. Pazopanib and sunitinib followed by anti-PD-1 antibody produced a comparable inhibition of tumor growth in a RCC syngeneic mouse model. Our findings suggest that pazopanib and sunitinib, showing similar immunomodulatory effects, may have a comparable impact on the subsequent effectiveness of PD-1/PD-L1 blockade.

GAS2 Upregulation Is a Targetable Vulnerability in Chronic Myeloid Leukemia

Tyrosine kinase inhibitors (TKIs), such as imatinib (IM), increase the survival of chronic myeloid leukemia (CML) patients but do not eradicate the disease as leukemia stem cells (LSCs) with primitive and quiescent signatures persist after TKI monotherapy, driving disease relapse. Using single-cell publicly available transcriptomic data, we investigated potentially tractable vulnerabilities in this persistent CML LSC population. GAS2 is significantly upregulated when comparing LSCs from CML patients in remission to normal hematopoietic stem cells (HSCs). A topoisomerase IIβ inhibitor, XK469, was proposed to be repurposed as a candidate small-molecule inhibitor of GAS2, and its effect was investigated in cell line models in combination with IM in vitro. Alone, XK469 could induce cell cycle arrest/differentiation in CML cells and reduce cell viability. In combination with IM, XK469 significantly increased CML cell apoptosis and reduced CML cell clonogenic capacity. These results suggest that GAS2 is a targetable vulnerability in CML LSCs and that using XK469 in combination with TKI potentiates the sensitivity of CML cells to IM.

First-Line Treatments and Management of Metastatic Renal Cell Carcinoma Patients: An Italian Interdisciplinary Uro-Oncologic Group Algorithm.

The treatment landscape for metastatic renal cell carcinoma (mRCC) has undergone significant transformations in recent years. The introduction of novel combination therapies involving tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors has resulted in improved oncological outcomes compared to traditional TKI monotherapy. In this evolving paradigm, the pivotal role of the multidisciplinary tumor board is underscored, particularly in shaping the therapeutic trajectory for patients eligible for locoregional interventions like cytoreductive nephrectomy and metastasectomy. In cases where systemic treatment is deemed appropriate, the absence of direct comparisons among the various combination therapies complicates the selection of a first-line approach. The clinician is faced with the challenge of making decisions based on patient-specific factors such as performance status, risk classification according to the International Metastatic Renal Cell Carcinoma Database Consortium, comorbidities, and disease characteristics, including the number and location of metastases and tumor histology. Considering these concerns, we propose, as a member of a Tuscany Interdisciplinary Uro-Oncologic Group, an algorithm to streamline the decision-making process for mRCC patients, offering guidance to clinicians in their day-to-day clinical practice.

Impact of immune checkpoint inhibitor-based combination therapy on palliative care utilization for patients with metastatic renal cell carcinoma.

e24086 Background: Palliative care (PC) is a vital tool in the treatment of patients with metastatic cancer, yet its role in metastatic renal cell cancer (mRCC) is poorly defined. These individuals are increasingly treated with immune checkpoint inhibitor-based combination therapies (ICT). While this approach confers a survival advantage, it comes with additional toxicity that may necessitate PC. Yet, little is known about how ICT impacts PC use for mRCC patients. Here we present real-world data from a single center with an embedded PC provider that evaluates the effect of ICT on PC utilization in mRCC and identifies predictors of PC use for these patients in the modern treatment era. Methods: A retrospective sample of patients who received systemic treatment for mRCC at the Jonsson Comprehensive Cancer Center from 2013 to 2023 was studied. With institutional approval, the electronic health record was queried for patient and disease characteristics. PC referral, engagement, and number of visits were compared between patients who did and did not receive ICT as first-line treatment using Pearson’s chi-squared and two-sample T tests. Predictors of PC utilization were identified using multivariable logistic modeling. Results: 146 patients were included. Mean age at mRCC diagnosis was 62.6 (SD 13.1) and 69.2% were male. The diverse patient sample was 6.4% non-Hispanic Black, 16.4% Hispanic, and 11.4% Asian. The majority (78.8%) had clear cell pathology and 20.5% had sarcomatoid features. More than 50% had more than 3 metastatic sites. More patients received ICT (45.2%) than tyrosine kinase inhibitor monotherapy (39.0%) or other single agents (15.7%). Patients travelled 53.2 (SD 98.0) miles for clinic visits. Overall, 48.6% had a PC referral and 43.8% completed a visit. Of the 46.6% of patients who died, 64.7% had a PC referral and 60.3% had a PC visit. There were no statistically significant differences in PC referral (55% vs. 44%, p = 0.19), PC engagement (50% vs. 39%, p = 0.17), or PC visits (mean 4.6 vs. 3.1, p = 0.19) for patients who received ICT compared to other treatments. Controlling for other variables, statistically significant predictors of PC referral were number of metastatic sites (OR 1.57, p = 0.01), distance from clinic (OR 0.99, p = 0.04), and presence of sarcomatoid features (OR 2.85, p = 0.02). Statistically significant predictors of PC engagement included number of metastatic sites (OR 1.61, p = 0.01). Conclusions: Using single institution real-world data, we found that PC referrals and engagement were driven by disease burden and adverse pathology, but not by treatment regimen. Patients receiving first-line ICT did not demonstrate increased need for PC, while patients who lived farther from clinic were slightly less likely to receive a PC referral. Further study of the role and timing of PC in the modern mRCC treatment era are warranted.

Real world, multicentre patterns of treatment and survival in metastatic renal cell carcinoma with the UK Renal Oncology Collaborative (UK ROC): Is it time to look favourably on first‐line immunotherapy containing combinations in all IMDC groups?

AbstractIntroductionClinical trials show improved progression‐free survival (PFS) and overall survival (OS) in first‐line metastatic renal cell carcinoma (mRCC) patients with immunotherapy containing systemic anti‐cancer therapies (SACT). However, in the favourable international metastatic renal cell cancer database consortium (IMDC) group there is no trial evidence for OS benefit despite clear PFS improvement when comparing anti‐VEGF tyrosine kinase inhibitor (TKI) monotherapy and (immunotherapy and TKI) IO/TKI combinations.ObjectiveTo assess the impact of first‐line SACT choice on the clinical outcomes of PFS and OS in mRCC. To evaluate this impact of initial SACT for allcomers and the favourable IMDC group.MethodsA multicentre retrospective review of patients who started SACT for mRCC (01/01/2018–30/06/2021) at 17 UK NHS trusts. Patient demographics and IMDC group were analysed. Survival data were compared using Kaplan–Meier curves, and the statistical significance of differences in outcome between the groups was assessed with the log‐rank test. Univariable and multivariable Cox proportional hazard modelling estimate the hazard ratios (HRs) for survival outcomes associated with IMDC and treatment subtype.ResultsOne thousand three hundred and nineteen patients were identified with a median age of 64. 294 (22.3%), 695 (52.7%) and 321 (24.3%) were IMDC group favourable, intermediate and poor, respectively. 311 (23.6%), 197 (14.9%) and 778 (59%) patients received checkpoint inhibitor and anti‐CTLA4 monoclonal antibody (IO/IO), IO/TKI and TKI first‐line SACT across all IMDC groups. Significant PFS improvement favouring IO/TKI versus TKI was demonstrated in allcomers HR = 0.61. In the favourable risk group, Log rank testing demonstrated a significant benefit for IO/TKI over TKI for PFS (HR = 0.60, 95% CI [0.39, 0.91]) and OS (HR = 0.42, 95% CI [0.18, 0.99]).ConclusionIn this real‐world evidence cohort, we have shown OS and PFS benefit with IO/TKI versus TKI in the favourable IMDC risk group. This has not been previously reported from trial outcomes and would support use of front‐line IO/TKI in mRCC favourable risk patients.

Real-world outcomes among patients with advanced/metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKls) monotherapy or TKI-IO combination therapy.

Real-world outcomes among patients with advanced/metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitors (TKls) monotherapy or TKI-IO combination therapy.

Efficacy of post-lenvatinib treatments in patients (pts) with advanced renal cell carcinoma (aRCC).

4538 Background: Lenvatinib is a tyrosine kinase inhibitor (TKI) that targets both vascular endothelial growth factor (VEGF) receptor and fibroblast growth factor receptor. It has demonstrated efficacy both in the upfront and refractory disease settings. However, there is a lack of data surrounding the efficacy of TKIs post-lenvatinib exposure. In this study, we investigate the activity of post-lenvatinib therapies in pts with aRCC. Methods: We conducted a retrospective analysis utilizing the International Metastatic Database Consortium (IMDC). Pts having received treatment post lenvatinib exposure were eligible and divided into two cohort: pts post-1st line lenvatinib (2nd line cohort) and pts post-2nd line lenvatinib (3rd line cohort). The primary objective was objective response rate (ORR) and time to treatment failure (TTF). ORR was summarized with 95% two-sided exact binomial confidence interval. TTF was defined as time from treatment initiation to drug cessation for any reason censored at the date of last follow-up. Results: Overall, 84 pts received 1st line lenvatinib of whom 43 (51%) remain on therapy, 20 (24%) received 2nd line treatment, and 21 (25%) received no subsequent treatment. All pts received 1st line pembrolizumab + lenvatinib (ORR 50%, median TTF 9.7 months). Reason for lenvatinib discontinuation was progression (50%), progression + toxicity (20%), toxicity (15%), or other (15%). For the 2nd line cohort, median age was 61 years, most pts were male (85%), had prior nephrectomy (75%), clear cell histology (85%), and were IMDC intermediate/poor risk (55%). 2nd line therapy regimens included TKI monotherapy (80%), TKI-IO (5%), and other (15%). The ORR to 2nd line treatment was 5% (95% CI 0.2-25) and median TTF was 5.8 months (95% CI 1.9-14.9). Of 2nd line lenvatinib-exposed pts (n=84), 24 (29%) remain on treatment, 34 (40%) received 3rd line treatment, and 26 (31%) did not receive additional therapy. Most pts received 2nd line everolimus + lenvatinib (97%) (ORR 39%, median TTF 5.9 months). Reason for lenvatinib discontinuation was progression (59%), progression + toxicity (9%), toxicity (12%), or other (21%). For the 3rd line cohort, median age was 67 years, most pts were male (68%), had prior nephrectomy (88%), clear cell histology (68%), and were IMDC intermediate/poor risk (77%). 3rd line treatments included TKI alone (50%), IO-TKI (38%), and other (12%). The ORR to 3rd line treatment was 12% (95% CI 3.3-27) and median TTF was 2.8 months (95% CI 1.9-7.4). Conclusions: In this analysis, we demonstrate modest activity of TKI-based therapy post-lenvatinib exposure. Our study highlights the need for improved treatment options for pts progressing on lenvatinib-based therapies.

#246 Understanding the impact of antiangiogenic drug-induced proteinuria on kidney function in cancer patients

Abstract Background and Aims Proteinuria is a common adverse event associated with the use of vascular endothelial growth factor (VEGF) inhibitor drugs, which are widely employed in oncology for treating various tumors. The incidence of proteinuria of all degrees ranges from 10% to 90%, with proteinuria in the nephrotic range occurring in 1-5% of cases. VEGF plays a crucial role in maintaining the integrity of the glomerular capillary wall. Podocytes, constitutively express VEGF, and VEGF receptors are present on both the surface of glomerular capillary endothelial cells and podocytes. Any disruption in the podocyte-endothelial VEGF axis can lead to the loss of endothelial fenestrations in glomerular capillaries, proliferation of glomerular endothelial cells, loss of podocytes, and subsequent proteinuria. The most common pathological findings include focal segmental glomerulosclerosis and minimal change nephropathy, typically associated with tyrosine kinase inhibitors (TKIs), as well as thrombotic microangiopathy (TMA), more frequently observed in pts treated with anti VEGF. Proteinuria is a recognized risk factor for progressive renal damage and end-stage renal disease. However, it's worth noting that the average treatment duration for patients on anti-angiogenic therapy is considerably shorter than the time indicated by clinical studies as necessary to induce renal damage from proteinuria in healthy individuals. However, the long-term impact of drug-induced proteinuria on renal function remains uncertain. The aim of the study is to investigate the association between proteinuria induced by anti-VEGF/VEGFR drugs and its long-term effects on renal function in cancer patients. Method A retrospective study was conducted on 124 patients undergoing anti-VEGF/VEGFR therapy for ≥6 months. 45% of the patients enrolled in the study were on TKI monotherapy, 36% received TKI plus immune checkpoint inhibitors (ICIs), 10% received anti- VEGF treatment, 7% received TKI + chemotherapy (CT), and 2% received anti-VEGF + ICIs. Among patients, 51% were undergoing treatment for kidney cancer, 25% for thyroid cancer, 14% for colon cancer, 7% for liver cancer, and 5% for lung cancer. The study assessed the time course of estimated glomerular filtration rate (eGFR), the influence of baseline eGFR on subsequent variations, the association between proteinuria and renal function, and the identification of risk factors for proteinuria or renal failure. Proteinuria was quantified as proteinuria/24 h. Results Among the 124 patients, 53 developed proteinuria &amp;lt;1 g/24 h, 41 between 1-3 g/24 h, and 30 &amp;gt;3 g/24 h. Specific data are outlined in Table 1. A trend toward a reduction in eGFR of −5 ml/min/1.73 m2 was observed in all patients after 2 years of treatment. The high proteinuria group exhibited a greater percentage change in eGFR compared to the other groups (−1.5% vs −8.5% vs −12.3%) as depicted in Fig. 1A, along with a time-dependent decrease in eGFR. There was no significant difference in the development of eGFR &amp;lt;30 ml/min/1.73 m2 between groups, and no patients permanently discontinued treatment due to nephrotoxicity. No differences in eGFR reduction were noted among the three groups categorized by baseline eGFR (Fig. 1B). Importantly, renal function after the end of therapy was found to be reversible. Conclusion The study did not find a correlation between the degree of proteinuria secondary to anti-VEGF/VEGFR and significant reductions in renal function. Therefore, treatment can be continued irrespective of the degree of proteinuria. Clinical decisions regarding the continuation of therapy with these drugs should weigh the benefits in terms of survival against the potential risks of toxicity, including a modest reduction in renal glomerular filtration rate.

Real-World Impact of Upfront Cytoreductive Nephrectomy in Metastatic Non-Clear Cell Renal Cell Carcinoma Treated with First-Line Immunotherapy Combinations or Tyrosine Kinase Inhibitors (A Sub-Analysis from the ARON-1 Retrospective Study).

About 20% of patients with renal cell carcinoma present with non-clear cell histology (nccRCC), encompassing various histological types. While surgery remains pivotal for localized-stage nccRCC, the role of cytoreductive nephrectomy (CN) in metastatic nccRCC is contentious. Limited data exist on the role of CN in metastatic nccRCC under current standard of care. This retrospective study focused on the impact of upfront CN on metastatic nccRCC outcomes with first-line immune checkpoint inhibitor (IO) combinations or tyrosine kinase inhibitor (TKI) monotherapy. The study included 221 patients with nccRCC and synchronous metastatic disease, treated with IO combinations or TKI monotherapy in the first line. Baseline clinical characteristics, systemic therapy, and treatment outcomes were analyzed. The primary objective was to assess clinical outcomes, including progression-free survival (PFS)and overall survival(OS). Statistical analysis involved the Fisher exact test, Pearson's correlation coefficient, analysis of variance, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Median OS for patients undergoing upfront CN was 36.8 (95% confidence interval [CI] 24.9-71.3) versus 20.8 (95% CI 12.6-24.8) months for those without CN (p = 0.005). Upfront CN was significantly associated with OS in the multivariate Cox regression analysis (hazard ratio 0.47 [95% CI 0.31-0.72], p < 0.001). In patients without CN, the median OS and PFS was 24.5 (95% CI 18.1-40.5) and 13.0 months (95% CI 6.6-23.5) for patients treated with IO+TKI versus 7.5 (95% CI 4.3-22.4) and 4.9 months (95% CI 3.0-8.1) for those receiving the IO+IO combination (p = 0.059 and p = 0.032, respectively). Our study demonstrates the survival benefits of upfront CN compared with systemic therapy without CN. The study suggests that the use of IO+TKI combination or, eventually, TKI monotherapy might be a better choice than IO+IO combination for patients who are not candidates for CN regardless of IO eligibility. Prospective trials are needed to validate these findings and refine the role of CN in current mRCC management.

Combination of EGFR-TKI and Chemotherapy Versus EGFR-TKI Monotherapy as Neoadjuvant Treatment of Stage III-N2 EGFR-Mutant Non-Small Cell Lung Cancer.

The efficacy of neoadjuvant treatment with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) monotherapy in patients with stage III-N2 EGFR-mutant remains unsatisfactory. This study explored the potential benefits of combining first-generation EGFR-TKI with chemotherapy as a neoadjuvant treatment for patients with stage III-N2 EGFR-mutant non-small cell lung cancer (NSCLC). The medical records of patients with III-N2 EGFR-mutant NSCLC who received neoadjuvant therapy with EGFR-TKI at Shanghai Chest Hospital from October 2011 to October 2022 were retrospectively reviewed. Patients with stage III-N2 EGFR-mutant NSCLC who received first-generation TKI combined with chemotherapy as neoadjuvant treatment were included in the combination group, and those who received EGFR-TKI monotherapy were included in the monotherapy group. The study assessed the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, disease-free survival (DFS), overall survival (OS), downstaging rates of pathologic lymph nodes (from stage N2 to N1 or N0), major pathologic response (MPR) rate, pathological complete response (PCR) rate, and safety. A total of 74 631 patients with EGFR-mutant NSCLC were screened, and 60 patients were included, 7 of whom did not undergo surgery after neoadjuvant targeted therapy. Of the remaining 53 patients, 15 received first-generation EGFR-TKI combined with chemotherapy as neoadjuvant treatment, and 38 received EGFR-TKI monotherapy. The median follow-up time was 44.12 months. The ORR was 50.0% (9/18) in the combination group and 40.5% (17/42) in the monotherapy group (P = .495). The MPR rate was 20.0% (3/15) and 10.5% (4/38) in the combination and monotherapy groups, respectively (P = .359). No patients achieved PCR in the combination group, while 3 (7.89%) attained PCR in the monotherapy group. The 2 groups did not differ in N2 downstaging rate (P = .459). The median DFS was not reached in the combination group, while it was 23.6 months (95% CI: 8.16-39.02) in the monotherapy group (P = .832). Adverse events observed were consistent with those commonly associated with the 2 treatments. Combination therapy with first-generation EGFR-TKI and chemotherapy could be considered a neoadjuvant treatment option for patients with stage III-N2 EGFR-mutant NSCLC, exhibiting acceptable toxicity. However, regarding short-term efficacy, combination therapy did not demonstrate superiority over EGFR-TKI monotherapy. Long-term follow-up is warranted for a more accurate assessment of the DFS and OS.

Patient Characteristics, Treatment Patterns, and Outcomes for Patients With Renal Cell Carcinoma in England: A Retrospective Cohort Study

Background and ObjectiveConsidering the rapidly evolving treatment landscape of renal cell carcinoma (RCC), recent descriptions of the RCC population in the UK are lacking, as are real-world data on treatment and patient outcomes. To analyse the demographic and clinical characteristics, treatment patterns, and overall survival of patients with RCC using national data sets in England. Patients and MethodsThis was a retrospective cohort study of patients diagnosed with RCC (all stages) between 2014-2018 using demographic, clinical, cancer registration, and treatment data. Patients were followed until death or study end (December 31, 2020). Treatments administered in each line were described to understand treatment sequencing. Kaplan–Meier methods were used for time-to-event analyses. Factors associated with discontinuation and survival were identified using Cox proportional hazard models. Results and LimitationsAmong 32,577 included patients, the median age at diagnosis was 66 years, 63.4% were male, and 6,786 (20.8%) had metastatic RCC at diagnosis. Tyrosine kinase inhibitor (TKI) monotherapy was the most common treatment class across lines. Over three quarters of patients (78.5% [95% CI: 78.0-78.9]) were alive one year after diagnosis (93.2% in the non-metastatic at diagnosis subgroup and 37.1% among patients with metastases at diagnosis). At three years post initial diagnosis, 18.0% patients were alive in the metastatic at diagnosis subgroup. Rapid evolution of the treatment landscape limits the results regarding lines of therapy. ConclusionThis large-scale study provides insight on characteristics of patients with RCC, and it highlights the need for better treatment options to improve survival.

Abstract 7203: Anti-HDGF antibody attenuates the rise of resistance to EGFR tyrosine kinase inhibitor in NSCLC patient-derived xenograft tumors

Abstract Mutant epidermal growth factor receptor (EGFR), a major oncogenic driver in non-small cell lung cancer (NSCLC), is found in the tumors of 15% (western countries) to 50% (Asian countries) of patients. EGFR-targeted therapy using tyrosine kinase inhibitors (TKIs) is a standard of care for those patients who developed metastatic or recurrent diseases. However, despite having an 80% initial response rate, most patients had partial tumor regression and their disease would progress when acquired resistance emerges. Thus, developing more effective treatment is an unmet need. The clinical response of these patients can be recapitulated in mouse models of patient-derived xenograft (PDX) tumor bearing sensitizing EGFR mutations. In this study, treating established PDX tumors with osimertinib, a third generation EGFR TKI, induced partial tumor regression (50% to 70% size reduction from baseline) followed by progression with a median progression-free survival (PFS) of 26 to 28 days. Interestingly, co-administering an antibody against hepatoma-derived growth factor (HDGF) with osimertinib resulted in enhanced tumor regression (98% to 100% size reduction from baseline) which translated into significantly extended animal survival with a median PFS of 103 or 135 days. Immunohistochemical and western blot examination of tumors collected at different treatment timepoints indicated that AKT/mTOR and MAPK pathways were reactivated after initial suppression in TKI monotherapy arm despite persistent EGFR inhibition. Since AKT/mTOR and MAPK pathways are key survival and proliferative signaling pathways, their reactivation can promote TKI tolerance of tumor cells and the emergence of TKI resistance. However, blocking HDGF attenuated the reactivation of these pathways which could partially explain the enhanced efficacy of osimertinib plus anti-HDGF antibody combination treatment seen in this study. Our results suggest tumor-derived HDGF could play a crucial role in the rise of acquired resistance to osimertinib. Identifying the exact cells and molecular pathways utilized by HDGF to promote tumor cell tolerance to TKI will help us understand how TKI sensitive tumor cells survive EGFR blockade and emerge as resistant cells. Citation Format: Cindy Q. Zhou, Ariel Li, Kaoru Ri, Ahmed Sultan, Hening Ren. Anti-HDGF antibody attenuates the rise of resistance to EGFR tyrosine kinase inhibitor in NSCLC patient-derived xenograft tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7203.

Real World Analysis of Peritoneal Metastasis From Renal Cell Carcinoma. Meet-Uro27

BackgroundPeritoneal metastases (PM) have been reported in approximately 1% of patients with metastatic Renal Cell Carcinoma (mRCC). Outcome data are limited due to the rarity of this metastatic site. Therefore, the aim of our study is to describe renal cell carcinoma (RCC) patients with PM treated as per clinical practice. Materials and MethodsBaseline characteristics and outcome data of patients with PM from RCC were retrospectively collected from 18 Italian oncological referral centers adhering to the Meet-Uro group, from January 2016 to January 2023. ResultsWe collect 81 RCC patients with PM. 78/81 received systemic treatment, 3/81 only best supportive care. First line treatment included tyrosine-kinase inhibitors (TKI) (46/78), ImmuneOncology (IO)-TKI (26/78) and IO-IO (6/78), with different Objective Response Rate (ORR) (43.4% in TKI monotherapy group vs 50% in IO-TKI group, respectively) and Disease Control Rate (DCR) (60.8% in TKI treated patients vs. 76.9% in IO-TKI treated patients). Median PFS was 6.4 months (95%CI 4.18-14.8) in patients treated with TKI monotherapy vs 23.7 months (95%CI 11.1-NR) in patients treated with IO-TKI (p < 0.015). The median OS (mOS) was 22.7 months (95%CI 13.32 – 64.7) in the TKI monotherapy group vs 34.5 mo (95%CI NR-NR) in the IO-TKI group with 53.8% of patients alive at 1 years in the latter group, (p < 0.16). Primary refractory patients were 36.9% for TKI and 15.3% for IO-TKI. According to International Metastatic renal cell carcinoma Database Consortium (IMDC) score, mPFS and mOS were consistent among risk categories. Median PFS was 36.6 months (95%CI 10.9-NR) for good risk patients compared to 10 months (95%CI 7.5-29.8) for intermediate risk and 2.96 months (95%CI 2.43-11.28) for poor risk population (p < 0.0005) whereas mOS was NR (95%CI 28.65-NR) for good risk patients compared to 35.3 months (95%CI 24.6-NA) and 12.4 months (95%CI 3.52-NR) for intermediate and poor risk population, respectively, (p < 0.0002). Only 34/78 (43.5%) received a second line treatment that was TKI (ORR 8.3% and DCR 41.6%) or IO (ORR 18.1% and DCR 40.9%). ConclusionWe report one of the largest case series regarding PM from RCC. Characteristics of patients suggest a more aggressive behavior of PM from mRCC. Outcome data suggest that TKI-IO as first line treatment, and TKI as second line, confirm their activity for these patients with dismal prognosis.