Single-agent Tyrosine Kinase Inhibitors Research Articles

Real-World Survival Outcomes of First-Line Therapies in Patients with Metastatic Clear Cell Renal Cell Carcinoma: A Retrospective Analysis from Two Centres in Saudi Arabia.

Background: Metastatic renal cell carcinoma (mRCC) represents a challenging condition characterised by poor prognosis and limited response to chemoradiotherapy. In this retrospective study, we compared the survival outcomes of first-line ICI regimens versus single-agent TKIs in patients with mRCC from two centres in Saudi Arabia. Methods: This study included 84 patients diagnosed with clear cell mRCC between January 2016 and December 2023. Patients were grouped based on treatment regimens. Progression-free survival (PFS) and overall survival (OS) were analysed using Kaplan-Meier curves and Cox proportional hazards regression. Results: The median first-line PFS was 9.7 months (95% CI: 5.3-14.1) for the overall cohort, with no significant difference between the single-agent tyrosine kinase inhibitor (TKI) group (9.4 months; 95% CI: 6.4-12.4), combination ICI group (9.0 months; 95% CI: 0.0-24.9), and single-agent ICI group (21.2 months; 95% CI: 2.6-39.8; p = 0.591). The median OS for the overall cohort was 42.0 months (95% CI: 14.9-69.2), with the single-agent TKI group having a median OS of 33.3 months (95% CI: 0.0-71.7), the combination ICI group, 42.0 months (95% CI: 0.06-84.0), and the single-agent ICI group, 23.0 months (95% CI: 19.2-26.7; p = 0.73). In comparison, the ICI-based combination therapy group exhibited a higher ORR of 41.0% (95% CI: 26.3-57.8%), while the single-agent ICI group had an ORR of 20.0% (95% CI: 3.5-55.8%). Cox regression identified liver metastasis as a significant independent predictor of PFS (HR = 1.8, p = 0.043), while a lower Karnofsky Performance Status was a significant independent predictor of OS (HR = 3.5, p < 0.001). Conclusions: In real-world practice from Saudi Arabia, first-line, single-agent ICI therapy offers promising anti-tumour activity and non-inferior survival outcomes compared to standard ICI-based combinations and single-agent TKIs.

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.

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?

Genomic alterations in metastatic renal cell carcinoma (mRCC): Impact on survival and clinical outcomes.

700 Background: Genomic alterations in RCC can serve as biomarkers for response to therapy. Wild type VHL has shown inferior response to VEGF inhibitors, while patients (pts) with mutated VHL have improved outcomes with immunotherapy (IO)/tyrosine kinase inhibitor (TKI) therapy. We describe the impact of genomic alterations on outcomes and response to front-line therapy. Methods: Pts with mRCC who underwent genomic sequencing between 2015-2022 at Indiana University and were treated with front-line therapy were included. Kaplan-Meier method was used to analyze progression free survival (mPFS) and overall survival (OS) using the log rank test to compare groups. Results: 141 pts were included. Median age was 58yrs (range, 24-81). Tumor histology was 68% clear cell, 10% papillary, 9% unclassified, 1% chromophobe, 1% poorly differentiated, and 9% other. 18% of pts had sarcomatoid features; 13% had rhabdoid. 47% pts had metastasis at diagnosis and 53% at relapse. Metastasis sites were lungs 60%, regional lymph nodes (LNs) 41%, bone 36%, distant LNs 21%, liver 17%, and brain 8%. IMDC risk was 18% good, 48% intermediate, 17% poor, and 17% unknown. Front-line therapy was IO/IO in 21%, IO/TKI in 18%, single-agent TKI in 29%, single-agent IO in 6%, and other in 26%. Genetic alterations included VHL in 50%, PBRM1 in 29%, SETD2 in 23%, BAP1 in 16%, and TP53 in 15%. Median follow-up was 2.74yrs (range 0.1-18.6). Overall mPFS with first line therapy was 1.2yrs (95%CI 0.9-1.5). 2-yr OS was 80% (95%CI: 71-86). For pts with a VHL mutation, mPFS was 1.4yrs (95% CI; 0.9-1.8) compared to 0.9yrs (0.5-1.4) for pts without (p=0.38). 2-yr OS for pts with a VHL mutation was 93% (95% CI: 82-97) vs. 68% (95%CI: 54-78) for pts without (p=0.01). No other mutations impacted overall mPFS or 2-yr OS. mPFS for pts treated with IO/IO was 0.6yrs (95%CI 0.3-0.9) vs. 0.9yrs (95%CI 0.5-1.4) for IO/TKI (p=0.09). 2-yr OS for pts treated with IO/IO was 70% (95% CI 44-85) compared to 94% (95% CI 65-99) for IO/TKI (p=0.29). For pts with SETD2 mutations treated with IO/IO, mPFS was 0.7yrs (95%CI 0.3-1.2) vs. 1.4yrs (95%CI 0.8-1.9) for IO/TKI (p=0.01). For pts with BAP1 mutations treated with IO/IO, mPFS was 0.4yrs (95%CI 0.2-1.2) vs. NE (95%CI 0.2-NE) for IO/TKI (p=0.04). The table outlines outcomes by genomic mutation and therapy. Conclusions: VHL mutation was associated with improved 2-yr OS. Pts with SETD2 and BAP1 mutations treated with IO/TKI had improved mPFS, though no differences in OS. [Table: see text]

Gonadal Function in Male Patients With Metastatic Renal Cell Cancer Treated With Sunitinib.

Single-agent tyrosine kinase inhibitors are still prescribed as first-line treatment to a relevant subgroup of patients with metastatic renal cell carcinoma (mRCC). These agents are known to cause disfunction of many endocrine glands (e.g., thyroid). In this two-step trial, we aimed to assess gonadal function among male patients with mRCC treated with sunitinib. We enrolled a first cross-sectional cohort of pre-treated (>6 months) patients and a subsequent cohort of treatment-naïve patients who were prospectively followed-up. All patients were screened for hypogonadism and received a Functional Assessment of Cancer Therapy - General (FACT-G) questionnaire at study entry and after 6 months of therapy. Patients who were candidates for testosterone replacement therapy (TRT) also received a FACT-G questionnaire at baseline and 3 months after supplementation. Among the 30 enrolled patients, the prevalence of hypogonadism was found to be higher in those receiving sunitinib for a longer period (27.3% at baseline, 41.7% in the first 6 months, and 68.4% after 9 months of therapy). The testosterone level of patients correlated with quality of life (R=0.32). A total of six patients received TRT, with a significant improvement in their global quality of life after the first 3 months of treatment. An increasing prevalence of hypogonadism was seen among male patients who received long-term treatment with sunitinib. TRT was associated with relevant improvements in quality of life. These findings corroborate similar published observations and encourage the assessment of gonadal function in male patients with mRCC under treatment with sunitinib.

Access to treatment among patients with advanced kidney cancer in Mexico.

130 Background: The socioeconomic status of patients diagnosed with metastatic renal cell carcinoma (mRCC) in developing countries could in many cases limit their access to the best available therapeutic options. We aimed to describe the clinical characteristics and access to treatment of Mexican patients with mRCC. Methods: We performed a retrospective analysis of all patients with a histopathologically confirmed diagnosis of renal cell carcinoma who were treated at an oncology referral center in Northeast Mexico over a 5-year period. Results: We included 233 patients in the analysis, of whom 63% were men. The mean age at diagnosis was 58.2 years; 87% of the tumors were histopathologically classified as clear cell carcinoma. Regarding laterality, 54% of the tumors originated from the right kidney. The distribution of cases by clinical stage (CS) was as follows: CS I 15%, CS II 8%, CS III 17%, CS IV 60%. All of the included patients had government health insurance coverage; however, specific treatment for renal cell cancer was not included in this coverage. In terms of access to first-line systemic management in the 139 patients with advanced kidney cancer who were candidates for treatment, 29% received treatment with a single-drug tyrosine kinase inhibitor (TKI), 4% were treated with combined or single-drug immunotherapy (IO), and 12% were treated with TKI combined with IO. All but one patient who was treated with a single drug or a combination of IO received these drugs in the context of a clinical trial. Fifty-five percent of patients with advanced disease did not have access to standard first-line therapy. The rate of loss to medical follow-up was 69% of cases. Conclusions: Despite the proven oncological benefit of the latest generation of therapies based on IO/IO or IO/TKI for mRCC, access to first-line standard management is still poor in our country, even with single agent TKI. Public health programs should be implemented to expand therapeutic options for this group of patients.

1463P Patterns of care and outcomes of metastatic renal cell carcinoma (mRCC) patients (pts) with bone metastases (BM): A UK multicenter review

BMs are associated with higher morbidity and mortality in mRCC patients. With the evolution of systemic therapies (ST), we conducted a UK multicentre retrospective review of outcomes in mRCC pts with BM. 1246 mRCC pts data from 15 UK centres, who commenced first line ST between 01/01/18 and 30/06/21 were reviewed. Data on BM, IMDC scores, ST, local therapies (LT) were collected. Progression free survival (PFS) & Overall survival (OS) were calculated as time between start of 1st ST and subsequent ST/ date of progression & date of death/last follow-up, respectively. PFS & OS were analysed using Kaplan Meier Analyses (log rank test). 353 (28%) pts had BM (62 bone only; 291 bone & visceral mets) with a median age of 65 (range: 27-90). 102 pts had LT (resection-25, stereotactic radiotherapy (RT)-4, palliative RT-72, vertebroplasty-1). 20 patients presented with cord compression. The IMDC risk groupings were favourable 48, intermediate 195, and poor 109. Pts just receiving 1, 2, 3 or more lines of ST were 171, 125, & 55, respectively. PFS was similar for the different ST (tyrosine kinase inhibitors (TKI), immunotherapy (IO), IO/TKI) either in 1st, 2nd or 3rd line therapies, or between patients with bone only or bone & visceral metastases (all risk groups). In intermediate & poor risk groups there was a trend in favour of PFS advantage with single agent TKI or IO/TKI compared to IO/IO (Table). The median OS of all BM pts was 21. The OS was significantly longer in the favourable IMDC group (favourable-34.4m vs. intermediate-24m vs. poor-8.7m; p<0.0001), pts with prior nephrectomy (32.7 vs. 16.4m; p<0.0001) and pts with bone only metastases (29.9 vs.19.7m; p<0.05).Table: 1463PMedian PFS: Intermediate & poor risk ptsCabozantinibOther TKIIpi/NivoIO/TKINivoBone only metastases (n=51)First-line17.114.64.614.7Second-lineNot reached9.1--2.1Bone + visceral metastases (n=254)First-line8.95.67.18.8Second-line7.16.1--3.6 Open table in a new tab Our analyses indicate that TKIs remain a standard of care in mRCC pts with BM and OS is consistent with published literature. The PFS in intermediate and poor risk mRCC pts with BM favours TKI based ST compared to IO/IO treatment.

Nivolumab drug holiday in patients treated for metastatic renal cell carcinoma: A real-world, single-centre experience.

IntroductionImmunotherapy with nivolumab (a monoclonal antibody that targets the programmed cell death protein 1, PD1) has become the standard treatment for patients with metastatic renal cell carcinoma (mRCC) after progression to single-agent tyrosine kinase inhibitors. However, the optimal duration of immunotherapy in this setting has not yet been established.Patients and methodsWe retrospectively reviewed all patients treated with nivolumab at our institution from January 2014 to December 2021 and identified those who discontinued treatment for reasons other than disease progression (PD). We then associated progression-free survival (PFS) and overall survival following treatment cessation with baseline clinical data.ResultsFourteen patients were found to have discontinued treatment. Four patients (28.6%) ceased treatment due to G3/G4 toxicities, whereas the remaining ten (71.4%) opted to discontinue treatment in agreement with their referring clinicians. The median duration of the initial treatment with nivolumab was 21.7 months (7.5-37.3); during treatment, two patients (14.3%) achieved stable disease as the best response, and the remaining twelve (85.7%) a partial response. At a median follow-up time of 24.2 months after treatment discontinuation, 7 patients (50%) were still progression-free. The median PFS from the date of discontinuation was 19.8 months (15.2 - not reached); a radiological objective response according to RECIST and treatment duration of more than 12 months were associated with a longer PFS. Three patients were re-treated with Nivolumab after disease progression, all of whom achieved subsequent radiological stability.ConclusionIn our experience, the majority of patients who discontinued treatment in the absence of PD were still progression-free more than 18 months after discontinuation. Patients whose initial treatment duration was less than 12 months or who did not achieve a radiological objective response had a greater risk of progression. Immunotherapy rechallenge is safe and seems capable of achieving disease control.

Immune checkpoint inhibitors and tyrosine kinase inhibitors in patients with advanced hepatocellular carcinoma: Does the sequence matter?

Combination therapy with immune checkpoint inhibitor (ICI) and antivascular endothelial growth factor (anti-VEGF) is currently the first line treatment for advanced hepatocellular carcinoma (aHCC). However, there are many patients who may not be able to receive combination therapy due to underlying comorbidities or resource limitations. For these patients, systemic treatment options include single agent tyrosine kinase inhibitors (TKIs) or ICI monotherapy. However, whether an optimal sequence of systemic therapy exists remains unknown. We aim to explore the impact of sequencing of TKI and ICI therapy in terms of response rates and to examine the safety of their use in sequential order. Patients with aHCC treated with both ICI and TKI between December 30, 2013 and June 13, 2018 were retrospectively identified. Patients were classified into two groups: those who received TKI in the first-line (TKI1), followed by ICI (ICI2) and those who received ICI (ICI1) in the first-line followed by TKI (TKI2). The primary objective of the study was to identify differences in objective response rate (ORR) and disease control rate (DCR), as evaluated based on response evaluation criteria in solid tumor v1.1 for TKI1, TKI2, ICI1, and ICI2. Secondary objectives included comparison of progression free survival (PFS) for each line of therapy, overall survival (OS) and adverse events (AEs). Twenty-seven and 23 patients were classified into group 1 and 2, respectively. Objective response rates of TKI1 and TKI2 were 3.8% and 17.6%, respectively (p=.28); DCR to TKI1 versus TKI2 was 23.1% versus 35.3% (p=.49). ORRs of ICI1 and ICI2 were 8.7% and 14.3%, respectively (p=.66); DCR to ICI2 versus ICI1 was 56.5% versus 42.9% (p=.37). Median PFS was not significant between TKI1 and TKI2 (PFS 3.06 versus 1.61 months, p=.097) as well as between ICI2 and ICI1 (PFS 1.84 versus 2.37 month, p=.32). Median OS was also not significantly different between both groups (OS 20.63 versus 13.93 months, p=.20) on univariable and multivariable analysis (OS adjusted hazard ratio [HR] 2.07, 95% CI .83-5.18, p=.118). The proportion of patients who experienced adverse events of any grade was similar in both groups (TKI1 59.3% versus TKI2 52.2%; ICI1 78.3% versus ICI2 70.4%). Our study suggests that the sequence of TKI versus ICI therapy in patients with aHCC may not matter, given similar efficacy and toxicity profile when either agent is received in the first or second-line setting. This finding is of value in the real-world setting, where patients may be frail or have comorbidities that render them unable to tolerate combination therapy (ICI and TKI/anti-VEGF). For these patients, sequential exposure to both classes of drugs (ICI and TKI) may be a suitable option.

Outcomes of tyrosine kinase inhibitors after immunotherapy in advanced hepatocellular carcinoma: A multi-center study.

e16181 Background: Immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) are widely adopted in contemporary advanced HCC (aHCC) treatment algorithms. Nevertheless, the optimal strategy for treatment after ICI exposure is unknown. We evaluated the pattern of use, response, survival and safety of TKIs in aHCC patients who previously received ICIs. Methods: We performed an international, multi-centre study of aHCC patients who received TKIs after prior treatment with ICIs. Objective response rate (ORR), disease control rate (DCR), time-to-progression (TTP), overall survival (OS) and adverse events (AE) were assessed. Results: Between January 2015 and December 2020, one-hundred and forty-eight patients were included. The median age was 63 (range 29-84) and 78.4% were of Child-Pugh Grade A. 75.7% had hepatitis-B related HCC. 64.9% received TKI as single agent and 35.1% received TKI in combination with other agents. 75% who received TKI combinations had concomitant ICIs. 48.6% had prior TKIs. The median follow-up was 23.3 months. For single agent TKI patients, the ORR was 14.6%, DCR was 38.5%, median TTP was 3.9 months (95% C.I. 3.3-4.5) and median OS was 8.6 months (95% C.I. 5.8-11.4). For patients receiving TKI combinations, the ORR was 25%, DCR was 38.5%, median TTP was 3.5 months (95% C.I. 1.7-5.2) and median OS was 15.1 months (95% C.I. 5.7-24.5). There were no significant differences in ORR, DCR and median OS between patients who had primary resistance to prior ICI compared to those with acquired ICI resistance and between those who were TKI-naive compared to those who were TKI-exposed. Notably, patients who received TKI-ICI combinations had significantly superior survival compared to single agent TKI patients (median OS 15.1 months (95% C.I. 6.7-23.5) vs. 8.6 months (95% C.I. 5.6-11.7), p = 0.011) but not significantly superior ORR, DCR or TTP. Amongst patients who received single agent TKI and were naive to both sorafenib and lenvatinib, those who received lenvatinib had significantly superior DCR, TTP and OS compared to those who received sorafenib (DCR 51.5% vs 25.8%, p = 0.035; median TTP 6.3 months (95% C.I. 3.0-9.7) vs. 1.8 months (95% C.I. 0-3.6), p = 0.003; median OS 12.0 months (95% C.I. 7.0-17.0) vs. 5.9 months (95% C.I. 1.9-10.0), p = 0.008). 70.3% and 15.5% of all patients, and 77.1% and 15.6% of patients who received single agent TKI experienced all grade and grade ≥3 AEs respectively. The most common AEs were hand foot syndrome, skin rash and diarrhea. Conclusions: TKIs can achieve encouraging anti-tumour response and survival outcomes with acceptable safety in prior ICI-treated aHCC patients. Moreover, TKI-ICI combinations were associated with better survival than single agent TKIs. Notably, among patients who received single agent TKIs, lenvatinib had significantly better responses and survival results than sorafenib.

Combination of immunotherapy and tyrosine kinase inhibitor in first-line metastatic renal cell carcinoma: A real-world Indian experience.

e16576 Background: Immuno-oncology (IO) agents in combination with oral tyrosine kinase inhibitors (TKIs) has become a standard first line therapy in metastatic renal cell carcinoma (mRCC) patients. Various combinations such as pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib and pembrolizumab + lenvatinib have all shown better results than sunitinib. There is very limited data about this from India. Methods: This is a single center, retrospective study of mRCC patients, who received first line treatment was nivolumab or pembrolizumab with axitinib or lenvatinib. The endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AE). Results: Between Jan 2019 to Jan 2021, 22 patients were treated with IO + TKI combination. 12 patients received axitinib, and 10 lenvatinib. Age range was 35 to 78 years with 18 males and 4 females. IMDC risk stratification showed 3 favorable (13.6%), 13 intermediate (59%) and 6 poor risk (27.2%) patients. 2 patients (9%) achieved complete response(CR), 13 (59%) partial response (PR), 4 (18.2%) had stable disease and 3 (13.6%) progressed. The ORR was 68%. Median PFS was 22 months (1 month- 24 months). OS at 1 year was 92%, and median OS was not reached. Grade 3/4 immune related adverse events (AEs) were seen in 3 (14.2%) patients (1 colitis,1 pneumonitis,1 encephalitis), for whom the IO was discontinued. TKI related grade 3/4 AEs were seen in 8 patients (38%), and were managed with dose reductions. Conclusions: Combination IO + TKI is a very effective first line therapy in mRCC. An ORR of 68%, median PFS of 22 months and 1 year OS of 92% is the best we have seen in our patients. The efficacy of this combination is seen in all IMDC subgroups. The combination is well tolerated, and the TKI AEs are comfortably managed with dose reduction. IO combinations should be preferred over single agent TKIs (sunitinib or pazopanib) as first line therapy.

Time to Resolution of Axitinib-Related Adverse Events After Treatment Interruption in Patients With Advanced Renal Cell Carcinoma.

Combined axitinib and immuno-oncology (IO) therapy is approved for first-line advanced renal cell carcinoma. Overlapping toxicities represent a clinical challenge. Calculating the time to resolution (TTR) of common axitinib-related adverse events (AEs) after treatment interruption may help to identify AE etiology and determine appropriate management strategies. Data from 5 randomized or single-arm axitinib monotherapy or combination studies were analyzed. Patients with histologically confirmed clear cell advanced renal cell carcinoma were pooled into 3 cohorts based on treatment received: axitinib monotherapy, axitinib+IO, and other tyrosine kinase inhibitor (TKI). Any grade and grade ≥3 treatment-emergent diarrhea, fatigue, hypertension, nausea, and palmar-plantar erythrodysesthesia syndrome were assessed. TTR was defined as the time from treatment interruption/discontinuation to resolution. The axitinib monotherapy cohort comprised 532 patients, the axitinib+IO cohort 541 patients, and the other TKI cohort 882 patients. Median TTR for all AEs (any grade) in the axitinib monotherapy cohort ranged from 1 to 3 days, except for fatigue (8 days). For diarrhea, hypertension, nausea, and palmar-plantar erythrodysesthesia syndrome, median TTRs were longer in the axitinib+IO (4-11 days) and other TKI (7-8 days) cohorts versus the monotherapy cohort. Results were similar when only AEs of grade ≥3 were considered. The TTR of monotherapeutic axitinib-related AEs is ≤3 days, except for fatigue, and generally shorter than for other single-agent TKIs and axitinib+IO. This has important implications for identifying AE etiology with combined axitinib-IO therapy and implementation of appropriate management strategies. ClinicalTrials.org identifiers: NCT00678392, NCT00920816, NCT02493751, NCT02684006, NCT02853331.

What is next in second- and later-line treatment of metastatic renal cell carcinoma? review of the recent literature.

The current treatment landscape of metastatic renal cell carcinoma has changed dramatically from the dominance of single-agent tyrosine kinase inhibitor (TKI) therapy to immune-checkpoint inhibitor (ICI)-based combinations in recent years. However, the optimal subsequent therapy remains ill-defined owing to the novelty of this approach. Treatment with TKIs after failure of single or dual ICI therapies may result in robust clinical efficacy. Nonetheless, there is a trend toward lower efficacy of TKIs after previous ICI-TKI combination therapy. Currently, tivozanib is the only drug whose third- and later-line use after failure of TKI and ICI is supported by evidence, with significantly longer progression-free survival and higher objective response rates than sorafenib. Data from retrospective studies highlight the safety and clinical activity of ICI rechallenge. Overall, the level of evidence remains low. Treatment after failure of dual ICI therapy is not well defined and may consist of any available TKI. Although first-line use of TKI is less common, strong evidence suggests cabozantinib or nivolumab as standard options in that setting. The recommendations after first-line TKI-ICI therapy failure mirror this recommendation, although the data are less robust.

Cancer-associated fibroblast secretion of PDGFC promotes gastrointestinal stromal tumor growth and metastasis

Targeted therapies for gastrointestinal stromal tumor (GIST) are modestly effective, but GIST cannot be cured with single agent tyrosine kinase inhibitors. In this study, we sought to identify new therapeutic targets in GIST by investigating the tumor microenvironment. Here, we identified a paracrine signaling network by which cancer-associated fibroblasts (CAFs) drive GIST growth and metastasis. Specifically, CAFs isolated from human tumors were found to produce high levels of platelet-derived growth factor C (PDGFC), which activated PDGFC-PDGFRA signal transduction in GIST cells that regulated the expression of SLUG, an epithelial-mesenchymal transition (EMT) transcription factor and downstream target of PDGFRA signaling. Together, this paracrine induce signal transduction cascade promoted tumor growth and metastasis in vivo. Moreover, in metastatic GIST patients, SLUG expression positively correlated with tumor size and mitotic index. Given that CAF paracrine signaling modulated GIST biology, we directly targeted CAFs with a dual PI3K/mTOR inhibitor, which synergized with imatinib to increase tumor cell killing and in vivo disease response. Taken together, we identified a previously unappreciated cellular target for GIST therapy in order to improve disease control and cure rates.

First-line treatment of metastatic clear cell renal cell carcinoma: a decision-making analysis among experts

BackgroundThe treatment landscape of metastatic clear cell renal cell carcinoma (mccRCC) has been transformed by targeted therapies with tyrosine kinase inhibitors (TKI) and more recently by the incorporation of immune checkpoint inhibitors (ICI). Today, a spectrum of single agent TKI to TKI/ICI and ICI/ICI combinations can be considered and the choice of the best regimen is complex.Materials and methodsWe performed an updated decision-making analysis among 11 international kidney cancer experts. Each expert provided their treatment strategy and relevant decision criteria in the first line treatment of mccRCC. After the collection of all input a list of unified decision criteria was determined and compatible decision trees were created. We used a methodology based on diagnostic nodes, which allows for an automated cross-comparison of decision trees, to determine the most common treatment recommendations as well as deviations.ResultsDiverse parameters were considered relevant for treatment selection, various drugs and drug combinations were recommended by the experts. The parameters, chosen by the experts, were performance status, International Metastatic renal cell carcinoma Database Consortium (IMDC) risk group, PD-L1 status, zugzwang and contraindication to immunotherapy. The systemic therapies selected for first line treatment were sunitinib, pazopanib, tivozanib, cabozantinib, ipilimumab/nivolumab or pembrolizumab/axitinib.ConclusionA wide spectrum of treatment recommendations based on multiple decision criteria was demonstrated. Significant inter-expert variations were observed. This demonstrates how data from randomized trials are implemented differently when transferred into daily practice.

Avelumab and axitinib combination therapy for the treatment of advanced renal cell carcinoma.

Owing to an improved understanding of the immunobiological profile of renal cell carcinoma (RCC), the past few years have ushered in significant changes in systemic therapies for advanced stage RCC. First-line treatment with single-agent tyrosine kinase inhibitors (TKI) has been virtually replaced for most patients by immunotherapy combinations. The first ofsuch treatments was the dual immune checkpoint inhibitor combination of ipilimumab and nivolumab. More recently, the combination of an immune checkpoint inhibitor and a TKI has also moved into the first-line setting. This review summarizes the pharmacologic properties, evidence for use and safety of avelumab, a PD-L1inhibitor and axitinib a small-molecule TKI, each as monotherapy, and in combination for the management of metastatic RCC.

Real-World Outcomes of Patients with Refractory or Relapsed FLT3-ITD Acute Myeloid Leukemia: A Toulouse-Bordeaux DATAML Registry Study.

Two recent phase 3 trials showed that outcomes for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukemia (AML) patients may be improved by a single-agent tyrosine kinase inhibitor (TKI) (i.e., quizartinib or gilteritinib). In the current study, we retrospectively investigated the characteristics and real-world outcomes of R/R FLT3-internal tandem duplication (ITD) acute myeloid leukemia (AML) patients in the Toulouse-Bordeaux DATAML registry. In the study, we included 316 patients with FLT3-ITD AML that received intensive chemotherapy as a first-line treatment. The rate of complete remission (CR) or CR without hematological recovery (CRi) was 75.2%, and 160 patients were R/R after a first-line TKI-free treatment (n = 294). Within the subgroup of R/R patients that fulfilled the main criteria of the QUANTUM-R study, 48.9% received an intensive salvage regimen; none received hypomethylating agents or low-dose cytarabine. Among the R/R FLT3-ITD AML patients with CR1 durations < 6 months who received intensive TKI-free treatment, the rate of CR or CRi after salvage chemotherapy was 52.8%, and these results allowed a bridge to be transplanted in 39.6% of cases. Finally, in this QUANTUM-R standard arm-matched cohort, the median overall survival (OS) was 7.0 months and 1-, 3- and 5-year OS were 30.2%, 23.7% and 21.4%, respectively. To conclude, these real-world data show that the intensity of the second-line treatment likely affects response and transplantation rates. Furthermore, the results indicate that including patients with low-intensity regimens, such as low-dose cytarabine or hypomethylating agents, in the control arm of a phase 3 trial may be counterproductive and could compromise the results of the study.

INMUNOSUN-SOGUG trial: A prospective phase II study to assess the efficacy and safety of sunitinib as second-line (2L) treatment in patients (pts) with metastatic renal cell cancer (RCC) who received immunotherapy-based combination upfront.

5060 Background: Immunotherapy (IO)-based combinations have replaced tyrosine kinase inhibitors (TKI) as standard upfront treatment of metastatic RCC pts. Selection of 2L treatment after progression to novel combinations in 1st-line (1L) is mostly based on retrospective series or subgroups analysis of randomized trials. We aim to evaluate the activity and safety of sunitinib in advanced RCC after progression on an IO-based 1L approach. Methods: This is a prospective, non-randomized, open-label and multicenter phase II study. Pts with ECOG 0-2 and locally advanced or metastatic RCC after treatment in 1L with a prior PD-1 and/or PD-L1 and/or CTLA-4 inhibitor were included. Sunitinib was administered at 50 mg/day on a 4/2 schedule until disease progression. Primary endpoint was overall response rate (ORR) by RECIST v 1.1 criteria. Results: Twenty pts were enrolled in the study. Median age was 66 yo, 70% had intermediate prognosis by Heng's scale, and 88% ECOG 1. 45% of pts received atezolizumab, 30% pembrolizumab, 20% nivolumab and 15% ipilimumab-based regimens as 1L. ORR to 1L treatment was 45%. Median time from end of 1L to sunitinib onset date was 1.1 months (0.3-22.1). Two (10%) pts had partial response with sunitinib and 11 (55%) stable disease for a total disease control rate of 65%. With a median follow-up of 8.8 months, median PFS was 6.8 months (0.0-13.9) and median OS 13.6 months (10.5-16.6). Median duration of treatment was 4 months (0.9-16-2). Most common treatment-related adverse events, all grades, were asthenia (55%), dysgeusia (35%), diarrhea (30%), hypertension (30%), mucosal inflammation (25%), palmar-plantar erythrodysesthesia (25%), anemia (20%), neutropenia (20%) and nausea (15%); grade 3 were asthenia (15%), hypertension (10%) and neutropenia (10%). Conclusions: To our knowledge, the INMUNOSUN trial is the first study to evaluate prospectively the activity of a single agent TKI in a pure 2L setting of metastatic RCC pts treated with an IO-based approach upfront. ORR and PFS with sunitinib seem lower than expected when used as a 1L. Consistency in toxicity profile was observed. Clinical trial information: NCT03066427 .

Venetoclax in Combination with Gilteritinib in Patients with Relapsed/Refractory Acute Myeloid Leukemia: A Phase 1b Study

Venetoclax in Combination with Gilteritinib in Patients with Relapsed/Refractory Acute Myeloid Leukemia: A Phase 1b Study

Antiangiogenic tyrosine kinase inhibitors in colorectal cancer: is there a path to making them more effective?

Antiangiogenic therapy has a proven survival benefit in metastatic colorectal cancer. Inhibition of the VEGF pathway using a variety of extracellular antibody approaches has clear benefit in combination with chemotherapy, while intracellular blockade using tyrosine kinase inhibitors (TKIs) such as sorafenib and regorafenib has had more limited success. Pharmacodynamic modeling using modalities such as DCE-MRI indicates potent antiangiogenic effects of these TKIs, yet numerous combination therapies, primarily with chemotherapy, have failed to demonstrate an additive benefit. The sole comparative study of a single agent TKI against placebo showed a survival benefit of regorafenib in patients with advanced, refractory disease. Preclinical data demonstrate synergy between antiantiogenic TKIs and targeted interventions including autophagy inhibition, and together with a renewed effort to define markers of susceptibility, such combinations may be a way to improve the limited efficacy of this once-promising drug class.