Combination Of Axitinib Research Articles

Pembrolizumab plus axitinib for the treatment of advanced renal cell carcinoma

ABSTRACT Introduction: The dominant paradigm of sequential therapy of metastatic renal cell carcinoma (mRCC) with single agents has recently been challenged by improved outcomes obtained with combined regimens with immune checkpoint inhibitors. These combined regimens include the combination of pembrolizumab plus axitinib. Areas covered: Here, we provide a brief overview of the current clinical data on the pembrolizumab plus axitinib combination including mechanism of action, pharmacokinetics, efficacy and safety profile. Expert opinion: Both agents targeting the vascular endothelial growth factor (VEGF) pathway and immune checkpoint inhibitors are active as single agents in mRCC. Improved outcomes have been demonstrated in phase 3 trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab, and ipilimumab plus nivolumab. Among these combinations, an OS benefit has, so far, demonstrated only for the combinations of axitinib with pembrolizumab and ipilimumab with nivolumab. Although there are currently no prospective data comparing the combination of ipilimumab and nivolumab with the combination of immune checkpoint inhibitors and VEGF inhibitors, currently available retrospective analyses indicate that these two approaches achieve comparable outcomes.

The impact of hypertension on response rates in patients with renal cell carcinoma.

287 Background: There are many clinical trials that demonstrate the benefits of immunotherapies and targeted therapies in patients (pts) with advanced or metastatic RCC (mRCC). Most of these studies specifically exclude many real-world pts with comorbidities such as autoimmune disease, heart failure, and hypertension. Data on treatment efficacy and adverse events in patients with a history of uncontrolled hypertension is lacking, as there have been few studies analyzing more recently approved RCC drug regimens in real-world practice. Methods: We retrospectively collected data from pts with mRCC treated with immunotherapy and/or targeted therapies. Patient characteristics, performance status, treatment type, reason for treatment discontinuation, treatment response/progression per RECIST v1.1, survival, and presence of clinical trial exclusion criteria such as hypertension, heart failure, presence of autoimmune disease, renal or liver failure, and International Metastatic RCC Database Consortium (IMDC) Risk score were collected. Results: A total of 198 pts were included. The majority of patients received Tyrosine Kinase Inhibitors (TKIs) (42.42% pazopanib (n = 84), 21.71% sunitinib (n = 43), 13.64% cabozantinib (n = 27)), whereas 10.61% were on combination of axitinib + pembrolizumab (n = 21) and 11.62% received ipilimumab + nivolumab (n = 23), and. 71.72% of patients who qualified for systemic therapy had a history of uncontrolled hypertension, whereas 28.28 % of total patients had no history of uncontrolled hypertension. The median time on first-line treatment was 5.17 months. A history of hypertension did not significantly affect Overall Survival (OS), 15.90 months median OS for those with hypertension vs 27.80 median OS for those with no hypertension (p = 0.38). Median OS for all patients was 22.80 months. There was also no difference in response rate between those with a history of hypertension vs those with no history of uncontrolled hypertension (p = 0.65) or in Progression Free Survival (PFS) (p = 0.97) Data on how many patients developed exacerbations of hypertension on therapy will be available at time of presentation. Conclusions: Uncontrolled hypertension typically excludes patients from clinical trial enrollment. We found no difference in median OS in those with a history of hypertension compared to those with normal blood pressures. Further large-scale studies are needed to further determine outcomes in patients with hypertension on systemic therapy for mRCC.

Symptomatic methemoglobinemia in a patient with metastatic clear cell renal cell carcinoma treated with pembrolizumab and axitinib combination therapy: a case report

BackgroundCombination regimens that include immune checkpoint (ICI) and vascular endothelial growth factor (VEGF) inhibition have opened the door to new treatment opportunities for patients with metastatic renal cell carcinoma (mRCC). While these treatment options have provided improved tolerability and better outcomes compared to older regimens, many patients still experience a myriad of treatment-related adverse events. Given that these regimens were recently approved for mRCC, the complete side effect profile may not be fully elucidated yet.Case presentationWe report a case of a 73-year old White male with mRCC who was managed with an ICI-VEGF inhibitor combination regimen. He experienced a partial response (Fig. 1) but had side effects including symptomatic cyanosis diagnosed as methemoglobinemia which led to treatment discontinuation. Upon holding his therapy, his methemoglobinemia and cyanosis resolved.ConclusionsCombination VEGF-ICI therapy provide novel regimens for advanced solid tumor malignancies including mRCC. While shown to have improved efficacy in clinical trials, it is crucial that oncologists uncover the full side effect profile of these novel agents especially as their use becomes more standard in the management of advanced malignancies. To our knowledge, this is the first reported case of a patient experiencing symptomatic methemoglobinemia as an adverse event associated with a VEGF-ICI combination regimen. While the cause of this side effect is unclear, in this paper we attempt to elucidate a process that is in line with the mechanism of action of these therapies to explain how these agents, specifically the axitinib, could have caused the methemoglobin to rise to a symptomatic level.

Axitinib in combination with radiotherapy for advanced hepatocellular carcinoma: a phase I clinical trial

BackgroundTo investigate maximum tolerated dose (MTD) of axitinib, a selective vascular endothelial growth factor receptor 1–3 inhibitor, in combination with radiotherapy (RT) for advanced hepatocellular carcinoma (HCC).MethodsThis phase I study followed the rule of traditional 3 + 3 design. Major eligibility included: (1) patients with advanced HCC unsuitable for surgery, radiofrequency ablation or transarterial chemoembolization, or who failed after prior local–regional treatment; (2) failure on sorafenib or no grant for sorafenib from health insurance system. Eligible patients with advanced HCC received axitinib for total 8 weeks during and after RT. Three cohorts with axitinib dose escalation were planned: 1 mg twice daily (level I), 2 mg twice daily (level II) and 3 mg twice daily (level III). The prescribed doses of RT ranged from 37.5 to 67.5 Gy in 15 fractions to liver tumor(s) and were determined based on an upper limit of mean liver dose of 18 Gy (intended isotoxic RT for normal liver). The primary endpoint was MTD of axitinib in combination with RT. The secondary endpoints included overall response rate (ORR), RT in-field response rate, acute and late toxicities, overall survival (OS) and progression free survival (PFS).ResultsTotal nine eligible patients received axitinib dose levels of 1 mg twice daily (n = 3), 2 mg twice daily (n = 3) and 3 mg twice daily (n = 3). Dose-limiting toxicity (DLT) did not occur in the 3 cohorts; the MTD was defined as 3 mg twice daily in this study. ORR was 66.7%, including 3 complete responses and 3 partial responses, at 3 months after treatment initiation. With a median follow-up of 16.6 months, median OS was not reached, 1-year OS was 66.7%, and median PFS was 7.4 months.ConclusionsAxitinib in combination with RT for advanced HCC was well tolerated with an axitinib MTD of 3 mg twice daily in this study. The outcome analysis should be interpreted with caution due to the small total cohort.Trial registration ClinicalTrials.gov (Identifier: NCT02814461), Registered June 27, 2016—Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02814461

A phase II/III randomized double-blind study of octreotide acetate LAR with axitinib versus octreotide acetate LAR with placebo in patients with advanced G1-G2 NETs of non-pancreatic origin (AXINET trial-GETNE-1107).

360 Background: Angiogenesis plays an important role in NET development and progression. Axitinib is a potent and selective VEGFR-1,2,3 inhibitor, with proven activity against several vascular-dependent solid tumors. The aim of this randomized, double-blind phase II/III study was to assess the efficacy of axitinib in patients with advanced G1-2 extra-pancreatic NETs. Methods: Eligible pts were randomized (1:1) to receive octreotide LAR (30 mg IM q4w) with axitinib (5 mg BID) or placebo BID until disease progression or unacceptable toxicity. Pteswere stratified by time from diagnosis to study entry ( > or < 12m), primary tumor site (GI tract vs non-GI) and Ki-67 index (< 5% vs > 5%). Prior therapy with SSA, IFN and up to 2 lines of systemic treatment was allowed, but not prior VEGF- or VEGFR-targeted drugs. Clinical and/or radiological disease progression within 12 months prior to study entry was required. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), time to progression, overall response rate (ORR), duration of response, biochemical response and safety. Results: 256 pts were randomized (106 in the Phase II part, and 150 additional pts in the Phase III part), 126 to axitinib and 130 to placebo. The main characteristics of the study population were: median age 61 years (range: 21-85), 52% male, PS 0-1 (64-35%), G1-2 (29%-71%), primary tumor site GI (40%)-Lung (17%)-Other (32%). Prior therapies included: SSA (46%), everolimus (13%), chemotherapy (13%), TACE (5%) and PRRT (2%). ORR was significantly higher in axitinib- vs placebo-treated patients (17.5% vs 3.8%, p = 0.0004). PFS per investigator assessment also favored axitinib vs placebo-treated patients, although the difference did not reach statistical significance (median PFS 17.2 vs 12.3 months, respectively, HR 0.816, p = 0.169). Grade 3-4 treatment-related AEs occurred more frequently in the axitinib vs placebo arm (52% vs 13.8%), and included hypertension (21% vs 6 %), cardiac disorders (3.2% vs 0.7%), diarrhoea (13% vs 1.5 %), asthenia (9% vs 3%) and nausea&vomiting (2% vs 0.7%). There were 3 treatment-related deaths, 1 in the axitinib arm (cardiac failure) and 2 in the placebo arm (myocardial infarction and hepatorenal syndrome). Conclusions: Although the study failed to demonstrate a significant PFS benefit per investigator assessment, axitinib in combination with octreotide LAR demonstrated activity and had a tolerable safety profile in patients with advanced G1-2 extra-pancreatic NETs. Data base cleaning and central blinded radiological PFS assessment are currently ongoing. Clinical trial information: NCT01744249.

The efficacy and safety of the combination of axitinib and pembrolizumab-activated autologous DC-CIK cell immunotherapy for patients with advanced renal cell carcinoma: a phase 2 study.

ObjectivesAlthough axitinib has achieved a preferable response rate for advanced renal cell carcinoma (RCC), patient survival remains unsatisfactory. In this study, we evaluated the efficacy and safety of a combination treatment of axitinib and a low dose of pembrolizumab‐activated autologous dendritic cells–co‐cultured cytokine‐induced killer cells in patients with advanced RCC.MethodsAll adult patients, including treatment‐naive or pretreated with VEGF‐targeted agents, were enrolled from May 2016 to March 2019. Patients received axitinib 5 mg twice daily and pembrolizumab‐activated dendritic cells–co‐cultured cytokine‐induced killer cells intravenously weekly for the first four cycles, every 2 weeks for the next four cycles, and every month thereafter.ResultsThe 43 patients (22 untreated and 21 previously treated) showed a median progression‐free survival (mPFS) of 14.7 months (95% CI, 11.16–18.30). mPFS in treatment‐naive patients was 18.2 months, as compared with 14.4 months in pretreated patients (log‐rank P‐value = 0.07). Overall response rates were 25.6% (95% CI, 13.5–41.2%). Grade 3 or higher adverse events occurred in 5% of patients included hypertension (11.6%) and palmar‐plantar erythrodysesthesia (7.0%). Peripheral blood lymphocyte immunophenotype and serum cytokine profile analyses demonstrated increased antitumor immunity after combination treatment particularly in patients with a long‐term survival benefit, while those with a minimal survival benefit demonstrated an elevated proportion of peripheral CD8+TIM3+ T cells and lower serum‐level immunostimulatory cytokine profile.ConclusionsThe combination therapy was active and well tolerated for treatment of advanced RCC, either as first‐ or second‐line treatment following other targeted agents. Changes in immunophenotype and serum cytokine profile may be used as prognostic biomarkers.

Combination of pembrolizumab and axitinib: a new gold standard in the first-line therapy for metastatic clear-cell renal-cell carcinoma?

The treatment strategy for metastatic renal cell carcinoma (mRCC) has evolved with the emergence of anti-angiogenic drugs, in particular tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR) and immune checkpoint inhibitors (ICIs). Both treatment options improved patient outcomes and altered the natural history of mRCC. Clinical studies have focused on evaluating combination regimens containing ICI and VEGFR-targeted TKIs. The combination of axitinib with pembrolizumab (KEYNOTE-426) showed better results compared to sunitinib in patients with mRCC who had not previously received systemic therapy. In this article, we discuss the rationale for the combination of ICI and TKI based on preclinical data, as well as the clinical results obtained with the combination of axitinib with pembrolizumab in first-line patients in clinical trials.

Pembrolizumab plus axitinib combination and the paradigm change in the treatment of advanced renal cell carcinoma.

Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved outcomes obtained with combination regimens based on immune checkpoint inhibitors. Most patients treated with sequential monotherapy eventually develop drug resistance and succumb to progressive disease, leading to the search for therapies that would overcome drug resistance and result in a more durable treatment response. Improved outcomes have been demonstrated in Phase III trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumaband ipilimumab plus nivolumab. A statistically significant improvement of both progression-free and overall survival has been demonstrated for the axitinib plus pembrolizumab combination.

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.

Pembrolizumab in Combination with Axitinib as First-Line Treatment for Patients with Renal Cell Carcinoma (RCC): Evidence to Date.

Over the last 18 months, 3 immunotherapy combination regimens (ipilimumab + nivolumab, pembrolizumab + axitinib, and axitinib + avelumab) were approved by the US Food and Drug Administration for the first-line treatment of metastatic renal cell carcinoma (mRCC), making selection of the optimal first-line treatment regimen very challenging. As of April 2020, preferred first-line treatment options for mRCC are pembrolizumab + axitinib and ipilimumab + nivolumab, based on the improvement in overall survival and progression-free survival compared to sunitinib, as observed in pivotal phase III clinical trials. Because the combination of 2 drugs is typically more toxic than a monotherapy, careful attention must be given to overlapping toxicities. The pembrolizumab + axitinib combination led to grade ≥3 adverse events in 75.8% of patients (vs 70.6% in the sunitinib group), while grade ≥3 adverse events were less frequent in the nivolumab + ipilimumab group compared to the sunitinib group. Discontinuation rates due to toxicity were 10.7% for pembrolizumab + axitinib (both drugs), 22% for ipilimumab + nivolumab and were comparable with sunitinib in both studies (13.9% and 12%, respectively). The combination of pembrolizumab + axitinib may have immune-modulating functions that may provide clinical benefit without the additional toxicity observed with ipilimumab + nivolumab. In addition, this tyrosine kinase inhibitor + immune checkpoint combination should have faster treatment response in patients with larger disease burden or in more symptomatic patients, which makes this combination an excellent choice for the first-line treatment regimen for mRCC. These combinations have proven to be tolerable, though long-term results are still lacking. As treatment options for mRCC are rapidly expanding, immunotherapy combinations could potentially change the treatment paradigm, with the ultimate goal of prolonging life and eventually curing mRCC.

First-Line Immune Checkpoint Inhibitor-Based Therapy for Metastatic Renal Cell Carcinoma: A Systematic Review

Background: Immune checkpoint inhibitors (CPIs) have come to the forefront as a major component of the management of metastatic renal cell carcinoma ( mRCC). Over a short period of time, several studies have shown benefit in using these agents in the first-line setting. Objective: In this systematic review, the available evidence regarding the use of CPI-based regimens in previously untreated mRCC was reviewed. Methods: A systematic search for phase II and III studies was conducted of the PubMed and Embase databases as per the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. The search retrieved abstracts to February 1, 2020. Data was compiled and summarized in narrative and tabular formats. Results: Fifty-five abstracts from 11 clinical trials were included, including four phase III clinical trials and seven phase II trials. The most recent phase III data demonstrates overall survival (OS) benefit for ipilimumab plus nivolumab (for intermediate and poor risk patients) and pembrolizumab plus axitinib combination regimens over sunitinib. Two other regimens (avelumab plus axitinib and atezolizumab plus bevacizumab) have shown benefits in progression free survival, but not in OS to date. Toxicity data shows varying patterns of adverse events between the four treatments. Phase II data indicate CPI has activity as a single agent, and in patients with non-clear cell subtypes of RCC. Conclusions: CPI-based regimens improve outcomes in virtually all subgroups of mRCC patients when used as front-line therapy. This is certain to change the landscape of mRCC treatment.

Safety and activity of Combined AVElumab with Axitinib in unresectable or metastatic Thymomas B3 and Thymic carcinomas: The CAVEATT study.

e21114 Background: Patients (pts) with advanced B3 thymoma (B3T) and thymic carcinoma (TC) resistant to chemotherapy have limited treatment options. Treatment with Anti-PD1 showed not negligible toxicity and limited activity, and anti-VEGFR drugs obtained limited and short lasting antitumor responses. No data on combined anti-PD1/PD-L1 with antiangiogenic drugs are available in B3T/TC. We report preliminary results on safety and activity of avelumab combined with axitinib in this pts population. Methods: The CAVEATT is a single arm, multicentric, phase II trial in immunotherapy-naive pts with advanced B3T or TC, progressing after at least one line of platinum based chemotherapy. Prior therapy with antiangiogenic drugs is allowed. Pts received Avelumab 10 mg/kg iv every 2 weeks and Axitinib 5 mg twice a day until progression or toxicity. The primary objective of the study is overall response rate (ORR) by RECIST 1.1; secondary endpoints include ORR by irRC and ITMIG, and QoL by EORTC QLQ-C30. An interim futility analysis is planned after the enrollment of the first 18 patients. If at least 5 out of 18 patients will obtain a PR, the accrual will continue to reach the total number of 33 pts, according with a Simon’s minimax design. Tumor and blood samples are collected at baseline and whenever feasible at disease progression, to identify predictive biomarkers of response and mechanisms of resistance to treatment. Results: 1 pt with B3T and 12 with TC were enrolled from April 2019 to January 2020. Median age was 59 years (range 33-77). 8 pts received ≥2 previous line of therapies, and 6 pts were pretreated with an antiangiogenic drug. The median follow-up was 5.1 months. 10 pts were evaluable for response. The proportions of patients who achieved a partial response (PR) or a stable disease (SD) were respectively 40% (95% CI 17%–69%) and 60% (95% CI 30%–83%). The median PFS was 7.9 months (95% CI 2.5–NA) 12 pts were evaluable for toxicity. Treatment-related adverse events (AE) of grade 1 or 2 occurred in 7 (58%) pts, and the most common was diarrhea (3 pts). Grade ≥3 AEs occurred in 2 (17%) pts: 1 had G3 hyperthension and 1 G3 hand foot syndrome, both leading to axitinib drug reduction. No immune-related AEs (irAEs) were observed. No patient stopped treatment for toxicity, 5 pts stopped for progressive disease, and 8 pts are still on treatment. Conclusions: Preliminary results suggest promising antitumor activity and a good toxicity profile of the combination of axitinib and avelumab in pts with advanced B3T and TC. Accrual is ongoing to reach the target of 33 pts Clinical trial information: 2017-004048-38 .

Challenges and opportunities in the management of metastatic renal cell carcinoma: combination therapy and the role of cytoreductive surgery.

As the biology of metastatic renal cell carcinoma (mRCC) continues to be elucidated, novel treatments focused around immunotherapies and targeted therapies will continue to emerge. In this review, we will highlight recent treatment advances and their implications for surgical and systemic therapy. Several new treatments, including the tyrosine kinase inhibitor cabozantinib, the combination of a programmed cell death protein 1 antibody (nivolumab) with a cytotoxic T-lymphocyte-associated antigen 4 antibody (ipilimumab), and the combination of axitinib with pembrolizumab or avelumab have been approved by the US Food and Drug Administration as first-line therapy for the treatment of mRCC. Although promising survival benefits have been seen with these new therapies, careful patient selection is still critical. The introduction of novel therapies and the investigation of combinatorial therapies have shifted the treatment paradigm for advanced RCC. Present trials have provided promising data that could lead to further therapeutic advances.

SEOM clinical guideline for treatment of kidney cancer (2019)

In this article, we review de state of the art on the management of renal cell carcinoma (RCC) and provide recommendations on diagnosis and treatment. Recent advances in molecular biology have allowed the subclassification of renal tumours into different histologic variants and may help to identify future prognostic and predictive factors. For patients with localized disease, surgery is the treatment of choice with nephron-sparing surgery recommended when feasible. No adjuvant therapy has demonstrated a clear benefit in overall survival. Considering the whole population of patients with advanced disease, the combination of axitinib with either pembrolizumab or avelumab increase response rate and progression-free survival, compared to sunitinib, but a longer overall survival has only been demonstrated so far with the pembrolizumab combo. For patients with IMDC intermediate and poor prognosis, nephrectomy should not be considered mandatory. In this subpopulation, the combination of ipilimumab and nivolumab has also demonstrated a superior response rate and overall survival vs. sunitinib. In patients progressing to one or two antiangiogenic tyrosine-kinase inhibitors, both nivolumab and cabozantinib in monotherapy have shown benefit in overall survival compared to everolimus. Although no clear sequence can be recommended, medical oncologists and patients should be aware of the recent advances and new strategies that improve survival and quality of life in patients with metastatic RCC.

P14.28 First report on the combination of axitinib and Tumor Treating Fields (TTFields) in three patients with recurrent glioblastoma

Abstract BACKGROUND Adding Tumor Treating Fields (TTFields) to first-line therapy in glioblastoma (GBM) demonstrated significantly improved survival in the EF-14 trial. Furthermore, in a post-hoc analysis of the EF-14 trial, median overall survival increased significantly upon recurrence (rGBM) for patients treated with bevacizumab (Bev) and TTFields compared to Bev monotherapy. Axitinib (Axi) is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors, thereby acting similar to Bev. In phase 2 trials, Axi improved response rate and progression free survival in rGBM patients compared to historical controls with a manageable toxicity profile. We report on three rGBM patients treated with TTFields and Axi (AxiTTFields). METHODS A 53-year-old male patient (#1) presented with a multifocal and consistently progressing GBM after initial surgery, radiochemotherapy (RCT) and after 4 cycles of temozolomide (TMZ), combined with TTFields. To meet the urgent need of an alternative treatment, Axi (5mg twice a day) was added to the treatment regimen. In a 46-year-old male patient (#2), an early progress occurred after surgery, RCT and 3 cycles of TMZ combined with TTFields. Similarly to #1, Axi was added to the treatment regimen. In a 61-year-old male patient (#3) with a rGBM after surgery and RCT at the time of the 6th cycle of TMZ, TTFields therapy was initiated at recurrence and treatment regimen was adapted to AxiTTFields. RESULTS In these three patients, AxiTTFields was safe and feasible. #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months initiating the combined treatment of AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. Although, Axi as well as TTFields may cause skin irritations, none were observed in this case series. With an average of 77 % in these three patients, the TTFields usage rate was above the independent prognostic threshold of 75 %, underlining the feasibility of this approach. There were no additional adverse events due to the combined therapy of AxiTTFields. CONCLUSION In summary, AxiTTFields was feasible and safe in three rGBM patients. As the addition of Axi to TTFields therapy is a promising approach, we plan to investigate the safety and feasibility of this combination in a pilot trial. Further studies might explore effects on outcome and survival of AxiTTFields in rGBM.

The Changing Therapeutic Landscape of Metastatic Renal Cancer

The practising clinician treating a patient with metastatic clear cell renal cell carcinoma (CCRCC) faces a difficult task of choosing the most appropriate therapeutic regimen in a rapidly developing field with recommendations derived from clinical trials. NCCN guidelines for kidney cancer initiated a major shift in risk categorization and now include emerging treatments in the neoadjuvant setting. Updates of European Association of Urology clinical guidelines also include immune checkpoint inhibition as the first-line treatment. Randomized trials have demonstrated a survival benefit for ipilimumab and nivolumab combination in the intermediate and poor-risk group, while pembrolizumab plus axitinib combination is recommended not only for unfavorable disease but also for patients who fit the favorable risk category. Currently vascular endothelial growth factor (VEGF) targeted therapy based on tyrosine kinase inhibitors (TKI), sunitinib and pazopanib is the alternative regimen for patients who cannot tolerate immune checkpoint inhibitors (ICI). Cabozantinib remains a valid alternative option for the intermediate and high-risk group. For previously treated patients with TKI with progression, nivolumab, cabozantinib, axitinib, or the combination of ipilimumab and nivolumab appear the most plausible alternatives. For patients previously treated with ICI, any VEGF-targeted therapy, not previously used in combination with ICI therapy, seems to be a valid option, although the strength of this recommendation is weak. The indication for cytoreductive nephrectomy (CN) is also changing. Neoadjuvant systemic therapy does not add perioperative morbidity and can help identify non-responders, avoiding unnecessary surgery. However, the role of CN should be investigated under the light of new immunotherapeutic interventions. Also, markers of response to ICI need to be identified before the optimal selection of therapy could be determined for a particular patient.

Updated European Association of Urology Guidelines on Renal Cell Carcinoma: Immune Checkpoint Inhibition Is the New Backbone in First-line Treatment of Metastatic Clear-cell Renal Cell Carcinoma

Recent randomised trials have demonstrated a survival benefit for a front-line ipilimumab and nivolumab combination therapy, and pembrolizumab and axitinib combination therapy in metastatic clear-cell renal cell carcinoma. The European Association of Urology Guidelines Panel has updated its recommendations based on these studies. Patient summaryPembrolizumab plus axitinib is a new standard of care for patients diagnosed with kidney cancer spread outside the kidney and who did not receive any prior treatment for their cancer (treatment naïve). This applies to all risk groups as determined by the International Metastatic Renal Cell Carcinoma Database Consortium criteria.

Abstract CT093: Axitinib in combination with pembrolizumab (AXI+PEMBRO) in patients (pts) with advanced renal cell carcinoma (aRCC): Analysis of immune-related biomarkers

Abstract Background: In an open-label, phase Ib dose-finding and dose-expansion study in pts with aRCC, AXI+PEMBRO was tolerable; objective response rate (ORR) was 73.1%, and median progression free survival (mPFS) was 20.9 months (Lancet Oncol. 2018;19:405-15). These planned exploratory analyses evaluated candidate biomarkers that may confer sensitivity/resistance to AXI+PEMBRO. Materials & Methods: Tumor tissue (de novo biopsy or archival), serum and whole blood samples were collected at baseline (BL). Biomarkers were chosen based on known angiogenesis/immunomodulation roles. Clinical outcomes included ORR and PFS. Comparisons for responders vs non-responders were made using Wilcoxon rank sum test. Comparisons of PFS for <median vs ≥median analyte values were made using Kaplan-Meier analysis. All statistical analyses were univariate. For T-cell receptor (TCR) repertoire sequencing analysis, richness, a measure of the number of different species in a repertoire, was assessed using the Daley-Smith estimate (Nat Methods. 2013;10:325-7). Dose-finding and dose-expansion cohorts were analysed together. Results: 52 pts were treated. Tumor tissue, serum and whole blood samples were analyzed from 39 (75.0%), 51 (98.1%) and 52 (100%) pts, respectively. Immunohistochemical analysis of tumor tissue biomarkers revealed no significant associations between CD68, CD8 or PD-L1 levels at BL and ORR or PFS. However, pts whose tumor CD8 % positive cells was ≥median had a numerically longer PFS than pts whose CD8 % positive cells was <median (median PFS 26.2 vs 15.4 months, respectively; hazard ratio (HR): 0.4; 95% CI: 0.2, 1.2; unadjusted 2-sided p=0.091). For serum biomarkers, higher CXCL10 levels at BL were associated with better ORR (2-sided p=0.0197; false discovery rate-adjusted p=0.2235). In addition, pts with BL CEACAM1 levels ≥median (26.0ng/mL) had a numerically longer PFS (HR: 0.5; 95% CI: 0.2, 1.1; unadjusted 2-sided p=0.085). There was no association between BL levels of other serum biomarkers and ORR or PFS. Whole blood sample assessment of TCR repertoire dynamics showed no association with clinical outcomes. While the Daley-Smith richness estimate at BL was not associated with ORR, the Daley-Smith estimates at cycle 2, day 1 and end of treatment showed a trend toward greater richness estimate being associated with better response (unadjusted p-values = 0.0866 and 0.0324, respectively). Conclusions: In pts with aRCC, higher tumor levels of CD8 and serum levels of CXCL10 and CEACAM1 at BL may indicate potential sensitivity to AXI+PEMBRO treatment. Further validation of the value of these biomarkers in an independent cohort with a large sample size is warranted. Citation Format: Michael Atkins, Jean-Francois Martini, Elizabeth Plimack, David McDermott, Igor Puzanov, Mayer Fishman, Daniel Cho, Ulka Vaishampayan, Brad Rosbrook, Kathrine Fernandez, Jamal Tarazi, Saby George, Toni Choueiri. Axitinib in combination with pembrolizumab (AXI+PEMBRO) in patients (pts) with advanced renal cell carcinoma (aRCC): Analysis of immune-related biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT093.

KRAS-mutant colon cancer cells respond to combined treatment of ABT263 and axitinib.

Significant challenges to develop selective and effective pharmacological inhibitors for important oncoproteins like RAS continue impeding the success to treat cancers driven by such mutations. In the present study, the ABT263 and axitinib combination imposed synergistic effects on RAS-mutant colon cancer cells. The combination inhibited in vitro and in vivo growth of the cancer cells by enhancing apoptosis. Furthermore, AKT and Wnt/β-catenin signaling pathways were slightly down-regulated by the combination in KRAS-mutant colon cancer cells. The current results indicate that oncogene addiction can be targeted for therapy in colon cancer cells harboring the RAS-mutant. Therefore, targeting oncogene addiction can be a viable strategy for treating refractory cancers driven by important oncogenes, such as KRAS, which are otherwise difficult to be targeted by small molecules.

Axitinib in Combination with Toripalimab, a Humanized IgG4 mAb Against Programmed Death-1 (PD-1) in Patients with Metastatic Mucosal Melanoma: A Non-Randomized, Open-Label, Dose-Finding, and Cohort-Expansion Phase 1b Trial

Background: Metastatic mucosal melanoma responds poorly to anti-PD-1 monotherapy. Vascular endothelial growth factor (VEGF) has been shown to play an important immunosuppressive role in the tumor microenvironment. Combination therapy of VEGF inhibition with PD-1 blockade provides therapeutic opportunities for patients otherwise refractory to either monotherapy. Methods: We conducted a single center phase Ib trial evaluating the safety and preliminary clinical efficacy of toripalimab, a humanized IgG4 mAb against programmed death-1 (PD-1) in combination with VEGFR inhibitor axitinib in chemotherapy naive advanced mucosal melanoma patients. Patients received toripalimab at 1 mg/kg or 3 mg/kg via IV infusion once every two weeks, in combination with 5 mg axitinib orally BID in a dose-escalation and cohort-expansion study until confirmed disease progression, unacceptable toxicity, or voluntary withdrawal. The primary objective was safety. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, immunogenicity and tumor tissue biomarkers. Findings: Thirty-three patients were enrolled in the study. No dose-limiting toxicities (DLTs) were observed. 97% of patients experienced treatment-related adverse events (TRAE). The most common TRAE were mild (grade 1/2), including diarrhea, proteinuria, hand and foot syndrome, fatigue, AST/ALT elevation, hypertension, hypo- or hyper-thyroidism, bilirubin elevation, and rash. Grade 3 and above TRAE occurred in 39.4% subjects. By the data cutoff date, 20 (60.6%; 95% CI 42.1-77.1) patients achieved an objective response (complete or partial response) and median progression-free survival was 9.1 months (95% CI 3.9 to NE). Interpretation: The treatment combination of toripalimab plus axitinib was tolerable and showed promising anti-tumor activity in patients with treatment-naive metastatic mucosal melanoma. A randomized phase III trial of toripalimab with axitinib versus standard of care is needed to validate the combination as a first-line treatment option for advanced mucosal melanoma. Trial Registration Number: Clinical trial (NCT03086174) Funding Statement: Study is sponsored by Shanghai Junshi Biosciences Co., LTD, Shanghai, China. This work was supported by grants from National Natural Science Foundation of China (81672696; 81772912), Beijing Municipal Administration of Hospitals Clinical medicine Development of special funding support (ZYLX201603), and Beijing Municipal Science & Technology Commission (Z161100000516062). Declaration of Interests: Kai Wang is employed by OrigiMed. Xiongwen Tang, Huaning Zhou, Hai Wu, Hui Feng and Sheng Yao are employed by Shanghai Junshi Bioscience. The rest of authors have no disclosures of potential conflicts of interests. Ethics Approval Statement: The study was approved by Peking University Cancer Hospital institutional review board and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. Each subject provided written informed consent.