Combination Of Axitinib Research Articles

New Anti-Angiogenic Therapy for Glioblastoma With the Anti-Depressant Sertraline.

Anti-angiogenic therapies prolong patient survival in some malignancies but not glioblastoma. We focused on the relationship between the differentiation of glioma stem like cells (GSCs) into tumor derived endothelial cells (TDECs) and, anti-angiogenic therapy resistance. Especially we aimed to elucidate the mechanisms of drug resistance of TDECs to anti-angiogenic inhibitors and identify novel anti-angiogenic drugs with clinical applications. The mouse GSCs, 005, were differentiated into TDECs under hypoxic conditions, and TDECs had endothelial cell characteristics independent of the vascular endothelial growth factor (VEGF) pathway. Invivo, inhibition of the VEGF pathway had no anti-tumor effect and increased the percentage of TDECs in the 005 mouse model. Novel anti-angiogenic drugs for glioblastoma were evaluated using a tube formation assay and a drug repositioning strategy with existing blood-brain barrier permeable drugs. Drug screening revealed that the antidepressant sertraline inhibited tube formation of TDECs. Sertraline was administered to differentiated TDECs invitro and 005 mouse models invivo to evaluate genetic changes by RNA-Seq and tumor regression effects by immunohistochemistry and MRI. Sertraline reduced Lama4 and Ang2 expressions of TDEC, which play an important role in non-VEGF-mediated angiogenesis in tumors. The combination of a VEGF receptor inhibitor axitinib, and sertraline improved survival and reduced tumor growth in the 005 mouse model. Collectively, our findings showed the diversity of tumor vascular endothelial cells across VEGF and non-VEGF pathways led to anti-angiogenic resistance. The combination of axitinib and sertraline can represent an effective anti-angiogenic therapy for glioblastoma with safe, low cost, and fast availability.

Efficacy and Safety of Pembrolizumab plus Axitinib combination for Metastatic Renal Cell Carcinoma in a Real-World Scenario: Data From the Prospective ProPAXI Study

BackgroundPembrolizumab/Axitinib combination is approved as first-line therapy in mRCC. The aim of this study is to evaluate outcomes of PAXI combo in the real-world in Italy. MethodsThis is a prospective study including patients diagnosed with mRCC who received combination as first-line therapy in recruiting Italian Centers. Data about patient characteristics, safety and outcome were collected. Results170 pts have been treated from December 2020 to September 2023. The majority had clear-cell histology (83%). Sarcomatoid feature was present in 33%of available cases. About one half of patients (55%) had synchronous metastasis. In 58% of cases nephrectomy was performed, of which 27% were cytoreductive and 4% were deferred nephrectomies. Lung metastases were identified in 106 patients (62%), bone and liver involvement in 66 and 29 patients (38.8% and 17.1%) respectively. Stratifying by IMDC criteria, 32 patients (18.8%) were at favorable-risk, 106 (62.4%) at intermediate-risk, and 32 (18.8%) at poor-risk. At time of analysis, treatment was ongoing in 49% of patients. Progression occurred in 45% of patients. Median PFS was 19.2 months (95% CI: 15-NR). With a median follow-up of 19.3 months (range 1.3-34.5), at 24-months and 36-months landmark analysis 62% (95% CI, 53-70) and 58% (95% CI, 47-69) of treated patients are still alive respectively. Disease control rate was achieved in 84.6% of patients: 4.3% reached a complete response, 52% had a partial response and 28.8% a stable disease. Primary progression was observed in 15.3% of patients. In the multivariate analysis, the prognostic significance of age ≥ 65 years, non-clear cell histology, IMDC score, and adverse events and gender interaction as predictors of worse OS were confirmed. ConclusionThis is the first available prospective study on first-line Pembrolizumab/Axitinib combination in real world scenario. Our findings support the effectiveness and safety of first-line this combination in mRCC and reveal that gender emerged as a prognostic factor in relation to the occurrence of adverse events.

Efficacy of axitinib in a US cohort of patients with programmed cell death protein 1-resistant mucosal melanoma.

Mucosal melanoma is a rare melanoma subtype, accounting for about 1% of all diagnosed melanomas. It is characterized by an aggressive phenotype with a poor prognosis and a low response rate to approved treatments. We retrospectively analyzed the clinical features, treatments, and outcomes of patients diagnosed with mucosal melanoma treated with axitinib ± anti-programmed cell death protein 1 (PD-1) therapy at a single US referral center between 2018 and 2021. Radiologic response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), v1.1. Twenty-three patients were included in this study. In all, 78% were females with a median age of 62 years. The originating site of mucosal melanoma was the sinonasal (35%), genitourinary (35%), and gastrointestinal (30%) tracts. Sixty-five percent of patients had M1c or M1d disease and 0% had BRAF V600 mutations detected. The majority (96%) had prior treatment inclusive of anti-PD-1, with a median of 2 prior lines, and 78% of patients received a combination of axitinib and PD-1 and the median duration of treatment was 3.2 months. The overall response rate was 13% and the disease control rate was 26%. The median progression-free survival was 3.2 months, and the median overall survival was 8.2 months. Overall, the regimen was well tolerated with 39% of patients requiring dose reduction and 9% requiring treatment cessation. Axitinib with anti-PD-1 therapy has modest clinical activity in heavily pretreated patients with mucosal melanoma outside of Asia, including some with long-term benefits. This data supports the worldwide clinical trials evaluating this combination and the role of incorporating vascular endothelial growth factor-based therapy in the therapeutic paradigm for patients with mucosal melanoma.

Axitinib in combination with anti–PD-1 ab (pucotenlimab) plus intra-hepatic injection of oncolytic virus (OH2), in patients with mucosal melanoma and liver metastasis: An open-label phase I trial.

e21524 Background: The combination of anti-PD-1 plus axitinib as systemic therapy had promising antitumor activity in mucosal melanoma, but with limit effect in mucosal melanoma with liver metastasis, which might due to immunosuppression in liver metastasis. Oncolytic virus can heighten the immune response and turn over the immunosuppressive state, which has shown its efficacy in liver metastaic as Intra-hepatic injection. So we initiated this phase I study to evaluate axitinib combination with anti–PD-1 ab plus oncolytic virus in liver metastasis mucosal melanoma. Methods: Eligible pts included those over 18 years old, mucosal melanoma with injectable liver metastasis confirmed by biopsy with or without extra-hepatic metastasis. Pts received intravenous pucotenlimab Q3W combined plus axitinib 5 mg orally twice a day, combined with ultrasound guided intratumoral injection of OH2 Q2W (107CCID50/mL, 8ml per injection). Liver biopsy would be performed at first tumor evaluation (8-12weeks). The primary endpoint was ORR; secondary endpoints included toxicity, disease control rate (DCR), PFS and OS. Results: From Dec 2021 to Jan 2024, 20 pts were eligible and enrolled. Baseline characteristics: median age 56 yrs; 70% got previous treatment, (35% PD-1 resistant). 90% got extra-hepatic metastasis: regional or distant lymph node 45%, lung 40%,; LDH>ULN 50%; median size of target lesions: 61.5mm(12-155mm); median number of liver metastasis: 3(1-18) with median liver lesions 42.5mm(13-230mm). Till the last flow up, 15 pts were evaluable with a median follow-up of 9.39 months. The global ORR was 26.7% (4/15) with 42.9% lesionshrink, injection lesions decrease (43.8%) and non-injection lesion 23.1%. The DCR was 46.7% (7/15). There are still 8 pts on treatment at last follow up. The median PFS was 4.5m, and no pts who had response showed progression till last follow up, the mean DOR was 11.0m. Median OS is not reached. Biopsies of 13 pts for injected lesions at 8 to 12 weeks after first injection were examined to determine the situation of tumor regression and TIL infiltration. Among them, 3 pts (2 PD and 1 PR) had no melanoma cells residual by immunohistochemistry with impressive TIL infiltration. The biopsy showed better pathological response than radiological response which might explain some pts still got survival benefit on treatment after radiological PD. Most adverse events (AE) were grade 1-2 and manageable. Grade 3-4 treatment-related AE showed 30% pts, with diarrhea and oral ulceration as the most common. No treatment-related deaths occurred. Conclusions: Systemic anti-PD-1 plus axitinib combined intralesional injection of Oncolytic virus has shown preliminary efficacy in mucosal melanoma pts with liver metastases with manageable toxicity. Clinical trial information: NCT04206358 , NCT05070221 .

Neoadjuvant toripalimab combined with axitinib in patients with locally advanced clear cell renal cell carcinoma: a single-arm, phase II trial

BackgroundA combination of axitinib and immune checkpoint inhibitors (ICIs) demonstrated promising efficacy in the treatment of advanced renal cell carcinoma (RCC). This study aims to prospectively evaluate the safety, efficacy,...

Retrospective experience of children with relapsed brain tumors treated with oral combination of axitinib and metronomic etoposide.

Metronomic chemotherapy-based combinations have received interest for relapsed/refractory malignancies. Preclinical and clinical studies showed activity of metronomic etoposide and axitinib. We report our retrospective experience in six children treated with axitinib and metronomic etoposide for refractory/relapsed brain tumors as an "off-label" combination. Three patients with medulloblastoma experienced partial response; one patient with atypical teratoid rhabdoid tumor (ATRT) displays an ongoing stable disease (12months); two patients with medulloblastoma had progressive disease. Grade 3-4 toxicities were observed in two patients (thrombocytopenia, anemia, diarrhea, fatigue). The axitinib-etoposide combination shows signals of efficacy in heavily pretreated patients with relapsed/refractory brain tumors. These results were based on real-world observation and will need formal evaluation in a phase I/II trial.

Avelumab Plus Intermittent Axitinib in Previously Untreated Patients with Metastatic Renal Cell Carcinoma. The Tide-A Phase 2 Study

Background and ObjectiveCombinations of VEGFR-TKIs plus ICI against PD1/PD-L1 are the standard first-line therapy for patients with mRCC, irrespective of the prognostic class. This study aims to investigate the feasibility and safety of withdrawing the VEGFR-TKI but continuing the anti- PD1/PD-L1 in patients who achieve response to their combination. MethodsThis was a single-arm phase 2 trial in patients with treatment naïve mRCC with prior nephrectomy, without symptomatic/bulky disease and no liver metastases. Enrolled patients received axitinib+avelumab, after 36 weeks of therapy those who achieved tumor response interrupted axitinib and continued avelumab maintenance until disease progression. The primary endpoint was the rate of patients without progression eight weeks after the axitinib interruption. Secondary endpoints were the median value for progression free (mPFS) and overall survival (mOS) and the safety in the overall population. Key Findings and Limitations79 patients were enrolled and 75 evaluated for efficacy. A total of 29 (38%) patients had axitinib withdrawn, as per the study design, with 72% of them having no progression after eight weeks and thus achieving the primary endpoint. The mPFS of the overall population was 24 months while the mOS was not reached. The ORR was 76% (12% CR, 64% PR), with 19% of patients having stable disease. In the patients who discontinued axitinib, the incidence of AEs of any grade was 59% and 3% for grade 3 or 4. This study was limited by the lack of the comparative arm. Conclusions and Clinical ImplicationsThe TIDE-A study demonstrates that the withdrawal of VEGFR-TKI with ICI maintenance is feasible for selected mRCC patients with evidence of response to the VEGFR-TKI+ICI combination employed in first-line therapy. Axitinib interruption with avelumab maintenance led to decreased side effects and should be further investigated as a new strategy to delay tumor progression.

Combination BRAFV600E Inhibition with the Multitargeting Tyrosine Kinase Inhibitor Axitinib Shows Additive Anticancer Activity in BRAFV600E-Mutant Anaplastic Thyroid Cancer.

Background: Anaplastic thyroid cancer (ATC) is uniformly lethal. BRAFV600E mutation is present in 45% of patients with ATC. Targeted therapy with combined BRAF and MEK inhibition in BRAFV600E-mutant ATC can be effective, but acquired resistance is common because this combination targets the same pathway. Drug matrix screening, in BRAFV600E ATC cells, of highly active compounds in combination with BRAF inhibition showed multitargeting tyrosine kinase inhibitors (MTKIs) had the highest synergistic/additive activity. Thus, we hypothesized that the combination of BRAFV600E inhibition and an MTKI is more effective than a single drug or combined BRAF and MEK inhibition in BRAFV600E-mutant ATC. We evaluated the effect of BRAFV600E inhibitors in combination with the MTKI axitinib and its mechanism(s) of action. Methods: We evaluated the effects of BRAFV600E inhibitors and axitinib alone and in combination in in vitro and in vivo models of BRAFV600E-mutant and wild-type ATC. Results: The combination of axitinib and BRAFV600E inhibitors (dabrafenib and PLX4720) showed an additive effect on inhibiting cell proliferation based on the Chou-Talalay algorithm in BRAFV600E-mutant ATC cell lines. This combination also significantly inhibited cell invasion and migration (p < 0.001) compared with the control. Dabrafenib and PLX4720 arrested ATC cells in the G0/G1 phase. Axitinib arrested ATC cells in the G2/M phase by decreasing phosphorylation of aurora kinase B (Thr232) and histone H3 (Ser10) proteins and by upregulating the c-JUN signaling pathway. The combination of BRAF inhibition and axitinib significantly inhibited tumor growth and was associated with improved survival in an orthotopic ATC model. Conclusions: The novel combination of axitinib and BRAFV600E inhibition enhanced anticancer activity in in vitro and in vivo models of BRAFV600E-mutant ATC. This combination may have clinical utility in BRAFV600E-mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition.

Relapsing cytokine release syndrome in a patient with metastatic renal cell carcinoma treated with pembrolizumab and axitinib therapy.

As immune checkpoint inhibitors become more widely available, the optimal management of immune-related adverse events (irAEs) is becoming increasingly important. Although irAEs are diverse, reports on cytokine release syndrome are rare. Here, we report a case of a 48-year-old man with relapsing cytokine release syndrome after receiving pembrolizumab and axitinib combination therapy for metastatic renal cell carcinoma. During dose reduction of prednisolone for immune-related hepatitis on day 33 after starting pembrolizumab plus axitinib, the patient suddenly developed abdominal pain, and a few hours later became hypotensive and poorly oxygenated. Despite the use of a ventilator and high doses of catecholamines, blood pressure and oxygenation could not be maintained. Extracorporeal membrane oxygenation and intra-aortic balloon pumping were also administered. The cytokine release syndrome (CRS) was treated with tocilizumab, and his general condition improved. Lower-grade CRS relapsed four times despite a moderate dose of oral prednisolone with mycophenolate mofetil or tacrolimus. After gradual reduction in prednisolone over 5months, the patient was discharged from the hospital. Partial remission of renal cell carcinoma continued for 21months, and salvage radical nephrectomy was performed. The patient remained disease-free without the need for further treatment 9months after surgery.

Updated analysis of real-world treatment outcomes of first-line axitinib plus pembrolizumab in patients with advanced renal cell carcinoma in the United States.

e16553 Background: The combination of axitinib plus pembrolizumab (AXI+PEM) is a standard of care in the first-line (1L) treatment of patients with advanced clear cell renal cell carcinoma (ccRCC). Previous analyses described the demographic and clinical characteristics, as well as outcomes of patients receiving 1L AXI+PEM in a real-world setting. We report updated data with longer follow-up for this cohort. Methods: Electronic medical record data from the Flatiron Health, nationwide de-identified Database (280 cancer clinics across 800 sites in the US) were used to select patients with confirmed Stage IV/metastatic RCC and who initiated 1L AXI+PEM on or after 1/1/2018 to 7/31/2022. Analyses included best overall response to 1L therapy; real-world progression-free survival (rwPFS) and overall survival (rwOS) are reported as patients without a clinical event (rwPFS; progression/death; rwOS; death) at landmark time periods (3, 6, 9, 12, 18 and 24 months); denominators include censored patients. Other data are reported as medians (min, max) unless otherwise noted. Results: Three hundred and forty patients received 1L AXI+PEM, with an extended mean follow-up of 19.2 (0.1–41.6) months. Most patients were male (69.1%) and mean age of 64.1 (21.0–83.0) years. At diagnosis, 56.5% of patients had Stage IV RCC and 78.2% of patients had clear cell histology. IMDC Risk Score was favorable, intermediate, and poor in 24 (6.8%), 123 (34.4%), and 78 (22.1%) patients, respectively (unknown = 125 (36.8%)). At the time of analysis, 192 patients (56.5%) received only 1L therapy with AXI+PEM, while 148 patients (43.5%) received ≥1 subsequent line of treatment. Vascular endothelial growth factor receptor (VEGF-R) inhibitors were the most commonly used second-line (2L) treatment (109 patients, 73.6%), with cabozantinib being the most frequently used VEGF-R inhibitor (84 patients, 77.1%). Median rwPFS was 8.6 (CI: 7.2-9.7) months with 15.0% of patients achieving rwPFS at 2 years. Median rwOS was 29.4 (CI: 24.2-37.3) months with 38.5% of patients alive at 2 years. Best overall response rate to 1L was 54.1% (complete or partial response observed in 184/340 patients). 51.5% of patients required a dose hold, of which 58.3% required it due to an adverse event. Conclusions: This updated analysis supports the use of 1L AXI+PEM in patients with advanced RCC across all IMDC risk groups, providing further understanding of the clinical outcomes and treatment patterns of patients with advanced RCC in the US. [Table: see text]

Efficacy of avelumab in the treatment of oncourological malignances. Results of registration studies and own experience

Background. In the JAVELIN Bladder 100 trial, 1st line maintenance with avelumab in combination with best supportive care significantly increased (9.2 months) overall survival compared to best supportive care in patients with locally advanced or metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy: 29.7 months versus 20.5 months, respectively. Trial results led to inclusion of avelumab into the international guidelines as a standard of care with the highest level of evidence. Combined therapy with avelumab + axitinib in patients with previously untreated metastatic renal cell carcinoma showed higher progression-free survival and objective response rate compared to sunitinib in all IMDC (International Metastatic Renal Cancer Database Consortium) groups. Avelumab + axitinib is one of the immuno-oncology combinations with proven effectiveness for progression-free survival and objective response rate.Aim. To evaluate the effectiveness of avelumab in treatment of oncological urological diseases in routine clinical practice. Materials and methods. At the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology - branch of the National Medical Research Radiology Center, 12 patients with locally advanced inoperable and metastatic urothelial cancer without progression after 1st line platinum-based chemotherapy in combination with gemcitabine received maintenance avelumab therapy. Median follow-up was 10 months. Primary endpoints were overall survival from the start of avelumab maintenance therapy and safety.Combined therapy with avelumab + axitinib was administered in 18 patients with metastatic renal cell carcinoma. Median follow-up was 9 (3-16) months. Overall survival, progression-free survival, response rate and safety in the overall population and according to IMDC groups were evaluated.Results. At data cut-off (March 2023) with median follow-up of 10 months, overall survival was 100 %, progression-free survival was 66.7 % (among patients who received more than 3 infusions - 100 %). Progression-free survival was higher in patients with tumors of the lower urinary tract compared to upper (72.5 % versus 60 %), complete response to induction platinum-based chemotherapy compared to partial response and stable disease (100 % versus 66.7 %) and presence of metastases in the lymph nodes only compared to visceral and bone metastases (100 % versus 66.7 %). Adverse events were observed in 4 (66.7 %) patients.Among 18 patients who received avelumab + axitinib, complete response was observed in 2 (11.1 %) patients, partial response in 6 (33.3 %) patients, stable disease in 9 (50 %) patients, disease progression in 1 (5.6 %) patient. Response to therapy was observed in patients of all prognosis groups; for large (&gt;5 cm) metastases in the lungs, soft tissues, lymph nodes and bones response was observed 3 months after treatment start. Overall survival for this follow-up duration was 100 %, progression-free survival was 96.4 ± 11.2 %. Adverse events were observed in 8 (44.4 %) patients, and in 6 (75 %) of them they were grade I—II and did not require infusion regimen correction or axitinib dose reduction.Conclusion. Avelumab maintenance therapy in the 1st line is the standard of care for patients with locally advanced and metastatic urothelial cancer without disease progression during 1st line platinum-based chemotherapy. Maintenance therapy allows to achieve better overall survival and progression-free survival irrespective of the choice of platinum regimen (cisplatin or carboplatin), response to platinum-based chemotherapy, number of chemotherapy cycles, tumor localization and advancement.Experience of the N.A. Lopatkin Scientific Research Institute of Urology and Interventional Radiology confirms results of the JAVELIN Bladder 100 trial on the effectiveness of avelumab maintenance therapy in routine clinical practice. Combination drug therapy with avelumab and axitinib in patients with metastatic renal cell carcinoma is an effective and safe treatment method which allows to achieve fast objective response and has good tolerability in patients irrespective of IMDC group or metastasis location. Effectiveness and favorable safety profile of avelumab + axitinib combination were proven in the context of routine clinical practice.

COMPLETE REMISSION OF METASTATIC RENAL CELL CARCINOMA AFTER PARTIAL NEPHRECTOMY FOLLOWING PEMBROLIZUMAB PLUS AXITINIB THERAPY: A CASE REPORT

This case is a 62-year-old man diagnosed with metastatic renal cell carcinoma. He was referred to our department due to the left renal mass pointed with ultra sound examination. Radiographical examination showed left-side 42 mm renal tumor with multiple lung tumors, suggesting renal cell carcinoma, cT1bN0M1 (pul). As an induction therapy, we selected Pembrolizumab plus Axitinib combination therapy. After 4 course of the therapy, the left kidney tumor shrank to 27 mm, and the lung metastasis disappeared with computed tomography imaging. For the next step, we performed laparoscopic partial nephrectomy. The pathological diagnosis was clear cell carcinoma, grade 2 with central necrosis. Since then, complete remission has been maintained without any treatment for 21 months.

Losartan Alleviates the Side Effects and Maintains the Anticancer Activity of Axitinib.

Axitinib is one of the most potent inhibitors of the vascular endothelial growth factor (VEGF) receptor and shows strong antitumor activity toward various malignant tumors. However, its severe side effects affect the quality of life and prognosis of patients. Losartan, which functions as a typical angiotensin receptor blocker, controls the average arterial pressure of patients with essential hypertension and protects against hypertension-related secondary diseases, including proteinuria and cardiovascular injury. To explore the effects of losartan on side effects caused by axitinib and its antitumor activity, several animal experiments were conducted. This study first analyzed and explored the effect of losartan on the amelioration of side effects in Wistar rats caused by axitinib. The results showed that the systolic blood pressure of Wistar rats was significantly increased by about 30 mmHg in 7 days of axitinib treatment, while the combination of losartan significantly reduced the blood pressure rise caused by axitinib. The Miles experimental model and mouse xenograft tumor model were further used to evaluate the effect of losartan on the antitumor effect of axitinib. The result clearly demonstrated that losartan has no significant influence on axitinib-related low vascular permeability and antitumor activity. In summary, our results showed that the combination of axitinib and losartan significantly reduced the side effects and maintained the antitumor effects of axitinib. This study provides information for overcoming VEGF receptor inhibitor-related side effects.

Real-world treatment outcomes of first-line axitinib plus pembrolizumab in patients with advanced renal cell carcinoma in the United States.

314 Background: The combination of axitinib plus pembrolizumab (AXI+PEM) is a standard of care in the first-line (1L) treatment of patients with advanced clear cell renal cell carcinoma (RCC). This analysis describes the demographic and clinical characteristics, treatment and outcomes of patients receiving 1L AXI+PEM in a real-world setting. Methods: Medical record data were extracted from the Flatiron Health Database, which includes ̃280 cancer clinics across 800 sites in the US. Patients had confirmed Stage IV or metastatic RCC and initiated 1L AXI+PEM on or after 1/1/2018 to 3/31/2021. Tumor response is reported as best overall response to 1L therapy; real-world progression-free survival (rwPFS) and overall survival (rwOS) are reported as patients without a clinical event (rwPFS; progression/death; rwOS; death) at landmark time periods (3, 6, 9, and 12 months); denominators include censored patients. Other data are reported as medians (min, max) unless otherwise noted. Results: Three hundred and fifty-five patients received 1L AXI+PEM, with follow-up of 9.7 (0.1–24.3) months. Most patients were male (69.6%), and age was 68.0 (21.0–84.0) years. At diagnosis, 55.5% of patients had Stage IV RCC and 77.2% of patients had clear cell histology. IMDC Risk Score was favorable, intermediate, and poor in 27 (7.6%), 126 (35.5%), and 76 (24.4%) patients, respectively. At the time of analysis, 270 patients (76.1%) received only 1L therapy with AXI+PEM, while 85 patients (24.3%) received ≥1 subsequent line of treatment. VEGF-R inhibitors were the most commonly used second-line (2L) treatment (51 patients, 60.0%), with cabozantinib as the most frequently used VEGF-R inhibitor (40 patients, 47.1%). rwPFS at 3 months and 1 year was achieved by 248 patients (69.9%) and 77 patients (21.7%), respectively. rwOS ranged from 293 patients (82.5%) surviving at 3 months to 142 patients (40.0%) surviving at 1 year. Best overall response rate to 1L was 47.9% (complete or partial response observed in 170/355 patients). Conclusions: This study provides real-world evidence for the use and effectiveness of 1L AXI+PEM in patients with advanced RCC. AXI+PEM was used across all IMDC risk groups. While these initial finding support the use of AXI+PEM, additional follow-up is warranted to provide further understanding of the clinical outcomes and treatment patterns of patients with advanced RCC in the US receiving 1L AXI+PEM.

Toripalimab plus axitinib in patients with metastatic mucosal melanoma: 3-year survival update and biomarker analysis

BackgroundMucosal melanoma is an aggressive melanoma subtype with poor response to antiprogrammed cell death-1 (PD-1) monotherapy. Axitinib in combination with toripalimab, a humanized IgG4 mAb against PD-1, showed a promising...

Toripalimab: the First Domestic Anti-Tumor PD-1 Antibody in China.

Toripalimab (Tuoyi™) is a selective, recombinant, humanized monoclonal antibody against programmed death protein 1 (PD-1) developed by Shanghai Junshi Bioscience Co., Ltd. Toripalimab is able to bind to PD-1 and block the interaction with its ligands. The binding of toripalimab to PD-1 is mainly attributed to the heavy chain of the former and the FG loop of the latter. Toripalimab received a conditional approval in China for the treatment of melanoma (second-line) in December, 2018. It has also received approvals to treat nasopharyngeal carcinoma (first-line and third-line) and urothelial carcinoma (second-line) in 2021. Additionally, several orphan drug designations were granted to toripalimab by the US Food and Drug Administration. Toripalimab has exhibited primary anti-tumor effects in tumors such as melanoma, lung cancer, digestive tract tumors, hepatobiliary and pancreatic tumors, neuroendocrine neoplasms, nasopharyngeal carcinoma and urothelial carcinoma. It showed a satisfactory anti-tumor effect and long-term survival benefits in Chinese melanoma patients, while the combination of axitinib with toripalimab exhibited an impressive result in metastatic mucosal melanoma. As a checkpoint inhibitor, toripalimab was generally well-tolerated in the enrolled patients. Due to different study populations, comparisons could not be made directly between toripalimab and other drugs in most cases. Nevertheless, the introduction of toripalimab may offer a valuable choice for decision-making in the treatment of tumors in the future.

Real-world efficacy and safety of axitinib in combination with anti-programmed cell death-1 antibody for advanced mucosal melanoma

PurposeThe combination of vascular endothelial growth factor receptor (VEGFR) inhibitor and programmed cell death-1 (PD-1) blockade provides promising therapeutic opportunities for advanced mucosal melanoma in early phase trials. The aim of this retrospective study was to evaluate the efficacy and safety of the combination regimen for advanced mucosal melanoma in the real world. MethodsPatients with advanced mucosal melanoma received an anti-PD-1 antibody plus the VEGFR inhibitor axitinib until confirmed disease progression or unacceptable toxicity. In addition, those with liver metastasis were allowed to take hepatic transcatheter arterial chemoembolisation (TACE). The primary endpoint was overall response rate (ORR). Secondary endpoints included disease control rate (DCR), time to treatment failure (TTF), duration of response (DOR), overall survival (OS) and treatment-related adverse events (TRAEs). ResultsEighty-one and sixty-six patients received axitinib plus immunotherapy as first-line and salvage therapy, respectively. Overall, ORR was 24.5% (95% CI, 17.3–31.6), DCR was 72.7% (95% CI, 65.3–80.1). Median TTF, DOR and OS were 5.2 months (95% CI, 3.7–6.6), 9.2 months (95% CI, 7.2–11.2) and 11.1 months (95% CI, 7.2–15.0). ORR was 30.0% (95% CI, 19.7–40.3) and 17.5% (95% CI, 7.8–27.1) as first-line and salvage therapy, respectively. No statistical difference among the primary sites was noted for ORR. The ORR of patients with liver metastasis with or without hepatic TACE was 26.1% (95% CI, 6.7–45.5) and 15.0% (95% CI, 2.1–32.1), respectively (P = 0.467). Elevated LDH and poor ECOG status are negative predictive factors. ConclusionThis is the largest analysis of anti-PD-1 plus VEGFR inhibitor therapy for mucosal melanoma to date. Immunotherapy plus anti-angiogenesis is applicable for advanced mucosal melanoma, especially as front-line. Hepatic TACE might act synergistically with systemic immunotherapy and anti-angiogenesis.

Autoimmune Myasthenia, Primary Adrenal Insufficiency, and Progressive Hypothyroidism Due to Pembrolizumab and Axitinib Combination Regimen

Immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) have been among the increasingly used antineoplastic agents for advanced cancers including renal cell carcinoma (RCC). Although these antineoplastic agents have broad range of efficacy, rare adverse events - mild and fatal, acute and chronic, immune and non-immune mediated - have been reported. We report a case of a 73-year-old Caucasian male patient with stage IV right-sided clear cell RCC who was treated with a pembrolizumab-axitinib combination regimen and suffered life-threatening, acute onset immune-related myasthenia gravis (MG), subsequently progressive hypothyroidism, and primary adrenal insufficiency.

Thymic carcinoma with Lynch syndrome or microsatellite instability, a rare entity responsive to immunotherapy

ImportanceThymic carcinoma (TC) is a rare aggressive tumour occurring in adults characterised by one of the lowest tumor mutational burdens (TMB). Microsatellite instability (MSI) is a mutational signature, caused by defects in the DNA MisMatch Repair (MMR) system, that predicts benefit from immunotherapy and causes high TMB. Fragmentary and unstructured evidence of these conditions co-occurring are reported in literature. ObjectiveReview available data on the co-occurrence of these two conditions and determine its frequency in our institute case series. DesignWe performed a systematic analysis of literature and a retrospective evaluation of all the cases of TET treated at our institution from 2000 to 2020, selecting patients with a medical history of multiple tumours to enhance a priori probability of identifying cases with underlying predisposition. ResultsLiterature yielded 3 cases of patients with MSI TC, for which MMR gene alteration was reported. None of them received immunotherapy. Of 366 patients with TETs treated in our institute, 32 had a medical history of multiple tumours and 25 of 32 (19 thymomas and 6 TCs) had available tissue for MMR analysis. One patient with TC showed a high TMB, and MSI due to MLH1 mutation and was treated in a phase II study with avelumab and axitinib combination obtaining a long-lasting partial response. MLH1 alterations are shared across MSI TC cases. Conclusions and relevanceThis analysis highlights the usefulness of MSI testing in patients with TC. The observation of cases of TC occurring in patients with Lynch syndrome and the unexpected homogeneity of gene alterations support further investigation.

Tolerability of axitinib in advanced renal cell carcinoma: A meta-analysis.

e16536 Background: Axitinib has been used extensively as a single agent or in combination with immunotherapy in the treatment of advanced renal cell carcinoma. It can be often discontinued due to adverse events. A meta-analysis of clinical trials was performed to evaluate the overall tolerability of axitinib in this setting. Methods: PubMed (Up to November 2020) was searched to identify clinical trials of axitinib in advanced or metastatic renal cell carcinoma. Reported data was collected to include axitinib and control discontinuation due to adverse events. A random or fixed effects model was used to determine summary incidences, relative risks, and 95% confidence intervals depending on the heterogeneity of included studies. Results: A total of 11 studies including 4,056 patients (axitinib alone n = 1384, axitinib combination n = 987, control n = 1685) were included for analysis. The summary discontinuation rate for axitinib due to adverse events was 13.4% (95% CI; 11.7-15.2%) with 8.9% (95% CI: 5.3-14.6%) as a single agent and 26.6% (95% CI:17.8 –37.8%) in combination with other agents. In comparison with controls based on randomized controlled studies, axitinib overall has similar discontinuation rate due to adverse events (RR: 1.18, 95% CI: 0.77-1.80). However, there was a significantly higher discontinuation rate with axitinib in combination with other agents including immunotherapeutic agents PD-L1 inhibitors than control treatment (RR: 1.52, 95% CI: 1.24-1.86). Conclusions: The tolerability of axitinib may vary significantly with its use as a single agent or in combination in the treatment of advanced renal cell carcinoma. Further studies are needed to improve its tolerability as a part of combination therapy.