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TiNivo: safety and efficacy of tivozanib-nivolumab combination therapy in patients with metastatic renal cell carcinoma

Open AccessPublished:September 29, 2020DOI:https://doi.org/10.1016/j.annonc.2020.09.021

      Background

      Treatment with tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (RCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile. We report final results from TiNivo, a phase Ib/II study of tivozanib combined with nivolumab.

      Patients and methods

      In phase Ib, patients with metastatic RCC received tivozanib 1.0 mg once daily (QD) for 21 days followed by 7 days off treatment (n = 3) or tivozanib 1.5 mg QD (n = 3) plus nivolumab 240 mg every 2 weeks. The maximum tolerated dose was determined to be tivozanib 1.5 mg, and 22 additional patients were enrolled at the maximum tolerated dose for phase II. Primary end points included safety and tolerability, with secondary end points of objective response rate, disease control rate, and progression-free survival.

      Results

      In total, 25 patients were treated with tivozanib 1.5 mg QD [12 (48%) treatment-naïve; 13 (52%) previously treated]. Treatment-related grade 3/4 AEs were reported in 20 patients (80%); 4 patients (17%) experienced AEs that led to dose reduction, and 8 (32%) discontinued due to AEs. The objective response rate was 56% (including one complete response) and disease control rate was 96%, with a median time to best response of 7.9 weeks. Twenty patients (80%) had tumor shrinkage. With a median follow-up of 19.0 months (range, 12.6–22.8), median progression-free survival was 18.9 months (95% confidence interval 16.4–not reached) in all patients and was similar in treatment-naïve and previously treated patients.

      Conclusions

      Tivozanib plus nivolumab combination therapy showed a generally tolerable AE profile and promising antitumor efficacy. These results support further development of tivozanib combined with nivolumab as a treatment option in patients with treatment-naïve or previously treated metastatic RCC.

      Clinical Trial number

      Key words

      Introduction

      Treatment of renal cell carcinoma (RCC) has been revolutionized over the past decade with anti-angiogenic small-molecule tyrosine kinase inhibitors (TKIs) targeting the vascular endothelial growth factor receptor (VEGFR), as well as with immunotherapy with checkpoint inhibitors.
      • de Velasco G.
      • Bex A.
      • Albiges L.
      • et al.
      Sequencing and combination of systemic therapy in metastatic renal cell carcinoma.
      These agents have become the standard of care for patients with advanced or metastatic RCC. However, durable responses are rare,
      • Choueiri T.K.
      • Escudier B.
      • Powles T.
      • et al.
      Cabozantinib versus everolimus in advanced renal-cell carcinoma.
      • Motzer R.J.
      • Hutson T.E.
      • Glen H.
      • et al.
      Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.
      • Rini B.I.
      • Escudier B.
      • Tomczak P.
      • et al.
      Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial.
      • Rini B.I.
      • Halabi S.
      • Rosenberg J.E.
      • et al.
      Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206.
      and the development of new and tolerable treatment options remains an area of investigation.
      Tivozanib and nivolumab are ideal candidates for combination therapy in RCC because of their individual efficacy and evidence suggesting a synergy between VEGFR and programmed death-1 (PD-1) inhibition.
      • Khan K.A.
      • Kerbel R.S.
      Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa.
      Tivozanib is a highly potent and selective VEGFR TKI approved by the European Medicines Agency for first-line treatment of patients with RCC.
      • Motzer R.J.
      • Nosov D.
      • Eisen T.
      • et al.
      Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial.
      It was designed to selectively optimize VEGFR-1, -2, and -3 blockade at picomolar concentrations. Unlike other multi-targeted kinase inhibitors that are approved for the treatment of patients with RCC, tivozanib's selectivity for VEGFR-1, -2, and -3 was designed to maximize pathway inhibition while minimizing off-target toxicities, resulting in a decreased need for dose interruptions and reductions.
      • Eskens F.A.
      • de Jonge M.J.
      • Bhargava P.
      • et al.
      Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors.
      ,
      • Haberkorn B.C.
      • Eskens F.A.
      Structure, development, preclinical and clinical efficacy of tivozanib (KRN-951, AV-951).
      Tivozanib's selectivity has led to a favorable adverse event (AE) profile in the majority of patients in clinical trials.
      • Motzer R.J.
      • Nosov D.
      • Eisen T.
      • et al.
      Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: results from a phase III trial.
      Additionally, in the relapsed or refractory setting, tivozanib has been shown to improve progression-free survival (PFS) in patients with RCC.
      • Rini B.I.
      • Pal S.K.
      • Escudier B.J.
      • et al.
      Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study.
      Nivolumab, an anti-PD-1 monoclonal antibody that blocks the interaction between PD-1 and its ligands (PD-L1 and PD-L2), has been associated with improved overall survival (OS) in patients with metastatic RCC treated past first-line therapy and is approved for patients with previously treated RCC.
      Generally, the antitumor activity of VEGFR TKIs (such as tivozanib) has been attributed to inhibition of angiogenesis.
      • Ohm J.E.
      • Gabrilovich D.I.
      • Sempowski G.D.
      • et al.
      VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression.
      However, VEGF inhibition has also been shown to modulate antitumor immunity through manipulation of the tumor microenvironment.
      • Khan K.A.
      • Kerbel R.S.
      Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa.
      ,
      • Binnewies M.
      • Roberts E.W.
      • Kersten K.
      • et al.
      Understanding the tumor immune microenvironment (TIME) for effective therapy.
      It is well understood that targeting the tumor microenvironment by inhibiting angiogenesis and stimulating an effective immune response are two key strategies that lead to the most favorable clinical response.
      • Binnewies M.
      • Roberts E.W.
      • Kersten K.
      • et al.
      Understanding the tumor immune microenvironment (TIME) for effective therapy.
      Increased VEGF in the tumor can suppress innate and adaptive immune responses, and tivozanib has been shown to significantly reduce regulatory T cell production.
      • Ohm J.E.
      • Gabrilovich D.I.
      • Sempowski G.D.
      • et al.
      VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression.
      ,
      • Voron T.
      • Colussi O.
      • Marcheteau E.
      • et al.
      VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.
      VEGF can also effectively induce proliferation of suppressive immune cells, including regulatory T cells and myeloid-derived suppressor cells.
      • Ohm J.E.
      • Carbone D.P.
      VEGF as a mediator of tumor-associated immunodeficiency.
      ,
      • Voron T.
      • Tartour E.
      • Taieb J.
      • Terme M.
      Tivozanib and nivolumab combined can therefore act synergistically on the tumor, and preclinical evidence of immunotherapy combined with antiangiogenic treatment supports this theory.
      Several clinical trials exploring this combinatorial strategy in patients with RCC have largely focused on the treatment-naïve population; clinical studies in previously treated patients are currently limited. Herein, we present the final results from the phase Ib/II TiNivo study, which explored tivozanib in combination with nivolumab as first-line and beyond treatment in patients with metastatic RCC.

      Methods

       Study design and participants

      TiNivo (tivozanib + nivolumab) was an open-label, multicenter study of tivozanib in combination with nivolumab in patients with metastatic RCC (NCT03136627). Eligible patients were aged 18 years or older, had histologically confirmed advanced RCC with a clear cell component, measurable or evaluable disease by RECIST v.1.1, Eastern Cooperative Oncology Group performance status 0 or 1, and a life expectancy of ≥3 months (see protocol in Supplementary Material, available at https://doi.org/10.1016/j.annonc.2020.09.021). This study was designed and conducted in compliance with the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines of the International Council for Harmonisation. The study protocol was approved by the institutional review board or independent ethics committee at each study site. Written informed consent was obtained from each patient before the initiation of study procedures.

       Procedures

      In phase Ib, on day 1 of cycle 1, patients initially received tivozanib 1.0 mg once daily (QD) for 21 days of treatment followed by 7 days off treatment (one cycle = 28 days). Nivolumab 240 mg was administered as an infusion every 2 weeks (Q2W) starting on day 1 of cycle 1, and again on day 15. The maximum tolerated dose (MTD) was defined as the maximum dose level at which no more than two of six patients experienced a dose-limiting toxicity (DLT) during the first cycle (4 weeks) in the dose escalation cohorts. Due to the lack of DLTs, MTD was determined to be tivozanib 1.5 mg QD plus nivolumab 240 mg Q2W. Additional patients with measurable disease were enrolled in an expansion cohort at the MTD.

       End points

      The primary end points were safety, tolerability, DLTs, MTD, and preliminary antitumor activity of tivozanib in combination with nivolumab in patients with metastatic RCC. Following completion of the dose escalation cohorts and MTD determination, the expansion cohort was enrolled to further evaluate safety, tolerability, and antitumor activity. All baseline assessments were carried out within 28 days before the start of cycle 1 and completed before the first dose of either study drug on day 1.
      AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.03. DLTs are defined in Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2020.09.021. Dose reductions were allowed for grade ≥3 events except for hypertension, which had to be treated with antihypertensive medication before dose reduction. If dose reduction was required, tivozanib was reduced to 1 mg/day. Discontinuation of tivozanib or nivolumab dosing occurred only after dose reductions and appropriate medical care of AEs were unsuccessful. If a non-DLT associated with treatment was managed by dose interruption, the period between any two scheduled doses was extended up to a maximum of 2 weeks beyond the next scheduled dose to allow for resolution of the toxicity. Treatment following dose interruption was allowed after the AE was fully resolved or ameliorated to one grade greater than baseline status. A safety monitoring committee reviewed safety data monthly.
      Response assessments were determined by the investigator using RECIST v.1.1 criteria. Computerized tomography and/or magnetic resonance imaging were used to evaluate disease status and were carried out every two cycles (8 weeks). Objective response rate [ORR; defined as complete response (CR) + partial response (PR)], PFS, and disease control rate [defined as CR + PR + stable disease (SD) for more than 8 weeks] were evaluated in all patients. The duration of an objective response was measured from the date of the initial response to the date of disease progression. Tumor measurements must have been confirmed by repeat evaluations more than 4 weeks after a PR or CR. Follow-up assessments must have met the SD criteria at least once after study entry at a minimum interval of 4 weeks. In order to qualify as being SD, the minimum duration of response was 8 weeks. Response assessments included extended follow-up in the event of an ongoing objective response or disease stabilization at the end of treatment (every 3 months during the first year, starting from the date of the last scan carried out before treatment discontinuation, and every 6 months thereafter, until disease progression or start of another anticancer therapy).

       Statistical analysis

      A traditional escalation rule (also known as the 3 + 3 rule) was used for this study, in which patients were treated in groups of three with each receiving the same dose. If none of the three patients experienced a DLT within cycle 1, the next group of three patients received the higher dose. Data were summarized using descriptive statistics for continuous variables (number of patients, mean, median, standard deviation, minimum, and maximum) and using frequency and percentages for discrete variables. No inferential statistics tests were carried out. A 95% confidence interval (CI) for objective tumor response rate (CR + PR) and clinical benefit rate (CR + PR + SD) was calculated. All patients who received at least one dose of tivozanib were considered assessable for safety. Efficacy analyses were based on the efficacy-evaluable population, which was defined as all patients who met entry criteria and received at least two cycles of tivozanib.

      Results

       Patients

      Six patients were enrolled in phase Ib. No patient experienced a DLT in cycle 1, and the MTD was determined to be tivozanib 1.5 mg plus nivolumab 240 mg Q2W. In the phase II expansion cohort, 22 additional patients were enrolled, providing a total of 25 patients who received the MTD (3 patients from phase Ib and 22 from phase II; Supplementary Figure S1, available at https://doi.org/10.1016/j.annonc.2020.09.021). Baseline patient characteristics of all 25 patients are described in Table 1. Median age was 64 years (range, 37–75), and the majority of patients (68%) were categorized as International Metastatic Renal Cell Carcinoma Database Consortium intermediate risk (Table 1). Thirteen patients (52%) had previous treatment [11 (44%) received one prior treatment and 2 (8%) received two or more prior treatments] while 12 (48%) were treatment-naïve. In total, 17 (68%) patients discontinued treatment, most commonly due to disease progression per RECIST v.1.1 (41% for tivozanib and 47% for nivolumab; Supplementary Figure S1, available at https://doi.org/10.1016/j.annonc.2020.09.021).
      Table 1Baseline patient characteristics
      Patients (N = 25)
      Age, years, median (range)64 (37–75)
      Sex, n (%)
       Male19 (76)
       Female6 (24)
      Prior therapy, n (%)
       012 (48)
       111 (44)
       2+2 (8)
      ECOG PS, n (%)
       015 (60)
       110 (40)
      IMDC, n (%)
       Favorable7 (28)
       Intermediate17 (68)
       Poor1 (4)
      ECOG PS, Eastern Cooperative Oncology Group performance status; IMDC, International Metastatic Renal Cell Carcinoma Database Consortium.

       Safety

      With a mean duration of treatment of 14.5 months, 20 patients (80%) experienced one or more treatment-related grade 3/4 AE (Table 2), the most common of which was hypertension [reported in 13 patients (52%)]. Apart from hypertension, the rate of treatment-related grade 3/4 AEs was 64%. Serious AEs were reported in eight patients (32%). Three unexpected serious adverse reactions suspected to be related to treatment were reported: hypertensive encephalopathy (related to tivozanib), systemic inflammatory response syndrome (related to nivolumab), and myocardial infarction (related to both tivozanib and nivolumab). Four patients (17%) experienced a dose reduction of tivozanib due to AEs, and 25 (100%) patients had at least one delay in the administration of nivolumab. In total, eight patients (32%) experienced treatment-related AEs that led to discontinuation (tivozanib, one patient; nivolumab, two patients; tivozanib and nivolumab, five patients).
      Table 2Treatment-related AEs of any grade (AEs in ≥30% of patients) and grade 3/4 (all AEs)
      All grades (AEs in ≥30% of patients) and grade ≥3 (all AEs).
      EventAny grade n (%)Grade 3/4 n (%)
      Patients (N = 25)
      Total25 (100)20 (80)
       Hypertension17 (68)13 (52)
       Asthenia15 (60)0
       Diarrhea11 (44)0
       Dysphonia11 (44)0
       Pruritus11 (44)0
       Arthralgia11 (44)0
       Stomatitis10 (40)0
       Anorexia10 (40)0
       Palmar-plantar erythrodysesthesia syndrome9 (36)2 (8)
       Dry skin8 (32)0
       Myalgia8 (32)0
       Fatigue4 (16)2 (8)
       Rash4 (16)1 (4)
       Increased ALT4 (16)1 (4)
       Increased AST4 (16)1 (4)
       Increased amylase2 (8)2 (8)
       Pain in extremity2 (8)1 (4)
       Malignant hypertension2 (8)2 (8)
       SIRS1 (4)1 (4)
       Increased blood alkaline phosphatase1 (4)1 (4)
       Increased gamma-glutamyl transferase1 (4)1 (4)
       Increased lipase1 (4)1 (4)
       Prolonged electrocardiogram QT1 (4)1 (4)
       Cerebrovascular accident1 (4)1 (4)
       Acute coronary syndrome1 (4)1 (4)
      AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; SIRS, systemic inflammatory response syndrome.
      a All grades (AEs in ≥30% of patients) and grade ≥3 (all AEs).

       Efficacy

      In patients who received the tivozanib 1.5 mg dose, investigator-assessed ORR was 56% (95% CI: 36.5–75.5; 1 CR; 13 PR) and disease control rate was 96% (Table 3), with only one patient presenting progressive disease as their best response. Median time to best response was 7.9 weeks. ORR was found to be comparable between treatment-naïve (50%) and previously treated patients (62%). In total, investigators assessed tumor shrinkage in 20 patients (80%; Figure 1). At the time of the data cut-off, eight patients (32%) remained on treatment, with SD or PR longer than 6 months from study initiation (Supplementary Figure S2, available at https://doi.org/10.1016/j.annonc.2020.09.021). With a median follow-up of 19.0 months (range, 12.6–22.8), median PFS was 18.9 months [95% CI: 16.4–not reached (NR); Figure 2A]. For treatment-naïve patients, median PFS was 18.9 months (95% CI: 4.7–NR), and for previously treated patients, median PFS had not been reached (95% CI: 11.0–NR; Figure 2B).
      Table 3Investigator-assessed response
      All patients (N = 25)Treatment-naïve (n = 12)Previously treated (n = 13)
      Best overall response, n (%)
       CR1 (4)1 (8)0
       PR
      One partial response was unconfirmed.
      13 (52)5 (42)8 (62)
       SD10 (40)5 (42)5 (38)
       PD1 (4)1 (8)0
      ORR (CR + PR)14 (56)6 (50)8 (62)
      One partial response was unconfirmed.
      Disease control rate (CR + PR + SD)24 (96)11 (92)13 (100)
      CR, complete response; ORR, overall response rate; PD, progressive disease; PR, partial response; SD, stable disease.
      a One partial response was unconfirmed.
      Figure thumbnail gr1
      Figure 1Change in tumor size by prior treatment.a
      Dotted horizontal line denotes the 30% RECIST criteria threshold for complete response.
      a One patient had progressive disease as their best response due to appearance of new lesions in their first scan and is not included in the reduction presented; therefore, this graph is representative of 24 patients, not 25.
      Figure thumbnail gr2
      Figure 2Progression-free survival in all patients (A) and by prior therapy (B).

      Discussion

      In this phase Ib/II study, patients with advanced RCC who received tivozanib 1.5 mg QD plus nivolumab 240 mg Q2W demonstrated a generally tolerable safety profile with minimal off-target effects when used as first-line and beyond treatment in patients with advanced RCC. The combination regimen also showed promising antitumor efficacy, with prolonged disease control lasting ≥60 weeks (including one patient with a CR) and a median PFS of 18.9 months. ORR and PFS were also comparable between treatment-naïve and previously treated patients.
      Anti-angiogenic therapy combined with immunotherapy in the first-line setting has shown not only superior activity, but more importantly superior efficacy in patients with advanced RCC compared with standard of care and single-agent therapies.
      • Albiges L.
      • Powles T.
      • Staehler M.
      • et al.
      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.
      In the phase III KEYNOTE-426 trial, treatment-naïve patients with advanced clear cell RCC treated with pembrolizumab (anti-PD-1) plus axitinib or sunitinib monotherapy had a 1-year OS rate of 89.9% versus 78.3%, respectively (hazard ratio: 0.53; 95% CI 0.38–0.74; P < 0.0001).
      • Rini B.I.
      • Plimack E.R.
      • Stus V.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      Interim results from the phase III JAVELIN trial showed that, in comparison with sunitinib, avelumab (anti-PD-L1) plus axitinib led to a longer median PFS (13.8 versus 8.4 months; hazard ratio: 0.69; P < 0.001) and a higher ORR (51.4% versus 25.7%).
      • Motzer R.J.
      • Penkov K.
      • Haanen J.
      • et al.
      Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      The efficacy benefits with respect to PFS and ORR in TiNivo are comparable and therefore support the additive effects of tivozanib and nivolumab observed in these trials. Conversely to the design of those phase III combination trials, the present trial included a high percentage of previously treated patients (52%), and the results in this subgroup are profound, with a high response rate and sustained activity (median PFS was not reached in these patients).
      The frequency and severity of AEs observed in TiNivo were, as expected, based on what is known of the safety profiles of both drugs and were generally tolerable and comparable with other VEGFR TKI-PD-(L)1 combinations. However, the rates of dose reductions and interruptions in TiNivo were lower or in line with the rates reported for the other TKI + PD-1 combinations in phase I/II trials and the phase III trials mentioned earlier, suggesting favorable tolerability with the TiNivo regimen.
      • Rini B.I.
      • Plimack E.R.
      • Stus V.
      • et al.
      Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      ,
      • Motzer R.J.
      • Penkov K.
      • Haanen J.
      • et al.
      Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma.
      Hypertension was among the more common grade ≥3 treatment-related AEs reported, consistent with the known on-target effects of treatment with this class of drugs. Notably, hypertension has also been previously suggested to be a biomarker of activity for tivozanib.
      • Eskens F.A.
      • de Jonge M.J.
      • Bhargava P.
      • et al.
      Biologic and clinical activity of tivozanib (AV-951, KRN-951), a selective inhibitor of VEGF receptor-1, -2, and -3 tyrosine kinases, in a 4-week-on, 2-week-off schedule in patients with advanced solid tumors.
      The incidences of grade ≥3 off-target effects of fatigue, diarrhea, and elevated hepatic enzymes were also low, as predicted by single-agent experience with tivozanib.
      A limitation of our trial was the short duration of follow-up; longer follow-up may be necessary to achieve CR or near CR. Longer follow-up is also required to determine whether this combinatorial strategy will improve OS. A phase III clinical trial is also warranted, potentially in the refractory RCC setting, and evaluation of combination therapies following initial immunotherapy.
      In conclusion, the results of the TiNivo trial demonstrate that treatment with tivozanib and nivolumab resulted in notable drug tolerability, with minimal off-target effects, and durable ORR among patients with treatment-naïve or previously treated advanced RCC. Plans are underway for a randomized trial, and company-sponsored studies in the second-line setting are being explored.

      Acknowledgements

      AVEO Oncology sponsored this study. Bristol Myers Squibb provided nivolumab. Editorial assistance was provided by Ashfield Healthcare Communications and was funded by AVEO Oncology and EUSA Pharma.

      Funding

      This work was supported by AVEO Oncology .

      Disclosure

      LA has served as a consultant to Pfizer, Novartis, Bristol Myers Squibb (BMS), Ipsen, Roche, MSD, Astra Zeneca, Merck, Amgen, Astellas, Exelixis, Corvus Pharmaceuticals, and Peloton Therapeutics. PB has served as an advisor to BMS, Eusa Pharma, MSD, Pfizer, Ipsen, and Jansen. MG-G has received honoraria from BMS, MSD, Roche, Ipsen, and Pfizer. SN has received research funding and honoraria from Pfizer and honoraria from BMS, Ipsen, Novartis, Eusa Pharma, and MSD. MN is an employee of AVEO Oncology. BE has served as an advisor to and received honoraria from Novartis, Pfizer, BMS, Ipsen, and Eusa Pharma, and has received honoraria from Genentech.

      Supplementary data

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