ABSTRACT
OBJECTIVE: The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. METHODS: Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. RESULTS: At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. CONCLUSION: These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.
Subject(s)
Antibodies, Monoclonal, Humanized , Drug Resistance, Neoplasm , Folate Receptor 1 , Immunoconjugates , Maytansine , Ovarian Neoplasms , Humans , Female , Ovarian Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovarian Neoplasms/mortality , Folate Receptor 1/metabolism , Middle Aged , Maytansine/analogs & derivatives , Maytansine/therapeutic use , Maytansine/administration & dosage , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Adult , Immunoconjugates/administration & dosage , Immunoconjugates/adverse effects , Immunoconjugates/therapeutic use , Aged, 80 and overABSTRACT
AIMS: Mirvetuximab soravtansine is a first-in-class antibody-drug conjugate recently approved for the treatment of folate receptor-α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration-time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S-methyl-DM4). METHODS: Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum-resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed-effects modelling approach. Stepwise covariate modelling was performed to identify covariates. RESULTS: We developed a semi-mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S-methyl-DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated. CONCLUSION: There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.
Subject(s)
Antibodies, Monoclonal, Humanized , Immunoconjugates , Maytansine , Ovarian Neoplasms , Humans , Female , Drug Resistance, Neoplasm , Ovarian Neoplasms/drug therapy , Immunoconjugates/adverse effects , Folic Acid/pharmacology , Folic Acid/therapeutic use , Maytansine/analogs & derivativesABSTRACT
PURPOSE: Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS: SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION: MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.
Subject(s)
Antineoplastic Agents , Immunoconjugates , Ovarian Neoplasms , Humans , Female , Carcinoma, Ovarian Epithelial/drug therapy , Bevacizumab/therapeutic use , Ovarian Neoplasms/drug therapy , Folate Receptor 1/therapeutic use , Immunoconjugates/adverse effects , Antineoplastic Agents/therapeutic use , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Adenosine Diphosphate Ribose/therapeutic useABSTRACT
PURPOSE: This first-in-human study assessed safety, immunogenicity, pharmacokinetics, and pharmacodynamics of RN909, a monoclonal antibody antagonist of the glucagon receptor, in type 2 diabetes (T2DM) subjects. METHODS: This study enrolled 84 T2DM subjects receiving stable metformin regimens. Forty-four subjects were randomized to receive single escalating doses of RN909 (0.3 to 6 mg/kg subcutaneously (SC), or 1 mg/kg intravenously (IV)), or placebo; 40 subjects were randomized to receive multiple escalating doses (50 to 150 mg SC) or placebo every 4 weeks for 12 weeks. RESULTS: RN909 was well tolerated; treatment-related elevated liver function tests (LFTs) were observed in 4/33 (12.1%) and 5/32 (15.6%) subjects treated with single and multiple doses, respectively, versus 1/10 (10%) and 0 in the respective placebo groups. RN909 dose-normalized AUCinf increased more than dose-proportionally following single SC doses, and after multiple doses, accumulation ratios ranged from 1.3 to 3.4. The incidence of antidrug antibodies (ADA) was 33% after single doses and 50% after multiple doses. RN909 produced dose-dependent, durable fasting plasma glucose (FPG)-lowering at day 29 (mean change -20.6 to -97.5 mg/dL) and day 85 (mean change; -27.2 to -43.5 mg/dL) after single and multiple doses, respectively. HbA1c also was reduced after single (mean change -0.30% to -1.44%), and multiple doses (-0.83% to -1.56%). CONCLUSION: RN909 was well tolerated after single and multiple doses in T2DM subjects, with diarrhea and elevated LFTs the most frequent adverse events. The appearance of ADA did not affect pharmacokinetics or efficacy. Robust lowering of FPG and HbA1c was observed.
Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/adverse effects , Receptors, Glucagon/antagonists & inhibitors , Receptors, Glucagon/immunology , Adolescent , Adult , Aged , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Blood Glucose/drug effects , Diabetes Mellitus, Type 2/immunology , Dose-Response Relationship, Drug , Double-Blind Method , Female , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Male , Metformin/therapeutic use , Middle Aged , Placebos , Young AdultABSTRACT
BACKGROUND: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. PATIENTS AND METHODS: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. RESULTS: Thirty patients were assigned to tivozanib 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8), fatigue (n = 8), and neutropenia (n = 6). MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. CONCLUSION: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Colorectal Neoplasms/pathology , Dose-Response Relationship, Drug , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Fluorouracil/therapeutic use , Humans , Leucovorin/administration & dosage , Leucovorin/adverse effects , Leucovorin/therapeutic use , Male , Maximum Tolerated Dose , Middle Aged , Organoplatinum Compounds/administration & dosage , Organoplatinum Compounds/adverse effects , Organoplatinum Compounds/therapeutic use , Phenylurea Compounds/administration & dosage , Quinolines/administration & dosage , Treatment OutcomeABSTRACT
PURPOSE: Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), -2, and -3. This phase III trial compared tivozanib with sorafenib as initial targeted therapy in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC, with a clear cell component, prior nephrectomy, measurable disease, and 0 or 1 prior therapies for metastatic RCC were randomly assigned to tivozanib or sorafenib. Prior VEGF-targeted therapy and mammalian target of rapamycin inhibitor were not permitted. The primary end point was progression-free survival (PFS) by independent review. RESULTS: A total of 517 patients were randomly assigned to tivozanib (n = 260) or sorafenib (n = 257). PFS was longer with tivozanib than with sorafenib in the overall population (median, 11.9 v 9.1 months; hazard ratio [HR], 0.797; 95% CI, 0.639 to 0.993; P = .042). One hundred fifty-six patients (61%) who progressed on sorafenib crossed over to receive tivozanib. The final overall survival (OS) analysis showed a trend toward longer survival on the sorafenib arm than on the tivozanib arm (median, 29.3 v 28.8 months; HR, 1.245; 95% CI, 0.954 to 1.624; P = .105). Adverse events (AEs) more common with tivozanib than with sorafenib were hypertension (44% v 34%) and dysphonia (21% v 5%). AEs more common with sorafenib than with tivozanib were hand-foot skin reaction (54% v 14%) and diarrhea (33% v 23%). CONCLUSION: Tivozanib demonstrated improved PFS, but not OS, and a differentiated safety profile, compared with sorafenib, as initial targeted therapy for metastatic RCC.
Subject(s)
Antineoplastic Agents/therapeutic use , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Neoadjuvant Therapy/methods , Niacinamide/analogs & derivatives , Phenylurea Compounds/therapeutic use , Quinolines/therapeutic use , Adult , Aged , Aged, 80 and over , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , Disease-Free Survival , Female , Health Status , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Male , Middle Aged , Molecular Targeted Therapy , Neoplasm Staging , Nephrectomy , Niacinamide/therapeutic use , Odds Ratio , Quality of Life , Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors , Sorafenib , Treatment OutcomeABSTRACT
PURPOSE: The antitumor activity and safety of tivozanib, which is a potent and selective vascular endothelial growth factor receptor-1, -2, and -3 inhibitor, was assessed in patients with advanced/metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: In this phase II, randomized discontinuation trial, 272 patients received open-label tivozanib 1.5 mg/d (one cycle equaled three treatment weeks followed by a 1-week break) orally for 16 weeks. Thereafter, 78 patients who demonstrated ≥ 25% tumor shrinkage continued to take tivozanib, and 118 patients with less than 25% tumor change were randomly assigned to receive tivozanib or a placebo in a double-blind manner; patients with ≥ 25% tumor growth were discontinued. Primary end points included safety, the objective response rate (ORR) at 16 weeks, and the percentage of randomly assigned patients who remained progression free after 12 weeks of double-blind treatment; secondary end points included progression-free survival (PFS). RESULTS: Of 272 patients enrolled onto the study, 83% of patients had clear-cell histology, 73% of patients had undergone nephrectomy, and 54% of patients were treatment naive. The ORR after 16 weeks of tivozanib treatment was 18% (95% CI, 14% to 23%). Of the 118 randomized patients, significantly more patients who were randomly assigned to receive double-blind tivozanib remained progression free after 12 weeks versus patients who received the placebo (49% v 21%; P = .001). Throughout the study, the ORR was 24% (95% CI, 19% to 30%), and the median PFS was 11.7 months (95% CI, 8.3 to 14.3 months) in the overall study population. The most common grade 3 and 4 treatment-related adverse event was hypertension (12%). CONCLUSION: Tivozanib was active and well tolerated in patients with advanced RCC. These data support additional development of tivozanib in advanced RCC.
Subject(s)
Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/mortality , Kidney Neoplasms/drug therapy , Kidney Neoplasms/mortality , Neoplasm Recurrence, Local/mortality , Phenylurea Compounds/administration & dosage , Quinolines/administration & dosage , Administration, Oral , Adult , Aged , Carcinoma, Renal Cell/pathology , Confidence Intervals , Cross-Over Studies , Disease-Free Survival , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Drug-Related Side Effects and Adverse Reactions , Female , Follow-Up Studies , Humans , Kaplan-Meier Estimate , Kidney Neoplasms/pathology , Male , Maximum Tolerated Dose , Middle Aged , Neoplasm Invasiveness/pathology , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/therapy , Neoplasm Staging , Patient Safety , Phenylurea Compounds/adverse effects , Quinolines/adverse effects , Reference Values , Risk Assessment , Survival Analysis , Treatment OutcomeABSTRACT
PURPOSE: To assess the maximum tolerated dose (MTD)/dose-limiting toxicities (DLT), safety, pharmacokinetics, and pharmacodynamics of tivozanib, a potent and selective oral VEGF receptor (VEGFR) tyrosine kinase inhibitor. EXPERIMENTAL DESIGN: Dose levels of 1.0, 1.5, and 2.0 mg/d tivozanib for 28 days followed by 14 days of medication were explored in patients with advanced solid tumors. RESULTS: Forty-one patients were enrolled. Animal data incorrectly predicted toxicity, resulting in DLTs at the starting dose (2.0 mg) consisting of grade 3 proteinuria and hypertension and grade 3 ataxia. At 1.0 mg, no DLT was observed. At an intermediate dose (1.5 mg), 1 patient experienced DLT consisting of grade 3 hypertension. This dose was determined as the MTD. Of 10 additional patients treated at 1.5 mg, 1 patient each experienced grade 3 hypertension and grade 3 fatigue, and 2 patients experienced grade 3 and 4 transaminase elevation. In 12 additional patients treated at 1.0 mg, no DLT was observed. Pharmacokinetics displayed long absorption time, dose proportional exposure, and a half-life of 4.7 days. Plasma levels of VEGF-A and soluble VEGFR-2 showed dose-dependent increases and decreases, respectively. Dynamic contrast-enhanced MRI indicated reduction in tumor perfusion. Clinical activity was observed in renal cell cancer, colorectal cancer, and other tumors. CONCLUSION: Tivozanib was well tolerated with manageable side effects. The pharmacokinetics profile revealed that tivozanib was suitable for once-daily dosing. Encouraging and durable clinical activity was observed. The recommended daily dose of tivozanib in a 4-week-on and 2-week-off dosing regimen is 1.5 mg.