Safety and Activity of Sorafenib in Addition to Vinflunine in Post-Platinum Metastatic Urothelial Carcinoma (Vinsor): Phase I Trial.

LESSONS LEARNED: First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients.A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia.An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed.
BACKGROUND: Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC.
METHODS: In addition to standard dose of vinflunine (320 or 280 mg/m2), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design.
RESULTS: Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m2 and 17 received 280 mg/m2. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m2 was 600 mg, and with vinflunine 320 mg/m2 it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8-41.7).
CONCLUSION: The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m2 plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m2. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials. © AlphaMed Press; the data published online to support this summary are the property of the authors.

Discussion

For mUC patients with rapidly progressive platinum‐resistant disease, development of effective treatment options remains a challenge and an unmet medical need. The combination of vinflunine in standard dose plus dose‐escalated sorafenib was evaluated for safety and toxicity in this phase I trial in second‐line treatment of mUC. All subjects had disease progression or relapse ≤6 months following previous platinum‐based chemotherapy, reflecting a cohort of patients with platinum‐resistant disease.

The observed high rate of toxicity for patients treated with vinflunine of 320 mg/m2 is in line with previously reported phase I vinflunine combination studies, including doublets with pazopanib and pemetrexed [1], [2]. It appears as if full‐dose vinflunine doublets for patients with platinum‐progressive disease require combination with compounds with low bone marrow toxicity. Hence, the combination with sorafenib in this trial proved only to be safe and tolerable with a vinflunine starting dose of 280 mg/m2 [3], [4], [5], [6]. The most frequent AE grades 3 + 4 in this study included neutropenia, hypertension, and hyponatremia. These side effects are potentially caused by both vinflunine and sorafenib, but more frequently reported in the former except for hypertension [7], [8].

The addition of sorafenib to vinflunine did not significantly improve median OS as compared with the vinflunine registration trial (7.0 vs. 6.9 months). For patients administered vinflunine 280 mg/m2 (e.g., Eastern Cooperative Oncology Group performance status [ECOG PS] 1, creatinine clearance 40–60 mL/minute) in this study, the prognosis was most likely even worse than for the average second‐line patient treated within the vinflunine registration trial. Considering this fact, the observed ORR of 41% and disease control rate (DCR) of 71% in this study is notable, especially compared with the ORR and DCR of 8.6% and 55.1% in the vinflunine registration trial [3]. The higher response rates are plausibly attributable to the addition of sorafenib, possibly resulting in an additive effect of this specific drug combination. Further, the results of the present study are in line with the RANGE study, reporting an advantage of combining docetaxel with another vascular endothelial growth factor receptor 2 active compound, ramucirumab, thus adding evidence that selected platinum‐refractory mUC patients may benefit from concomitant standard chemotherapy plus antiangiogenic targeted therapy [9].

Within the context of this phase I trial, an RPTD for the treatment combination of vinflunine and sorafenib was identified for mUC patients with platinum‐resistant and progressive disease. The observed side effects were expected but with a higher incidence of grade 3 + 4 hyponatremia than previously reported for vinflunine and sorafenib each administered as monotherapy. Clinically meaningful disease stabilization and objective responses were observed but with large differences in OS (Figs. 1 and 3). Future trials should aim to evaluate this treatment combination in a randomized setting, define biomarkers for treatment benefit, and explore the effects in patients with both platinum‐ and immunotherapy‐resistant disease.

Figure 1.

Tumor response by RECIST version 1.1. Percentage change in sum of the diameters of tumor lesions from baseline.

Abbreviations: CT, computed tomography; PD, progressive disease; PR, partial response; SD, stable disease.

Figure 3.

Kaplan‐Meier plot of overall survival outcome. Overall survival in days from date of study assignment until recorded death among the efficacy‐evaluable patients (n = 17).

Waterfall plot of individual patient's tumor response by RECIST version 1.1. Best percentage change in the sum of size (diameters) of tumor lesions from baseline until the end of study treatment. One patient (number 17) developed brain metastases (new nontarget tumor lesions) during cycle 2. No formal treatment evaluation of this patient's target lesions was performed.

Trial Information

Bladder cancer

Metastatic/advanced

One prior regimen

Phase I

3 + 3

Maximum tolerated dose

Recommended phase II dose

Efficacy; response and survival outcomes

Active and should be pursued further

Drug Information

Vinflunine

Javlor

Pierre Fabre

Small molecule

Tubulin/Microtubules targeting agent

280 and 320 mg/m

IV

Day 1, Q3W

Sorafenib

Nexavar

Bayer Healthcare AG

Small molecule

Raf ‐ BRAF

400, 600, or 800 per day (200 + 200, 200 + 400, or 400 + 400) mg per flat dose

p.o.

Morning and evening (b.i.d.) on days 2–21, Q3W

Dose Escalation Table

Patient Characteristics

13

9

Metastatic urothelial cancer (all patients)

Median (range): 62.5 years, range 44–71 years

Median (range): 1, range 1–1

0 — 9

1 — 13

2 — 0

3 — 0

Unknown — 0

Primary Assessment Method

Efficacy assessment

69

22

19

17

RECIST 1.1

n = 0 (0%)

n = 7 (41%)

n = 5 (29%)

n = 5 (29%)

n = 0 (0%)

4.5 months

4.2 months

7.0 months

2.3 months

Kaplan‐Meier Time Units

Adverse Events

Serious Adverse Events

Dose‐Limiting Toxicities

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

Although the recently approved immunotherapies can induce impressive and durable responses, the majority of patients with metastatic urothelial cancer (mUC) do not have major responses. In the randomized second‐line phase III trial of pembrolizumab, the overall response rate (ORR) was limited to 21.1%, and the response rates reported for atezolizumab, durvalumab, avelumab, and nivolumab are in the same range [10], [11], [12], [13], [14]. For these postimmunotherapy patients, as well as for patients with rapidly progressive platinum‐resistant disease, further development of effective treatment options remains a challenge and an unmet medical need.

The combination of vinflunine in standard dose with dose‐escalated sorafenib was evaluated for safety and toxicity in this phase I trial for patients with mUC. All included patients in this study had disease progression or relapse within 6 months following previous platinum‐based chemotherapy, reflecting a cohort of typically platinum‐resistant patients with aggressive disease.

The observed high rate of toxicity for patients treated with a start dose of vinflunine of 320 mg/m2 is in line with previously reported phase I vinflunine combination studies, including doublets with pazopanib and pemetrexed [1], [2]. It appears as if full‐dose vinflunine doublets for patients with progressive disease after cisplatin requires combination compounds with low bone marrow toxicity. Hence, the combination with sorafenib proved only to be safe and tolerable with a vinflunine start dose of 280 mg/m2. Side effects of grade 1 and 2 were mainly gastrointestinal (constipation and diarrhea), fatigue, nausea/vomiting, and skin rash. Constipation and pain have more commonly been reported with vinflunine, whereas diarrhea is frequently seen with tyrosine kinase inhibitor therapies and fatigue with either [3], [4], [5], [6]. The top three reported adverse events (AEs) of grade ≥3 in this study included neutropenia (31.6%), hyponatremia (26.3%), and febrile neutropenia (26.3%). These side effects are potentially caused by both vinflunine and sorafenib, but are more frequent in the former except for hypertension [7], [8]. No definite treatment‐related death was recorded, but one patient had fatal pulmonary embolism (unlikely relation to study treatment). Overall, the AEs are in line with previous studies combining vinflunine and other cytotoxic agents [1], [2], [15].

The addition of sorafenib to vinflunine did not improve median overall survival (OS) as compared with the registration trial by Bellmunt et al. evaluating monotherapy with vinflunine with best supportive care (BSC) versus BSC alone (7.0 vs. 6.9 months). For the cohort of patients receiving the vinflunine start dose of 280 mg/m2 (e.g., Eastern Cooperative Oncology Group performance status 1, creatinine clearance 40–60 mL/minute), and in which the recommended phase II dose (RPTD) was defined, the prognosis is, however, most likely even worse than for the average second‐line patient treated within the vinflunine registration trial [3]. In this view, the observed ORR of 41% and DCR of 71% in this study of platinum‐refractory mUC is notable, especially compared with the ORR and DCR of 8.6% and 55.1% in the vinflunine phase III trial, and 16%–18% and 57%–67%, respectively, in previous phase II trials [3], [16], [17]. It can be speculated that the reduction of metastatic tumor burden and stabilization of disease could translate into clinical meaningful palliation and increased quality of life for some mUC patients with otherwise aggressive disease and few treatment options. Interestingly, both rash and hypertension, two side effects correlated with treatment benefit in renal cell carcinoma, were common in patients with partial response or disease stabilization. The favorable overall response rates in this study are plausibly attributable to the addition of sorafenib to vinflunine, possibly resulting in an additive effect of this specific drug combination. Further, the results of the present study are in line with the recently reported outcome of the RANGE study, reporting an advantage of combining docetaxel with another vascular endothelial growth factor receptor 2 active compound, ramucirumab, thus adding evidence that patients with platinum‐refractory mUC may benefit from combined treatment with standard chemotherapy and antiangiogenic targeted therapy [9]. Nevertheless, the overall positive response rate of this trial could still be at random considering the limited size and phase I design. In comparison, a phase II randomized study of gemcitabine and cisplatin plus sorafenib or placebo in first‐line mUC resulted in an ORR of 52.5% and DCR of 75% versus 50% and 79%, showing no additional response effect of sorafenib [18]. If this trial could be repeated, eligible patients would include those with relapse within 12 months of platinum‐containing systemic treatment, thus increasing inclusion rate. Future trials should aim to evaluate this treatment combination in a randomized setting, define biomarkers for treatment benefit, and explore the effects in patients with both platinum‐ and immunotherapy‐resistant disease.

Within the context of this phase I trial, a RPTD for the treatment combination of vinflunine and sorafenib was identified for mUC patients with platinum‐resistant and progressive disease. The observed side effects were as expected and reversible but with a higher incidence of grade 3 and 4 hyponatremia than previously reported for vinflunine and sorafenib administered as monotherapy. Clinically meaningful disease stabilization and objective responses were observed in a number of patients with poor prognosis along with interindividual variation in OS.

Number of cases that reported adverse events and grade of adversity as defined by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Three patients did not complete the initial two treatment cycles and were not diagnosed with a dose‐limiting toxicity, hence the variation in n.

Abbreviation: NC/NA, no change from baseline/no adverse event.

Attribution (if not identical relation to sorafenib and vinflunine): febrile neutropenia (DLT) G4 ‐ definite vinflunine (sorafenib: unlikely), pain G2 ‐ probable vinflunine (sorafenib: not related), constipation G2 ‐ probable vinflunine (sorafenib: unlikely) × 2, febrile neutropenia (DLT) G3 ‐ definite vinflunine (sorafenib: probable) × 2, neutropenia (DLT) G4 ‐ definite vinflunine (sorafenib: unlikely), hypertension (DLT) G3 ‐ definite sorafenib (vinflunine: not related).

Abbreviation: DLT, dose‐limiting toxicity.

Table 1.

Baseline characteristics, including previous treatment and prognostic factors

Two patients received both adjuvant and palliative cisplatin and gemcitabine.

Abbreviations: ECOG PS, Eastern Cooperative Oncology Group performance status.