Author:

Nicholas Pavlidis

Abstract

Vinorelbine (also named Navelbine) is an anti-tumor semi-synthetic vinca-alkaloid compound discovered in France and mainly used in breast cancer and non-small cell lung cancer. The original vinca-alkaloids were derived from the dried leaves of the Madagascan periwinkle (vinca rosea). Vinorelbine is known to the oncology department of the Pierre Potier (pharmacist) be a promoter of apoptosis in cancer cells. It is administered either by the intravenous or the oral route. It is mainly active in non-small cell lung cancer and in breast cancer and also in combination with other cytostatics in i.e lymphomas, soft-tissue sarcomas and urological cancers. In view of his mild toxicity it has been widely used to treat older patients as single agent or in combination.

Regarding the molecular mechanisms of action, vinorelbine is known to be a promoter of apoptosis in cancer cells.

Introduction

The Madagascan periwinkle Catharanthus roseus L is the source for a number of important natural products including catharanthine and vindoline and the vinca alkaloids (leurosine and the chemotherapy agents vinblastine and vincristine) all obtained from the plant. Vinorelbine was invented by the pharmacist Pierre Potier and his team from the CNRS in France in the 1980s and was licensed to the oncology department of the Pierre Fabre Group. The drug was approved in France in 1989 under the brand name Navelbine for the treatment of NSCLC. It gained approval to treat metastatic breast cancer in 1991. It also received approval by the United Stated Food and Drug Administration Group (FDA) in December 1994 sponsored by Burroughs Wellcome Company. Pierre Fabre Group now markets Navelbine in the US, where the drug went generic in February 2003. The chemical structure of Vinorelbine is demonstrated in Figure 1.

Fig 1. Chemical structure of vinorelbine. Weigt:1378 (base:778+2 tartric acid :300)

The antitumor activity refers to the inhibition of mitosis through tubulin interaction. The mechanisms of action include induction of tumor suppressor gene p53 as well as the induction of a number of several protein kinases such as the Bc12 or BAX (Wang 1999, Binet 1989). It differs from the natural compounds by the presence of an 8 rather than 9 - member catharanine ring. Vinorelbine is provided by the oral or intravenous route. It can also be given as single drug or in combination with other chemotherapeutic, endocrine or targeted treatment (Marty M 2001).

Clinical Efficacy in NSCLC

1991 - 1998. In a review article with 12 Phase II studies, intravenous vinorelbine as single agent treatment administered in NSCLC patients achieved an overall response rate of 24% and a median survival around nine weeks. In the same article, a collection of six studies treated with the combination of vinorelbine and cisplatin demonstrated a response rate of 37% and a median survival of 37 weeks (Gregory R et al 2000).

1994. In a randomized phase III trial lead by Cesare Gridelli at the Istituto Nazionale Tumori of Neaples older patients with advanced NSCLC were randomyzed to receive either vinorelbine or best supportive care. The overall response rate in patients who received vinorelbine was 32% versus 14% for the non-treated arm (p=0.003). Vinorelbine-treated patients scored better than control patients on Quality of Life functioning scales, and they reported fewer lung cancer-related symptoms Main toxicity include constipation, nausea, hair loss and neuropathy, but overall, toxicity associated with vinorelbine was mild. This drug was then shown to be a well-tolerated anticancer drug agent for elderly patients (The Journal of the National Cancer Institute 91(1): 61-72, The Elderly Lung Cancer Vinorelbine Italian Study Group, 1994).

1994. In a three-arm randomized Phase III study designed by the Elderly Lung Cancer Vinorelbine Italian Study consisting of vinorelbine plus cisplatin (NVB-P), vindesine plus cisplatin VDS-P (VDS-P) and vinorelbine alone (NVB), showed a response rate of 30%, 19% and 14%, respectively. Also, NVB-P yields a longer survival duration (40 weeks).(T. Le Chevalier, 1994).

2020. Metronomic vinorelbine has also been investigated in advanced NSCLC with an overall response rate of 18% and stable disease of 54%. Adverse events leading to treatment discontinuation were only reported in 5% of patients (Estevinho F 2020).

2019, 2021. In a similar study with 270 patients, overall response rate was 17.8% and 44% experienced stable disease, while median overall survival was nine months. In another study metronomic oral vinorelbine prolonged median PFS in unfit for platinum-based chemotherapy patients. (Camerini A et al, 2019 and Camerini A et al 2021).

2019. An individual patient-data meta-analysis of metronomic oral vinorelbine out of nine studies and 418 patients, overall median survival was 8.7 months. The most common toxicity was grade 3-4 anemia (Pujol, JL et al 2019).

Clinical Efficacy in Advanced Breast Cancer

Vinorelbine as single administration either intravenously or in metronomic form or in combination with other anticancer drugs seemed to be active and well-tolerated in advanced breast cancer patients.

1989-1996. Up to the year 2000, eight Phase II studies have been published investigating the activity of vinorelbine as single agent in metastatic breast cancer. Overall response rate was 48% and median overall survival 16 months (Gregory et al 2000). Also, Fumoleau et al demonstrated a response rate of 40% to 60% in a study published in 1993. (Fumoleau 1993).

1993-1998. The efficacy of vinorelbine has also been studied in combination with other chemotherapy drugs, such as capecitabine, doxorubicin, epirubicin, mitoxantrone, pemetrexed, cisplatin, gemcitabine or paclitaxel (Torres A 2019, Cazzaniga ME 2019). Between 1993 to 1998 eight publications using navelbine in combination with anthracyclines, (doxorubicin or epirubicin) showed an overall response rate of 67.5% (ranging from 54% to 77%) and an overall survival of 17 months.

2012. A total of 31 studies in a review paper including more than 1.000 patients were analyzed. Oral vinorelbine either as a single-agent or in combination has shown efficacy with response rates between 27% and 85% in first line. A number of studies utilizing metronomic chemotherapy with vinorelbine or in combination with other drugs i.e cyclophosphamide or capecitabine experienced more or less similar results. In addition, taxanes in combination with vinorelbine in metastatic breast cancer remains an active regimen (Aapro 2012). Encouraging results has also been achieved by using navelbine in combination with various targeted treatment such as Pertuzumab, Afatinib, Lapatinib, Trastuzumab) (Hickish T 2022, Harbeck N 2016, Montmurro F et al), or with endocrine therapy such as Fulvestran or Aromatase Inhibitors (Bailleux 2023).

Clinical Efficacy in other Malignant Tumors

Vinorelbine has also a relative anticancer activity in some recurrent malignant tumors. Antitumor responses have mainly been observed in soft-tissue sarcomas i.e rhabdomyosarcoma both in pediatric or in elderly populations (Ferrari A 2020, Dileo P 2007). Positive results have also been elicited in combination with other cytostatic drugs such as ifosphamide, actinomycin-D, gemcitabine, cyclophosphamide, etc. In addition, some other relapsed tumors such as non-Hodgkin’s and Hodgkin disease or urological cancers i.e metastatic urothelial or renal cancer have demonstrated some response to vinorelbine. (Panda T 2024)

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