U.S. Food and Drug Administration (FDA)-Approved Indications

Compendial Uses

Cabazitaxel is available as Jevtana (sanofi-aventis U.S. LLC). Cabazitaxel, a microtubule inhibitor, binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions (sanofi-aventis, 2021).

Jevtana carries black box warnings for neutropenia and hypersensitivity. Neutropenic deaths have been reported. Healthcare professionals will need to obtain frequent blood counts to monitor for neutropenia. Jevtana is contraindicated in patients with neutrophil counts of less than or equal to 1,500 cells/mm3. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Healthcare professionals will need to consider primary prophylaxis with G-CSF in all patients receiving a dose of 25 mg/m2. Severe hypersensitivity can occur and may include generalized rash/erythema, hypotension and bronchospasm. Jevtana is to be discontinued immediately if severe reactions occur and administer appropriate therapy. Jevtana is contraindicated if patients has a history of severe hypersensitivity reactions to cabazitaxel or to drugs formulated with polysorbate 80.

The label for Jevtana also carries warnings and precautions for bone marrow suppression (particulary neutropenia), increased toxicities in elderly patients, gastrointestinal disorders, renal failure, urinary disorders (including cystitis), respiratory disorders (interstitial pneumonia/pneumonitis, interstitial lung disease and acute respiratory distress syndrome), hepatic impairment, and embryo-fetal toxicity. The most common all grades adverse reactions and laboratory abnormalities (10% or more) with Jevtana 20 mg/m2 or 25 mg/m2 are neutropenia, anemia, diarrhea, nausea, fatigue, asthenia, vomiting, hematuria, constipation, decreased appetite, back pain, and abdominal pain. It is recommended to avoid coadministration of Jevtana with strong CYP3A inhibitors. If patients require coadministration of a strong CYP3A inhibitor, consider a 25% Jevtana dose reduction (sanofi-aventis, 2021).

Prostate Cancer

Prostate cancer is the second leading cause of cancer-related death among American men, exceeded only by lung cancer. The disease is histologically evident in as many as 34 % of men during their fifth decade of life and in up to 70 % of men aged 80 years old and older. In the United States, more than 3.1 million men have been diagnosed with prostate cancer (ACS, 2021). The median survival for men with metastatic castrate-resistant prostate cancer (MCRPC) is 1 to 2 years, with improvements in survival seen primarily with cytotoxic chemotherapy (docetaxel-based chemotherapy). In the field of MCRPC, systemic therapy options are limited and survival benefit remains to be seen with the new therapies (Lassi and Dawson, 2010).

In a review on immunological strategies for the treatment of prostate cancer, Drake and Antonarakis (2010) stated that along with initial therapy using cryotherapy, radiotherapy, or surgery, hormonal therapy is the mainstay of treatment. For men with metastatic disease, docetaxel-based chemotherapy is Food and Drug Administration (FDA)-approved, and provides a significant survival advantage. This relative paucity of treatment options drives an ongoing quest for additional treatment modalities; among these is immunotherapy. The concept that prostate cancer is a malignancy that can be targeted by the immune system may seem counter-intuitive; certainly kidney cancer and melanoma are more traditionally thought of as immune responsive cancers. However, prostate cancer arises in a relatively unique organ and may express a number of antigens against which an immune response can be generated. Several of these agents have now demonstrated a significant survival benefit in randomized controlled clinical trials. On April 29, 2010, the FDA approved sipuleucel-T (Provenge, Dendreon Corporation, Seattle, WA) for the treatment of asymptomatic or minimally symptomatic prostate cancer that has metastasized and is resistant to standard hormone treatment.

Cabazitaxel, a microtubule inhibitor, is a chemotherapeutic agent for the treatment of advanced prostate cancer. It is an anti-neoplastic agent that belongs to the taxane class. It is a semi‐synthetic taxane prepared with a precursor extracted from yewneedles. Cabazitaxel binds to tubulin and promotes its assembly into microtubules while simultaneously inhibiting disassembly. This leads to the stabilization of microtubules resulting in the inhibition of mitotic and inter-phase cellular functions. Unlike other taxanes, Jevtana (cabazitaxel) is a poor substrate for the multidrug resistance P‐glycoprotein efflux pump and may be useful for treating multidrug‐resistant tumors.

Jevtana (cabazitaxel) is indicated in combination with prednisone for the treatment of patients with hormone‐refractory metastatic prostate cancer previously treated with a docetaxel‐containing treatment regimen. In a review on current and emerging treatment strategies for MCRPC, Di Lorenzo and colleagues (2010) noted that recent results from 2 large phase III clinical trials of sipuleucel-T and cabazitaxel show that these 2 agents significantly prolong overall survival (OS) in patients with MCRPC.

On June 17, 2010, the FDA approved cabazitaxel (Jevtana) for use in combination with prednisone for the treatment of men with prostate cancer. Cabazitaxel is the first treatment for advanced, hormone-refractory, prostate cancer that has worsened during or after treatment with docetaxel. The safety and effectiveness of cabazitaxel was established in a single clinical study (n = 755); all subjects had previously received docetaxel. The study was designed to measure OS (the length of time before death) in men who received cabazitaxel in combination with prednisone compared with those who received the mitoxantrone in combination with prednisone. Patients were randomized to receive either cabazitaxel 25 mg/m2 intravenously every 3 weeks in combination with prednisone 10 mg/day (n = 378), or mitoxantrone 12 mg/m2 intravenously every 3 weeks in combination with prednisone 10 mg/day (n = 377). They were treated until disease progression, death, unacceptable toxicity, or completion of 10 cycles of therapy. This study included patients over 18 years of age with hormone-refractory metastatic prostate cancer either measurable by Response Evaluation Criteria in Solid Tumors (RECIST) criteria or non-measurable disease with rising prostate-specific antigen levels or appearance of new lesions, and Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2. Patients had to have neutrophils greater than 1,500 cells/mm3, platelets greater than 100,000 cells/mm3, hemoglobin greater than 10 g/dL, creatinine less than 1.5 x upper limit of normal (ULN), total bilirubin less than 1 x ULN, aspartate transaminase less than 1.5 x ULN, and alanine transaminase less than 1.5 x ULN. Patients with a history of congestive heart failure, or myocardial infarction within the last 6 months, or patients with uncontrolled cardiac arrhythmias, angina pectoris, and/or hypertension were not included in the study.

The median OS time was 15.1 months (95 % confidence interval [CI]: 14.1 to 16.3 months) for patients who received the cabazitaxel regimen compared with 12.7 months (95 % CI: 11.6 to 13.7 months; hazard ratio, 0.7 (95 % CI: 0.59 to 0.83; p < 0.0001) for those who received the with mitoxantrone regimen. Additionally, investigator-assessed tumor response of 14.4 % (95 % CI: 9.6 to 19.3) was higher for patients in the cabazitaxel regimen group compared to 4.4 % (95 %CI: 1.6 to 7.2) for patients in the mitoxantrone regimen group (p = 0.0005). No complete responses were observed on either arm.

Side effects associated with the use of cabazitaxel included anemia, asthenia, constipation, diarrhea, fatigue, leukopenia, nausea, neutropenia, renal failure, thrombocytopenia, and vomiting. Cabazitaxel is contraindicated in patients with neutrophil counts of less than or equal to 1,500/mm3, and in those who have a history of severe hypersensitivity reactions to cabazitaxel or to other drugs formulated with polysorbate 80.

On September 14, 2017, the FDA approved a lower dose of cabazitaxel (20 mg/m

every 3 weeks) in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen.

The approval was based on data from a noninferiority, multicenter, randomized, open-label trial (PROSELICA) of 1200 patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing regimen. This trial was conducted as a post-marketing requirement to evaluate a lower dose compared with the approved dose of 25 mg/m2. Patients received either cabazitaxel 25 mg/m2 (n=602) or the 20 mg/m2 (n=598) dose.

The trial demonstrated noninferiority in overall survival (OS) of cabazitaxel 20 mg/m2 in comparison with 25 mg/m2 in an intent-to-treat population. The estimated median OS was 13.4 months for patients on the lower dose compared with 14.5 months for patients receiving the higher dose (hazard ratio=1.024; 97.78% CI: 0.886, 1.184). Based on the per-protocol population, the estimated median OS was 15.1 and 15.9 months on cabazitaxel 20 mg/m2 and cabazitaxel 25 mg/m2 respectively (hazard ratio=1.042; 97.78% CI: 0.886, 1.224). The major safety findings, myelosuppression, infections and increased toxicity, occurred with greater frequency on the 25 mg/m2 arm compared to the lower dose. Deaths within 30 days of the last study drug dose (5.4% vs. 3.8%), and early infection-related deaths within 30 days of the treatment initiation (1.3% vs 0.7%) were more common on the 25 mg/m2 arm compared to the 20 mg/m2 arm. All of the early infection-related deaths occurred in patients greater than 60 years of age. Primary prophylaxis with G-CSF is recommended in patients with high-risk clinical features. Adverse reactions and laboratory abnormalities occurring in greater than 10% of patients treated with cabazitaxel on clinical trials were neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, and anorexia. Grade 3-4 infections were reported in 20% patients on the 25 mg/m2 arm and 10% patients on the lower dose. Febrile neutropenia occurred in 9% of patients on the 25 mg/m2 arm and in 2% on the 20 mg/m2 arm. The most common reasons for dose discontinuation were fatigue and hematuria.

Adrenocortical Carcinoma

Lagana et al (2022) stated that adreno-cortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis. No effective therapeutic options are currently available for patients with advanced metastatic disease with disease progression to standard etoposide, doxorubicin, cisplatin and mitotane (EDP-M) therapy. In a single-center, phase-II clinical trial, these researchers examined the activity and tolerability of cabazitaxel as a 2nd/3rd-line approach in metastatic ACC. Patients included in this study had disease progression to a cisplatin-containing regimen (such as EDP) plus mitotane, plus/minus a further chemotherapy line. Cabazitaxel was administered intravenously at 25 mg/m2 on day 1 of a 21-day cycle, for a maximum of 6 cycles. The primary endpoint was a disease control rate after 4 months. From March 2018 to September 2019, a total of 25 eligible patients were enrolled. A disease control rate after 4 months was obtained in 6 patients (24 %). No patients attained a disease response according to RECIST 1.1, 9 patients (36 %) had SD and 16 patients (64 %) progressive disease. Median PFS and OS were 1.5 months (range of 0.3 to 7 months) and 6 months (range of 1 to 22.2 months), respectively. Cabazitaxel therapy was well-tolerated and only 3 (12 %) patients developed grade-3 toxicity which were nausea in 1 patient (4 %) and anemia in 2 patients (8 %). The authors concluded that cabazitaxel had a manageable toxicity profile but is poorly active as 2nd/3rd-line treatment in advanced ACC patients; these results did not support further evaluation of cabazitaxel in this setting.

Bladder (Urothelial) Cancer

In a multi-center, randomized, open-label, phase II/III clinical trial, Bellmunt and colleagues (2017) compared the effectiveness of cabazitaxel versus vinflunine in the treatment of patients with metastatic or locally advanced transitional cell carcinoma of the bladder (urothelial cancer). This study followed a Simon's optimal method with stopping rules based on an interim futility analysis and a formal efficacy analysis at the end of the phase II; ECOG Performance Status, anemia and liver metastases were stratification factors. Primary objectives were ORR for the phase II and OS for the phase III. A total of 70 patients were included in the phase II across 19 institutions in Europe. Baseline characteristics were well balanced between the 2 arms; 3 patients (13 %) obtained a PR on cabazitaxel (95 % CI: 2.7 to 32.4) and 6 patients (30 %) in the vinflunine arm (95 % CI: 11.9 to 54.3). Median PFS for cabazitaxel was 1.9 months versus 2.9 months for vinflunine (p = 0.039). The study did not proceed to phase III since the futility analysis showed a lack of efficacy of cabazitaxel. A trend for OS benefit was found favoring vinflunine (median 7.6 versus 5.5 months). Grade 3 to 4 related AEs were seen in 41 % patients with no difference between the 2o arms. The authors concluded that the findings of this phase II/III 2nd-line bladder study comparing cabazitaxel with vinflunine was closed when the phase II showed a lack of efficacy of the cabazitaxel arm; vinflunine results were consistent with those known previously.

Challapalli and colleagues (2021) stated that neoadjuvant cisplatin-based combination chemotherapy improves survival in muscle-invasive bladder cancer; however, response rates and survival remain suboptimal. In a single-arm, phase-II clinical trial, these researchers examined the safety, , safety, tolerability, and efficacy of cisplatin plus cabazitaxel. This trial was designed to recruit at least 26 evaluable patients. This would give 80 % power to detect the primary endpoint, an ORR defined as a pathologic CR plus PR (pathologic down-staging), measured by pathologic staging at cystectomy (p0 = 0.35 and p1 = 0.60, α = 0.05). Objective response was observed in 15 of 26 evaluable patients (57.7 %) and more than 1/3 of patients achieved a pathologic CR (9/26; 34.6 %); 78 % of the patients (21/27) completed all cycles of treatment, with only 6.7 % of the reported AEs being grade-3 or grade-4. There were 6 treatment-related serious AEs reported, but no suspected unexpected serious AEs. In the patients who achieved an objective response, the median PFS and OS were not reached (median follow-up of 41.5 months). In contrast, the median PFS (7.2 months) and OS (16.9 months) were significantly worse (p = 0.001, log-rank) in patients who did not achieve an objective response. The authors concluded that cabazitaxel plus cisplatin for neoadjuvant treatment of muscle-invasive bladder cancer can be considered a well-tolerated and effective regimen before definitive therapy with higher rates (57.7 %) of objective response, comparing favorably to that with of cisplatin/gemcitabine (23 % to 26%). Moreover, these researchers stated that these findings warrant further evaluation in a larger, randomized, phase-III clinical trial.

Breast Cancer

In a phase I/II clinical trial, Villanueva et al (2011) evaluated the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and activity of cabazitaxel plus capecitabine in patients with metastatic breast cancer (MBC) who had been previously treated with taxanes and anthracyclines. In part I, these investigators used a 3+3 dose-escalation scheme to assess the MTD of intravenous cabazitaxel (day 1) with oral capecitabine twice-daily (days 1 to 14) every 3 weeks. In part II, they assessed the objective response rate (ORR) at the MTD. A total of 33 patients were enrolled and treated (15 in part I; 18 in part II). Cabazitaxel 20 mg/m2 plus capecitabine 1,000 mg/m2 was the MTD. Pharmacokinetic analysis showed no apparent drug-drug interaction. In all patients, the main grade 3 to 4 toxicities were asthenia (n = 5), hand-foot syndrome (n = 5), neutropenia (n = 21), neutropenic infection (n = 1), and neutropenic colitis (n = 1). One patient had febrile neutropenia. Anti-tumor activity was observed at all dose-levels with 2 complete responses, 5 partial responses (PRs), and 20 disease stabilizations (7 unconfirmed PR). At the MTD, 21 patients were evaluable for efficacy. The ORR was 23.8 % (95 % CI: 8.2 to 47.2 %). The median response duration was 3.1 months (95 % CI: 2.1 to 8.4 months), with 4 of 5 lasting for more than 3 months. Median time to progression was 4.9 months. The authors concluded that cabazitaxel combined with capecitabine is active, has a safety profile consistent with a taxane plus capecitabine combination and warrants further investigation in patients with MBC.

In a prospective, multi-center, randomized, open-label, phase II clinical trial, Kummel and colleagues (2017) compared the safety and effectiveness of four 3-weekly cycles cabazitaxel versus 12 weeks of paclitaxel given as neoadjuvant treatment. Primary end-point was the pathological complete response (pCR) rate defined as the complete absence of invasive carcinoma on histological examination of the breast irrespective of lymph node involvement (ypT0/is, ypN0/+) after the taxane treatment. Patients could receive an anthracycline-based therapy thereafter. A total of 333 patients were randomized and started treatment with 74.7 % and 83.2 % of patients completing treatment in the cabazitaxel and paclitaxel arms, respectively. Patients in cabazitaxel arm had a significantly lower pCR rate compared to the paclitaxel arm (1.2 % versus 10.8 %; p = 0.001). A total of 42 (25.3 %) patients in the cabazitaxel arm and 17 (10.2 %) in the paclitaxel arm had at least 1 serious adverse event (SAE; p < 0.001). Dose reductions were observed in 9.6 % patients in the cabazitaxel arm compared to 11.4 % in the paclitaxel arm (p = 0.721). Main reason for dose reductions was non-hematological toxicities in 3.0 % versus 7.8 % (p = 0.087), respectively. The authors concluded that the GENEVIEVE study showed no short-term effect of cabazitaxel in triple-negative or luminal B/HER2-negative primary BC, while there seemed to be no differences in drug exposure and patient compliance between the 2 arms.

Cao and colleagues (2021) noted that limited therapeutic options are available for triple-negative BC (TNBC), emphasizing an urgent need for more effective therapeutic approaches. The development of strategies by targeting tumor-associated macrophages (TAMs) to stimulate their ability of programmed cell removal (PrCR) provides a promising new immunotherapy for the treatment of patients with TNBC. CD47 is a critical self-protective "don't eat me" signal on multiple human cancers against macrophage immunosurveillance. Using human and mouse TNBC pre-clinical models, these researchers examined the efficacy of PrCR-based immunotherapy by blocking CD47. They carried out high-throughput screens on FDA-approved anti-cancer small molecule compounds for agents potentiating PrCR and enhancing the efficacy of CD47-targeted therapy for TNBC treatment. These investigators showed that CD47 was widely expressed on TNBC cells and TAMs represented the most abundant immune cell population in TNBC tumors. Blockade of CD47 enabled PrCR of TNBC cells, but the efficacy was not satisfactory. The high-throughput screens identified cabazitaxel in enhancing PrCR-based immunotherapy. A combination of CD47 blockade and cabazitaxel treatment yielded a highly effective treatment strategy, promoting PrCR of TNBC cells and inhibiting tumor development and metastasis in pre-clinical models. These researchers demonstrated that cabazitaxel potentiated PrCR by activating macrophages, independent of its cytotoxicity toward cancer cells. When treated with cabazitaxel, the molecular and phenotypic signatures of macrophages were polarized toward M1 state, and the NF-kB signaling pathway became activated. The authors concluded that the combination of CD47 blockade and macrophage activation by cabazitaxel synergized to vastly enhance the elimination of TNBC cells. These researchers stated that these findings showed that targeting macrophages is a promising and effective strategy for TNBC treatment. Moreover, these investigators stated that further analysis at the single-cell level may be carried out to characterize TAM subpopulations and identify populations that are sensitive to cabazitaxel, with the most potential for phagocytosis on administration of treatment, which may serve as a predictive parameter for selecting TNBC patients most likely to benefit from the enhanced PrCR therapy.

Dedifferentiated Liposarcoma

Sanfilippo et al (2022) noted that therapeutic options for patients with unresectable and/or metastatic dedifferentiated liposarcoma (DDLPS) are limited; new drugs are needed. These researchers examined if cabazitaxel showed sufficient anti-tumor activity in patients with metastatic or inoperable locally advanced DDLPS to justify further investigation in a phase-III clinical trial setting. This open-label, multi-center, single-arm, phase-II clinical trial was carried out at 10 institutions in 4 European countries from March 2015 to March 2019. Eligible patients had to have metastatic or locally advanced histologically proven DDLPS with evidence of disease progression within the past 6 months and had to have received no more than 1 previous line of chemotherapy. After mandatory central review of tumor blocks, if the DDLPS diagnosis was confirmed, patients started treatment within 72 hours after registration. Cabazitaxel was administered at a dose of 25 mg/m2 IV infusion over 1 hour every 21 days until intolerance, progression, or withdrawal of consent. The primary endpoint was PFSR at 12 weeks per RECIST 1.1. Based on a Simon 2-stage design, at least 4 of 17 (stage 1) and 11 of 37 (stage 2) eligible and evaluable patients who were progression-free at 12 weeks were needed. The final analysis report was completed on November 17, 2021. A total of 40 patients were registered, with 2 patients being ineligible. The number of cycles ranged from 1 to 30, with a median of 5; 26 patients (65 %) received at least 4 cycles of cabazitaxel. PFS at 12 weeks was 55 %, achieving the primary study endpoint. At a median follow-up of 21.6 months, median PFS was 6 months and median OS 21 months. Response rate was 8 % with 1 clinical response and 2 PR. 23 (60.5 %) patients had a SD. Disease control (PR +S D) was achieved in 26 patients (68 %). The authors concluded that this non-randomized phase-II clinical trial met its primary endpoint, with 21 of 38 patients (55 %) being progression-free at 12 weeks. These researchers stated that these findings suggested important activity of cabazitaxel in patients with metastatic or inoperable locally advanced DDLPS; this drug is worth being further examined in these tumors in a phase- III clinical trial setting.

Esophagogastric Junction Cancer

In a single-arm, multi-center, phase-II clinical trial, Schmalenberg and associates (2018) determined the prolonged (greater than or equal to 4 months) disease control rate with cabazitaxel administered in second-(or later) setting for patients with advanced or metastatic adenocarcinoma of the esopha-gogastric junction (EGJ) and stomach. A total of 65 patients with advanced EGJ and stomach cancer were treated with 20 mg/m2 cabazitaxel every 3 weeks for a maximum of 6 cycles. The main objective of the study was a prolonged disease control rate (pDCR: CR, PR or SD lasting at least 4 months). Secondary outcome measures were OS, PFS, RR by subgroup (with versus without previous treatment with a taxane) and toxicity. Patients were assessed for tumor response every 6 weeks during therapy and during the follow-up (up to 12 months). A total of 65 patients (median age of 63, range of 31 to 86 years) were assigned to treatment. Median number of prior therapies that had received prior taxane therapy was 2. Patients received a median of 2 cycles of cabazitaxel. Efficacy results were for the intention-to-treat (ITT) population. The mDCR in n = 65 patients was 10.8 % (95 % CI: 4.4 to 20.9 %). There was a control of disease (CR + PR + SD) in n = 26 patients of n = 65, corresponding to a DCR of 40.0 % (95 % CI: 28.0 to 52.9 %). In patients without prior taxane use, it was 46.2 % (95 % CI: 25.1 to 80.8 %) and in patients with only 1 prior therapy, DCR was 50.0 % (95 % CI: 31.3 to 68.7 %). The median OS was 4.6 months (95 % CI: 3.16 to 5.59) in the whole ITT population. In patients with only 1 prior therapy, median OS was 5.4 months (95 % CI: 2.60 to 7.43) and in patients without taxane pre-treatment, it was 6.4 months (95 % CI: 1.38 to 14.17). The median PFS time was 1.5 months (95 % CI: 1.32 to 2.27) in the whole ITT population, 2.9 months (95 % CI: 0.72 to 4.67) without prior taxane therapy and was 1.7 (95 % CI: 1.28 to 3.35) months in patients with only 1 prior therapy median. The authors concluded that cabazitaxel was active in heavily pretreated patients with metastatic and advanced esophagogastric junction and gastric adenocarcinoma. Efficacy results in a classic second line population were comparable to other second line studies, therefore, under the limitations of this trial, (single-arm, phase-II design) cabazitaxel might be an option especially in patients without prior taxane therapy, in second line and even further line therapy of metastatic and advanced esophagogastric junction and gastric adenocarcinoma.

Gliomas

In a phase-I/II clinical trial, Manley and colleagues (2018) evaluated cabazitaxel in pediatric patients with refractory solid tumors including tumors of the CNS. Phase-I determined the maximum tolerated dose (MTD) in patients with recurrent/refractory solid tumors, including CNS tumors. Phase-II evaluated activity in pediatric recurrent high-grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG). In phase-I, a 3 + 3 dose-escalation study design was followed. Cabazitaxel was administered at a starting dose of 20 mg/m2; dose limiting toxicities (DLTs) during cycle 1 were assessed to determine the MTD. Tumor response and cabazitaxel pharmacokinetics were also assessed. In phase-II, patients received cabazitaxel at the MTD determined in phase-I. Tumor responses were assessed every 9 weeks (modified Response Assessment in Neuro-oncology criteria); PFS and cabazitaxel pharmacokinetics were evaluated, and OS was estimated. In phase-I, a total of 23 patients were treated, including 19 with CNS tumors; 1 patient had a partial response (PR); 5 had stable disease (SD) for greater than 3 cycles. Common AEs included fatigue, diarrhea, nausea and vomiting, febrile neutropenia, and hypersensitivity reactions; 2 of 3 DLTs (febrile neutropenia) occurred with a dose of 35 mg/m2 ; the MTD was 30 mg/m2 . Slightly higher cabazitaxel clearance was observed compared with adult trials. In phase-II, a total of 16 patients (8 HGG and 8 DIPG) were enrolled; 11 were evaluable for response and 5 withdrew (3 due to anaphylaxis). All 11 patients progressed within 4 cycles. No responses were observed; the study was stopped due to futility. The authors concluded that the safety profile of cabazitaxel was consistent with previous studies; the MTD (30 mg/m2) was higher than the adult MTD. Cabazitaxel did not demonstrate activity in recurrent/refractory HGG or DIPG.

Head and Neck Cancers

In a phase II clinical trial, Michaels and co-workers (2016) examined the effects of cabazitaxel in patients with recurrent squamous cell carcinoma of the head and neck (SCCHN). Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of non-hematological AEs greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). Patients were stratified according to their ECOG performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary end-point was the PFS rate (PFSR) at 18 weeks. Of the 101 patients, 53 and 48, with a median age of 58.0 years (range of 41 to 80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2 % (95 % CI: 5 % to 25 %) for cabazitaxel and 8.3 % (95 % CI: 2 % to 20 %) for methotrexate. The median PFS was 1.9 months in both arms. The median OS was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced SAEs with cabazitaxel than with methotrexate (54 % versus 36 %). The most common drug-related grade 3 to 4 AE in the cabazitaxel arm was febrile neutropenia (17.3 %). The authors concluded that the findings of this study did not meet its primary end-point; cabazitaxel had low activity in recurrent SCCHN and the toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17 %).

In a phase I clinical trial, Camille and colleagues (2017) determined the DLT and MTD of cabazitaxel when combined with cisplatin and 5-fluorouracil (PF) in induction chemotherapy (IC) for patients with locally advanced SCCHN (LA-SCCHN). Cabazitaxel-PF IC administered in 3 cycles (each 21 days) followed by concurrent chemo-radiation (CRT) or surgery has been evaluated to assess ORR and PFS in this population. This study employed a standard 3+3 design; DLT was defined as grade 4 or 5 toxicity or grade 3 toxicity lasting more than 7 days. Out of 40 consented patients with stage IV, curable, previously untreated, LA-SCHHN and poor prognosis, 35 (32 men and 3 women) were enrolled and evaluated for toxicity: 19 oropharynx, 10 larynx, 2 oral cancer, 1 nasopharynx and 3 hypopharynx. Five dose levels of cabazitaxel (10, 12.5, 15, 17.5 and 20 mg/m2) were tested in combination with cisplatin 100 mg/m2 and 5-fluorouracil (5-FU) 800 mg/m2/d × 4days. Dose escalation for cabazitaxel was terminated upon the occurrences of 2 DLTs and the establishment of MTD. Cabazitaxel was then further escalated with cisplatin 75 mg/m2 and 5-FU 800 mg/m2/d × 4days in the subsequent 3 dose levels (17.5, 20 and 22.5 mg/m2). In the expansion cohort, 9 patients were enrolled at the 22.5 mg/m2 dose level. Following 3 cycles of IC, patients were evaluated for clinical, radiographic, and pathologic response to cabazitaxel-PF before beginning CRT or surgery. There were 2 DLTs (grade 4 hyperuricemia; neutropenic fever, sepsis, and grade 4 thrombocytopenia) among 2 patients in cohort 5 at the dose of 20 mg/m2 of cabazitaxel. There were no DLTs reported with cohorts using a lower dose of cisplatin, even in the expansion cohort. The study was stopped at the dose of 22.5 mg/m2 in accordance with the initial study design. With 33 evaluable patients for response, the ORR rate was 57.6 %: 9.1. Complete responses (CR) and 48.5 % PR were noted. The authors concluded that the recommended phase II dose for cabazitaxel in combination with cisplatin 75 mg/m2 and 5-FU 800 mg/m2/d × 4days is 22.5 mg/m2 and for cisplatin 100 mg/m2 and 5-FU 800 mg/m2/d × 4 days is 17.5 mg/m2. With a median follow-up of 39 months, PFS for the entire non-metastatic population at 3 years was approximately 58 %.

In a multi-center, phase II clinical trial, Fayette and associates (2017) examined the effects of cabazitaxel in patients with SCCHN who had failed platinum-, cetuximab- and taxanes-based chemotherapy. This study included progressive patients with an ECOG of less than or equal to 2. Cabazitaxel was given at 25 mg/m²/3 weeks (maximum of 10 cycles), with growth factors support. Efficacy was centralized and assessed every 6 weeks. The primary end-point was control rate at 6 weeks. A Simon's 2-stage optimal design (P0 = 0.10; P1 = 0.30) required 29 evaluable patients. At the end of trial, at least 6 non-progressions were needed to consider the drug worthy of further study. Out of the 31 enrolled patients, 29 were eligible; 42 % had received at least 3 previous lines of chemotherapy. For the primary end-point, 8 patients (27.6 %; 95 % CI: 12.7 % to 47.2 %) had a SD at 6 weeks. Median PFS was 1.05 months (95 % CI: 0.69 to 2.07). All patients were analyzed for toxicity: 6 patients had febrile neutropenia. During the 81 cycles administered, 49 grade 3 to 5 events were observed concerning 81 % of the patients, including 35 SAEs of which 15 were related to cabazitaxel. The authors concluded that although cabazitaxel met its primary end-point to deserve further investigations, its toxicity made it difficult to use in frail patients and new schemes are needed (e.g., 20 mg/m2) if further investigations are launched.

Hepatocellular Carcinoma

Chen and colleagues (2018) stated that the prognosis of advanced hepato-cellular carcinoma (HCC) patients remains extremely poor, partially due to the development of acquired resistance to sorafenib and chemotherapy. Cabazitaxel has been FDA-approved for the treatment of docetaxel-resistant prostate cancer. However, no studies have been performed on the effect of cabazitaxel on HCC, and whether cabazitaxel remains sensitive in chemotherapy-resistant and sorafenib-resistant HCC cells is unclear. These researchers demonstrated that cabazitaxel was highly toxic to HCC cell lines in a time- and dose-dependent manner by inducing G2/M phase arrest and apoptosis in-vitro. Cabazitaxel also significantly suppressed HCC tumor growth in-vivo. In chemotherapy-resistant HCC cell Huh-TS-48 with P-gp-overexpression, cabazitaxel showed less cross-resistant to other chemotherapeutic agents. The resistance fold of cabazitaxel, doxorubicin, paclitaxel, docetaxel and vinorelbine is 1.53, 8.60, 38.58, 15.53 and 18.06, respectively. Furthermore, sorafenib-resistant HCC cell SK-sora-5 was still sensitive to cabazitaxel. The IC50 values of cabazitaxel after 72 hours exposure for parental cell SK-hep-1 and resistant cell SK-sora-5 were 0.84 and 0.73 nM, respectively. The authors concluded that these findings showed that cabazitaxel is a potential agent to treat HCC after developing chemotherapy resistance caused by over-expression of P-gp and acquired resistance to sorafenib, and might improve prognosis in advanced HCC patients. Moreover, these researchers stated that additional studies involving HCC patients and patient-derived xenograft models are needed to refine response prediction of cabazitaxel and optimize selection in clinic. They stated that further studies are needed to identify the molecular basis of cabazitaxel resistance that may promote the development of effective drug combination strategies and maximize the anti-tumor effects of cabazitaxel.

Other Malignancies

Cabazitaxel is also being investigated in the treatment of other malignancies. There are ongoing clinical trials that examine the combinations of cabazitaxel with cisplatin (completion date: September 2011) as well as cabazitaxel with gemcitabine (completion date: March 2012) for the treatment of advanced solid malignancies (Worldwide Clinical Trials Listings, 2010).

Dieras and colleagues (2013) noted that although the taxanes paclitaxel and docetaxel are among the most active agents for the treatment of a wide range of cancers, tumors often develop resistance to these treatments. Cabazitaxel is a novel taxane active in both pre-clinical models of chemotherapy-sensitive and -resistant human tumors and patients with advanced prostate cancer that progressed following docetaxel treatment. In a phase I clinical study, these researchers aimed to establish the MTD and dose-limiting toxicities (DLTs) of cabazitaxel. Cabazitaxel was administered every 3 weeks to patients with advanced solid tumors. The design allowed intra-patient dose escalation. The primary objective was to determine the MTD. Secondary objectives were to describe the safety profile, establish an appropriate dose, determine the pharmacokinetic (PK) profile of cabazitaxel, and assess anti-tumor activity. A total of 21 patients were recruited. The MTD was reached at 30mg/m

, at which 3 of 5 patients experienced hematologic DLTs during the first cycle; DLTs during subsequent cycles were mainly hematologic and reported at 25 and 30mg/m

dosing levels. Nail disorders and severe alopecia were not reported, and neurotoxicity, fluid retention and hypersensitivity were mild and infrequent. Cabazitaxel demonstrated linear PK, a tri-phasic elimination profile, with a long half-life and high clearance. Of the 19 patients evaluable for response, 1 unconfirmed partial response and 6 occurrences of stable disease (SD) were reported. The authors concluded that the 25mg/m

dose of cabazitaxel was recommended for use in future clinical studies. In this study, cabazitaxel had an acceptable tolerability profile and activity in cervical, colorectal, endometrial and lung cancers.

Girard and colleagues (2015) stated that there is an unmet need in the treatment of pediatric brain tumors for chemotherapy that is efficacious, avoids damage to the developing brain, and crosses the blood-brain barrier. These researchers evaluated the effectiveness of cabazitaxel in mouse models of pediatric brain tumors. The anti-tumor activity of cabazitaxel and docetaxel were compared in flank and orthotopic xenograft models of patient-derived atypical teratoid rhabdoid tumor (ATRT), medulloblastoma, and central nervous system primitive neuroectodermal tumor (CNS-PNET). Effectiveness of cabazitaxel and docetaxel were also assessed in the Smo/Smo spontaneous mouse medulloblastoma tumor model. This study observed significant tumor growth inhibition in pediatric patient-derived flank xenograft tumor models of ATRT, medulloblastoma, and CNS-PNET after treatment with either cabazitaxel or docetaxel. Cabazitaxel, but not docetaxel, treatment resulted in sustained tumor growth inhibition in the ATRT and medulloblastoma flank xenograft models. Patient-derived orthotopic xenograft models of ATRT, medulloblastoma, and CNS-PNET showed significantly improved survival with treatment of cabazitaxel. The authors concluded that these data support further testing of cabazitaxel as a therapy for treating human pediatric brain tumors.

Rixe and colleagues (2015) noted that taxane-gemcitabine combinations have demonstrated anti-tumor activity. In a phase I clinical trial, these researchers determined the MTD and DLTs of cabazitaxel plus gemcitabine and evaluated the preliminary efficacy of this combination. The patients included had metastatic or unresectable solid tumors and had exhausted standard treatment. Cohorts of 3 to 6 patients received cabazitaxel (15 to 20 mg/m) before (part 1a) or after (part 1b) gemcitabine (700 to 1,000 mg/m) on Day 1 and gemcitabine alone on Day 8. Prophylactic growth factors were not allowed in cycle 1. In part 1a (n = 12), 5 patients received 20 mg/m cabazitaxel plus 1,000 mg/m gemcitabine (20/1,000), 5 received 15/900, 2 received 15/700. In part 1b, all 6 patients received the lowest dose (700/15). At all doses, 2 or more patients experienced a DLT, regardless of administration sequence, including febrile neutropenia (n = 4), grade 4 neutropenia (n = 2), grade 4 thrombocytopenia (n = 2), and grade 3 aspartate transaminase increase (n = 1). The MTD was not established as all cohorts exceeded the MTD by definition. All patients experienced an adverse event; the most frequent all-grade non-hematologic events were fatigue (66.7 %), decreased appetite (50.0 %), and diarrhea (44.4 %). The most frequent grade 3 to 4 hematologic abnormalities were neutropenia (83.3 %), leukopenia (77.8 %), and lymphopenia (72.2 %). Toxicity was sequence-independent but appeared worse with gemcitabine followed by cabazitaxel. Durable PRs were observed in 3 patients (prostate cancer, appendiceal cancer, and melanoma). The unacceptable DLTs with cabazitaxel plus gemcitabine, at doses reduced more than 25 % from single-agent doses, precluded further investigation.

In a phase I, dose-escalation study (GASTANA), Kang and associates (2015) evaluated the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of cabazitaxel in Asian patients with advanced gastric adenocarcinoma failing 2 prior chemotherapy regimens. Cabazitaxel safety/tolerability was determined using a standard 3 + 3 dose-escalation design based on DLTs in cycle 1; 3 dose levels (DL) were planned: 20, 25 and 15 mg/m2 (DL 1, DL 2 and DL -1). A total of 15 patients were evaluable for DLTs. At DL 1, no DLTs occurred in 3 patients; at DL 2, 4 patients were enrolled (1 patient discontinued), with only 1 DLT observed [Grade 4 febrile neutropenia (FN)]; however, all 4patients experienced FN, hence 3 more patients were enrolled at DL 1 who experienced 2 DLTs (Grade 4 neutropenia greater than 7 days). In response, DL -1 was opened, with no DLTs observed in 6 patients. In the total population (n = 16), frequent Grade 3/4 toxicities included neutropenia (63 %) and FN (38 %), best overall responses included 1 PR (6.3 %; DL -1) and 8 SD (50 %), and median progression-free survival (PFS) was 83 days. The authors concluded that no unexpected safety findings were observed; significant toxicities included neutropenia and FN, potentially due to patients being heavily pre-treated and the accumulated toxicity of prior taxane therapy.

Criteria for Initial Approval

Metastatic castration-resistant prostate cancer (CRPC)

Aetna considers cabazitaxel (Jevtana) medically necessary for the treatment of metastatic castration-resistant prostate cancer when previously treated with

of the following:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational or Not Medically Necessary, and Background sections).

Continuation of Therapy

Aetna considers continuation of cabazitaxel (Jevtana) therapy medically necessary for an indication listed in Section I when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.