SUMMARY

• CASSINI was a phase 3, multicenter, randomized, double-blind study designed to evaluate efficacy and safety of XARELTO 10 mg once daily compared with placebo for prevention of cancer-associated thrombosis in ambulatory cancer patients who were initiated on systemic cancer therapy and at high risk for venous thromboembolism (VTE). XARELTO did not significantly reduce VTE and VTE-related death for the intent-to-treat (ITT) population. In a supportive analysis of the on-treatment period (last dose plus 2 days), there was a substantially lower rate of VTE and VTE-related death. Thirty-nine percent of the events occurred following the discontinuation of the trial regimen. Incidence of major bleeding (MB) was low.¹
• In a secondary analysis evaluating the full benefit of thromboprophylaxis which included all components of primary composite endpoint, as well as confirmed arterial or visceral thromboembolism, and asymptomatic lower extremity distal deep vein thrombosis (DVT), fewer events occurred in patients being treated with XARELTO 10 mg compared to placebo (6.9% vs. 11.6%; hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.36-0.90).²
• In a prespecified subgroup analysis of patients with pancreatic cancer in the CASSINI trial, there was no difference in the primary efficacy (HR, 0.70; 95% CI, 0.34-1.43; P=0.328) or safety endpoint (HR, 0.67; 95% CI, 0.11-3.99; P=0.654) for patients being treated with XARELTO 10 mg compared to placebo during the full observation period.³
• A post-hoc analysis of the CASSINI trial evaluated the efficacy and safety of rivaroxaban versus placebo in patients with gastric or gastroesophageal junction (G/GEJ) tumors or non-G/GEJ tumors. There was no significant difference in the primary composite endpoint in patients with G/GEJ tumors receiving XARELTO or placebo (3.4% vs 6.9%; HR, 0.45; 95% CI, 0.11-1.80). In patients with non-G/GEJ tumors, the primary composite endpoint occurred in 6.6% and 9.3% of patients receiving XARELTO or placebo, respectively (HR, 0.70; 95% CI, 0.40-1.21). The rates of MB reported were 4.6% and 1.2% of patients with G/GEJ tumors (HR, 3.77; 95% CI, 0.42-33.73) versus 1.3% and 0.9% of patients with non-G/GEJ tumors (HR, 1.33; 95% CI, 0.30-5.94) after receiving XARELTO or placebo, respectively.⁴
• A substudy of CASSINI trial has been included in the REFERENCES section for your review.⁵

CLINICAL STUDY

CASSINI

Khorana et al (2019)¹ conducted a randomized, double-blind, placebo-controlled, multicenter, multinational, phase 3b superiority study to evaluate efficacy and safety of XARELTO vs placebo for thromboprophylaxis in adult ambulatory patients initiating a new systemic cancer regimen for various cancers and high risk of VTE (defined as Khorana score of ≥2).

Study Design/Methods

• Key inclusion criteria included: ≥18 years of age; ambulatory with a solid tumor or lymphoma with locally-advanced or metastatic disease; baseline Khorana score ≥2 (higher scores indicating a higher risk of VTE); and had an expected survival of >6 months, with a plan to start a new systemic regimen within 1 week of initiating study drug.
• Key exclusion criteria included: primary brain tumor or known brain metastases; Eastern Cooperative Oncology Group performance status score of ≥3; or active bleeding/risk for bleeding.
• Patients without thrombosis were randomized 1:1 to XARELTO 10 mg once daily or placebo once daily for up to 180 (±3) days and were stratified by whether pancreas was the primary site. Follow-up visits occurred at week 8 (±7 days), week 16 (±7 days), and day 180/end of treatment (±3 days), with compression ultrasonography conducted at each visit.
• Primary efficacy endpoint: composite of objectively-confirmed symptomatic or asymptomatic lower-extremity proximal DVT, symptomatic upper- or lower-extremity distal DVT, symptomatic or incidental pulmonary embolism (PE), and VTE-related death, as adjudicated by an independent blinded clinical endpoint committee.
• Primary safety endpoint: occurrence of MB, as defined by the International Society on Thrombosis and Hemostasis (bleeding requiring transfusion or >2 g/dL fall in hemoglobin), during the on-treatment period (first dose of study drug through last dose plus 2 days).
• Key secondary efficacy and safety endpoints included: components of the primary, including symptomatic VTE, as well as clinically relevant events not included in the primary composite, such as all-cause mortality, confirmed arterial thromboembolism, and confirmed visceral thromboembolism; secondary safety endpoints: clinically relevant nonmajor (CRNM) bleeding.
• A supportive analysis of the primary endpoint was also conducted for the on-treatment period, which consisted of the last dose of study drug plus 2 days.
• Safety analyses were conducted for patients who received at least 1 dose of study drug during the on-treatment period.

Results

Baseline Characteristics

• A total of 1080 patients were enrolled into the study.
• The intention-to-treat efficacy analyses included 841 randomized patients (XARELTO, n=420; placebo, n=421).
• Except for a greater number of XARELTO-treated patients having a history of VTE, baseline characteristics were well-balanced between groups. Median age was 63 years, 50.9% of patients were male, the most common primary cancer was pancreatic (32.6%), and 54.5% of solid tumor patients had metastatic disease.
• A total of 809 were included in the safety analysis.

Efficacy/Safety

• The primary efficacy composite endpoint occurred in 25/420 (6.0%) patients and in 37/421 (8.8%) patients in the XARELTO and placebo groups, respectively (HR, 0.66; 95% CI, 0.40-1.09; P=0.10).
  • Of the patients who experienced VTE, 24/62 (39%) experienced events following discontinuation of study drug.
• In a prespecified analysis of randomized patients during the on-treatment period, the primary efficacy composite endpoint occurred in 11/420 (2.6%) patients and in 27/421 (6.4%) patients in the XARELTO and placebo groups, respectively (HR, 0.40; 95% CI, 0.20-0.80).
• The composite of the primary efficacy endpoint and arterial and visceral events occurred in 6.9% of XARELTO-treated patients and in 10.7% of placebo-treated patients (HR, 0.62; 95% CI, 0.39-0.99).
• Arterial thromboembolism occurred in 4/420 patients (1.0%) and 7/421 patients (1.7%) in the XARELTO and placebo groups, respectively.
• The all-cause mortality in the up-to-day-180 period were 84 deaths (20.0%) in the XARELTO group and 100 deaths (23.8%) in the placebo group (HR, 0.83; 95% CI, 0.62-1.11).
• A prespecified composite of the primary efficacy endpoint and all-cause mortality occurred in 23.1% of XARELTO-treated patients and in 29.5% of placebo-treated patients (HR, 0.75; 95% CI, 0.57-0.97).
• MB occurred in 8/405 (2.0%) patients and in 4/404 (1.0%) patients in the XARELTO and placebo groups, respectively (HR, 1.96; 95% CI, 0.59-6.49; P=0.26), while CRNM bleeding occurred in 11/405 (2.7%) patients and in 8/404 (2.0%) patients, respectively (HR, 1.34; 95% CI, 0.54-3.32 P=0.53).
  • The primary site of MB was gastrointestinal (n=8).
• Adverse events (AEs) were comparable between groups. Serious AEs were reported in 41.5% of XARELTO-treated patients and in 43.3% of placebo-treated patients.
  • Serious AEs were classified as those that resulted in death or were life-threatening, required inpatient hospitalization or prolonged existing hospitalization, resulted in persistent serious disability or incapacity, were a congenital anomaly, or were a medically important event.
  • One fatal bleeding event occurred in the XARELTO group.

Khorana et al (2020)² conducted a secondary analysis to evaluate the full benefit of thromboprophylaxis in CASSINI study participants. The full benefit of thromboprophylaxis was evaluated using a modified total thromboembolic endpoint which included all components of the primary efficacy endpoint, as well as confirmed arterial thromboembolism (myocardial infarction, ischemic stroke, and systemic arterial embolism), visceral thromboembolism, and asymptomatic (screen detected) lower extremity distal DVT. The analysis was based on the ITT analysis population, or all patients who had undergone randomization, with data from randomization through day 180. In addition, analysis during the intervention period was conducted (start of treatment through end of treatment plus 2 days). See Table: Full Benefit of Thromboprophylaxis in CASSINI Study Participants.

• Total thromboembolic events occurred in fewer patients randomized to XARELTO during the full study period than placebo (6.9% vs. 11.6%; HR, 0.57; 95% CI, 0.36-0.90). Of those events, 27 (34.6%) occurred after drug discontinuation. Similarly, during the intervention period, fewer XARELTO patients experienced thromboembolic events compared to placebo (3.1% vs 9.0%; HR, 0.33; 95% CI, 0.18-0.62).

Vadhan-Raj et al (2020)³ conducted a prespecified subgroup analysis of CASSINI trial participants with pancreatic cancer to evaluate the benefit vs risk of thromboprophylaxis with XARELTO 10 mg vs placebo. In the CASSINI trial, patients were stratified by tumor type (pancreas or non-pancreas) at randomization. Primary efficacy and safety endpoints have been previously described. All efficacy analyses were based on the ITT analysis population, comprised of all randomized subjects with data from randomization through day 180, as well as for the intervention period.

• Of the 841 participants randomized in the CASSINI trial, 273 (32.5%) had pancreatic cancer and were analyzed; 261 of those patients received at least one dose of study drug and were included in the safety analysis (safety population).
• Baseline characteristics among pancreatic cancer participants were generally well balanced in the XARELTO and placebo treatment arms. The median duration of treatment was longer in the XARELTO arm (163.5 days) than in the placebo arm (128 days). A greater proportion of patients in the placebo arm discontinued therapy compared with the XARELTO arm (58.0% vs. 50.0%)
• Fewer events occurred in patients receiving XARELTO (9.6%) compared with patients receiving placebo (13.0%) during the up-to-day-180 observation period. There was no statistical difference for the primary composite endpoint during the full observation period (HR, 0.70; 95% CI, 0.34-1.43); most of these events occurred after drug discontinuation.  During the intervention period alone, 5 events (3.7%) occurred in the XARELTO treatment arm and 14 events (10.1%) occurred in the placebo arm (HR, 0.35; 95% CI, 0.13-0.97).
• No heterogeneity of treatment effect was observed between the two treatment periods.
• There was no statistical difference in the primary safety endpoint for patients receiving XARELTO compared to placebo (1.5% vs 2.3%, XARELTO and placebo, respectively; HR, 0.67; 95% CI, 0.11-3.99). There was no statistical difference (HR, 2.47; 95% CI, 0.48-12.72) in CRNM bleeding between the two arms (3.9% vs 1.5%, XARELTO and placebo, respectively).

Mones et al (2021)⁴ conducted a post-hoc analysis of the CASSINI trial to evaluate the safety and efficacy of XARELTO versus placebo for thromboprophylaxis in patients with G/GEJ tumors or non-G/GEJ tumors (N=841).

Study Design/Methods

• Post-hoc analysis of the CASSINI study.  
• The classification of the efficacy and safety endpoints were consistent with the CASSINI study during the 180-day intention-to-treat population observation period.

Results

Patient Characteristics

• A total of 841 patients were evaluated in which 176 patients had G/GEJ tumors (XARELTO, n=89; placebo, n=87) and 665 patients had non-G/GEJ tumors (XARELTO, n=331; placebo, n=334).
• The median age of patients with G/GEJ tumors and non-G/GEJ tumors who received XARELTO was 60 years (range, 29-82 years) and 64 years (range, 23-87 years), respectively.

Efficacy

• In the total population of patients with G/GEJ tumors or non-G/GEJ tumors (N=841), the primary composite endpoint occurred in 25 (6.0%) and 37 (8.8%) patients receiving XARELTO or placebo, respectively (HR, 0.66; 95% CI, 0.40-1.09).
  • Of the patients with G/GEJ tumors, the primary composite endpoint occurred in 3 (3.4%) and 6 (6.9%) patients receiving XARELTO or placebo, respectively (HR, 0.45; 95% CI, 0.11-1.80).
  • Of the patients with non-G/GEJ tumors, the primary composite endpoint occurred in 22 (6.7%) and 31 (9.3%) patients receiving XARELTO or placebo, respectively (HR, 0.70; 95% CI, 0.40-1.21).

Safety

• The time to the first occurrence of the safety endpoints in patients with G/GEJ or non-G/GEJ tumors during the on-treatment observation period is described in Table: Safety Outcomes in Patients with G/GEJ Tumors or Non-G/GEJ Tumors Receiving XARELTO or Placebo.

LITERATURE SEARCH

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT^® (and/or other resources, including internal/external databases) was conducted on 09 May 2024.