|The following article features coverage from the American Society of Hematology (ASH) 2018 meeting. Click here to read more of Cancer Therapy Advisor‘s conference coverage.|
Results from the randomized, phase 3b superiority study, CASSINI, on rivaroxaban thromboprophylaxis in high-risk patients who received systemic therapy, were revealed during a late-breaking abstract session at the 2018 American Society of Hematology (ASH) Annual Meeting and Exposition in San Diego, California.1 The investigators determined that rivaroxaban, which is not yet approved in this setting, significantly reduced venous thromboembolism (VTE) and VTE-related death during the on-treatment period — but, this benefit was not seen during the full study period.
Researchers, led by Alok Khorana, MD, of the Cleveland Clinic in Ohio, were seeking to determine if “rivaroxaban is superior to placebo for reducing the risk of the primary composite outcome as defined by objectively confirmed symptomatic lower extremity proximal deep vein thrombosis (DVT), asymptomatic lower extremity proximal DVT, symptomatic lower extremity distal DVT, symptomatic upper extremity DVT, symptomatic non-fatal pulmonary embolism (PE), incidental PE, and venous thromboembolism (VTE)-related death in ambulatory adult participants with various cancer types receiving systemic cancer therapy who are at high risk of developing a VTE,” according to the trial’s record listing (ClinicalTrials.org Identifier: NCT02555878).
CASSINI was a massive undertaking, said Dr Khorana, and was conducted at 143 study centers in 11 countries. Patients with various solid tumors and lymphomas who were starting a new systemic regimen and were deemed to be at high risk of VTE were enrolled. Patients were stratified by tumor type (ie, whether they had advanced pancreatic cancer or not) and received either 10 mg rivaroxaban or placebo for 180 plus or minus 3 days with follow-up visits every 8 weeks (plus or minus 7 days). After 24 weeks, a 30-day follow-up period occurred.
To be eligible for the trial, participants had to be aged 18 years or older, have histologically confirmed solid tumors or metastatic/advanced lymphoma, have a Khorana score of 2 or higher, have an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or lower, and have a plan to initiate systemic cancer therapy during a double-blind treatment period. They were excluded from the study for a variety of criteria; an important exclusion criterion was if they had evidence of VTE on screening 30 days or less before randomization.
The primary composite efficacy end points were DVT, PE, or VTE-related death; secondary efficacy end points were confirmation of arterial thromboembolism, visceral thrombosis, and all-cause mortality. The primary safety-related end point was the appearance of major bleeding, as defined by the International Society on Thrombosis and Haemostasis.
Approximately 800 patients were included to provide enough power to show an approximately 60% reduction in VTE with rivaroxaban. The efficacy analysis was conducted for the intent-to-treat population (all randomized patients). The final patient count was 841 participants, with 421 assigned to receive placebo and 420 to receive rivaroxaban. The safety populations for each arm had 404 and 405 patients, respectively.
In the placebo group, 203 patients (50.2%) discontinued treatment, whereas 177 patients (43.7%) discontinued rivaroxaban early. Although the researchers included patients across 10 primary tumor sites, the 3 most common sites among patients included in the placebo and rivaroxaban arms were pancreatic tumors (32.8% and 32.4%, respectively), gastrointestinal cancers (20.7% and 21.2%, respectively), and lung cancers (17.1% and 14.8%, respectively).
Rivaroxaban administration significantly reduced VTE and VTE-related death during the on-treatment period, but not after the study was over and when the study drug was discontinued. At this time over one-third of thrombotic events occurred. In sum, across the cohorts, a total thrombotic rate of 17% was found.
“Given that one-third of these events start at baseline, considerations should be given to baseline screening of high-risk patients starting systemic therapy; an approach that they have already updated at the given clinic at my institution, and [on which] they have recently published,” Dr Khorana said.
“That second thromboprophylaxis trial, with a similarly designed study population of a Khorana score of 2 or higher, has recently been completed and the results of that trial…are eagerly awaited.” he continued. “If the findings of that trial are consistent with ours, then we certainly hope that these findings should inform future recommendations regarding thromboprophylaxis for high-risk, ambulatory cancer patients, and that the landscape of anticoagulation in the cancer population should start to shift from the management of events to primary prevention.”
An audience member asked Dr Khorana why, after investigators saw there was no difference between treatment groups after the first 40 to 50 days, the investigators didn’t split the cohorts further into a “group C.” Replied Dr Khorana, “I believe this is because of the introduction of the baseline screening process. All patients that were enrolled in the study had a baseline screening for VTE, and only the negative patients were randomized… [In] trying to be methodologically robust, we ensure the thrombosis population at study entry, but also what I think we did is interrupt the natural history of disease, and many of these events would probably have happened that first couple of months, but because we excluded those patients, these events did not happen. I suddenly think that … number needed to treat is actually an underestimate, because it’s not routine practice to screen cancer patients before they start.”
Dr Khorana added that the comparison of their work to that of the other published research will be interesting, because those trials did not use baseline screening. “It’s possible that would help us understand the differences between the study [subsets].”
Disclosure: This study was supported by Janssen and Bayer. For a complete list of author disclosures, please refer to original abstract.
Read more of Cancer Therapy Advisor‘s coverage of the ASH 2018 meeting by visiting the conference page.
- Khorana AA, Soff GA, Kakkar AK, et al. Rivaroxaban thromboprophylaxis in high-risk ambulatory cancer patients receiving systemic therapy: results of a randomized clinical trial (CASSINI). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, California. Abstract LBA-1.