Venous Thromboembolic Risk Does Not Increase After a Third Dose of SARS-CoV-2 mRNA-BNT162b2 Vaccine in Cancer Patients Receiving Active Systemic Therapies: Updated Results from the Vax-On-Third-Profile Study

(1) Background: Clinical evidence has raised concerns regarding a potential link between COVID-19 mRNA-based vaccines and the occurrence of thromboembolic events. So far, no research has explored the effects of this possible interaction in cancer patients undergoing active treatment. We leveraged prospective monitoring from the Vax-On-Third-Profile study to examine the development of venous thromboembolism (VTE) after the third dose of mRNA-BNT162b2 (tozinameran) and its association with antibody and lymphocyte responses. (2) Methods: Patients who had received a third dose of tozinameran and had not experienced any VTE in the previous 30 days were eligible. A serological evaluation was conducted before the booster vaccination (timepoint-1) and four weeks thereafter (timepoint-2) to measure antibody titers against the SARS-CoV-2 spike protein, as well as to determine the absolute counts of T-helper cells, T-cytotoxic cells, B cells, and NK cells. Data were acquired from November 2021 to October 2022 and analyzed from November 2022 to October 2023. (3) Results: The present study involved 429 patients who were given a third dose of tozinameran from 26 September to 30 October 2021. Among the active treatments of interest, 109 (25.4%) patients received targeted therapy, 111 (25.9%) received cytotoxic chemotherapy, 39 (9.1%) received immune checkpoint inhibitors, 21 (4.9%) received endocrine therapy, and 30 (7.0%) received a combination of chemotherapy and targeted agents in the eight weeks preceding the booster dosing. In addition, 119 (27.7%) patients who had discontinued any systemic therapy for at least 12 weeks accounted for the reference subgroup. After a median follow-up time of 10.6 (95% CI 8.1-11.7) months, we observed 31 venous thromboembolic events in the general population, for an overall incidence rate of 7.2% (95% CI 5.0-10.1). The median time to VTE development after booster immunization was 99 (95% CI 85-112) days. In a univariate comparison, patients exposed to targeted therapies (11.3% [95% CI 6.0-18.9]; <i>p</i> = 0.030) or immune checkpoint inhibitors (16.2% [95% CI 6.2-32.0]; <i>p</i> = 0.012) had a significantly higher incidence of VTE than the reference cohort (3.4% [95% CI 0.9-8.5]). Univariate analysis of immune responses showed that only dynamic changes pertaining to NK cell distributions correlated significantly with VTE occurrence. Multivariate regression analysis confirmed only a high-level NK cell response (OR 6.10 [9% CI 2.16-17.21]; <i>p</i> = 0.001), a history of thromboembolic events (OR 9.81 [3.99-24.13]; <i>p</i> < 0.001), and the presence of a central venous catheter (OR 5.02 [95% CI 1.84-13.67]; <i>p</i> = 0.002) as independently associated with an increased risk of VTE. (4) Conclusions: This prospective cohort study provides unprecedented evidence that cancer patients have no increased risk of developing VTE after the third dose of tozinameran, regardless of the type of active therapy. The specific pattern of lymphocyte response appears to increase thromboembolic risk, underlying immune dysregulation as a causal cofactor. These findings emphasize the need for additional monitoring after periodic COVID-19 vaccination in cancer patients.