Cardio-Oncology Resource Center

Cardio-Oncology Resource Center

Disclosures: Icht reports personal fees from AstraZeneca outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.
May 09, 2021
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VTE incidence in NSCLC varies by treatment type

Disclosures: Icht reports personal fees from AstraZeneca outside the submitted work. Please see the study for all other authors’ relevant financial disclosures.
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Venous thromboembolism rates among patients with advanced non-small cell lung cancer varied by treatment type, according to retrospective study results.

Patients treated with platinum-based chemotherapy appeared more likely to develop VTE than those treated with immune checkpoint inhibitors; however, the sample size was not large enough to demonstrate a statistically significant difference.

Venous thromboembolism rates among patients with advanced non-small cell lung cancer varied by treatment type.
Data were derived from Icht O, et al. J Thromb Haemost. 2021;doi:10.1111/jth.15272.

Data are limited about VTE incidence among patients with NSCLC treated with immune checkpoint inhibitors. In addition, the utility of the Khorana score — a risk-stratification tool used to predict VTE risk among individuals with cancer — for patients treated with immune checkpoint inhibitors had not been established.

Oded Icht, MD
Oded Icht

“The use of immune checkpoint inhibitors is rapidly growing and has revolutionized treatment of metastatic NSCLC,” Oded Icht, MD, of the thoracic cancer unit at Davidoff Cancer Center at Rabin Medical Center in Israel, told Healio. “However, the association between VTE and immune checkpoint inhibitor treatment is unclear.

“Furthermore, we felt this question is not only theoretical but also practical: Should these patients be offered thromboprophylaxis, and can we rely on the Khorana score — which is validated only in chemotherapy-treated patients — to aid us in this decision?” Icht added. “In light of these knowledge gaps, our group — led by Avi Leader, MD — sought to compare VTE rates and assess the Khorana score in chemotherapy-treated vs. immune checkpoint inhibitor-treated patients.”

The retrospective cohort study included 345 patients with nonresectable or metastatic NSCLC treated at Institute of Oncology at Rabin Medical Center.

Exclusion criteria included VTE prior to index, anticoagulation for any indication at index, synchronous malignancy or incomplete follow-up data.

The final analysis included 176 consecutive patients treated with immune checkpoint inhibitors between 2015 and 2017. Regimens included single-agent nivolumab (Opdivo, Bristol Myers Squibb; 67%), single-agent pembrolizumab (Keytruda, Merck; 26.1%) or a combination (2.3%). Information about type of immune checkpoint inhibitor therapy was missing for 4.5% of patients.

Researchers compared outcomes in this group with those of a preexisting data set that included 169 patients treated with platinum-based chemotherapy doublet between 2013 and 2015.

Treatment groups were balanced with regard to median age at diagnosis (66 years for immune checkpoint inhibitor vs. 65.7 years for chemotherapy), sex (male, 60.8% vs. 64.5%), histology and anaplastic lymphoma kinase rearrangement.

Patients in the immune checkpoint inhibitor group were more likely to be past smokers (52.3% vs. 33.7%) and to have stage IV disease (85.8% vs. 72.8%). Those who received chemotherapy were more likely to be never-smokers (24.8% vs. 15.3%) or current smokers (37.9% vs. 26.1%).

Six-month cumulative incidence of VTE served as the main study outcome.

Median follow-up was 187 days, during which time eight VTE events occurred in the immune checkpoint inhibitor group (lower-extremity deep vein thrombosis, n = 3; upper-extremity DVT, n = 1; pulmonary emboli, n = 3; sinus vein thrombosis, n = 1) and 12 occurred in the chemotherapy group (lower-extremity DVT, n = 6; pulmonary emboli, n = 5; both, n = 1).

Results showed higher 6-month cumulative incidence of VTE in the chemotherapy group (7.1% vs. 4.5%; HR = 1.6; 95% CI, 0.66-3.9).

“I did expect VTE rates to be higher in the chemotherapy group, as they indeed were; however, this result was not statistically significant as could be expected by the low event rate of VTE in both groups,” Icht said.

Researchers also performed subgroup analyses of patients based on low-risk or high-risk Khorana score (0-1 vs. 2). Approximately half of patients in each treatment group had low-risk scores (54.5% for immune checkpoint inhibitor vs. 49.7% for chemotherapy).

In the chemotherapy group, researchers reported a trend toward higher 6-month cumulative VTE incidence among patients with high-risk Khorana scores compared with low-risk scores (10.5% vs. 3.5%; HR = 3.04; 95% CI, 0.82-11.22).

In the immune checkpoint inhibitor group, researchers observed a trend toward lower VTE incidence among patients with high-risk Khorana scores compared with low-risk scores (1.2% vs. 7.3%; HR = 0.17; 95% CI, 0.02-1.36).

“As we know from previous studies, the Khorana score’s ability to stratify [patients with lung cancer] into VTE risk groups is not very accurate,” Icht told Healio. “Additionally, we have very few data on VTE under immune checkpoint inhibitor treatment, so I can’t say I’m surprised, nor am I complacent, by the score’s inability to distinguish low- from high-risk patients.”

There are potential explanations for this finding, Icht said.

“Firstly, the Khorana score was tested and validated in multiple studies [of] chemotherapy-treated patients, so its ability to stratify these patients into risk groups in our study is not surprising,” Icht told Healio. “Secondly, it is possible that the mechanism by which VTEs are formed is different between chemotherapy- and immune checkpoint inhibitor-treated patients. The VTEs among immune checkpoint inhibitor-treated patients are associated with changes in the tumor microenvironment and a surge in the inflammatory process, as opposed to chemotherapy-associated VTEs, which have more to do with endothelial damage. These processes, however, are still under investigation and warrant further laboratory work.”

The results support guidelines that recommend thromboprophylaxis only for patients with high-risk Khorana scores who are treated with chemotherapy, Icht and colleagues concluded.

Because the Khorana score did not identify high-risk patients in the immune checkpoint inhibitor group, development of a specific risk model for this treatment modality is warranted, they added.

“As cancer treatments become more effective and patients have better prognosis than ever, I believe there is a growing need for an immune checkpoint inhibitor-specific model to aid in thromboprophylaxis decision-making,” Icht said. “It is important to note that, while the overall 4.5% 6-month VTE incidence is numerically lower than the chemotherapy-treated group, this still represents a significant thrombotic load, especially if a high-risk subgroup can be derived from this population. Given some emerging data and advances in the field of VTE risk prediction in cancer, I am very optimistic about its development.”

Based on the VTE rates observed in this analysis, a future study would require 662 patients in each treatment group to achieve statistical significance, Icht and colleagues wrote. This sample size could be feasible in a multicenter collaborative effort, they added, noting such a study should include a cohort of patients treated with both chemotherapy and immune checkpoint inhibitors.

VTE occurrence in the entire study cohort appeared associated with higher all-cause mortality (HR = 5.8; 95% CI, 3.3-10.3). The association persisted when researchers analyzed the immune checkpoint inhibitor (HR = 12.2; 95% CI, 4.58-32.43) and chemotherapy (HR = 3.6; 95% CI, 1.78-7.3) groups separately.

Icht and colleagues acknowledged limitations to the study, including the potential for confounding due to imbalances between cohorts.

Standard first-line treatment for advanced NSCLC consisted of chemotherapy until 2017, so nearly all patients in this analysis received chemotherapy as first-line treatment. The FDA approved immune checkpoint inhibitors as second-line treatment in 2015, so many patients received these agents in second- or third-line settings.

“Consequently, the immune checkpoint inhibitor cohort is enriched with VTE risk factors, such as more advanced line of treatment and metastatic disease, compared with the chemotherapy cohort,” researchers wrote. “This may cause an overestimation of the VTE incidence in the immune checkpoint inhibitor cohort, meaning that the actual risk — relative to chemotherapy — is lower.”

However, higher rates of smoking and a higher rate of prior treatment with bevacizumab (Avastin, Genentech) in the chemotherapy group (12.4% vs. 0%) may be linked to higher VTE risk, potentially overestimating the risk in this cohort, researchers wrote.

Finally, the current standard of care consists of combined treatment with chemotherapy and immune checkpoint inhibitors rather than single-agent therapy.

For more information:

Oded Icht, MD, can be reached at Davidoff Cancer Center, Rabin Medical Center, 39 Jabotinsky, Petah Tikva 4941492, Israel; email: odedicht@gmail.com.