The incidence of VTE in NSCLC varies depending on the type of treatment

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Disclosures: Icht reports AstraZeneca’s personal expenses outside of the submitted job. Please see the study for relevant financial information from all other authors.


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The rates of venous thromboembolism in patients with advanced non-small cell lung cancer varied depending on the type of treatment, according to the results of retrospective studies.

Patients treated with platinum-based chemotherapy appeared to be 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.

The rates of venous thromboembolism in patients with advanced non-small cell lung cancer varied depending on the type of treatment.
Data are from Icht O, et al. J Thromb Haemost. 2021; doi: 10.1111 / jth.15272.

Data on the incidence of VTE in patients with NSCLC treated with immune checkpoint inhibitors are limited. In addition, the usefulness of the Khorana score – a risk stratification tool used to predict the risk of VTE in people with cancer – for patients treated with immune checkpoint inhibitors has not been established.

Oded Icht, MD

Oded Icht

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

“In addition, we felt that this question is not only theoretical but also practical: should we offer these patients thromboprophylaxis, and can we trust the Khorana score – which is only validated in patients treated with chemotherapy – to help us in this decision? ” Icht added. “In light of these knowledge gaps, our group – led by Chief Avi, MD – sought to compare VTE rates and assess the Khorana score in patients treated with chemotherapy versus patients treated with an immune checkpoint inhibitor.

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

Exclusion criteria included pre-index VTE, anticoagulation for any index indication, 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 nivolumab monotherapy (Opdivo, Bristol Myers Squibb; 67%), pembrolizumab monotherapy (Keytruda, Merck; 26.1%) or a combination (2.3%). Information on the type of immune checkpoint inhibitor therapy was missing for 4.5% of patients.

The researchers compared the results of this group with those of a pre-existing dataset that included 169 patients treated with platinum-based chemotherapy doublets between 2013 and 2015.

The treatment groups were balanced for median age at diagnosis (66 years for immune checkpoint inhibitor vs. 65.7 years for chemotherapy), gender (male, 60.8% vs. 64.5%), histology and rearrangement of anaplastic lymphoma kinases.

Patients in the immune checkpoint inhibitor group were more likely to be former 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 smokers (24.8% vs. 15.3%) or current smokers (37.9% vs. 26.1%).

The six-month cumulative incidence of VTE served as the primary study outcome.

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

The results showed a higher cumulative incidence over 6 months of VTE in the chemotherapy group (7.1% vs. 4.5%; HR = 1.6; 95% CI 0.66-3.9).

“I expected the VTE rates to be higher in the chemotherapy group, as they actually were; however, this result was not statistically significant as one would expect from the low rate of VTE events in both groups, ”said Icht.

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

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

In the immune checkpoint inhibitor group, the researchers observed a trend for a lower incidence of VTE in patients with high-risk Khorana scores compared to low-risk scores (1.2% vs. 7. 3%; HR = 0.17; 95% CI, 0.02-1.36).

“As we have learned from previous studies, the ability of the Khorana score to stratify [patients with lung cancer] in groups at risk for VTE is not very specific, ”Icht told Healio. “In addition, we have very little data on VTE under immune checkpoint inhibitor therapy, so I can’t say I’m surprised or satisfied with the score’s inability to distinguish low-risk patients.” high-risk patients. “

There are potential explanations for this finding, Icht said.

“First, the Khorana score has been tested and validated in several studies [of] chemotherapy-treated patients, so its ability to stratify these patients into risk groups in our study is not surprising, ”Icht told Healio. “Second, it is possible that the mechanism by which VTEs form is different between patients treated with chemotherapy and with an immune checkpoint inhibitor. VTE in patients treated with an immune checkpoint inhibitor are associated with changes in the tumor microenvironment and an outbreak of the inflammatory process, as opposed to VTE associated with chemotherapy, which is more related to 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 being treated with chemotherapy, Icht and colleagues concluded.

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

“As cancer treatments become more effective and patients have a better prognosis than ever before, I believe there is a growing need for a specific immune checkpoint inhibitor model to aid in decision making. when it comes to thromboprophylaxis, ”said Icht. “It is important to note that although the overall incidence of 4.5% of VTE at 6 months is numerically lower than that of the chemotherapy group, this still represents a significant thrombotic burden, particularly if an under- high risk group can be derived from this population. Considering some emerging data and advancements in the area of ​​predicting the risk of VTE in cancer, I am very optimistic about its development.

Based on the VTE rates seen 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 might be achievable in a collaborative, multi-center effort, they added, noting that such a study would include a cohort of patients treated with both chemotherapy and immune checkpoint inhibitors.

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

Icht and his colleagues recognized the limitations of the study, including the potential for confusion due to imbalances between cohorts.

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

“Therefore, the immune checkpoint inhibitor cohort is enriched with risk factors for VTE, such as a more advanced line of treatment and metastatic disease, compared to the chemotherapy cohort,” the researchers wrote. . “This may overestimate the incidence of VTE in the immune checkpoint inhibitor cohort, which means the actual risk – compared to chemotherapy – is lower.”

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

Finally, the current standard of care is combination therapy with chemotherapy and immune checkpoint inhibitors rather than monotherapy.

For more information:

Oded Icht, MD, can be reached at Davidoff Cancer Center, Rabin Medical Center, 39 Jabotinsky, Petah Tikva 4941492, Israel; email: [email protected]



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