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Study IDs Biomarker of Treatment Efficacy for CDK 4/6 Inhibitors in Breast Cancer; FDA Filing Planned


This story has been updated to include additional information on the intended use of the assay.

NEW YORK – A recent study has provided additional evidence that the enzyme thymidine kinase-1 may serve as a biomarker of how well CDK4/6 inhibitor therapy is working in metastatic breast cancer patients. 

Monitoring of this biomarker may enable identification of patients who are not benefiting from treatment and who should potentially be switched to other therapeutic options. Biovica, a Swedish biotechnology firm, has developed an assay called DiviTum that measures thymidine kinase-1 levels in the blood. 

"If it is going up, you have more cells replicating, [and] that is not good news from the cancer perspective," Robert Dann, the marketing advisor for Biovica, said. "But if it is staying stable or going down, that is good news."

The new study found that in treatment-sensitive breast cancer cell lines, thymidine kinase-1 levels changed following treatment with the CDK4/6 inhibitor therapy palbociclib (Pfizer's Ibrance). Additionally, metastatic breast cancer patients from the To Reverse ENDocrine Resistance Trial (TREnd) trial whose thymidine kinase-1 levels declined after a month of palbociclib therapy had better outcomes than patients whose thymidine kinase-1 levels increased in that same time, suggesting thymidine kinase-1 levels may reflect both sensitivity to treatment as well as patient outcomes.

Based on these and results from additional analyses — including one using SWOG data — Biovica plans to make a 510(k) submission to the US Food and Drug Administration for its DiviTum test within the year. The firm envisions the intended use of the assay to be a means of monitoring disease progression among women with hormone receptor-positive advanced breast cancer who are on aromatase inhibitor-based therapies, in conjunction with other approaches like imaging.

DiviTum is an ELISA-based assay that assesses thymidine kinase-1 levels. Thymidine kinase-1 plays a role in DNA replication and is a marker of cellular proliferation, suggesting it could be a measure of tumor aggressiveness. Its synthesis is regulated by the E2F pathway, which, in conjunction with the retinoblastoma protein (Rb), regulates apoptosis.

CDK4/6 inhibitors like palbociclib, meanwhile, reduce Rb phosphorylation to lead to a decrease in E2F activity and, eventually, cell cycle arrest. As its synthesis is regulated by E2F, thymidine kinase-1 levels could reflect CDK4/6 inhibitor activity.

In the new study, researchers led by Prato Hospital Italy's Luca Malorni examined thymidine kinase-1 as a biomarker of palbociclib response. In a series of seven estrogen-receptor-positive breast cancer cell lines, they measured how palbociclib treatment affected thymidine kinase-1 activity using Biovica's DiviTum assay.  

As they reported earlier this month in Clinical Cancer Research, Malorni and his colleagues found that thymidine kinase-1 activity declined following palbociclib treatment in cell lines known to be sensitive to the drug, but that thymidine kinase-1 activity was unchanged following palbociclib treatment in cell lines resistant to the drug. This suggested to the researchers that modulation of thymidine kinase-1 activity might serve as a marker of palbociclib response. 

This study has confirmed but also expanded upon what's known about thymidine kinase-1 activity, Biovica's Dann said. For instance, he said there might have been a hunch that cell lines with intrinsic resistance would have thymidine kinase-1 levels just go up, but researchers have now been able to pick this apart in the various cell lines analyzed.

In a retrospective analysis, Malorni and his colleagues also measured thymidine kinase-1 activity — again using Biovica's DiviTum — in women from the TREnd trial who were treated with palbociclib. That trial aimed to gauge the activity of palbociclib alone or in combination with endocrine therapy to reverse endocrine resistance in advanced breast cancer patients. 

For this analysis, the researchers obtained blood samples taken from the women at baseline before they started treatment, during treatment, and after disease progression but before starting a new treatment line. Through this, they found that patients whose thymidine kinase-1 levels remained steady or decreased after a month of treatment — which was the majority of the group — had a median progression-free survival of nine months. A smaller group had a rise in their thymidine kinase-1 levels and had a statistically significant shorter median progression-free survival of three months.

Additionally, Malorni and his colleagues reported a correlation between thymidine kinase-1 activity at progression and how women in the TREnd trial fared on their next line of therapy. Patients with low thymidine kinase-1 activity had significantly longer median time to treatment failure, 8.7 months, than patients with high thymidine kinase-1 activity, who had a median time to treatment failure of 2.9 months.

In a statement, Malorni said these findings were encouraging, but needed confirmation in larger studies.

Biovica noted that DiviTum has already been examined in more than 10 studies encompassing more than 1,700 patients. According to Dann, the firm is continuing to analyze DiviTum in additional studies, including using SWOG Cancer Research Network data.

Last September, Biovica signed an agreement with the SWOG Cancer Research Network to use DiviTum to assay blood samples collected from individuals with metastatic hormone receptor-positive breast cancer from its SWOG 0226 clinical trial.

According to Dann, this is a key cohort to study, as the investigators collected a number of serial assessments on the patients that they can then try to align to their DiviTum results. For instance, they could examine whether a rise in DiviTum-measured thymidine kinase-1 activity correlated with disease progression as determined by traditional assessments. Additionally, they may be able to examine whether there is an association between DiviTum-measured thymidine kinase-1 levels among women treated with a combination of aromatase and CDK 4/6 inhibitors and continued clinical benefit or disease progression.

Findings from these analyses will form the basis of a 510(k) submission to the US Food and Drug Administration for DiviTum, according to Biovica CEO Anders Rylander.

Dann said they hoped to receive clearance for DiviTum quickly and bring it to the market shortly thereafter, within about a year. "Let's finish proving this in people, convince the FDA that we've done that adequately, and bring [the assay] to market as quick as we can," Dann said

Once on the market and assuming further confirmatory studies, he said clinicians could possibly use DiviTum to monitor treatment efficacy and identify patients whose disease may be progressing and who may benefit from earlier assessment with traditional approaches or determine if a patient should be switched to a different therapeutic approach.

While Biovica is currently focusing on the application of DiviTum to monitor breast cancer, Dann noted that it could also potentially be applied to other cancer types, such as lung cancer.