User login
Among 29 patients with heavily pretreated EEC, outcomes of DKN-01 monotherapy were best in patients with Wnt activating mutations, high levels of DKK1 expression, or PIK3CA activating mutations.
Patients in these groups had better disease control rates and progression-free survival (PFS), reported Rebecca C. Arend, MD, of the University of Alabama at Birmingham.
“Future development will focus on biomarker-selected patients, specifically patients with Wnt activating mutations, high tumoral DKK1, and PIK3CA activating mutations,” Dr. Arend said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10717).
She explained that DKK1 has been shown to modulate signaling in the Wnt/beta-catenin pathway, a key regulator of cellular functions in humans and animals that has been highly conserved throughout evolution.
“DKK1 activates P13 kinase/AKT signaling by binding to the CKAP4 receptor to promote tumor growth,” Dr. Arend explained.
Focus on monotherapy
Dr. Arend and colleagues conducted a phase 2 basket trial of DKN-01 either as monotherapy or in combination with paclitaxel in patients with EEC, epithelial ovarian cancer, and carcinosarcoma (malignant mixed Mullerian tumor). The trial design required at least 50% of patients to have Wnt signaling alterations.
Dr. Arend reported results for 29 patients with EEC who received DKN-01 monotherapy.
There were nine patients with Wnt activating mutations. None of them achieved a complete response (CR) or partial response (PR), but six had stable disease (SD), for a disease control rate of 67%. Of the 20 patients without Wnt activating mutations, 1 achieved a CR, 1 achieved a PR, and 3 had SD, for a disease control rate of 25%.
The median PFS was 5.5 months in patients with Wnt activating mutations and 1.8 months in patients without the mutations.
“Importantly, patients whose tumors have a Wnt activating mutation have a correlation with increased tumoral expression of DKK1 by 14.4-fold higher,” Dr. Arend noted.
When she and her colleagues analyzed patients by DKK1 expression, the team found that high levels of DKK1 correlated with better clinical outcomes. The disease control rate was 57% for patients in the highest third of DKK1 expression (1 PR, 3 SD) vs. 7% (1 SD) for those in the lowest two-thirds. The median PFS was 3 months and 1.8 months, respectively.
Of the seven patients whose tumors could not be evaluated for DKK1 expression, one patient had a CR and 5 had SD, for a disease control rate of 86%. The median PFS in this group was 8.0 months. Three of these patients had known Wnt activating mutations.
“Given this correlation [between] higher DKK1 expression [and] Wnt activating mutations, one could consider that, at a minimum, these patients would have had a higher DKK1 expression as well,” Dr. Arend said.
She and her colleagues also found that patients with PIK3CA activating mutations and two or fewer prior lines of therapy had a 33% overall response rate (1 CR, 1 PR), compared with 0% for patients without these mutations who had two or fewer prior therapies. Patients with PIK3CA activating mutations also had a better disease control rate (67% vs. 40%) and median PFS (5.6 months vs. 1.8 months).
Although Dr. Arend did not present safety data from the study at SGO 2021, she reported some data in a video investor call for Leap Therapeutics, which is developing DKN-01. She said the most common treatment-emergent adverse events with DKN-01 were nausea in 28.8% of patients, fatigue in 26.7%, and constipation in 11.5%. Serious events included acute kidney injury, dyspnea, nausea, and peripheral edema (occurring in 1.9% of patients each).
Monotherapy or combination?
In the question-and-answer session following Dr. Arend’s presentation, comoderator Joyce Liu, MD, of the Dana-Farber Cancer Institute in Boston, said that “even in the DKK1-high tumors, the activity of DKN-01 as a monotherapy is a little bit limited.”
She asked whether the future of targeting inhibitors in the Wnt/beta-catenin pathway will be limited to biomarker-specific populations or if agents such as DKN-01 should be used in combinations.
“I do think that we need a lot more data to determine,” Dr. Arend replied. “I think that there may be a subset of patients, especially those that don’t tolerate the [lenvatinib/pembrolizumab] combo who may have an upregulation of beta-catenin or a Wnt mutation who could benefit from monotherapy.”
Dr. Arend added that data from her lab and others suggest that DKN-01 in combination with other agents holds promise for improving outcomes in biomarker-selected populations.
The current study is funded by Leap Therapeutics. Dr. Arend disclosed advisory board activity for the company and others. Dr. Liu reported personal fees from several companies, not including Leap Therapeutics.
Among 29 patients with heavily pretreated EEC, outcomes of DKN-01 monotherapy were best in patients with Wnt activating mutations, high levels of DKK1 expression, or PIK3CA activating mutations.
Patients in these groups had better disease control rates and progression-free survival (PFS), reported Rebecca C. Arend, MD, of the University of Alabama at Birmingham.
“Future development will focus on biomarker-selected patients, specifically patients with Wnt activating mutations, high tumoral DKK1, and PIK3CA activating mutations,” Dr. Arend said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10717).
She explained that DKK1 has been shown to modulate signaling in the Wnt/beta-catenin pathway, a key regulator of cellular functions in humans and animals that has been highly conserved throughout evolution.
“DKK1 activates P13 kinase/AKT signaling by binding to the CKAP4 receptor to promote tumor growth,” Dr. Arend explained.
Focus on monotherapy
Dr. Arend and colleagues conducted a phase 2 basket trial of DKN-01 either as monotherapy or in combination with paclitaxel in patients with EEC, epithelial ovarian cancer, and carcinosarcoma (malignant mixed Mullerian tumor). The trial design required at least 50% of patients to have Wnt signaling alterations.
Dr. Arend reported results for 29 patients with EEC who received DKN-01 monotherapy.
There were nine patients with Wnt activating mutations. None of them achieved a complete response (CR) or partial response (PR), but six had stable disease (SD), for a disease control rate of 67%. Of the 20 patients without Wnt activating mutations, 1 achieved a CR, 1 achieved a PR, and 3 had SD, for a disease control rate of 25%.
The median PFS was 5.5 months in patients with Wnt activating mutations and 1.8 months in patients without the mutations.
“Importantly, patients whose tumors have a Wnt activating mutation have a correlation with increased tumoral expression of DKK1 by 14.4-fold higher,” Dr. Arend noted.
When she and her colleagues analyzed patients by DKK1 expression, the team found that high levels of DKK1 correlated with better clinical outcomes. The disease control rate was 57% for patients in the highest third of DKK1 expression (1 PR, 3 SD) vs. 7% (1 SD) for those in the lowest two-thirds. The median PFS was 3 months and 1.8 months, respectively.
Of the seven patients whose tumors could not be evaluated for DKK1 expression, one patient had a CR and 5 had SD, for a disease control rate of 86%. The median PFS in this group was 8.0 months. Three of these patients had known Wnt activating mutations.
“Given this correlation [between] higher DKK1 expression [and] Wnt activating mutations, one could consider that, at a minimum, these patients would have had a higher DKK1 expression as well,” Dr. Arend said.
She and her colleagues also found that patients with PIK3CA activating mutations and two or fewer prior lines of therapy had a 33% overall response rate (1 CR, 1 PR), compared with 0% for patients without these mutations who had two or fewer prior therapies. Patients with PIK3CA activating mutations also had a better disease control rate (67% vs. 40%) and median PFS (5.6 months vs. 1.8 months).
Although Dr. Arend did not present safety data from the study at SGO 2021, she reported some data in a video investor call for Leap Therapeutics, which is developing DKN-01. She said the most common treatment-emergent adverse events with DKN-01 were nausea in 28.8% of patients, fatigue in 26.7%, and constipation in 11.5%. Serious events included acute kidney injury, dyspnea, nausea, and peripheral edema (occurring in 1.9% of patients each).
Monotherapy or combination?
In the question-and-answer session following Dr. Arend’s presentation, comoderator Joyce Liu, MD, of the Dana-Farber Cancer Institute in Boston, said that “even in the DKK1-high tumors, the activity of DKN-01 as a monotherapy is a little bit limited.”
She asked whether the future of targeting inhibitors in the Wnt/beta-catenin pathway will be limited to biomarker-specific populations or if agents such as DKN-01 should be used in combinations.
“I do think that we need a lot more data to determine,” Dr. Arend replied. “I think that there may be a subset of patients, especially those that don’t tolerate the [lenvatinib/pembrolizumab] combo who may have an upregulation of beta-catenin or a Wnt mutation who could benefit from monotherapy.”
Dr. Arend added that data from her lab and others suggest that DKN-01 in combination with other agents holds promise for improving outcomes in biomarker-selected populations.
The current study is funded by Leap Therapeutics. Dr. Arend disclosed advisory board activity for the company and others. Dr. Liu reported personal fees from several companies, not including Leap Therapeutics.
Among 29 patients with heavily pretreated EEC, outcomes of DKN-01 monotherapy were best in patients with Wnt activating mutations, high levels of DKK1 expression, or PIK3CA activating mutations.
Patients in these groups had better disease control rates and progression-free survival (PFS), reported Rebecca C. Arend, MD, of the University of Alabama at Birmingham.
“Future development will focus on biomarker-selected patients, specifically patients with Wnt activating mutations, high tumoral DKK1, and PIK3CA activating mutations,” Dr. Arend said at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10717).
She explained that DKK1 has been shown to modulate signaling in the Wnt/beta-catenin pathway, a key regulator of cellular functions in humans and animals that has been highly conserved throughout evolution.
“DKK1 activates P13 kinase/AKT signaling by binding to the CKAP4 receptor to promote tumor growth,” Dr. Arend explained.
Focus on monotherapy
Dr. Arend and colleagues conducted a phase 2 basket trial of DKN-01 either as monotherapy or in combination with paclitaxel in patients with EEC, epithelial ovarian cancer, and carcinosarcoma (malignant mixed Mullerian tumor). The trial design required at least 50% of patients to have Wnt signaling alterations.
Dr. Arend reported results for 29 patients with EEC who received DKN-01 monotherapy.
There were nine patients with Wnt activating mutations. None of them achieved a complete response (CR) or partial response (PR), but six had stable disease (SD), for a disease control rate of 67%. Of the 20 patients without Wnt activating mutations, 1 achieved a CR, 1 achieved a PR, and 3 had SD, for a disease control rate of 25%.
The median PFS was 5.5 months in patients with Wnt activating mutations and 1.8 months in patients without the mutations.
“Importantly, patients whose tumors have a Wnt activating mutation have a correlation with increased tumoral expression of DKK1 by 14.4-fold higher,” Dr. Arend noted.
When she and her colleagues analyzed patients by DKK1 expression, the team found that high levels of DKK1 correlated with better clinical outcomes. The disease control rate was 57% for patients in the highest third of DKK1 expression (1 PR, 3 SD) vs. 7% (1 SD) for those in the lowest two-thirds. The median PFS was 3 months and 1.8 months, respectively.
Of the seven patients whose tumors could not be evaluated for DKK1 expression, one patient had a CR and 5 had SD, for a disease control rate of 86%. The median PFS in this group was 8.0 months. Three of these patients had known Wnt activating mutations.
“Given this correlation [between] higher DKK1 expression [and] Wnt activating mutations, one could consider that, at a minimum, these patients would have had a higher DKK1 expression as well,” Dr. Arend said.
She and her colleagues also found that patients with PIK3CA activating mutations and two or fewer prior lines of therapy had a 33% overall response rate (1 CR, 1 PR), compared with 0% for patients without these mutations who had two or fewer prior therapies. Patients with PIK3CA activating mutations also had a better disease control rate (67% vs. 40%) and median PFS (5.6 months vs. 1.8 months).
Although Dr. Arend did not present safety data from the study at SGO 2021, she reported some data in a video investor call for Leap Therapeutics, which is developing DKN-01. She said the most common treatment-emergent adverse events with DKN-01 were nausea in 28.8% of patients, fatigue in 26.7%, and constipation in 11.5%. Serious events included acute kidney injury, dyspnea, nausea, and peripheral edema (occurring in 1.9% of patients each).
Monotherapy or combination?
In the question-and-answer session following Dr. Arend’s presentation, comoderator Joyce Liu, MD, of the Dana-Farber Cancer Institute in Boston, said that “even in the DKK1-high tumors, the activity of DKN-01 as a monotherapy is a little bit limited.”
She asked whether the future of targeting inhibitors in the Wnt/beta-catenin pathway will be limited to biomarker-specific populations or if agents such as DKN-01 should be used in combinations.
“I do think that we need a lot more data to determine,” Dr. Arend replied. “I think that there may be a subset of patients, especially those that don’t tolerate the [lenvatinib/pembrolizumab] combo who may have an upregulation of beta-catenin or a Wnt mutation who could benefit from monotherapy.”
Dr. Arend added that data from her lab and others suggest that DKN-01 in combination with other agents holds promise for improving outcomes in biomarker-selected populations.
The current study is funded by Leap Therapeutics. Dr. Arend disclosed advisory board activity for the company and others. Dr. Liu reported personal fees from several companies, not including Leap Therapeutics.
FROM SGO 2021