AKT inhibition not superior to everolimus for RCC

The AKT inhibitor MK-2206 was not superior to everolimus (Afinitor) for patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor inhibitors, according to a phase II trial from the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 3.68 months in the 29 patients randomized to MK-2206, versus 5.98 months in the 14 randomized to everolimus, leading to closure of the study, reported Eric Jonasch, MD, of the department of genitourinary medical oncology at MD Anderson, and his associates.

However, dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm.

“Whereas patients treated with everolimus for the large part had minimal changes in tumor size, MK-2206 induced a fairly dichotomous response dynamic, with [a few] patients demonstrating profound response, [but] a number of patients exhibiting rapid growth,” Dr. Jonasch and associates said (Ann Oncol. 2017 Jan 3. pii: mdw676. doi: 10.1093/annonc/mdw676).

Several studies have shown that upregulation of the PI3K/AKT pathway is associated with poor prognosis in renal cell carcinoma (RCC), making the pathway an attractive target for therapeutic intervention. The trial “results indicate that potential exists for effective blockade of the PI3K pathway in patients with RCC, but considerable work is required to better understand the nuances of this pathway before we can consistently modulate it to benefit patients with RCC,” the investigators said.

Molecular analysis failed to find a biomarker for response, but did demonstrate that deleterious tumor protein 53 or ataxia telangiectasia mutations or deletions were associated with poor prognosis. Among patients who progressed, 57.1% had TP53 or ATM aberrations; TP53 and ATM defects were absent in patients who did not progress.

Malfunction of DNA repair driven by TP53 and ATM gene modifications, the group said, “are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC ... This subcategory of patients clearly needs new approaches based on our emerging understanding of the significance of TP53 mutations in RCC biology.”

MK-2206 induced significantly more rash and pruritus than did everolimus, with dose reduction in 37.9% of MK-2206 versus 21.4% of everolimus patients.

Subjects were a median of 63.5 years old in the everolimus group and 59 years in the MK-2206 group. The majority of patients were white men. More than 65% of the patients had performance status 1 and around 60% were in the Memorial Sloan Kettering Cancer Center intermediate risk group. The majority of patients in both treatment arms had clear cell histology; 57.1% (8) in the everolimus group and 82.8% (24) in the MK-2206 group had lung metastasis; half of the everolimus and 59% (17) of MK-2206 subjects were previously treated with sunitinib (Sutent).

The National Institutes of Health funded the work. The authors reported no conflicts of interest.

[email protected]

The AKT inhibitor MK-2206 was not superior to everolimus (Afinitor) for patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor inhibitors, according to a phase II trial from the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 3.68 months in the 29 patients randomized to MK-2206, versus 5.98 months in the 14 randomized to everolimus, leading to closure of the study, reported Eric Jonasch, MD, of the department of genitourinary medical oncology at MD Anderson, and his associates.

However, dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm.

“Whereas patients treated with everolimus for the large part had minimal changes in tumor size, MK-2206 induced a fairly dichotomous response dynamic, with [a few] patients demonstrating profound response, [but] a number of patients exhibiting rapid growth,” Dr. Jonasch and associates said (Ann Oncol. 2017 Jan 3. pii: mdw676. doi: 10.1093/annonc/mdw676).

Several studies have shown that upregulation of the PI3K/AKT pathway is associated with poor prognosis in renal cell carcinoma (RCC), making the pathway an attractive target for therapeutic intervention. The trial “results indicate that potential exists for effective blockade of the PI3K pathway in patients with RCC, but considerable work is required to better understand the nuances of this pathway before we can consistently modulate it to benefit patients with RCC,” the investigators said.

Molecular analysis failed to find a biomarker for response, but did demonstrate that deleterious tumor protein 53 or ataxia telangiectasia mutations or deletions were associated with poor prognosis. Among patients who progressed, 57.1% had TP53 or ATM aberrations; TP53 and ATM defects were absent in patients who did not progress.

Malfunction of DNA repair driven by TP53 and ATM gene modifications, the group said, “are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC ... This subcategory of patients clearly needs new approaches based on our emerging understanding of the significance of TP53 mutations in RCC biology.”

MK-2206 induced significantly more rash and pruritus than did everolimus, with dose reduction in 37.9% of MK-2206 versus 21.4% of everolimus patients.

Subjects were a median of 63.5 years old in the everolimus group and 59 years in the MK-2206 group. The majority of patients were white men. More than 65% of the patients had performance status 1 and around 60% were in the Memorial Sloan Kettering Cancer Center intermediate risk group. The majority of patients in both treatment arms had clear cell histology; 57.1% (8) in the everolimus group and 82.8% (24) in the MK-2206 group had lung metastasis; half of the everolimus and 59% (17) of MK-2206 subjects were previously treated with sunitinib (Sutent).

The National Institutes of Health funded the work. The authors reported no conflicts of interest.

[email protected]

The AKT inhibitor MK-2206 was not superior to everolimus (Afinitor) for patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor inhibitors, according to a phase II trial from the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 3.68 months in the 29 patients randomized to MK-2206, versus 5.98 months in the 14 randomized to everolimus, leading to closure of the study, reported Eric Jonasch, MD, of the department of genitourinary medical oncology at MD Anderson, and his associates.

However, dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm.

“Whereas patients treated with everolimus for the large part had minimal changes in tumor size, MK-2206 induced a fairly dichotomous response dynamic, with [a few] patients demonstrating profound response, [but] a number of patients exhibiting rapid growth,” Dr. Jonasch and associates said (Ann Oncol. 2017 Jan 3. pii: mdw676. doi: 10.1093/annonc/mdw676).

Several studies have shown that upregulation of the PI3K/AKT pathway is associated with poor prognosis in renal cell carcinoma (RCC), making the pathway an attractive target for therapeutic intervention. The trial “results indicate that potential exists for effective blockade of the PI3K pathway in patients with RCC, but considerable work is required to better understand the nuances of this pathway before we can consistently modulate it to benefit patients with RCC,” the investigators said.

Molecular analysis failed to find a biomarker for response, but did demonstrate that deleterious tumor protein 53 or ataxia telangiectasia mutations or deletions were associated with poor prognosis. Among patients who progressed, 57.1% had TP53 or ATM aberrations; TP53 and ATM defects were absent in patients who did not progress.

Malfunction of DNA repair driven by TP53 and ATM gene modifications, the group said, “are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC ... This subcategory of patients clearly needs new approaches based on our emerging understanding of the significance of TP53 mutations in RCC biology.”

MK-2206 induced significantly more rash and pruritus than did everolimus, with dose reduction in 37.9% of MK-2206 versus 21.4% of everolimus patients.

Subjects were a median of 63.5 years old in the everolimus group and 59 years in the MK-2206 group. The majority of patients were white men. More than 65% of the patients had performance status 1 and around 60% were in the Memorial Sloan Kettering Cancer Center intermediate risk group. The majority of patients in both treatment arms had clear cell histology; 57.1% (8) in the everolimus group and 82.8% (24) in the MK-2206 group had lung metastasis; half of the everolimus and 59% (17) of MK-2206 subjects were previously treated with sunitinib (Sutent).

The National Institutes of Health funded the work. The authors reported no conflicts of interest.

[email protected]