Novel Olaparib Combination Shows Activity in Ovarian, Breast Cancers

“A combination treatment composed of the PARP inhibitor olaparib and the investigational PI3K inhibitor BKM120 demonstrated activity and safety for women with triple-negative breast cancer or high-grade serous ovarian cancer, according to study findings presented at the American Association for Cancer Research Annual Meeting.

“High-grade serous ovarian cancer and triple-negative breast cancer are similar in that they often have germline BRCA mutations, have a sensitivity to platinum agents and have high copy number alterations based on The Cancer Genome Atlas, according to study background. Further, preclinical data have suggested olaparib (Lynparza, AstraZeneca) is synergistic with BKM120 (Novartis) and BYL719 (Novartis) in both cancers.

“Ursula A. Matulonis, MD, medical director of gynecologic oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute and associate professor of medicine at Harvard University Medical School, and colleagues evaluated olaparib plus BKM120 in 12 patients with triple-negative breast cancer and 34 patients with high-grade serous ovarian cancer. Thirty-five patients had germline BRCA mutations.

“ ‘This is one area where we in ovarian cancer are in the forefront,’ Matulonis said during a press conference. ‘We are using an FDA-approved biomarker through germline BRCA status to basically say when a patient is eligible to receive olaparib.’ “


Targeted Therapy Combo Shows Benefit in Breast and Ovarian Cancer

“Combination treatment with the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib plus the phosphatidylinositol 3-kinase (PI3K) inhibitor BKM120 resulted in clinical activity in women with triple-negative breast cancer and those with high-grade serous ovarian cancer.

“Patients that had BRCA-mutant and BRCA wild-type tumors responded to the treatment.

“The results of this phase I trial were presented at a press briefing at the American Association for Cancer Research (AACR) Annual Meeting, held April 18 to 22 in Philadelphia.”


Adding Pictilisib to Anastrozole Treatment Might Improve Responses for Patients with Early-Stage, ER+, HER2-, Luminal B Breast Cancer

The gist: The drug pictilisib might improve response to treatment with the drug anastrozole for patients with early-stage, ER-positive, HER2-negative, luminal B breast cancer. In a clinical trial, patients who took pictilisib with anastrozole had better responses than patients who took anastrozole alone.

“The addition of pictilisib to anastrozole improved anti-proliferative response through the reduction of Ki67 in patients with early-stage breast cancer and particularly among those with luminal B tumors, according to study results presented at the San Antonio Breast Cancer Symposium…

“Schmid and colleagues evaluated data from 73 post-menopausal women with newly diagnosed breast cancer. All women had ER-positive, HER-2–negative disease. Fifty-three percent of the women had luminal A tumors, and 47% had luminal B tumors.

“Researchers randomly assigned patients 2:1 to the PI3K inhibitor pictilisib (GCD-0941, Genentech) plus 1 mg anastrozole (n=50) or anastrozole alone (n=23) for 2 weeks prior to surgery. The dose of pictilisib was reduced from 340 mg to 260 mg due to a concern for side effects demonstrated on other studies…

“ ‘The data presented show that the addition of the PI3 kinase inhibitor pictilisib significantly increases the anti-proliferative response of anastrozole in ER-positive breast cancer,’ Schmid said. ‘Subsequent analyses suggest increased benefit of pictilisib for patients with luminal B and highly proliferative tumors.’ ”


SABCS 2014: PI3K Inhibition With Pictilisib in Hormone Receptor–Positive Breast Cancer Not Ready for Prime Time

The gist: Researchers are hoping a treatment approach called ‘PI3K inhibition’ might improve outcomes for people with hormone receptor-positive breast cancer. But it’s unclear whether the approach will be successful, and a recent attempt did not give stellar results. In a clinical trial, researchers gave patients the PI3K inhibitor drug pictilisib along with the drug fulvestrant (Faslodex). It did not significantly lengthen the amount of time patients went without their cancer worsening. But later analysis showed that it did stave off cancer getting worse in certain patients: women whose breast cancer is both estrogen receptor-positive (ER+) and progesterone receptor–positive (PR+). Further research is needed to see if any PI3K drugs are particularly effective. For more information, click through to the full article and see this other article from Cancer Network.

“Interest is high in studying the PI3K pathway in hormone receptor–positive breast cancer, but it is not clear which of the PI3K inhibitors under development—if any—will be a ‘home run.’

“Adding the pan-class I selective PI3K inhibitor pictilisib to fulvestrant (Faslodex) did not significantly improve progression-free survival in women with estrogen receptor–positive breast cancer, but in an exploratory analysis of the trial, progression-free survival was significantly extended in women with both estrogen receptor–positive and progesterone receptor–positive breast cancer. The findings were presented at the 2014 San Antonio Breast Cancer Symposium (Abstract S2-02).

“ ‘When we considered only women with breast cancer positive for both estrogen receptor and progesterone receptor, adding pictilisib resulted in a significant doubling of progression-free survival in an exploratory analysis. We plan to investigate whether the benefit of pictilisib for women with estrogen receptor-/progesterone receptor–positive breast cancer holds true in an additional cohort of patients within this study,’ stated lead author Ian Krop, MD, Director of Clinical Research for the Breast Oncology Program at the Dana-Farber Cancer Institute, Boston.”


Squamous Lung Cancer ‘Master Protocol’ Brings Cancer Research into the 21st Century


Clinical trials help determine whether new cancer treatments are safe and effective, and they provide access to cutting-edge drugs that patients wouldn’t otherwise be able to have. But the clinical trial system is notoriously inefficient, slow, expensive, and laborious. Now, a new and ambitious clinical trial design called the Lung Cancer Master Protocol seeks to overhaul the system, promising to benefit patients and drug companies alike. Continue reading…


Melanoma: A 2013 ‘Progress Report’


The past year saw some remarkable advances in melanoma clinical research and treatment. This feature explores the most notable melanoma news of 2013: Continue reading…


Phase I Safety, Pharmacokinetic and Pharmacodynamic Study of SAR245408 (XL147), A Novel Oral Pan-Class I PI3K Inhibitor, in Patients with Advanced Solid Tumors

SAR245408 is a pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules (first 21 days of a 28-day period [21/7] and continuous once-daily dosing [CDD]), pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy.

 

SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600mg administered orally with CDD.


Conjunctival Melanomas Harbor BRAF and NRAS Mutations

The mutation BRAFV600E is found in conjunctival melanoma at approximately the same frequency as in cutaneous melanoma. The presence of this mutation should make this rare type of melanoma eligible for treatment with the BRAF inhibitors vemurafenib and dabrafenib, which have significant antitumor activity in BRAF V600E–mutant cutaneous melanoma. However, there are no published data on the use of BRAF inhibitors in patients with conjunctival melanoma. This letter reports that treatment of a patient with metastatic conjunctival melanoma using vemurafenib did not halt disease progression and had to be discontinued.  This could be due to the previously described frequent loss of the tumor suppressor PTEN and consequent activation of the PI3K pathway in conjunctival melanoma, warranting further studies of combination treatment of these tumors with BRAF and PI3K or AKT inhibitors.


ETV4 Promotes Metastasis in Response to Activation of PI3-Kinase and Ras Signaling in a Mouse Model of Advanced Prostate Cancer

“Combinatorial activation of PI3-kinase and RAS signaling occurs frequently in advanced prostate cancer and is associated with adverse patient outcome. We now report that the oncogenic Ets variant 4 (Etv4) promotes prostate cancer metastasis in response to coactivation of PI3-kinase and Ras signaling pathways in a genetically engineered mouse model of highly penetrant, metastatic prostate cancer. Using an inducible Cre driver to simultaneously inactivate Pten while activating oncogenic Kras and a fluorescent reporter allele in the prostate epithelium, we performed lineage tracing in vivo to define the temporal and spatial occurrence of prostate tumors, disseminated tumor cells, and metastases. These analyses revealed that though disseminated tumors cells arise early following the initial occurrence of prostate tumors, there is a significant temporal lag in metastasis, which is temporally coincident with the up-regulation of Etv4 expression in primary tumors. Functional studies showed that knockdown of Etv4 in a metastatic cell line derived from the mouse model abrogates the metastatic phenotype but does not affect tumor growth. Notably, expression and activation of ETV4, but not other oncogenic ETS genes, is correlated with activation of both PI3-kinase and Ras signaling in human prostate tumors and metastases. Our findings indicate that ETV4 promotes metastasis in prostate tumors that have activation of PI3-kinase and Ras signaling, and therefore, ETV4 represents a potential target of therapeutic intervention for metastatic prostate cancer.”