CDK4/6 Inhibitor Shows Promise as Single Agent in HR+ Breast Cancer

Excerpt:

“As a single agent, abemaciclib has shown exciting potential in heavily pretreated patients with refractory, hormone-receptor (HR)–positive, HER2-negative advanced breast cancer, following phase II findings of the MONARCH 1 trial.

“Results of the single-arm study, which were presented during the 2016 ASCO Annual Meeting1, show that the CDK4/6 inhibitor induced a response rate of nearly 20% in this patient population. The median progression-free survival (PFS) was 6 months (95% CI 4.2-7.5) and the median overall survival (OS) was 17.7 months (95% CI, 16 to not reached). Previously, abemaciclib received a breakthrough therapy designation in this setting from the FDA in October 2015.”

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Lilly Announces Results from MONARCH 1 Trial of Abemaciclib Monotherapy

Excerpt:

“Eli Lilly and Company (LLY) today announced results from the MONARCH 1 Phase 2 study of abemaciclib, a cyclin-dependent kinase (CDK) 4 and CDK 6 inhibitor, in patients with hormone-receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. The data, which were presented at the 2016 American Society of Clinical Oncology (ASCO) Annual Meeting by Maura Dickler, M.D., of Memorial Sloan Kettering Cancer Center, showed that single-agent activity was observed in metastatic breast cancer patients, for whom endocrine therapy was no longer a suitable treatment option. The MONARCH 1 results (abstract #510) confirmed objective response (ORR), durability of response (DoR), clinical benefit rate (CBR) and progression-free survival (PFS).

“The single-arm study, designed to evaluate the safety and efficacy of abemaciclib monotherapy, enrolled 132 patients who were given 200 mg of abemaciclib orally every 12 hours until disease progression. Patients enrolled in the study were heavily pretreated, having experienced progressive disease on or after prior endocrine therapy, and had received prior chemotherapy with one or two chemotherapy regimens for metastatic disease. The primary objective of the trial was investigator-assessed ORR, with secondary endpoints of DoR, CBR and PFS.”

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FDA Expands Palbociclib Approval for Breast Cancer

“The Food and Drug Administration (FDA) has granted an expanded indication for the cyclin-dependent kinase 4/6 inhibitor palbociclib (Ibrance). The drug is now approved for use in combination with fulvestrant in women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer whose disease progressed following endocrine therapy.

“Palbociclib was initially approved in February 2015 for the treatment of estrogen receptor–positive, HER2-negative metastatic breast cancer, in women who had not yet received endocrine therapy. The new approval was granted under the FDA’s breakthrough therapy designation.

“The additional indication for palbociclib is based on results from the PALOMA-3 trial, which was stopped early in April 2015 after an interim analysis showed benefit in combination with fulvestrant when compared to fulvestrant and placebo.”


Targeted Therapy Combinations Still Key in Metastatic Melanoma

“Combinations of targeted therapies continue to advance toward full regulatory approval for patients with metastatic or unresected melanoma, given the substantial benefits seen with these agents. At this time, the FDA is considering two applications for separate combinations of BRAF and MEK inhibiting agents for patients with unresectable or metastatic BRAFV600 mutation-positive melanoma.

“ ‘The future of the treatment of melanoma is clearly going to be in combinations, both for targeted therapy and for immunotherapy,’ said Jeffrey S. Weber, MD, PhD, who recently joined the NYU Langone Medical Center. ‘Already, there is an FDA-approved combination therapy that is targeted; that is dabrafenib and trametinib. There are new combinations coming up, mainly concerning CDK 4/6 and MEK inhibitors in NRAS-mutated but BRAF wild-type melanoma, which is an unmet medical need.’ “


Lilly Receives FDA Breakthrough Therapy Designation for Abemaciclib – a CDK 4 and 6 Inhibitor – in Advanced Breast Cancer

“Eli Lilly and Company (NYSE: LLY) today announced that the U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation to abemaciclib, a cyclin-dependent kinase (CDK) 4 and 6 inhibitor, for patients with refractory hormone-receptor-positive (HR+) advanced or metastatic breast cancer. This designation is based on data from the breast cancer cohort expansion of the company’s Phase I trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. Patients in this cohort had received a median of seven prior systemic treatments. These data were presented at the San Antonio Breast Cancer Symposium in 2014.”


Ibrance Trial Stopped Early Because of Strong Evidence of Drug's Efficacy in Metastatic ER+ HER2- Breast Cancer

“Pfizer Inc. PFE, +1.01% today announced that the Phase 3 PALOMA-3 trial for IBRANCE® (palbociclib) met its primary endpoint of demonstrating an improvement in progression-free survival (PFS) for the combination of IBRANCE plus fulvestrant compared with fulvestrant plus placebo in women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer following disease progression during or after endocrine therapy. The study was stopped early due to efficacy based on an assessment by an independent Data Monitoring Committee (DMC). These are the first randomized Phase 3 trial results for IBRANCE, a new anti-cancer medicine with the novel mechanism of cyclin-dependent kinase 4/6 (CDK 4/6) inhibition.

“ ‘The results of this trial are especially important because they help us understand the potential of IBRANCE to improve outcomes in patients with this difficult to treat cancer. We’re gratified to be able to stop the trial early and are engaging in discussions with health authorities regarding a regulatory path forward,’ said Dr. Mace Rothenberg, senior vice president of Clinical Development and Medical Affairs and chief medical officer for Pfizer Oncology.

“The adverse events observed with IBRANCE in combination with fulvestrant in PALOMA-3 were generally consistent with their respective known adverse event profiles. Detailed efficacy and safety results from PALOMA-3 will be submitted for presentation at the American Society of Clinical Oncology (ASCO) 2015 Annual Meeting.”


Promising Drug Staves Off Cancer Worsening in Hormone Receptor-Positive Breast Cancer Patients

The gist: A drug called palbociclib may increase the amount of time that passes without cancer worsening for patients with advanced, estrogen receptor (ER)-positive, HER2-negative breast cancer. In a clinical trial, some patients were treated with palbociclib along with letrozole, and some were treated with letrozole alone. Patients who took both drugs went for twice as long without their cancer worsening than patients who took only letrozole. Learn more about palbociclib in breast cancer.

“In a groundbreaking study that offers new hope for women with advanced breast cancer, researchers from UCLA’s Jonsson Comprehensive Cancer Center have published final clinical trial results that showed the amount of time patients were on treatment without their cancer worsening (called progression-free survival) was effectively doubled in women with advanced breast cancer who took the experimental drug palbociclib.

“An investigational drug discovered and being developed by Pfizer Inc., palbociclib targets a key family of proteins (CDK4/6) responsible for cell growth by preventing them from dividing. Results of the multi-year phase 2 study showed a significant increase in PFS for patients with advanced breast cancer that was estrogen receptor positive (ER+), HER2-negative (HER2-), who were given a combination of the standard anti-estrogen treatment, letrozole, and palbociclib compared to letrozole alone.

” ‘We’re essentially putting the brakes on cell proliferation and causing these tumor cells to stop growing,’ said Dr. Richard Finn, associate professor of medicine at UCLA and lead author of the study.

“The study was published online ahead of print in the journal The Lancet Oncology.”


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…


An F876L Mutation in Androgen Receptor Confers Genetic and Phenotypic Resistance to MDV3100 (Enzalutamide)

“Castration resistant prostate cancer (CRPC) is the most aggressive, incurable form of prostate cancer. MDV3100 (enzalutamide), an antagonist of the androgen receptor (AR), was approved for clinical use in men with metastatic CRPC. Although this compound showed clinical efficacy, many initial responders later developed resistance. To uncover relevant resistant mechanisms, we developed a model of spontaneous resistance to MDV3100 in LNCaP prostate cancer cells. Detailed characterization revealed that emergence of F876L mutation in AR correlated with blunted AR response to MDV3100 and sustained proliferation during treatment. Functional studies confirmed that AR-F876L confers an antagonist-to-agonist switch that drives phenotypic resistance. Lastly, treatment with distinct anti-androgens or CDK4/6 inhibitors effectively antagonized AR-F876L function. Together, these findings suggest that emergence of F876L may 1) serve as a novel biomarker for prediction of drug sensitivity, 2) predict a “withdrawal” response to MDV3100, and 3) be suitably targeted with other anti-androgens or CDK4/6 inhibitors.”