Lilly Receives Additional FDA Approval for Verzenio (abemaciclib), as Initial Treatment for Advanced Breast Cancer

In continuation of my update on Abemaciclib

Eli Lilly and Company  announced the U.S. Food and Drug Administration (FDA) has approval of  Verzenio (abemaciclib) in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. This additional FDA approval marks the third indication for Verzenio within five months. In September 2017, Verzenio became the first and only cyclin-dependent kinase (CDK)4 & 6 inhibitor approved in combination and as a single agent in metastatic breast cancer. Specifically, Verzenio was approved for use in combination with fulvestrant for the treatment of women with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy, and as monotherapy for the treatment of adult patients with HR+, HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.

The recommended dose of Verzenio in combination with an AI is 150 mg orally twice daily, continued until disease progression or unacceptable toxicity. Verzenio is available in four tablet strengths (200 mg, 150 mg, 100 mg, and 50 mg).

This approval of Verzenio as initial therapy in combination with an AI is based on the efficacy and safety demonstrated in the pivotal MONARCH 3 clinical trial. MONARCH 3 is a Phase 3, randomized, double-blind, placebo-controlled trial evaluating Verzenio in combination with an AI as initial endocrine-based therapy that enrolled 493 postmenopausal women with HR+, HER2- advanced breast cancer who had no prior systemic treatment for advanced disease. In patients who received neoadjuvant/adjuvant endocrine therapy, a disease-free interval of more than 12 months since completion of endocrine therapy was required. This Verzenio new drug application was given Priority Review as part of the FDA's Expedited Programs for Serious Conditions, a program used for therapies that address an unmet medical need in the treatment of serious or life-threatening conditions, such as metastatic breast cancer. Verzenio was also granted Breakthrough Therapy Designation in 2015 based on the Phase 1 JPBA trial.

In MONARCH 3, Verzenio dosed orally at 150 mg twice daily on a continuous schedule with an AI demonstrated a greater than 28-month median progression-free survival (PFS) in patients who received initial endocrine-based therapy for metastatic disease (28.2 months [95% CI: 23.5-NR] vs 14.8 months [95% CI: 11.2-19.2] with placebo plus an AI [HR: 0.54; 95% CI: 0.418-0.698, P <0.0001]). In patients with measurable disease who received Verzenio plus an AI (n=267), an objective response rate of 55.4 percent was achieved (ORR; defined as complete response plus partial response [CR + PR], and based upon confirmed responses; PR defined as ≥30% reduction in target lesions)¹ (n=148; 95% CI: 49.5-61.4), with 52.1 percent of patients having achieved a PR (n=139) and 3.4 percent having achieved a CR (n=9).² In comparison, in the placebo-plus-AI group of patients with measurable disease (n=132), ORR was 40.2 percent (n=53; 95% CI: 31.8-48.5), with all women being partial responders. Median duration of response (DoR) was 27.4 months with Verzenio plus an AI (95% CI: 25.7-NR) versus 17.5 months with placebo plus an AI (95% CI: 11.2-22.2).

"This approval is an important milestone, as it shows that Verzenio plus an aromatase inhibitor substantially reduced tumor size and delayed disease progression in women with HR+, HER2- metastatic breast cancer. Notably, the MONARCH 3 trial included patients with certain concerning clinical characteristics, such as a pattern of disease that spread to the liver," said Joyce O'Shaughnessy, M.D., Celebrating Women Chair in Breast Cancer Research and chair, Breast Cancer Research Program, Baylor University Medical Center, Texas Oncology and U.S. Oncology, Dallas, TX. "This information will help inform treatment decisions for each patient, which can be complicated in advanced breast cancer."

The labeling for Verzenio contains warnings and precautions for diarrhea, neutropenia, hepatotoxicity, venous thromboembolism, and embryofetal toxicity. Instruct patients at the first sign of loose stools to initiate antidiarrheal therapy, increase oral fluids, and notify their healthcare provider. Perform complete blood counts and liver function tests prior to the start of Verzenio treatment, every two weeks for the first two months, monthly for the next two months, and as clinically indicated. Based on results, Verzenio may require dose modification. Monitor patients for signs and symptoms of thrombosis and pulmonary embolism and treat as medically appropriate. Advise patients of potential risk to a fetus and to use effective contraception. See full Prescribing Information for further management instructions. The most common adverse reactions in the MONARCH 1, 2, and 3 trials (all grades, ≥20%) were diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, and thrombocytopenia.

"The speed with which our team has been able to work with the FDA to gain approval for this additional Verzenio indication underscores Lilly's commitment to delivering meaningful medicines that can help more people living with advanced breast cancer," said Sue Mahony, Ph.D., senior vice president and president of Lilly Oncology. "Verzenio has now been developed, studied and clinically proven in three key trials to be effective for women with HR+, HER2- metastatic breast cancer – helping to ensure we are providing support to those who need it most."

"For those facing a diagnosis of metastatic breast cancer or learning that their disease has spread further, each new indication and clinical development is critical," said Marc Hurlbert, Ph.D., chairman, Metastatic Breast Cancer Alliance. "Today's news represents continued progress towards helping more people living with this devastating disease."

Lilly Receives Additional FDA Approval for Verzenio (abemaciclib), as Initial Treatment for Advanced Breast Cancer

FDA Approves Verzenio (abemaciclib) for Certain Advanced or Metastatic Breast Cancers

 

We know that, Abemaciclib is a kinase inhibitor for oraladministration. It is a white to  yellow powder with the empirical formula C₂₇H₃₂F₂N₈

and a molecular weight 506.59.

The chemical name for abemaciclib is 2-Pyrimidinamine,
N-[5-[(4-ethyl-1-piperazinyl)methyl]-2-pyridinyl]-5-fluoro-4-[4fluoro-2-methyl-1-(1-methylethyl)-1H-benzimidazol-6-yl]-Abemaciclib  has the above  structure:

The U.S. Food and Drug Administration today approved Verzenio (abemaciclib) to treat adult patients who have hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negativeadvanced or metastatic breast cancer that has progressed after taking therapy that alters a patient’s hormones (endocrine therapy). Verzeniois approved to be given in combination with an endocrine therapy, called fulvestrant, after the cancer had grown on endocrine therapy. It isalso approved to be given on its own, if patients were previously treated with endocrine therapy and chemotherapy after the cancer hadspread (metastasized).

"Verzenio provides a new targeted treatment option for certain patients with breast cancer who are not responding to treatment, and unlike other drugs in the class, it can be given as a stand-alonetreatment to patients who were previously treated with endocrine therapy and chemotherapy," said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

Combination treatment with CDK4/6 inhibitor improves progression-free survival in HR breast cancer patients

The addition of the CDK4/6 inhibitor ribociclib to letrozole therapy significantly improves progression-free survival in postmenopausal women with hormone receptor-positive advanced breast cancer, researchers reported today at the ESMO 2016 Congress in Copenhagen.

The first interim analysis of data from the randomized, double-blind MONALEESA study showed a 44% improvement in progression-free survival with ribociclib plus letrozole as a first-line treatment combination.

"This was THE definitive study to demonstrate the superiority of the combination of ribociclib and letrozole over letrozole alone," said principle investigator, Professor Gabriel Hortobagyi, from the University of Texas MD Anderson Cancer Center in Houston, Texas, US.

Researchers randomized 668 postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer, who had not undergone any prior systemic treatment, to ribociclib (600 mg/day, 3 weeks on/1 week off) and letrozole (2.5 mg/day, continuous), or letrozole plus placebo.

                                

ribociclib                                                                                  letrozole

In the ribociclib arm, there was a 44% improvement in the primary objective of progression-free survival compared to the placebo arm (HR: 0.556, p = 0.00000329). Median progression-free survival was 14.7 months in the placebo arm, but was not reached in the ribociclib arm at data cut-off.

"The results of this trial represent a compelling proof of principle, and suggest a paradigm shift in metastatic, HR+ breast cancer. They also suggest that testing combinations of ribociclib with other inhibitors of various signaling pathways might lead to additional progress in the management of several subtypes of breast cancer," Hortobagyi said.

Patients with measurable disease at baseline showed a significantly higher objective response rate to ribociclib plus letrozole compared to letrozole alone (53% vs. 37%; p=0.00028), and improved clinical benefit rate (80% vs. 72% p=0.02).

Serious adverse events occurred in fewer than 5% of patients in both arms but other adverse events were significantly more common in the ribociclib arm. Neutropenia occurred in 59% of patients in the ribociclib arm compared to 1% of the placebo arm; leukopenia occurred in 21% vs 1%; lymphopenia in 7% vs. 1%, and patients in the ribociclib arm had a higher incidence of elevated alanine aminotransferase and elevated aspartate aminotransferase.

The number of deaths in the study was too low to enable a reliable analysis of the impact of ribociclib therapy on overall survival.

Commenting on the findings, Professor Giuseppe Curigliano, Director of the New Drugs and Early Drug Development for Innovative Therapies Division at the European Institute of Oncology, Milan, Italy, said, "I believe the results of this study are significant because now we have a new CDK4/6 inhibitor for patients with estrogen-receptor positive metastatic breast cancer, in addition to palbociclib (already FDA approved) and abemaciclib (under development)."

"The addition of ribociclib to letrozole does increase the rate of toxicity, but overall, if we evaluate the magnitude of clinical benefit, there is definitely a benefit to be gained from adding ribociclib."

Curigliano also suggested that further studies of ribociclib should examine the use of cancer biomarkers to better identify patients who would respond to the combination.

Lilly Announces Results From MONARCH 1 Trial Of Abemaciclib Monotherapy

In  continuation of my update on abemaciclib

Eli Lilly and Company (NYSE: LLY)    announced the 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).

  abemaciclib

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.

"After endocrine therapies are no longer considered appropriate for HR+ metastatic breast cancer patients, when the disease is refractory or aggressive, chemotherapy is the only option. The side effects can be distressing and may be long lasting, limiting the options for patients," said José Baselga, M.D., Ph.D., physician-in-chief and chief medical officer, Memorial Sloan Kettering Cancer Center, and senior study author. "To see this level of anti-tumor activity, combined with the toxicity profile observed in MONARCH 1, is compelling."

At the final analysis of response (minimum of 12 months follow-up), patients treated with abemaciclib achieved an ORR of 19.7 percent (95% confidence interval (CI): 13.3 – 27.5%), with a median time to response of 3.7 months and a median DoR of 8.6 months. The median PFS was six months with a CBR (defined as patients who achieved complete response, partial response or stable disease for six months or longer) of 42.4 percent. Of the 13 patients who remained on treatment at the time of this analysis, nine were responders and four had stable disease (SD).

"In this population of heavily pretreated patients with a particularly poor prognosis, abemaciclib has shown promising single agent activity and tolerability," said Richard Gaynor, M.D., senior vice president, product development and medical affairs for Lilly Oncology. "These data reinforce our belief in abemaciclib as a potential best-in-class CDK 4 and CDK 6 inhibitor and add to the growing body of evidence that sustained target inhibition can lead to improved patient outcomes."

The safety and toxicity profile of twice daily, continuously dosed abemaciclib was consistent with previous Phase 1 experience. The most common grade 3 non-laboratory treatment emergent adverse events (AEs) were diarrhea (19.7%) and fatigue (12.9%), with no grade 4 non-laboratory events reported. The most common laboratory AEs were neutropenia (22.3% grade 3, 4.6% grade 4) and leukopenia (27.4% grade 3) in this population; 7.6 percent of patients discontinued treatment due to AEs, one due to diarrhea.

Beyond MONARCH 1, Lilly has an active clinical development program studying abemaciclib in breast cancer. Abemaciclib is being evaluated in two Phase 3 clinical trials: MONARCH 2 to evaluate the combination of abemaciclib and fulvestrant for treatment of HR+, HER2- advanced or metastatic breast cancer in postmenopausal women, and MONARCH 3 to evaluate the combination of abemaciclib and a nonsteroidal aromatase inhibitor in HR+, HER2- locoregionally recurrent or metastatic breast cancer in postmenopausal women.

Lilly plans to publish further data from the MONARCH 1 trial later this year.

About Metastatic Breast Cancer

Breast cancer is the most common cancer in women worldwide with nearly 1.7 million new cases diagnosed in 2012.1 In the U.S. this year, approximately 246,660 new cases of invasive breast cancer will be diagnosed and about 40,450 people will die from breast cancer.2 Of all early stage breast cancer cases diagnosed in the U.S., approximately 30 percent will become metastatic, spreading to other parts of the body. In addition, an estimated six to 10 percent of all new breast cancer cases are initially diagnosed as being stage IV, or metastatic.3 Metastatic breast cancer is considered incurable, but is generally treatable.

About Abemaciclib

Abemaciclib (LY2835219) is an investigational, oral cell cycle inhibitor, designed to block the growth of cancer cells by specifically inhibiting cyclin-dependent kinases, CDK 4 and CDK 6. In many cancers, uncontrolled cell growth arises from a loss of cell cycle regulation due to increased signaling from CDK 4 and CDK 6. Abemaciclib inhibits both CDK 4 and CDK 6, and was shown in cell-free enzymatic assays to be most active against Cyclin D 1 and CDK 4.

In 2015, the U.S. Food and Drug Administration granted abemaciclib Breakthrough Therapy Designation based on data from the breast cancer cohort expansion of the company's Phase 1 trial, JPBA, which studied the efficacy and safety of abemaciclib in women with advanced or metastatic breast cancer. In addition to its current MONARCH clinical trials evaluating abemaciclib in breast cancer, a Phase 3 trial of abemaciclib in lung cancer is also underway.

Investigational drug abemaciclib shows durable clinical activity for variety of cancer types

In continuation of my  updates on palbociclib (Ibrance)  and letrozole

Bottom Line: The investigational anticancer therapeutic abemaciclib, which targets CDK4 and CDK6, showed durable clinical activity when given as continuous single-agent therapy to patients with a variety of cancer types, including breast cancer, non-small cell lung cancer (NSCLC), glioblastoma, and melanoma, according to results from a phase I clinical trial.

Journal in Which the Study was Published: Cancer Discovery, a journal of the American Association for Cancer Research.

Senior authors: Amita Patnaik, MD, associate director of clinical research at South Texas Accelerated Research Therapeutics in San Antonio, Texas, and Geoffrey I. Shapiro, MD, PhD, director of the Early Drug Development Center at the Dana-Farber Cancer Institute in Boston.

Background: In February 2015, the U.S. Food and Drug Administration (FDA) approved the CDK4/6 inhibitor palbociclib (Ibrance) for use in combination with the aromatase inhibitor letrozole for treating postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer.

  letrozole  palbociclib

The oral CDK4/6 inhibitor abemaciclib is a very different molecule from palbociclib, with distinct attributes that contribute to its discrete therapeutic effects, in particular, its single-agent activity, according to Shapiro. For example, abemaciclib has greater selectivity for CDK4 compared with palbociclib, which may explain why it does not affect white blood cell counts as severely, allowing it to be taken on a continuous schedule without treatment holidays, he said. Abemaciclib also penetrates the central nervous system, whereas palbociclib does not, raising the possibility that it could be used to treat primary or metastatic brain tumors, he added.

 abemaciclib

How the Study Was Conducted and Results: Patnaik, Shapiro, and colleagues enrolled 225 patients with a variety of types of advanced cancer in the phase I clinical trial designed to evaluate the safety and preliminary efficacy of abemaciclib. In the dose escalation phase, the researchers determined that the maximum tolerated dose was 200 milligrams (mg) every 12 hours; the dose-limiting toxicity was grade 3 fatigue.

In the expansion phase, single-agent abemaciclib was administered to 47 patients with breast cancer, 68 with NSCLC, 17 with glioblastoma, 26 with melanoma, and 15 with colorectal cancer. Among these patients, the most common treatment-related adverse events were fatigue, diarrhea, nausea, vomiting, anorexia, weight loss, kidney dysfunction, and decreased red and white blood cell counts.

Radiographic responses were observed for some patients with breast cancer, NSCLC, and melanoma. Among the 36 patients with hormone receptor-positive breast cancer, 11 had a partial response, with four of the 11 responders having continued prior endocrine therapy, and an additional 18 patients had stable disease. Among the 68 patients with NSCLC, two had a partial response and 31 had stable disease; one patient who had a partial response and 12 who had stable disease were known to have KRAS-mutant NSCLC. Among the 26 patients with melanoma, one had a partial response and six had stable disease. Three of the 17 patients with glioblastoma had stable disease, with two of them continuing to receive treatment without disease progression for 19 and 23 cycles, respectively.

Author Comment: "These data show that abemaciclib is an oral drug that can be taken on a continuous schedule and achieve durable clinical activity against multiple tumors including breast and lung cancers," said Shapiro.

"The results of the trial supported the FDA decision to grant breakthrough therapy designation to abemaciclib (previously known as LY2835219) for patients with refractory hormone receptor-positive advanced or metastatic breast cancer," added Patnaik.

Limitations: Patnaik explained that because this study included 225 patients with different types of cancer, confirmatory clinical trials in specific patient populations are necessary to precisely define the role of abemaciclib in cancer care. Multiple clinical trials have already been initiated to evaluate abemaciclib as a treatment for certain groups of patients with breast cancer and NSCLC, as well as children with primary brain tumors and adults with brain metastases, she noted.

FDA grants Breakthrough Therapy Designation to Lilly's abemaciclib for treatment of metastatic breast cancer

Eli Lilly and Company (NYSE: LLY)   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.

According to the FDA, Breakthrough Therapy Designation is a process designed to expedite the development and review of drugs that are intended to treat a serious condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapy on a clinically significant endpoint.

FDA grants Breakthrough Therapy Designation to Lilly's abemaciclib for treatment of metastatic breast cancer