FDA Approves Orserdu (elacestrant) for Patients with ESR1 Mutations in ER+, HER2- Advanced or Metastatic Breast Cancer

The Menarini Group (“Menarini”), a leading Italian pharmaceutical and diagnostics company, announced  the U.S. Food and Drug Administration (FDA)   approval of  Orserdu for the treatment of postmenopausal women or adult men, with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. Stemline Therapeutics (“Stemline”), a wholly-owned subsidiary of the Menarini Group, headquartered in New York and focused on bringing transformational oncology treatments for cancer patients, will commercialize Orserdu in the U.S.

“The FDA approval of Orserdu marks the first ever therapy for ER+, HER2- advanced or metastatic breast cancer patients with ESR1 mutations and we are very proud to offer a targeted therapy addressing this huge unmet need,” commented Elcin Barker Ergun, Chief Executive Officer of the Menarini Group. “We are grateful to the patients, investigators and administrators who participated in the clinical trials that led to this remarkable innovation.”

Orserdu is approved under the FDA’s Priority Review and Fast Track designation based on the results of the registrational Phase III trial EMERALD, that demonstrated statistically significant progression-free survival (PFS) with elacestrant vs SOC endocrine monotherapy (fulvestrant, letrozole, anastrozole, exemestane), meeting both primary endpoints in all patients and in those patients whose tumors harbor ESR1 mutations.

In the group of patients whose tumors had ESR1 mutations, elacestrant reduced the risk of progression or death by 45% (PFS HR=0.55, 95% CI: 0.39, 0.77) vs SOC. A post-hoc analysis of the PFS results based on the duration of prior CDK4/6i inhibitors (CDK4/6i) usage was presented at San Antonio Breast Cancer Symposium (SABCS) in December 2022. The median PFS was 8.6 months on elacestrant vs 1.9 months for SOC, in those patients whose tumors harbored ESR1 mutations and had been treated with a CDK4/6i for at least 12 months.

Safety data is consistent with the other endocrine therapies. Most of the adverse events (AEs), including nausea and musculoskeletal pain were grade 1 and 2. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia.

“Advanced or metastatic ER+, HER2- breast cancer pre-treated with endocrine-based therapy remains an area of unmet medical need. The last endocrine therapy approved was about 20 years ago, and effective endocrine options for this patient population are needed,” said Dr. Aditya Bardia, MD, MPH, Director of Breast Cancer Research at Mass General Cancer Center, Associate Professor at the Medicine Department at Harvard Medical School, and Principal Investigator for the EMERALD trial. “ESR1 mutations are a known driver of resistance to standard endocrine therapy, and so far, have been difficult to treat. The approval of elacestrant is welcomed as it offers a novel option for patients with ER+, HER2- metastatic breast cancer. This therapy targets the ESR1 mutations in metastatic breast cancer and provides patients with a convenient oral once-daily dose.”

“Each year 300,000 Americans are diagnosed with breast cancer and metastatic breast cancer causes the vast majority of deaths from the disease: more than 43,000 annually. We urgently need new and better treatment options to extend and improve the lives of people with metastatic breast cancer,” said Sonya Negley, Executive Director, Metavivor. “We are thrilled to see the approval of Orserdu, a new oral endocrine therapy, for patients who have tumors that harbor ESR1 mutations, which are present in up to 40% of ER+, HER2- advanced or metastatic breast cancer. We advise patients to get tested for ESR1 mutations at progression in their metastatic treatment, so that their healthcare team can identify the right treatment options for their disease.“

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https://en.wikipedia.org/wiki/Elacestrant

FDA Approves Orserdu (elacestrant) for Patients with ESR1 Mutations in ER+, HER2- Advanced or Metastatic Breast Cancer

Specific sequence of drugs reduces cost of treating metastatic breast cancer while preserving quality of life

The researchers developed three different computer models to predict how a hypothetical set of 10,000 patients with specific types of metastatic breast cancer would respond to different sequences and types of chemotherapy. For this study, the patient's cancer was either no longer responding to hormone therapies (endocrine resistant) or was a type of the disease called triple-negative breast cancer.

Currently, there are many chemotherapy choices to treat metastatic breast cancer. Oncologists have some preferences of which drugs to use early in treatment, but there is little clear evidence on the best order in which to give the drugs. The researchers consulted oncologists and experts in the field to choose which chemotherapy drugs were preferred choices to include in the study.

Mimicking clinical practice, and based upon existing data, the researchers then assumed that if a person started treatment with one drug, they would change to a second-choice treatment after their cancer stopped responding to the first drug, or if the side effects weren't tolerable. The purpose of the study was to test whether putting the drugs in one sequence compared to another could keep the patient on treatment for similar times while decreasing their side effect and/or cost burden.

"The cost of cancer drugs in the U.S. has rapidly increased, even for generics. As a society, we urgently need more strategies to reduce cancer drug costs without compromising outcomes, and our analysis provides quantifiable evidence to help providers choose lower priced, but equally effective sequences of drugs," said Stephanie B. Wheeler, PhD, MPH, professor of health policy & management at UNC Gillings and associate director of community outreach and engagement at UNC Lineberger and corresponding author of the article. "More spending on cancer care does not necessarily confer greater health benefits."

The costs calculated in this study were inclusive of medical and nonmedical costs borne by patients, including lost productivity. In this simulation, after two years, nearly all women would have completed the first three sets of treatment, but the cancer would cause the death of about one-third of the women. Productivity days lost due to sickness were similar across chemotherapy sequences, so most of the cost difference was due to drug savings. In the simulation, patients were placed in three groups, depending on what treatments they had already received for earlier episodes of breast cancer.

Outcomes in the three groups were:

• For people who had not previously received the common chemotherapy drug categories, including a taxane (e.g., paclitaxel) or an anthracycline (e.g., capecitabine), treatment with paclitaxel then capecitabine followed by doxorubicin corresponded to the highest expected gains in quality of life and lowest costs.
• For people who had previously received a taxane and an anthracycline drug, treatment with carboplatin, followed by capecitabine, followed by eribulin, corresponded to the highest expected gains in quality of life and lowest costs.
• For people who had previously received a taxane but not an anthracycline, treatment sequences beginning with capecitabine or doxorubicin, followed by eribulin, were most cost-effective.

"The drugs we studied are already recommended and reimbursed for the treatment of metastatic breast cancer, but the optimal sequencing of them has been unclear, which has led to considerable variation in physician preference and practice. Our study suggests that treatment sequencing approaches that minimize costs early may improve the value of care," Wheeler said. "The implications of this study are fairly straightforward for medical oncologists and those developing value-based clinical pathways to implement in practice now."

UNC Lineberger's Katherine E. Reeder-Hayes, MD, MBA, MSc, section chief of breast oncology and associate professor of medicine at UNC School of Medicine and one of the study's authors, said the treatment choices for metastatic breast cancer are constantly changing, and new options for targeted therapy have emerged even since this study was conducted. "Many oncologists and patients find that there aren't any more targeted therapies that fit the cancer's molecular profiles, so they are left with the choice of a number of chemotherapy drugs that may feel pretty similar or have an unclear balance of pros and cons.

"In that scenario, I hope our study will help expand the framework that we use to make these decisions from one where we just think about the biologic action of the drug to one where we also consider the bigger picture of what the treatment experience is like for the patient, including their financial burden, investment of time, and side effects," Reeder-Hayes added. "The most potent drug isn't always the next best choice depending on what the patient values and wants to accomplish with their treatment."

Looking ahead, the researchers have developed a financial navigation program to further support patients in managing the out-of-pocket costs of their cancer care. This program has been effective and well received by patients, caregivers and providers. The team is currently scaling up the intervention in nine rural and non-rural oncology practices across North Carolina to understand how well it works in different care settings. Cancer patients who need financial support managing the cost of their cancer care are being recruited for this undertaking.

Ref : https://ascopubs.org/doi/10.1200/JCO.21.02473

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.

New small molecule inhibitor could be a safe and first-line treatment for metastatic breast cancer

Mesupron® (see structure below) is a new small molecule inhibitor, taken as a pill, that inhibits the uPA system. The results from a recent phase II clinical study suggest that the drug could be a safe and first-line treatment that extends progression-free survival for metastatic breast cancer patients, when combined with the chemotherapeutic drug Capecitabine.

The study included 132 patients with metastatic breast cancer from 20 centers in five countries. In the trial, patients who took Mesupron combined with Capecitabine went without the return of disease for a median 8.3 months after the therapy. Patients who only took Capecitabine had a progression-free survival of 7.5 months.

"The combination of oral agents was convenient for and well tolerated by the patients," says Goldstein. "Plans for future studies are ongoing."

The drug was developed by WILEX, a German pharmaceutical company that focuses on the development of small molecule inhibitors and other new targeted cancer drugs designed to give patients treatment options with fewer side effects than traditional chemotherapy. In the Phase II study, Goldstein and her collaborators also investigated the safety and efficacy of the drug, as well as the objective response rate  the patient population who had no sign of disease after a specific amount of time.

Nine percent of the patients who received only Capecitabine had a complete objective response after 24 weeks. The objective response rate among the patients taking the combination therapy was nearly twice that, at 17 percent. The researchers also looked at different subgroups of participants to try to identify which patients might receive the most benefit from a combination therapy involving Mesupron. Among 109 Caucasian patients, the progression free survival was 7.5 months for patients who received Capecitabine alone, and 9.1 months for those who also received Mesupron.

The drug also showed a significant improvement for patients who had previously received treatment  before their disease became metastatic. In the subgroup of patients (n=95) who received adjuvant chemotherapy following the primary diagnosis of breast cancer, progression free survival improved from 4.3 months in the Capecitabine alone group to 8.3 months in the Mesupron combination group.....

Ref : http://www.fccc.edu/information/news/press-releases/2012/2012-12-07-SABC-Goldstein-WILEX.html

New small molecule inhibitor could be a safe and first-line treatment for metastatic breast cancer