Where Big Pharmas Faltered, Stemline Succeeds and Lands FDA Nod in Breast Cancer

Hormone therapies are well established in breast cancer treatment, working by blocking or reducing levels of hormones that feed tumor growth. If the disease progresses, the next line of therapy includes an injectable drug that specifically targets the estrogen receptor on cancer cells. Several big pharmaceutical companies have been trying to develop drugs that work the same way, but in a more convenient pill formulation. Stemline Therapeutics has beaten all of them to win the first FDA approval of an oral medicine in this drug class.

The Friday regulatory decision for the drug, elacestrant, covers postmenopausal women or adult men whose breast cancer has progressed after at least one line of hormone therapy. Stemline, a New York-based subsidiary of Italian company Menarini Group, will market its new once-daily pill under the name “Orserdu.”

The Stemline drug is what’s called a selective estrogen receptor degrader (SERD). The first such drug to reach the market was Faslodex, an AstraZeneca cancer treatment that became a blockbuster following its 2002 approval. But generic versions launched in recent years have eaten away at Faslodex sales, which totaled $431 million in 2021. The branded AstraZeneca medicine and the follow-on generic SERDs are all given as intramuscular injections into the buttocks.

The FDA decision for Orserdu is based on the results of a Phase 3 test that enrolled 478 patients with advanced breast cancer that was classified as estrogen receptor (ER) positive and HER2 negative. The total enrollment included 228 patients whose breast cancer also had a mutation called ESR1. All of the study participants had cancer that progressed after one or two earlier hormone therapies. Patients were randomly assigned to receive the study drug or standard of care hormone therapies, including Faslodex.

The main goal of the study was to measure progression-free survival, which is how long patients lived without their cancer worsening. In the patients with ESR1 mutations, median progress-free survival was 3.8 months in the Orserdu arm versus 1.8 months in the control arm. The FDA said an exploratory analysis in the patients whose cancer did not have the ESR1 mutation indicated that the improvement observed in all randomized patients was due primarily to the results in patients with ESR1 mutations. The FDA nod for Orserdu covers only these patients. That mutation must be detected by a companion diagnostic from Guardant Health, which also won FDA approval.

“ESR1 mutations are a known driver of resistance to standard endocrine therapy, and so far, have been difficult to treat,” Aditya Bardia, director of breast cancer research at Mass General Cancer Center and the principal investigator for Phase 3 study, said in a prepared statement. “The approval of elacestrant is welcomed as it offers a novel option for patients with ER positive, HER2 negative metastatic breast cancer.”

The most common adverse effects observed in the studies include nausea, muscle pain, higher cholesterol, increased levels of liver enzymes, and fatigue. Those side effects are comparable to reactions to Faslodex.

Menarini acquired global rights to Orserdu in 2020 from Radius Health, which led clinical development of the small molecule. Approval of Orserdu means Radius will receive milestone payments as well as royalties from sales of the drug. Menarini is responsible for further development of the drug in other markets.

Orserdu’s approval follows the clinical trial stumbles of oral SERDs from big pharma companies. Last March, Sanofi reported the Phase 2 failure of drug candidate amcenestrant in advanced ER positive, HER2 negative breast cancer. Sanofi withdrew from oral SERD race last summer following a Phase 3 of that drug as a first-line therapy. Meanwhile, Roche’s oral SERD, giredestrant, failed its Phase 2 test. AstraZeneca is still in the hunt with an oral SERD called camizestrant. Last October, the pharma giant reported Phase 2 results showing both doses of the drug led improvement in progression-free survival compared to treatment with Faslodex.

Two other recent regulatory approvals expanded the treatment options for cancer patients. Here’s a recap of those decisions:

Eli Lilly Lands FDA Nod in Mantle Cell Lymphoma

Eli Lilly’s pirtobrutinib, a cancer drug added to its pipeline via the $8 billion acquisition of Loxo Oncology in 2019, is now FDA approved for treating a rare blood cancer called mantle cell lymphoma (MCL). Lilly will market the pill as “Jaypirca.”

MCL is a cancer of B lymphocytes, a type of white blood cell. It’s named for the mantle zone of the outer edge of lymph nodes, where this type of cancer often begins. Jaypirca is indicated for those whose MCL has relapsed or has not responded to at least two lines of systemic therapy, including a class of drugs that blocks Bruton’s tyrosine kinase (BTK), an enzyme that plays a role in the proliferation of blood cancers.

Jaypirca is a non-covalent, or reversible, BTK inhibitor. That capability means it can reestablish BTK inhibition in MCL patients who were previously treated with a covalent BTK-inhibitor. The new Lilly drug provides another treatment option for those who can’t tolerate BTK inhibitors as well as those whose cancer progressed during treatment with a covalent BTK-blocking drug. Michael Wang, a professor of lymphoma and myeloma at the University of Texas MD Anderson Cancer Center, said in a prepared statement that Jaypirca could extend the length of time that patients may benefit from a therapy that works by BTK inhibition.

The FDA decision for Jaypirca was an accelerated approval. Lilly said that the confirmatory study required of such speedy approvals is currently enrolling patients.

Merck’s Keytruda Is Approved as Adjuvant Therapy for Lung Cancer

Keytruda, the mega-blockbuster Merck immunotherapy whose long list of approved uses includes several in non-small cell lung cancer (NSCLC), has notched another one. The agency approved the drug as an adjuvant, a treatment given after a primary treatment, such as surgery, to keep cancer from returning. The FDA decision permits the Merck drug to be used after surgical removal of NSCLC tumors classified according to size as stage Ib, II, or IIIA.

This latest Keytruda approval was based on the results of a placebo-controlled Phase 3 study that enrolled 1,177 patients, the vast majority of whom had received adjuvant chemotherapy. Those patients were randomly assigned to receive intravenously infused Keytruda or a placebo administered every three weeks for up to one year.

The main goal was to measure disease-free survival—how long patients lived without any signs or symptoms of cancer. The FDA said that the trial met the main goal in the overall study population. In the patients who had previously received chemo as a adjuvant, median disease-free survival was 58.7 months compared to 34.9 months in the placebo arm. Approval of Keytruda as an adjuvant covers NSCLC patients who received adjuvant chemotherapy following surgery.

Public domain image by the National Cancer Institute