On December 11, 2024 Eli Lilly and Company (NYSE: LLY) reported results from the Phase 3 EMBER-3 study of imlunestrant, an investigational, oral selective estrogen receptor degrader (SERD), in patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC), whose disease progressed on a prior aromatase inhibitor (AI), with or without a CDK4/6 inhibitor (Press release, Eli Lilly, DEC 11, 2024, View Source [SID1234649042]). Imlunestrant demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) as monotherapy in patients with an ESR1 mutation versus standard of care endocrine therapy (SOC ET), reducing the risk of disease progression or death by 38%. Imlunestrant in combination with Verzenio (abemaciclib; CDK4/6 inhibitor) reduced the risk of progression or death by 43% versus imlunestrant alone, in all patients.

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These results were published in The New England Journal of Medicine and will be shared in a late-breaking oral presentation at the San Antonio Breast Cancer Symposium (SABCS) today, Wednesday, December 11 at 9:15 AM CT/10:15 AM ET. These data are being submitted to regulatory health authorities globally.

"The median progression free survival observed in EMBER-3 is among the most compelling we’ve seen in CDK4/6 pre-treated ER+, HER2- advanced breast cancer patients and indicates a potential shift in the therapy options we provide for these patients, which are currently very limited," said Komal Jhaveri, M.D., section head, endocrine therapy research and clinical director, early drug development at Memorial Sloan Kettering Cancer Center, and one of the study’s principal investigators. "The benefit and safety profile of the imlunestrant and abemaciclib combination signal a potential new all-oral option for patients."

In the EMBER-3 study, patients were randomized 1:1:1 to receive imlunestrant alone, SOC ET, or the imlunestrant-abemaciclib combination. Randomization was stratified by prior CDK4/6 inhibitor use, the presence of visceral metastases and geographic region. Patients enrolled as first line (1L) treatment for ABC (32%), following disease recurrence on or within 12 months of completing adjuvant AI, with or without CDK4/6 inhibitor for early breast cancer (EBC), or as second line (2L) treatment for ABC (64%), following progression on AI, with or without CDK4/6 inhibitor as initial therapy for ABC. Primary endpoints were investigator-assessed PFS of imlunestrant versus SOC ET therapy in patients with ESR1 mutations, imlunestrant versus SOC ET in all patients, and imlunestrant-abemaciclib versus imlunestrant in all patients.

Imlunestrant versus standard of care endocrine therapy

Imlunestrant significantly improved PFS versus SOC ET in patients with an ESR1 mutation. In patients with an ESR1 mutation, median PFS was 5.5 months with imlunestrant versus 3.8 months with SOC ET [HR=0.62 (95% CI 0.46-0.82); p-value<0.001]. The overall response rate (ORR) with imlunestrant was 14% compared to 8% with SOC ET in patients with an ESR1 mutation. In all patients, the median PFS was 5.6 months with imlunestrant versus 5.5 months with SOC ET [HR=0.87 (95% CI 0.72-1.04); p-value 0.12] and did not reach statistical significance.

Consistent with preclinical data demonstrating central nervous system (CNS) penetrance and CNS-activity of imlunestrant, CNS progression rates from a post-hoc analysis were lower with imlunestrant in all patients (HR=0.47; 95% CI, 0.16-1.38), as well as patients with an ESR1 mutation (HR=0.18; 95% CI, 0.04-0.90), however, these analyses are limited by low event numbers and lack of mandated serial asymptomatic CNS imaging in all patients.

Imlunestrant in combination with abemaciclib versus imlunestrant alone

Imlunestrant-abemaciclib significantly improved PFS compared to imlunestrant in all patients, regardless of ESR1 mutation status, with median PFS of 9.4 months for imlunestrant-abemaciclib versus 5.5 months for imlunestrant alone [HR=0.57 (95% CI 0.44-0.73); p-value <0.001]. The PFS benefit of the combination was consistent across subgroups, regardless of ESR1 mutation, or PI3K pathway mutation status, and including in patients who had previously received CDK4/6 inhibitor treatment. In all patients, the ORR with imlunestrant-abemaciclib was 27% compared to 12% with imlunestrant alone.

Safety in the imlunestrant-abemaciclib arm was consistent with the known safety profile of fulvestrant in combination with abemaciclib, with mostly low-grade adverse events including diarrhea (86%), nausea (49%), neutropenia (48%) and anemia (44%), and had a low discontinuation rate (6.3%).1,2

Overall survival (OS) results for EMBER-3 were immature at the time of analysis. The trial will continue to assess OS as a secondary endpoint.

"EMBER-3 is the first Phase 3 trial to show benefit of combining an oral SERD with a CDK4/6 inhibitor for a patient population where an all-oral regimen would represent a meaningful advance," said David Hyman, M.D., Chief Medical Officer, Lilly. "We’re highly encouraged by these data for both imlunestrant as monotherapy and in combination with Verzenio, as well as the safety and tolerability profile, which demonstrate the potential for imlunestrant to be a meaningful new oral endocrine therapy option for patients. We look forward to sharing these results with the oncology community and completing regulatory submissions to global health authorities."

An estimated 70 to 80% of hormone receptor positive breast cancers are ER+ and after progression on initial endocrine therapy, are predominantly treated with fulvestrant, which is administered by intramuscular injection in a doctor’s office.3,4 According to patient-reported outcomes data from EMBER-3, 72% of patients receiving fulvestrant in the standard ET group reported injection site pain, swelling, or redness. Imlunestrant is an orally administered, brain penetrant, pure ER antagonist that delivers continuous ER target inhibition.

Imlunestrant is also being investigated in the adjuvant setting in people with ER+, HER2- early breast cancer (EBC) with an increased risk of recurrence. This Phase 3 trial, EMBER-4, is expected to enroll 6,000 EBC patients worldwide.

About EMBER-3
EMBER-3 is a Phase 3, randomized, open-label study of imlunestrant, investigator’s choice of endocrine therapy, and imlunestrant in combination with abemaciclib in patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) locally advanced or metastatic breast cancer whose disease has recurred or progressed during or following an aromatase inhibitor (AI) therapy with or without a CDK 4/6 inhibitor. The trial enrolled 874 adult patients, 32% of which enrolled from the adjuvant setting into first-line treatment of ABC and 64% as second line treatment following progression on initial therapy for ABC. Enrolled trial participants were randomized between imlunestrant, investigator’s choice of fulvestrant or exemestane, or imlunestrant plus abemaciclib. More information on the EMBER-3 study can be found on clinicaltrials.gov.

About Metastatic/Advanced Breast Cancer
Metastatic/advanced breast cancer (ABC) is a cancer that has spread from the breast tissue to other parts of the body. Locally advanced breast cancer means the cancer has grown outside the organ where it started but has not yet spread to other parts of the body.1 Of all high risk early-stage breast cancer cases diagnosed in the U.S., approximately 30% will become metastatic5 and an estimated 6-10% of all new breast cancer cases are initially diagnosed as being metastatic.6 Survival is lower among women with a more advanced stage of disease at diagnosis: five-year relative survival is 99% for localized disease, 86% for regional/locally advanced disease, and 30% for metastatic/advanced disease.7 Other factors, such as tumor size, also impact five-year survival estimates.7

About Breast Cancer
Breast cancer is the second most commonly diagnosed cancer worldwide (following lung cancer), according to GLOBOCAN. The estimated 2.3 million new cases indicate that close to 1 in every 4 cancers diagnosed in 2022 is breast cancer. With approximately 666,000 deaths in 2022, breast cancer is the fourth-leading cause of cancer death worldwide.8 In the U.S., it is estimated that there will be more than 310,000 new cases of breast cancer diagnosed in 2024. Breast cancer is the second leading cause of cancer death in women in the U.S.9

About Imlunestrant
Imlunestrant is a brain-penetrant, oral selective estrogen receptor degrader (SERD), that delivers continuous ER inhibition, including in ESR1-mutant cancers. The estrogen receptor (ER) is the key therapeutic target for patients with estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Novel degraders of ER may overcome endocrine therapy resistance while providing consistent oral pharmacology and convenience of administration. Imlunestrant is currently being studied as a treatment for advanced breast cancer and as an adjuvant treatment in early breast cancer, including: NCT04975308, NCT05514054, NCT04188548, NCT05307705.

About Verzenio (abemaciclib)
Verzenio (abemaciclib) is approved to treat people with certain HR+, HER2- breast cancers in the adjuvant and advanced or metastatic setting. Verzenio is the first CDK4/6 inhibitor approved to treat node-positive, high risk early breast cancer (EBC) patients.10 For HR+, HER2- breast cancer, The National Comprehensive Cancer Network (NCCN) recommends consideration of two years of abemaciclib (Verzenio) added to endocrine therapy as a Category 1 treatment option in the adjuvant setting.11 NCCN also includes Verzenio plus endocrine therapy as a preferred treatment option for HR+, HER2- metastatic breast cancer.11

The collective results of Lilly’s clinical development program continue to differentiate Verzenio as a CDK4/6 inhibitor. In high risk EBC, Verzenio has shown a persistent and deepening benefit beyond the two-year treatment period in the monarchE trial, an adjuvant study designed specifically to investigate a CDK4/6 inhibitor in a node-positive, high risk EBC population.12 In metastatic breast cancer, Verzenio has demonstrated statistically significant OS in the Phase 3 MONARCH 2 study.13 Verzenio has shown a consistent and generally manageable safety profile across clinical trials.

Verzenio is an oral tablet taken twice daily and available in strengths of 50 mg, 100 mg, 150 mg, and 200 mg. Discovered and developed by Lilly researchers, Verzenio was first approved in 2017 and is currently authorized for use in more than 90 counties around the world. For full details on indicated uses of Verzenio in HR+, HER2- breast cancer, please see full Prescribing Information, available at www.Verzenio.com.

INDICATIONS FOR VERZENIO
VERZENIO is a kinase inhibitor indicated:

in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for the adjuvant treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive, early breast cancer at high risk of recurrence.
in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer.
in combination with fulvestrant for the treatment of adult patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer with disease progression following endocrine therapy.
as monotherapy for the treatment of adult patients with HR-positive, HER2-negative advanced or metastatic breast cancer with disease progression following endocrine therapy and prior chemotherapy in the metastatic setting.
IMPORTANT SAFETY INFORMATION FOR VERZENIO (abemaciclib)
Severe diarrhea associated with dehydration and infection occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, diarrhea occurred in 81 to 90% of patients who received Verzenio. Grade 3 diarrhea occurred in 8 to 20% of patients receiving Verzenio. Most patients experienced diarrhea during the first month of Verzenio treatment. The median time to onset of the first diarrhea event ranged from 6 to 8 days; and the median duration of Grade 2 and Grade 3 diarrhea ranged from 6 to 11 days and 5 to 8 days, respectively. Across trials, 19 to 26% of patients with diarrhea required a Verzenio dose interruption and 13 to 23% required a dose reduction.

Instruct patients to start antidiarrheal therapy, such as loperamide, at the first sign of loose stools, increase oral fluids, and notify their healthcare provider for further instructions and appropriate follow-up. For Grade 3 or 4 diarrhea, or diarrhea that requires hospitalization, discontinue Verzenio until toxicity resolves to ≤Grade 1, and then resume Verzenio at the next lower dose.

Neutropenia, including febrile neutropenia and fatal neutropenic sepsis, occurred in patients treated with Verzenio. Across four clinical trials in 3691 patients, neutropenia occurred in 37 to 46% of patients receiving Verzenio. A Grade ≥3 decrease in neutrophil count (based on laboratory findings) occurred in 19 to 32% of patients receiving Verzenio. Across trials, the median time to first episode of Grade ≥3 neutropenia ranged from 29 to 33 days, and the median duration of Grade ≥3 neutropenia ranged from 11 to 16 days. Febrile neutropenia has been reported in <1% of patients exposed to Verzenio across trials. Two deaths due to neutropenic sepsis were observed in MONARCH 2. Inform patients to promptly report any episodes of fever to their healthcare provider.

Monitor complete blood counts prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, or delay in starting treatment cycles is recommended for patients who develop Grade 3 or 4 neutropenia.

Severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis can occur in patients treated with Verzenio and other CDK4/6 inhibitors. In Verzenio-treated patients in EBC (monarchE), 3% of patients experienced ILD or pneumonitis of any grade: 0.4% were Grade 3 or 4 and there was one fatality (0.1%). In Verzenio-treated patients in MBC (MONARCH 1, MONARCH 2, MONARCH 3), 3.3% of Verzenio-treated patients had ILD or pneumonitis of any grade: 0.6% had Grade 3 or 4, and 0.4% had fatal outcomes. Additional cases of ILD or pneumonitis have been observed in the postmarketing setting, with fatalities reported.

Monitor patients for pulmonary symptoms indicative of ILD or pneumonitis. Symptoms may include hypoxia, cough, dyspnea, or interstitial infiltrates on radiologic exams. Infectious, neoplastic, and other causes for such symptoms should be excluded by means of appropriate investigations. Dose interruption or dose reduction is recommended in patients who develop persistent or recurrent Grade 2 ILD or pneumonitis. Permanently discontinue Verzenio in all patients with Grade 3 or 4 ILD or pneumonitis.

Grade ≥3 increases in alanine aminotransferase (ALT) (2 to 6%) and aspartate aminotransferase (AST) (2 to 3%) were reported in patients receiving Verzenio. Across three clinical trials in 3559 patients (monarchE, MONARCH 2, MONARCH 3), the median time to onset of Grade ≥3 ALT increases ranged from 57 to 87 days and the median time to resolution to Grade <3 was 13 to 14 days. The median time to onset of Grade ≥3 AST increases ranged from 71 to 185 days and the median time to resolution to Grade <3 ranged from 11 to 15 days.

Monitor liver function tests (LFTs) prior to the start of Verzenio therapy, every 2 weeks for the first 2 months, monthly for the next 2 months, and as clinically indicated. Dose interruption, dose reduction, dose discontinuation, or delay in starting treatment cycles is recommended for patients who develop persistent or recurrent Grade 2, or any Grade 3 or 4 hepatic transaminase elevation.

Venous thromboembolic events (VTE) were reported in 2 to 5% of patients across three clinical trials in 3559 patients treated with Verzenio (monarchE, MONARCH 2, MONARCH 3). VTE included deep vein thrombosis, pulmonary embolism, pelvic venous thrombosis, cerebral venous sinus thrombosis, subclavian and axillary vein thrombosis, and inferior vena cava thrombosis. In clinical trials, deaths due to VTE have been reported in patients treated with Verzenio.

Verzenio has not been studied in patients with early breast cancer who had a history of VTE. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism and treat as medically appropriate. Dose interruption is recommended for EBC patients with any grade VTE and for MBC patients with a Grade 3 or 4 VTE.

Verzenio can cause fetal harm when administered to a pregnant woman, based on findings from animal studies and the mechanism of action. In animal reproduction studies, administration of abemaciclib to pregnant rats during the period of organogenesis caused teratogenicity and decreased fetal weight at maternal exposures that were similar to the human clinical exposure based on area under the curve (AUC) at the maximum recommended human dose. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Verzenio and for 3 weeks after the last dose. Based on findings in animals, Verzenio may impair fertility in males of reproductive potential. There are no data on the presence of Verzenio in human milk or its effects on the breastfed child or on milk production. Advise lactating women not to breastfeed during Verzenio treatment and for at least 3 weeks after the last dose because of the potential for serious adverse reactions in breastfed infants.

The most common adverse reactions (all grades, ≥10%) observed in monarchE for Verzenio plus tamoxifen or an aromatase inhibitor vs tamoxifen or an aromatase inhibitor, with a difference between arms of ≥2%, were diarrhea (84% vs 9%), infections (51% vs 39%), neutropenia (46% vs 6%), fatigue (41% vs 18%), leukopenia (38% vs 7%), nausea (30% vs 9%), anemia (24% vs 4%), headache (20% vs 15%), vomiting (18% vs 4.6%), stomatitis (14% vs 5%), lymphopenia (14% vs 3%), thrombocytopenia (13% vs 2%), decreased appetite (12% vs 2.4%), ALT increased (12% vs 6%), AST increased (12% vs 5%), dizziness (11% vs 7%), rash (11% vs 4.5%), and alopecia (11% vs 2.7 %).

The most frequently reported ≥5% Grade 3 or 4 adverse reaction that occurred in the Verzenio arm vs the tamoxifen or an aromatase inhibitor arm of monarchE were neutropenia (19.6% vs 1%), leukopenia (11% vs <1%), diarrhea (8% vs 0.2%), and lymphopenia (5% vs <1%).

Lab abnormalities (all grades; Grade 3 or 4) for monarchE in ≥10% for Verzenio plus tamoxifen or an aromatase inhibitor with a difference between arms of ≥2% were increased serum creatinine (99% vs 91%; .5% vs <.1%), decreased white blood cells (89% vs 28%; 19.1% vs 1.1%), decreased neutrophil count (84% vs 23%; 18.7% vs 1.9%), anemia (68% vs 17%; 1% vs .1%), decreased lymphocyte count (59% vs 24%; 13.2 % vs 2.5%), decreased platelet count (37% vs 10%; .9% vs .2%), increased ALT (37% vs 24%; 2.6% vs 1.2%), increased AST (31% vs 18%; 1.6% vs .9%), and hypokalemia (11% vs 3.8%; 1.3% vs 0.2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 3 for Verzenio plus anastrozole or letrozole vs anastrozole or letrozole, with a difference between arms of ≥2%, were diarrhea (81% vs 30%), fatigue (40% vs 32%), neutropenia (41% vs 2%), infections (39% vs 29%), nausea (39% vs 20%), abdominal pain (29% vs 12%), vomiting (28% vs 12%), anemia (28% vs 5%), alopecia (27% vs 11%), decreased appetite (24% vs 9%), leukopenia (21% vs 2%), creatinine increased (19% vs 4%), constipation (16% vs 12%), ALT increased (16% vs 7%), AST increased (15% vs 7%), rash (14% vs 5%), pruritus (13% vs 9%), cough (13% vs 9%), dyspnea (12% vs 6%), dizziness (11% vs 9%), weight decreased (10% vs 3.1%), influenza-like illness (10% vs 8%), and thrombocytopenia (10% vs 2%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 3 were neutropenia (22% vs 1%), diarrhea (9% vs 1.2%), leukopenia (7% vs <1%)), increased ALT (6% vs 2%), and anemia (6% vs 1%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 3 in ≥10% for Verzenio plus anastrozole or letrozole with a difference between arms of ≥2% were increased serum creatinine (98% vs 84%; 2.2% vs 0%), decreased white blood cells (82% vs 27%; 13% vs 0.6%), anemia (82% vs 28%; 1.6% vs 0%), decreased neutrophil count (80% vs 21%; 21.9% vs 2.6%), decreased lymphocyte count (53% vs 26%; 7.6% vs 1.9%), decreased platelet count (36% vs 12%; 1.9% vs 0.6%), increased ALT (48% vs 25%; 6.6% vs 1.9%), and increased AST (37% vs 23%; 3.8% vs 0.6%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 2 for Verzenio plus fulvestrant vs fulvestrant, with a difference between arms of ≥2%, were diarrhea (86% vs 25%), neutropenia (46% vs 4%), fatigue (46% vs 32%), nausea (45% vs 23%), infections (43% vs 25%), abdominal pain (35% vs 16%), anemia (29% vs 4%), leukopenia (28% vs 2%), decreased appetite (27% vs 12%), vomiting (26% vs 10%), headache (20% vs 15%), dysgeusia (18% vs 2.7%), thrombocytopenia (16% vs 3%), alopecia (16% vs 1.8%), stomatitis (15% vs 10%), ALT increased (13% vs 5%), pruritus (13% vs 6%), cough (13% vs 11%), dizziness (12% vs 6%), AST increased (12% vs 7%), peripheral edema (12% vs 7%), creatinine increased (12% vs <1%), rash (11% vs 4.5%), pyrexia (11% vs 6%), and weight decreased (10% vs 2.2%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions that occurred in the Verzenio arm vs the placebo arm of MONARCH 2 were neutropenia (25% vs 1%), diarrhea (13% vs 0.4%), leukopenia (9% vs 0%), anemia (7% vs 1%), and infections (5.7% vs 3.5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 2 in ≥10% for Verzenio plus fulvestrant with a difference between arms of ≥2% were increased serum creatinine (98% vs 74%; 1.2% vs 0%), decreased white blood cells (90% vs 33%; 23.7% vs .9%), decreased neutrophil count (87% vs 30%; 32.5% vs 4.2%), anemia (84% vs 34%; 2.6% vs .5%), decreased lymphocyte count (63% vs 32%; 12.2% vs 1.8%), decreased platelet count (53% vs 15%; 2.1% vs 0%), increased ALT (41% vs 32%; 4.6% vs 1.4%), and increased AST (37% vs 25%; 3.9% vs 4.2%).

The most common adverse reactions (all grades, ≥10%) observed in MONARCH 1 with Verzenio were diarrhea (90%), fatigue (65%), nausea (64%), decreased appetite (45%), abdominal pain (39%), neutropenia (37%), vomiting (35%), infections (31%), anemia (25%), thrombocytopenia (20%), headache (20%), cough (19%), constipation (17%), leukopenia (17%), arthralgia (15%), dry mouth (14%), weight decreased (14%), stomatitis (14%), creatinine increased (13%), alopecia (12%), dysgeusia (12%), pyrexia (11%), dizziness (11%), and dehydration (10%).

The most frequently reported ≥5% Grade 3 or 4 adverse reactions from MONARCH 1 with Verzenio were diarrhea (20%), neutropenia (24%), fatigue (13%), and leukopenia (5%).

Lab abnormalities (all grades; Grade 3 or 4) for MONARCH 1 with Verzenio were increased serum creatinine (99%; .8%), decreased white blood cells (91%; 28%), decreased neutrophil count (88%; 26.6%), anemia (69%; 0%), decreased lymphocyte count (42%; 13.8%), decreased platelet count (41%; 2.3%), increased ALT (31%; 3.1%), and increased AST (30%; 3.8%).

Strong and moderate CYP3A inhibitors increased the exposure of abemaciclib plus its active metabolites to a clinically meaningful extent and may lead to increased toxicity. Avoid concomitant use of ketoconazole. Ketoconazole is predicted to increase the AUC of abemaciclib by up to 16-fold. In patients with recommended starting doses of 200 mg twice daily or 150 mg twice daily, reduce the Verzenio dose to 100 mg twice daily with concomitant use of strong CYP3A inhibitors other than ketoconazole. In patients who have had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the Verzenio dose to 50 mg twice daily with concomitant use of strong CYP3A inhibitors. If a patient taking Verzenio discontinues a strong CYP3A inhibitor, increase the Verzenio dose (after 3 to 5 half-lives of the inhibitor) to the dose that was used before starting the inhibitor. With concomitant use of moderate CYP3A inhibitors, monitor for adverse reactions and consider reducing the Verzenio dose in 50 mg decrements. Patients should avoid grapefruit products.

Avoid concomitant use of strong or moderate CYP3A inducers and consider alternative agents. Coadministration of strong or moderate CYP3A inducers decreased the plasma concentrations of abemaciclib plus its active metabolites and may lead to reduced activity.

With severe hepatic impairment (Child-Pugh C), reduce the Verzenio dosing frequency to once daily. The pharmacokinetics of Verzenio in patients with severe renal impairment (CLcr <30 mL/min), end stage renal disease, or in patients on dialysis is unknown. No dosage adjustments are necessary in patients with mild or moderate hepatic (Child-Pugh A or B) and/or renal impairment (CLcr ≥30-89 mL/min).

Please see full Prescribing Information and Patient Information for Verzenio.

On December 11, 2024 Champions Oncology, Inc. (Nasdaq: CSBR), a global preclinical and clinical research services provider that offers end-to-end oncology solutions, reported its financial results for its second quarter of fiscal 2025, ended October 31, 2024 (Press release, Champions Oncology, DEC 11, 2024, View Source [SID1234649041]).

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Second Quarter and Recent Highlights:

•Total revenue increased 17% to $13.5 million
•Gross profit of $6.1 million; margin of 45%
•Net income of approximately $730,000
•Adjusted EBITDA of $1.1 million
•Development of new data revenue stream

First Half 2025 Highlights:

•Total revenue increased 14% to $27.6 million
•Gross profit of $13.1 million; margin of 47%
•Net income of $2.1 million
•Adjusted EBITDA of $3.2 million

Ronnie Morris, CEO of Champions, commented, "Our second quarter’s performance solidified our confidence in the Company’s turnaround that we’ve been discussing the last several quarters. We remain cautiously optimistic that the pharma and biotech environment is improving which will continue to contribute to our long-term growth." Morris added, "In addition to our core business, we made significant strides in monetizing our data platform, establishing an additional revenue stream that can be transformative for the Company."

David Miller, CFO of Champions, added, "We continued to deliver strong financial results in our second quarter as revenue increased 17% to $13.5M while we reduced total costs by $771,000. As a result, we recorded adjusted EBITDA of $1.1 million." Miller added, "With the renewed underlying strength in our core business coupled with the expected revenue contribution from our data platform, we’re projecting revenue growth for the year of at least 10% – 15%."

Second Fiscal Quarter Financial Results

Total revenue for the second quarter of fiscal 2025 was $13.5 million compared to $11.6 million for the same period last year, an increase of 17%. The combination of operational improvements and efficiencies implemented, which led to an increase in our revenue conversion percentage, and the acceleration in our bookings, generated an increase in revenue for both the three months and six months ended October 31, 2024. Total costs and operating expenses for the second quarter of fiscal 2025 were $12.8 million compared to $13.5 million for the second quarter of fiscal 2024, a decrease of $771,000 or 5.7%.

For the second quarter of fiscal 2025, Champions reported income from operations of $732,000, including $9,000 in stock-based compensation and $399,000 in depreciation and amortization expenses, compared to a loss from operations of $2.0 million, inclusive of $53,000 in stock-based compensation and $484,000 in depreciation and amortization expenses, in the second quarter of fiscal 2024. Excluding stock-based compensation, depreciation and amortization expenses, Champions reported adjusted EBITDA of $1.1 million for the second quarter of fiscal 2025 compared to an adjusted EBITDA loss of $1.4 million in the second quarter of fiscal 2024.

Cost of oncology services was $7.4 million for the three-months ended October 31, 2024, an increase of $810,000, or 12.2% compared to $6.6 million for the three-months ended October 31, 2023. The increase in cost of oncology services was primarily from an increase in mice and lab costs to support revenue growth. For the three-months ended October 31, 2024, total margin was 45% compared to 43% for the three-months ended October 31, 2023. The improved margin resulted primarily from an increase in revenue and a lower cost base due to operational efficiencies implemented, but was under some specific pressure due to the cost of humanized mice.

Research and development expense for the three-months ended October 31, 2024 was $1.7 million, a decrease of $826,000 or 32.8%, compared to $2.5 million for the three-months ended October 31, 2023. The decrease was primarily due to reduced investment in research and development, including our target discovery program. Sales and marketing expense for the three-months ended October 31, 2024 was $1.8 million, a slight decrease of $44,000, or 2.5%, compared to $1.8 million for the three-months ended October 31, 2023. General and administrative expense for the three-months ended October 31, 2024 was $1.9 million, a decrease of $711,000, or 27.3%, compared to $2.6 million for the three-months ended October 31, 2023. The decrease was primarily from a decline in compensation and recruitment expenses and a one-time reduction in our credit loss reserve.

Net cash used in operating activities was approximately $283,000 for the three-months ended October 31, 2024 and was primarily due to an increase in accounts receivable and a decrease in accounts payable offset by net income for the quarter. Net changes in our working capital accounts were in the ordinary course of business. Net cash used in investing activities for the three-months ended October 31, 2024 was approximately $94,000 and was for lab and computer equipment. Net cash provided by financing activities for the three-months ended October 31, 2024 was approximately $239,000 resulting primarily from proceeds from options exercise.

The Company ended the quarter with cash on hand of approximately $2.8 million. The Company has no debt.

Year-to-Date Financial Results

Total revenue for the first half of fiscal 2025 was $27.6 million compared to $24.1 million for the same period last year, an increase of 14.2%. Total costs and operating expenses for the first half of fiscal 2025 were $25.5 million compared to $28.6 million for the first half of fiscal 2024, a decrease of $3.2 million or 11.0%.

For the first half of fiscal 2025, Champions reported income from operations of $2.1 million, including $267,000 in stock-based compensation and $848,000 in depreciation and amortization expenses, compared to a loss from operations of $4.5 million, inclusive of $476,000 in stock-based compensation and $929,000 in depreciation and amortization expenses, in the first half of fiscal 2024. Excluding stock-based compensation, depreciation and amortization expenses, Champions reported adjusted EBITDA of $3.2 million for the first half of fiscal 2025 compared to an adjusted EBITDA loss of $3.1 million in the first half of fiscal 2024.

Cost of oncology services was $14.5 million for the six-months ended October 31, 2024, an increase of
$198,000, or 1.4% compared to $14.3 million for the six-months ended October 31, 2023. The increase in cost of oncology services was primarily from an increase in mice costs. For the six-months ended October 31, 2024, total margin was 47% compared to 41% for the six-months ended October 31, 2023. The improved margin resulted primarily from a combination of an increase in revenue while minimizing cost increases due to operational efficiencies implemented and other cost reduction initiatives.

Research and development expense for the six-months ended October 31, 2024 was $3.1 million, a decrease of $2.2 million or 40.8%, compared to $5.3 million for the six-months ended October 31, 2023. The decrease was primarily due to reduced investment in research and development in non-essential services, including our target discovery program. Sales and marketing expense for the six-months ended October 31, 2024 was $3.4 million, a slight decrease of $61,000, or 1.7%, compared to $3.5 million for the six-months ended October 31, 2023. General and administrative expense for the six-months ended October 31, 2024 was $4.4 million, a decrease of $1.1 million, or 20.3%, compared to $5.5 million for the six-months ended October 31, 2023. The decrease was primarily from a reduction in compensation, recruitment, and stock-based compensation expenses.

Conference Call Information:
The Company will host a conference call today at 4:30 p.m. EST (1:30 p.m. PST) to discuss its second quarter financial results. To participate in the call, please call 888-506-0062 (Domestic) or 973-528-0011 (International) and enter the access code 710610, or provide the verbal reference "Champions Oncology".
Full details of the Company’s financial results will be available by or before December 16, 2024 in the Company’s Form 10-Q at www.championsoncology.com.

On December 11, 2024 Candel Therapeutics, Inc. (Candel or the Company) (Nasdaq: CADL), a clinical-stage biopharmaceutical company focused on developing multimodal biological immunotherapies to help patients fight cancer, reported results from a multicenter phase 3 clinical trial evaluating CAN-2409 viral immunotherapy in localized prostate cancer patients (Press release, Candel Therapeutics, DEC 11, 2024, View Source [SID1234649040]).

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In the United States alone, over 100,000 men are diagnosed with localized prostate cancer every year, and over 50,000 men currently receive radiotherapy. Prostate cancer continues to be the second leading cause of cancer death among men in the United States and there has not been any new treatment or significant change in the standard of care of localized, non-metastatic prostate cancer for over 20 years. The localized prostate cancer addressable market for CAN2409 is potentially worth over $10 billion in the U.S. alone.

The phase 3 clinical trial of CAN-2409 in intermediate-to-high-risk, localized prostate cancer met its primary endpoint, by demonstrating statistically significant improvement in disease-free survival in patients who received CAN-2409 plus prodrug (valacyclovir) combined with standard of care compared to standard of care alone.

The 2:1 randomized, double-blind, placebo-controlled, multicenter clinical trial enrolled 745 patients (intent to treat population, ITT) to evaluate the effectiveness and safety of CAN-2409 plus prodrug (valacyclovir) viral immunotherapy in combination with standard of care external beam radiation therapy to improve disease-free survival (DFS) in patients with intermediate-to-high risk, localized prostate cancer. Patients were randomized and stratified for the use of short-term (< 6 months) androgen deprivation therapy (ADT).

CAN-2409 is an investigational, off-the-shelf, replication-defective adenovirus that delivers the herpes simplex virus thymidine kinase (HSV-tk) gene to tumor cells. CAN-2409, when administered with valacyclovir, is designed to induce immunogenic cell death of tumor cells with exposure of tumor antigens in the context of an activated tumor microenvironment. Together, this regimen is designed to induce an individualized and specific CD8+ T cell-mediated response against the tumor, based on in situ vaccination against a variety of tumor antigens. Preclinical and clinical evidence suggests that CAN-2409 can be synergistic with local radiotherapy, providing further support for the design of the current phase 3 clinical trial.

"The improvement observed in disease-free survival in this phase 3 clinical trial is clinically meaningful. We have not seen significant advances in this indication in decades. CAN-2409 has demonstrated the potential to significantly improve long-term outcomes without adding substantial toxicity to standard of care radiation," said Glen Gejerman, M.D., MBA, Co-Director of Urologic Oncology at Hackensack Meridian Health, and one of the principal investigators of the study. "If approved, this approach has the potential to transform the treatment paradigm in prostate cancer, offering patients with localized disease an effective treatment option that may reduce the risk of disease recurrence."

Phase 3 Trial Results in Intermediate-High Risk Disease

The study met its primary endpoint, demonstrating a statistically significant improvement in disease-free survival compared to the control arm.

Key topline results include:

•
Statistically significant improvement in DFS for CAN-2409 plus radiation therapy (n=496) vs. radiation therapy alone (n=249) (p=0.0155; HR 0.7) in the intent to treat population

•
We observed a 14.5% relative improvement in DFS at 54 months for the CAN-2409 treatment arm compared to the placebo control arm

•
DFS improvement was observed both in patients receiving short term ADT and in patients not receiving ADT

•
In an analysis that focused on prostate-specific outcomes (e.g., censored mortality due to other causes), CAN-2409 showed a highly significant effect (p=0.0046; HR 0.6) on prostate cancer-free survival

•
Significant increase in the proportion of patients achieving a prostate-specific antigen (PSA) nadir (<0.2 ng/ml) was observed in the treatment arm compared to the placebo control arm (67.1% vs. 58.6%, respectively; p<0.0164)

•
CAN-2409 induced 80.4% pathological complete responses (pCRs) in the 2-year post-treatment biopsies compared to 63.6% observed in the control arm (p=0.0015)

The median follow-up time for the recruited population was 50.3 months. The primary outcome measure included the evaluation of post-treatment biopsies, performed at two years from the end of radiation, for the presence of tumor recurrence. Local or systemic recurrence and death from any cause were also part of the DFS endpoint. 

The safety profile of CAN-2409 was generally consistent with previous studies, with no new safety signals identified. The most common CAN-2409-related adverse events were flu-like symptoms, fever and chills, which were generally mild to moderate in severity and self-limited.

The company also reported today that the phase 2 clinical trial of monotherapy CAN-2409 in 190 patients with low-to-intermediate risk localized prostate cancer undergoing active surveillance showed numerical improvement in time to radical treatment and the percentage of patients achieving negative (prostate cancer-free) biopsies at 1-year post-treatment. However, these differences did not reach statistical significance. The safety profile of CAN-2409 was generally consistent with that reported in the phase 3 clinical trial.

"We are thrilled to report the phase 3 results for CAN-2409 in intermediate-to-high risk, localized prostate cancer," said Paul Peter Tak, M.D., Ph.D., FMedSci, President and Chief Executive Officer of Candel. "This study validates previous observations of CAN-2409 activity seen in difficult-to-treat solid tumors, often resistant to immunotherapy, and confirms our previous observation of synergies with radiation therapy in models of prostate cancer. Importantly, this study was conducted under a Special Protocol Assessment (SPA) agreed with the U.S. Food and Drug Administration (FDA), on key aspects of study design, meaning that safety and efficacy data generated from the study could be sufficient for the Company to seek regulatory approval for CAN-2409 in this indication. We look forward to working with the FDA, as a next step, to seek approval to bring CAN-2409 to patients in the U.S., and advance our broad viral immunotherapy pipeline across other large oncology indications of high unmet need."

Based on these results, Candel intends to initiate discussions with the FDA regarding the regulatory pathway for CAN-2409 in intermediate-to-high-risk localized prostate cancer. The Company will present the totality of the data for both studies at upcoming medical conferences.

Conference Call and Webcast

Candel will host a webcast and conference call today, at 8:30 a.m. EDT. The webcast can be accessed (Here) and also on the Candel website at www.candeltx.com under News & Events, in the IR section,of the website. An archived webcast will be available on Candel’s website for 30 days following the presentation. Participants may register for the conference call (Here) to receive the dial-in numbers and unique PIN to access the call seamlessly. It is recommended that you join 10 minutes prior to start of the event (although you may register and dial in at any time during the call).

About CAN-2409

CAN-2409, Candel’s most advanced multimodal biological immunotherapy candidate, is an investigational, off-the-shelf, replication-defective adenovirus designed to deliver the herpes simplex virus thymidine kinase (HSV-tk) gene to a patient’s specific tumor and induce an individualized, systemic immune response against the tumor. HSV-tk is an enzyme that locally converts orally administered valacyclovir into a toxic metabolite that kills nearby cancer cells. Together, this regimen is designed to induce an individualized and specific CD8+ T cell-mediated response against the injected tumor and uninjected distant metastases for broad anti-tumor activity, based on in situ vaccination against a variety of tumor antigens. Because of its versatility, CAN-2409 has the potential to treat a broad range of solid tumors. Encouraging monotherapy activity as well as combination activity with standard of care radiotherapy, surgery, chemotherapy, and immune checkpoint inhibitors have previously been shown in several preclinical and clinical settings. More than 1,000 patients have been dosed with CAN-2409 with a favorable tolerability profile to date, supporting the potential for combination with other therapeutic strategies without inordinate concern of overlapping adverse events.

Currently, Candel is evaluating CAN-2409 in non-small cell lung cancer (NSCLC), borderline resectable pancreatic ductal adenocarcinoma (PDAC), and localized, non-metastatic prostate cancer in ongoing clinical trials. CAN-2409 plus prodrug (valacyclovir) has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of PDAC, stage III/IV NSCLC in patients who are resistant to first line PD-(L)1 inhibitor therapy and who do not have activating molecular driver mutations or have progressed on directed molecular therapy, and localized primary prostate cancer. Candel’s pivotal phase 3 clinical trial in prostate cancer has been conducted under a Special Protocol Assessment agreed with the FDA. The FDA has also granted Orphan Drug Designation to CAN-2409 for the treatment of PDAC.

On December 11, 2024 Ariceum Therapeutics, a private biotech company developing radiopharmaceutical products for the diagnosis and treatment of certain hard-to-treat cancers, and NorthStar Medical Radioisotopes, LLC, a global innovator in the development, production and commercialization of radiopharmaceuticals used for therapeutic applications and medical imaging, reported the signing of a supply agreement for the therapeutic medical radioisotope, Actinium-225 (Ac-225) (Press release, Ariceum Therapeutics, DEC 11, 2024, View Source [SID1234649039]).

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Under the terms of the agreement, NorthStar will provide Ariceum with non-carrier-added (n.c.a.), high purity, Ac-225, a rare and critical isotope that is in high demand, providing Ariceum with an additional clinical source of supply for its evolving pipeline development programs. Ariceum will use NorthStar’s Ac-225 to radiolabel its proprietary peptide (SS0110) satoreotide, a first-in-class antagonist of the somatostatin receptor 2 (SSTR2). Satoreotide is being developed as a ‘theranostic pair’ for the combined diagnosis and targeted radionuclide treatment of multiple indications expressing SSTR2, such as small cell lung cancer (SCLC), pancreatic cancers, Merkel Cell Carcinoma, and other aggressive cancers.

Manfred Rüdiger, Chief Executive Officer of Ariceum Therapeutics, commented: "Satoreotide is the first Ac-225 labelled antagonist of the SSTR2 receptor targeting SCLC. The compound is scheduled to enter clinical development in the US as part of a transatlantic trial soon. The compound has demonstrated its potential as a Lutetium-177-labelled version in our ongoing Phase 1b clinical study in end stage-SCLC. Based on NorthStar’s industry leadership and commercial expertise in cutting-edge, accelerator-based radioisotope production technology, we believe that they are a reliable partner to meet Ariceum’s specific needs. In partnership with NorthStar, we look forward to progressing our clinical studies with Ac-225 and accelerating our future commercialization opportunities as we seek to deliver targeted theranostic treatments for patients."

"Ariceum’s impressive development portfolio is focused on very aggressive, difficult-to-treat cancers and its early trial results are very exciting," said Frank Scholz, President and Chief Executive Officer of NorthStar. "At NorthStar, our goal is to reduce or eliminate concerns about adequate availability of Ac-225 for clinical trials and patient medicines, which have held back exploration of powerful new pathways to attack these diseases for the millions of patients who today have limited treatment options available. We are proud to use our expertise and capabilities to provide innovative companies like Ariceum with high purity, n.c.a. Ac-225, that will help make potential new treatment therapies a prospect for the benefit of patients."

On December 11, 2024 Aprea Therapeutics, Inc. (Nasdaq: APRE) ("Aprea", or the "Company"), a clinical-stage precision oncology company developing innovative therapies for cancers with specific genetic alterations to potentially minimize damage to healthy cells, reported that the first patient has been dosed at Dose Level 7, evaluating ATRN-119 550 mg twice daily, in the ongoing ABOYA-119 Phase 1/2a clinical trial (Press release, Aprea, DEC 11, 2024, View Source [SID1234649038]).

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The ABOYA-119 trial is evaluating ATRN-119 as monotherapy in patients with advanced solid tumors having at least one mutation in a defined panel of DNA damage response (DDR)-related genes. The study was initially designed to dose patients with ATRN-119 once daily and has tested doses of 50 to 800 mg to date. A protocol amendment allows for twice daily dosing, beginning with 550 mg twice daily (for a total daily dose of 1,100 mg). This strategic dose adjustment is driven by robust scientific evidence suggesting that more frequent dosing of ATRN-119 will maintain optimal therapeutic levels and potentially enhance the drug’s efficacy.

Twice daily dosing is expected to optimize ATRN-119’s activity across a 24-hour cycle thereby providing better target coverage and maximal benefit. This will increase the likelihood of achieving superior clinical outcomes and may potentially accelerate the path to regulatory approval and commercialization. It could also strengthen Aprea’s competitive positioning by addressing key pharmacokinetic and pharmacodynamic factors.

"The addition of twice daily dosing in the ABOYA-119 trial underscores Aprea’s commitment to delivering innovative treatments while continuously refining our approach based on the latest data and insights," said Oren Gilad, Ph.D., President and Chief Executive Officer of Aprea. "Twice daily dosing represents a proactive step to de-risk the trial, potentially increasing the probability of success. Importantly, it reflects our commitment to scientific excellence and we believe it positions the ATRN-119 program as a high-value asset that may be differentiated from other ATR inhibitors. To our knowledge, we believe ATRN-119 is the only ATR inhibitor in clinical development that is currently being tested as monotherapy on a continuous twice daily schedule. We believe this adjustment will further enhance shareholder value and support the long-term success of our mission."

Dr. Gilad added, "This approach not only enhances our development strategy but also creates new opportunities for partnership that could accelerate commercialization of ATRN-119 and expand patient access globally."

Anthony Tolcher, M.D., FRCPC, FACP, CEO of NEXT Oncology and Investigator in the ABOYA-119 trial commented, "Inhibition of ATR has emerged as a promising strategy for cancer treatment that exploits synthetic lethal interactions with proteins that are involved in DNA damage repair. This mechanism holds considerable promise for patients with difficult-to-treat cancers. We are pleased to continue to enroll our patients in this important study and recognize that a twice daily dosing regimen of ATRN-119 may allow us to maximize the therapeutic potential of the drug."

Dose escalation in the ABOYA-119 trial is expected to continue with both once-daily and the twice-daily dosing schedules, to be studied independently. The primary endpoint of the trial is the tolerability and pharmacokinetics of ATRN-119. Under the current updated protocol, Aprea anticipates the Phase 1 readout in the second half of 2025. For more information, please refer to clinicaltrials.gov NCT04905914.

About ATRN-119

ATRN-119 is a potent and highly selective first-in-class macrocyclic ATR inhibitor, designed to be used in patients with mutations in DDR-related genes. Cancers with mutations in DDR-related genes represent a high unmet medical need. Patients with DDR-related gene mutations have a poor prognosis and, currently, there are no effective therapies available for them.