On June 17, 2024 Actinium Pharmaceuticals, Inc. (NYSE AMERICAN: ATNM) (Actinium or the Company), a leader in the development of Antibody Radiation Conjugates (ARCs) and other targeted radiotherapies, reported that an abstract detailing the first ever preclinical data from the combination of menin inhibitors with Actinium’s ARC Actimab-A in acute myeloid leukemia (AML) models was presented at the 2024 European Hematology Association (EHA) (Free EHA Whitepaper) Congress held June 13 – 16, 2024, in Madrid, Spain (Press release, Actinium Pharmaceuticals, JUN 17, 2024, View Source [SID1234644403]). Actinium studied Actimab-A in combination with the leading menin inhibitors, revumenib (Syndax Pharmaceuticals, Inc.) and ziftomenib (Kura Oncology, Inc.), which are being developed for patients with KMT2A rearrangements and NMP1 mutations, which are present in approximately 10% and 30% of AML patients, respectively.

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Actimab-A + Menin inhibitor combination results include:

Actimab-A as a single agent showed potent in vitro AML cell killing activity in both MV-4-11 and MOLM-13 KMT2A mutant cell lines, compared to the non-radio conjugated CD33 antibody lintuzumab (p<0.0001)

Actimab-A enhanced AML cell death when combined with both revumenib and ziftomenib at all dose levels in difficult to treat KMT2A mutant AML

The combination of Actimab-A with leading menin inhibitors triggered an acute increase in AML necrosis and cell death in vivo relative to single agent therapy within 72 hours of dosing

Anti-tumor effect was significantly potentiated and prolonged when combining Actimab-A with a leading menin inhibitor compared to monotherapies in xenograft leukemia models in vivo (p<0.0024 Actimab-A + menin) as shown in the exhibit below
The Actimab-A + Menin Inhibitor combination presentation can be accessed on the investor relations page of Actinium’s website here.

Actimab-A targets CD33, a marker expressed ubiquitously in patients with AML, and is conjugated with the alpha-partible payload Actinium-225. The broad expression of CD33 and the differentiated mutation agnostic cell-killing mechanism of targeted radiotherapy make Actimab-A broadly applicable for combinations with chemotherapy, targeted agents including venetoclax, FLT3 and menin inhibitors, immunotherapies and cellular therapies supporting its potential backbone therapy profile across the AML patient treatment journey.

Sandesh Seth, Actinium’s Chairman and CEO, said, "Combining with menin inhibitors is an exciting expansion of the already broad potential of Actimab-A in AML. Across single agent and combination studies, Actimab-A has produced high rates of response, MRD negativity and improved survival in high-risk, relapsed and refractory patients including those with a TP53 mutation and venetoclax failures. The broad expression of CD33 in AML coupled with the potency of Actinium-225 make Actimab-A an ideal agent for treating radiation sensitive AML. We are encouraged by this highly promising initial data and the synergistic potential of Actimab-A with menin inhibitors, which has broad potential across the AML treatment continuum including frontline, maintenance and relapsed/refractory settings. We are eager to continue to study this combination and generate additional data that could support advancing into clinical studies of Actimab-A with menin inhibitors."

Menin inhibitors are a class of drug candidates being developed for patients with AML that have a rearrangement of the KMT2A gene, previously known as the mixed-lineage leukemia (MLL) or mutation of the NPM1 gene. There are multiple menin inhibitors in development for these patients with revumenib (Syndax Pharmaceuticals, Inc.) being most advanced having a PDUFA data of September 2024 and ziftomenib (Kura Oncology, Inc.) enrolling patients in a registration Phase 2 trial. Multiple menin inhibitors are being studied in Phase 1 clinical trials by companies including Johnson & Johnson, Sumitomo Pharma Co., Ltd., Hutchmed, Biomea Fusion, Inc. and BioNova Pharmaceuticals Pvt Ltd.

On June 17, 2024 AstraZeneca reported that Imfinzi (durvalumab) in combination with carboplatin and paclitaxel followed by Imfinzi monotherapy has been approved in the US as treatment for adult patients with primary advanced or recurrent endometrial cancer that is mismatch repair deficient (dMMR) (Press release, AstraZeneca, JUN 17, 2024, View Source [SID1234644379]).

The approval by the Food and Drug Administration (FDA) was based on the results of a prespecified exploratory subgroup analysis by MMR status in the DUO-E Phase III trial. Results from DUO-E were published in the Journal of Clinical Oncology.

In the trial, Imfinzi plus carboplatin and paclitaxel followed by Imfinzi monotherapy (Imfinzi arm) reduced the risk of disease progression or death by 58% in patients with dMMR endometrial cancer versus chemotherapy alone (hazard ratio 0.42; 95% confidence interval 0.22-0.80).2

In the US, endometrial cancer is the fourth most common cancer in women, with more than 66,000 patients diagnosed and almost 12,000 deaths in 2022.3,4 Patients diagnosed at an early stage of disease have a five-year survival rate of approximately 80-90%, but there is a significant need for new treatment options for people with advanced disease, where the survival rate falls to less than 20%.5,6

Shannon N. Westin, Professor of Gynecologic Oncology and Reproductive Medicine at The University of Texas MD Anderson Cancer Center, and principal investigator of the trial, said, "With the incidence and mortality of endometrial cancer expected to continue to increase significantly in the coming decades, it is more important than ever that we bring new treatment options to patients at the earliest possible moment in their care. This approval underlines clear evidence that durvalumab plus chemotherapy followed by durvalumab monotherapy delivers important clinical benefits for patients with mismatch repair deficient endometrial cancer."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "There have been limited advances in the treatment of endometrial cancer in the last few decades, and continued innovation is critical as the burden of this cancer is expected to grow in the future. Immunotherapy in combination with chemotherapy is emerging as a new standard of care in this setting, and the approval of Imfinzi offers an important new option for patients with mismatch repair deficient disease."

The safety and tolerability profile of the Imfinzi and chemotherapy regimen was generally manageable, well tolerated and broadly consistent with prior clinical trials with no new safety signals.1,2

The Lynparza (olaparib) and Imfinzi arm, which investigated Imfinzi plus chemotherapy followed by Imfinzi plus Lynparza as maintenance therapy, also met the primary endpoint of progression-free survival (PFS). The trial continues to assess OS as a key secondary endpoint for both arms. Regulatory applications for both Imfinzi as well as Imfinzi and Lynparza regimens are currently under review in the EU, Japan and several other countries based on the DUO-E results.

Notes

Endometrial cancer
Endometrial cancer is a highly heterogeneous disease that originates in the tissue lining of the uterus and is most common in women who have already been through menopause, with the average age at diagnosis being over 60 years old.7-10 It is the sixth most common cancer in women worldwide.11,12 Incidence and mortality of endometrial cancer are expected to increase by approximately 61% and 87% respectively (from 420,400 cases and 97,700 deaths in 2022 to 676,300 cases and 183,100 deaths) in 2050.13

The majority of patients with endometrial cancer are diagnosed at an early stage of disease, where the cancer is confined to the uterus.9,10 They are typically treated with surgery and/or radiation, and the five-year survival rate is high (approximately 80-90%).5,6 Patients with advanced disease (Stage III-IV) usually have a much poorer prognosis, with the five-year survival rate falling to less than 20%.5,6 Immunotherapy combined with chemotherapy is emerging as a new standard of care for advanced endometrial cancer, particularly for patients with dMMR disease, who make up approximately 20-30% of all patients with this type of cancer.6,14,15,16 There remains a high unmet need for treatments for the remaining 70-80% of endometrial cancer patients with pMMR disease.15,16

DUO-E
The DUO-E trial (GOG 3041/ENGOT-EN10) is a three-arm, randomised, double-blind, placebo-controlled, multicentre Phase III trial of 1st-line Imfinzi (durvalumab) plus platinum-based chemotherapy (carboplatin and paclitaxel) followed by either Imfinzi monotherapy or Imfinzi plus Lynparza (olaparib) as maintenance therapy versus platinum-based chemotherapy alone as a treatment for patients with newly diagnosed advanced or recurrent endometrial cancer.

The DUO-E trial randomised 699 patients with newly diagnosed advanced or recurrent epithelial endometrial carcinoma to receive either Imfinzi (1120mg) or placebo, given every three weeks in addition to standard-of-care platinum-based chemotherapy. After 4-6 cycles of chemotherapy, patients (whose disease had not progressed) then received either Imfinzi (1500mg) or placebo every four weeks as maintenance, plus 300mg Lynparza (300mg BID [2x150mg tablets, twice a day]) or placebo until disease progression.

The dual primary endpoint was PFS of each treatment arm versus standard of care. Key secondary endpoints included overall survival (OS), safety and tolerability. The trial continues to assess OS for both Imfinzi monotherapy and Imfinzi plus Lynparza as maintenance therapy in the overall trial population. Mismatch repair (MMR) status, recurrence status and geographic location were stratification factors. The trial was sponsored independently by AstraZeneca and conducted in 253 study locations across 22 countries including the US, Europe, South America and Asia.

For more information about the trial, please visit ClinicalTrials.gov.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

In addition to its indications in unresectable, Stage III NSCLC and ES-SCLC, Imfinzi is currently approved in a number of countries in combination with a short course of tremelimumab (Imjudo) and chemotherapy for the treatment of metastatic NSCLC.

Imfinzi is also approved in a number of countries in combination with chemotherapy in locally advanced or metastatic biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma (HCC). Imfinzi is also approved as a monotherapy in unresectable HCC in Japan and the EU.

Since the first approval in May 2017, more than 220,000 patients have been treated with Imfinzi. As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, breast cancer, several gastrointestinal cancers and other solid tumours.

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On June 17, 2024 Johnson & Johnson (NYSE: JNJ) reported the submission of a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for a fixed combination of amivantamab and recombinant human hyaluronidase for subcutaneous administration (SC amivantamab) for all currently approved or submitted indications of intravenous (IV) RYBREVANT (amivantamab-vmjw) in certain patients with non-small cell lung cancer (NSCLC) (Press release, Johnson & Johnson, JUN 17, 2024, View Source [SID1234644406]).

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Data from the Phase 3 PALOMA-3 study (NCT05388669) presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting and published in the Journal of Clinical Oncology showed SC amivantamab had comparable overall response rates to IV administration in patients with NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletion or L858R mutations. SC amivantamab also demonstrated significantly shorter administration time and a five-fold reduction in infusion-related reactions, alongside longer overall survival, progression-free survival and duration of response.1 Efficacy results like these have not been seen before in a study assessing IV and SC comparability. The BLA submission includes data from the Phase 2 PALOMA-2 (NCT05498428) study evaluating SC amivantamab in settings where IV amivantamab has been previously submitted for approval and is intended to support dosing schedules of every two and every three weeks.2

"RYBREVANT administered intravenously is a foundational treatment for patients with EGFR-mutated NSCLC," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Johnson & Johnson Innovative Medicine. "This subcutaneous option, administered in approximately five minutes, is a clinically important advancement that could transform the treatment experience for patients, oncologists and nursing staff. We look forward to working with the FDA and global regulators in the review of these applications."

Today’s submission follows two recent milestones for the RYBREVANT IV formulation, including the approval of RYBREVANT in combination with chemotherapy as the first FDA-approved therapy for first-line treatment of patients with NSCLC with EGFR exon 20 insertion mutations supported by the Phase 3 PAPILLON study and a CHMP positive opinion for RYBREVANT in combination with chemotherapy for this indication in Europe.

About PALOMA-3

PALOMA-3 (NCT05388669), which enrolled 418 patients, is a randomized, open-label Phase 3 study evaluating the pharmacokinetics (PK), efficacy and safety of subcutaneous amivantamab (administered via manual injection) combined with lazertinib compared to IV amivantamab and lazertinib in patients with EGFR-mutated advanced or metastatic NSCLC after progression on osimertinib and chemotherapy. The co-primary PK endpoints of the study were trough concentration (Ctrough on Cycle [C] 2 Day [D] 1 or C4D1) and C2 area under the curve (AUCD1-D15). Key secondary endpoints were objective response rate and progression-free survival. Overall survival was a predefined exploratory endpoint. Prophylactic anticoagulation was recommended for the first four months of treatment.1

About the PALOMA-2 Study

PALOMA-2 (NCT05498428) is an open-label Phase 2 study evaluating the efficacy, safety, and PK of first-line SC amivantamab (administered via manual injection) combined with lazertinib and/or chemotherapy in patients with EGFR-mutated advanced or metastatic NSCLC. Sixty-eight and 58 patients were enrolled in Cohorts 1 and 6, respectively. Prophylactic anticoagulation for the first four months of treatment was recommended in Cohort 1 and mandatory in Cohort 6. The primary endpoint was objective response rate (ORR) as assessed by the investigator per RECIST v1.1.2

About RYBREVANT

RYBREVANT (amivantamab-vmjw), a fully-human bispecific antibody targeting EGFR and MET with immune cell-directing activity, is approved in the U.S., Europe, and in other markets around the world as monotherapy for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.3 In the subcutaneous formulation, amivantamab is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

RYBREVANT is also approved in the U.S. in combination with chemotherapy (carboplatin and pemetrexed) for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test. In October 2023, a type II extension of indication application was submitted to the European Medicines Agency (EMA) seeking approval of RYBREVANT for this indication.

In December 2023, Johnson & Johnson submitted a supplemental Biologics License Application (sBLA) together with a New Drug Application (NDA) to the U.S. FDA for RYBREVANT in combination with lazertinib for the first-line treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or L858R substitution mutations, as detected by an FDA-approved test. This submission is based on the Phase 3 MARIPOSA study and was granted Priority Review in February 2024. A marketing authorization application (MAA) and type II extension of indication application were also submitted to the EMA seeking approval of lazertinib in combination with RYBREVANT based on the MARIPOSA study.

In November 2023, Johnson & Johnson submitted an sBLA to the U.S. FDA for RYBREVANT in combination with chemotherapy for the treatment of patients with EGFR-mutated NSCLC who progressed on or after osimertinib based on the MARIPOSA-2 study. A type II extension of indication application was also submitted to the EMA seeking approval of RYBREVANT for this indication.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for NSCLC§ prefer next-generation sequencing–based strategies over polymerase chain reaction–based approaches for the detection of EGFR exon 20 insertion variants. The NCCN Guidelines include:

Amivantamab-vmjw (RYBREVANT) plus carboplatin and pemetrexed as a preferred (Category 1 recommendation) first-line therapy in treatment-naive patients with newly diagnosed advanced or metastatic EGFR exon 20 insertion mutation-positive advanced NSCLC, or as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.4 †‡

Amivantamab-vmjw (RYBREVANT) plus chemotherapy as a preferred (Category 1 recommendation) subsequent therapy for patients with locally advanced or metastatic NCSLC with EGFR exon 19 deletions or exon 21 L858R mutations who experienced disease progression after treatment with osimertinib.4 †‡

Amivantamab-vmjw (RYBREVANT) as a subsequent therapy option (Category 2A recommendation) for patients that have progressed on or after platinum-based chemotherapy with or without an immunotherapy and have EGFR exon 20 insertion mutation-positive NSCLC.4 †‡
RYBREVANT is being studied in multiple clinical trials in NSCLC, including:

The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab subcutaneous delivery.5

The Phase 2 PALOMA-2 (NCT05498428) study assessing subcutaneous amivantamab in patients with advanced or metastatic solid tumors including EGFR-mutated NSCLC.2

The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab compared to intravenous amivantamab in patients with EGFR-mutated advanced or metastatic NSCLC.1

The Phase 3 PAPILLON (NCT04538664) study assessing RYBREVANT in combination with carboplatin-pemetrexed versus chemotherapy alone in the first-line treatment of patients with advanced or metastatic NSCLC with EGFR exon 20 insertion mutations.6

The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of RYBREVANT (with or without lazertinib) and carboplatin-pemetrexed versus carboplatin-pemetrexed alone in patients with locally advanced or metastatic EGFR ex19del or L858R substitution NSCLC after disease progression on or after osimertinib.7

The Phase 3 MARIPOSA (NCT04487080) study assessing RYBREVANT in combination with lazertinib versus osimertinib and versus lazertinib alone in the first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR ex19del or L858R substitution mutations.8

The Phase 1 CHRYSALIS (NCT02609776) study evaluating RYBREVANT in patients with advanced NSCLC.9

The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating RYBREVANT in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.10

The Phase 1/2 METalmark (NCT05488314) study assessing RYBREVANT and capmatinib combination therapy in locally advanced or metastatic NSCLC.11

The Phase 1/2 PolyDamas (NCT05908734) study assessing RYBREVANT and cetrelimab combination therapy in locally advanced or metastatic NSCLC.12

The Phase 2 SKIPPirr study (NCT05663866) exploring how to decrease the incidence and/or severity of first-dose infusion-related reactions with RYBREVANT in combination with lazertinib in relapsed or refractory EGFR-mutated advanced or metastatic NSCLC.13
For more information, visit: View Source

About Lazertinib

Lazertinib is an oral, third-generation, brain-penetrant EGFR tyrosine kinase inhibitor (TKI) that targets both the T790M mutation and activating EGFR mutations while sparing wild type-EGFR. An analysis of the efficacy and safety of lazertinib from the Phase 3 study was published in The Journal of Clinical Oncology in 2023. In 2018, Janssen Biotech, Inc., entered into a license and collaboration agreement with Yuhan Corporation for the development of lazertinib.14

About Non-Small Cell Lung Cancer

Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases.15,16 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma, and large cell carcinoma.17 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase controlling cell growth and division.18 EGFR mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients.17, 18, 19, 20, 21, 22 EGFR ex19del or EGFR L858R mutations are the most common EGFR mutations.23 The five year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent.24, 25 EGFR exon 20 insertion mutations are the third most prevalent activating EGFR mutation.26 Patients with EGFR exon 20 insertion mutations have a real-world five-year overall survival (OS) of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.27

RYBREVANT IMPORTANT SAFETY INFORMATION3

WARNINGS AND PRECAUTIONS

The safety population of RYBREVANT with carboplatin and pemetrexed described in Warnings and Precautions was based on 151 patients in the PAPILLON study.

The safety population of RYBREVANT as a single agent described in Warnings and Precautions was based on 129 patients in the CHRYSALIS study.

Infusion-Related Reactions

RYBREVANT can cause infusion-related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.

RYBREVANT with Carboplatin and Pemetrexed

RYBREVANT in combination with carboplatin and pemetrexed can cause infusion-related reactions. Based on the safety population, infusion-related reactions occurred in 42% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (1.3%) adverse reactions. The incidence of infusion modifications due to IRR was 40%, and 0.7% of patients permanently discontinued RYBREVANT.

RYBREVANT as a Single Agent

Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT as a single agent. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62%, and 1.3% of patients permanently discontinued RYBREVANT due to IRR.

Premedicate with antihistamines, antipyretics, and, glucocorticoids and infuse RYBREVANT as recommended. Administer RYBREVANT via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity.

Interstitial Lung Disease/Pneumonitis

RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis.

RYBREVANT with Carboplatin and Pemetrexed

Based on the safety population, Grade 3 ILD/pneumonitis occurred in 2.6% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed. All patients required permanent discontinuation.

RYBREVANT as a Single Agent

Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.

Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.

Dermatologic Adverse Reactions

RYBREVANT can cause rash (including dermatitis acneiform), pruritus, and dry skin.

RYBREVANT with Carboplatin and Pemetrexed

RYBREVANT in combination with carboplatin and pemetrexed can cause dermatologic adverse reactions. Based on the safety population, rash occurred in 89% of patients treated with RYBREVANT in combination with carboplatin and pemetrexed, including Grade 3 (19%) adverse reactions. Rash leading to dose reductions occurred in 19% of patients; and 2% permanently discontinued RYBREVANT, and 1.3% discontinued pemetrexed.

RYBREVANT as a Single Agent

Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients.

Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT as a single agent.

Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad-spectrum UVA/UVB sunscreen. Alcohol-free emollient cream is recommended for dry skin.

If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity.

Ocular Toxicity

RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis.

RYBREVANT with Carboplatin and Pemetrexed

Based on the safety population, RYBREVANT in combination with carboplatin and pemetrexed can cause ocular toxicity including blepharitis, dry eye, conjunctival redness, blurred vision, and eye pruritus. All events were Grade 1-2.

RYBREVANT as a Single Agent

Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce, or permanently discontinue RYBREVANT based on severity.

Embryo-Fetal Toxicity

Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the last dose of RYBREVANT.

Adverse Reactions

RYBREVANT with Carboplatin and Pemetrexed

For the 151 patients in the PAPILLON clinical trial who received RYBREVANT in combination with carboplatin and pemetrexed, the most common adverse reactions (≥20%) were rash (90%), nail toxicity (62%), stomatitis (43%), infusion-related reaction (42%), fatigue (42%), edema (40%), constipation (40%), decreased appetite (36%), nausea (36%), COVID-19 (24%), diarrhea (21%), and vomiting (21%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased albumin (7%), increased alanine aminotransferase (4%), increased gamma-glutamyl transferase (4%), decreased sodium (7%), decreased potassium (11%), decreased magnesium (2%), and decreases in white blood cells (17%), hemoglobin (11%), neutrophils (36%), platelets (10%), and lymphocytes (11%).

Serious adverse reactions occurred in 37% of patients who received RYBREVANT in combination with carboplatin and pemetrexed. Serious adverse reactions in ≥2% of patients included rash, pneumonia, ILD, pulmonary embolism, vomiting, and COVID-19. Fatal adverse reactions occurred in 7 patients (4.6%) due to pneumonia, cerebrovascular accident, cardio-respiratory arrest, COVID-19, sepsis, and death not otherwise specified.

RYBREVANT as a Single Agent

For the 129 patients in the CHRYSALIS clinical trial who received RYBREVANT as a single agent the most common adverse reactions (≥20%) were rash (84%), IRR (64%), paronychia (50%), musculoskeletal pain (47%), dyspnea (37%), nausea (36%), fatigue (33%), edema (27%), stomatitis (26%), cough (25%), constipation (23%), and vomiting (22%). The most common Grade 3 to 4 laboratory abnormalities (≥2%) were decreased lymphocytes (8%), decreased albumin (8%), decreased phosphate (8%), decreased potassium (6%), increased alkaline phosphatase (4.8%), increased glucose (4%), increased gamma-glutamyl transferase (4%), and decreased sodium (4%).

Serious adverse reactions occurred in 30% of patients who received RYBREVANT. Serious adverse reactions in ≥2% of patients included pulmonary embolism, pneumonitis/ILD, dyspnea, musculoskeletal pain, pneumonia, and muscular weakness. Fatal adverse reactions occurred in 2 patients (1.5%) due to pneumonia and 1 patient (0.8%) due to sudden death.

Please read full Prescribing Information for RYBREVANT.

On June 16, 2024 Electra Therapeutics, Inc., a clinical stage biotechnology company developing antibody therapies against novel targets for immunological diseases and cancer, reported the presentation of clinical data for ELA026 in secondary hemophagocytic lymphohistiocytosis (sHLH), a life-threatening hyperinflammatory condition (Press release, Electra Therapeutics, JUN 16, 2024, View Source [SID1234644353]). The results were presented today as one of six abstracts selected for oral presentation in a late-breaking session at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress in Madrid, Spain.

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Results were reported for sHLH patients in the ongoing Phase 1b clinical study, which has enrolled a majority of patients with the deadliest sHLH subtype, malignancy-associated HLH (mHLH). In treatment naive mHLH patients, ELA026 achieved a 100% overall response rate (ORR) by week 4 and improved survival at two months compared to natural history studies. ELA026 also demonstrated a high response rate across a range of sHLH patients and a favorable safety profile in this patient population.

ELA026 is a first-in-class monoclonal antibody that targets signal regulatory protein (SIRP)-α/β1/γ on the cell surface of myeloid cells and T lymphocytes, the pathological immune cells that induce hyperinflammation in sHLH. The Phase 1b study is an ongoing open-label, multi-dose, single-arm, multicenter study designed to evaluate the safety and efficacy of ELA026, assess biomarkers, and identify a dose for Phase 2/3 testing (ClinicalTrials.gov identifier: NCT05416307).

"These data show very promising results for ELA026 as a potential treatment for sHLH, which is a challenging disease that is devastating for patients and has no approved treatment options," said Swaminathan P. Iyer, MD, Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center. "Notably, the analysis reveals improved survival was achieved with ELA026 in treatment-naïve mHLH patients, suggesting benefit from early treatment intervention for patients with this rapidly progressing disease."

Study Results Presented at EHA (Free EHA Whitepaper) 2024 Congress
The oral presentation at EHA (Free EHA Whitepaper)2024, entitled "ELA026 Targeting of SIRP(+) Immune Cells Results in a High Response Rate and Improved 2-Month Survival of Treatment-naïve Malignancy-associated Hemophagocytic Lymphohistiocytosis in a Phase 1 Study," was presented by the lead author, Abhishek Maiti, MD, Assistant Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. The data describe analysis of sHLH patients in three cohorts of the ongoing Phase 1b clinical study, including the following highlights:

A majority of enrolled patients had malignancy-associated HLH (mHLH) which has the poorest prognosis, with a mortality rate of approximately 50% at two months. 1
ELA026 was observed to have a favorable safety profile, with manageable adverse events, in this patient population.
In Cohorts 1 and 2, which have completed enrollment (n=12), ELA026 achieved an overall response rate (ORR) of 75% by week 4. Enrollment in Cohort 3 is ongoing (n=5 as of April 17, 2024).
Across all cohorts, 8 patients had treatment-naïve mHLH; in this group, ELA026 achieved an ORR of 100% by week 4 and survival was 88% at two months.
In the study, pharmacodynamic and biomarker responses correlated with clinical responses.
The Phase 1b study has expanded to include up to 20 patients in Cohort 3 and will continue to evaluate ELA026 in frontline treatment settings in patients with various subtypes of sHLH.
"We are delighted that the results of the clinical study of ELA026 in sHLH were recognized and selected as a late-breaking presentation at EHA (Free EHA Whitepaper). This interim data is extremely encouraging, particularly with the high response rates and improved survival at two months achieved in treatment-naïve mHLH patients, and suggests ELA026’s promise as a first-line treatment. Survival at two months is a clinically meaningful benefit for this patient population and demonstrates the ability of ELA026 to rapidly extinguish the hyperinflammation in sHLH, enabling mHLH patients to pursue curative therapies for their underlying cancer," said Kim‑Hien Dao, DO, PhD, Chief Medical Officer at Electra. "We look forward to continuing enrollment in this study and advancing the clinical program to further assess the safety and efficacy of ELA026 in sHLH patients who currently have no approved therapies."

About Secondary Hemophagocytic Lymphohistiocytosis (sHLH)
Secondary hemophagocytic lymphohistiocytosis (sHLH) is a rare, life-threatening inflammatory disease for which there is no approved treatment. It can be triggered by cancer (malignancy-associated HLH, or mHLH), infection, autoimmune disease, or immunotherapy. sHLH is associated with a systemic inflammatory response for which patients require immediate intervention. Without treatment, patients may experience multiple organ failure and death. sHLH has a high mortality rate during the first months of diagnosis, with mHLH patients having the poorest outcomes.

On June 16, 2024 Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) reported that 14-month median follow-up data from the pivotal Phase 1/2 LINKER-MM1 trial of linvoseltamab in patients with relapsed/refractory (R/R) multiple myeloma (MM) were shared during an oral presentation at the European Hematology Association (EHA) (Free EHA Whitepaper) Congress 2024 and published in the Journal of Clinical Oncology (Press release, Regeneron, JUN 16, 2024, View Source [SID1234644354]). These longer-term results show a deepening of responses following the 11-month median follow-up data presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in April. Linvoseltamab is an investigational bispecific antibody designed to bridge B-cell maturation antigen (BCMA) on multiple myeloma cells with CD3-expressing T cells to facilitate T-cell activation and cancer-cell killing.

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"Previous results from LINKER-MM1 have demonstrated that linvoseltamab has compelling efficacy characterized by deep and durable responses. With 14-months of median follow-up, 50% of patients achieved a complete response or better, despite their cancer being refractory to or relapsing on standard therapies," said Suzanne Lentzsch, MD, PhD, Director of the Multiple Myeloma and Amyloidosis Program at Columbia University. "Additionally, a study using US-based electronic health record data to indirectly compare linvoseltamab to real-world standard-of-care treatment also support the overall body of evidence for this investigational medicine in heavily pretreated multiple myeloma. Collectively, these presentations underscore the exciting potential of linvoseltamab as we await decisions from regulatory authorities."

The 14-month median follow-up LINKER-MM1 data for linvoseltamab among patients treated at the 200 mg dose (N=117) reinforce the durability and increasing depth of response shown in previous data cuts. Per the presentation and publication, results showed:

71% objective response rate (ORR), with 50% of patients achieving a complete response (CR) or better and 63% achieving a very good partial response (VGPR) or better, as determined by an independent review committee.
Median duration of response (DoR) of 29 months for all responders, while median DoR was not reached for those who achieved a CR or better. In analyses that were not pre-specified, there was an 81% and 95% estimated probability of maintaining a response at 12 months after achieving a partial response or better among all patients and those who achieved a CR or better, respectively.
Median progression-free survival (PFS) was not reached. There was a 70% estimated probability of being progression free at 12 months among all patients; the estimated probability was 96% among those who achieved a CR or better, per an analysis that was not pre-specified.
Median overall survival (OS) of 31 months for all patients (95% CI: 22 months to NE). In analyses that were not pre-specified, the median OS was not reached for patients who achieved a CR or better, and there was a 75% and 100% estimated probability of survival at 12 months among all patients and those who achieved a CR or better, respectively.
High rates of CRs or better in prespecified subgroups, including 55% (17 of 31 patients) among those aged 75 years or older, 48% (22 of 46 patients) among those with high cytogenetic risk, 45% (9 of 20 patients) among Black or African American patients, and 28% (10 of 36 patients) among those with plasmacytomas (including extramedullary and paramedullary).
Safety data at the 14-month median follow-up was generally consistent with those at the 11-month median follow-up. Cytokine release syndrome (CRS) was the most commonly occurring treatment-emergent adverse event (TEAE) and was observed in 46% of patients; 35% were Grade 1, 10% were Grade 2 and one case (1%) was Grade 3. Adjudicated immune effector cell-associated neurotoxicity syndrome (ICANS) events of any grade occurred in 8% of patients, including three cases that were Grade 3 and no cases that were ≥Grade 4. Infections occurred in 74% of patients – including 36% that were Grade 3 or 4 – and decreased in frequency and severity after 6 months. The most common Grade 3 or 4 TEAEs (≥20%) were neutropenia (42%) and anemia (31%). Six deaths considered due to TEAEs by investigators occurred on treatment or within 30 days of the last treatment dose; five were due to infection, and one was due to renal failure.

Also shared at EHA (Free EHA Whitepaper) was a retrospective study comparing outcomes of linvoseltamab 200 mg Phase 2 patients (N=105) in LINKER-MM1 at 14-months of median follow-up to those of real-world external control patients (N=101) who received standard-of-care (SOC) treatment in clinical practice (approximately 80 varied regimens). Patients receiving SOC treatment also met similar inclusion/exclusion criteria to the LINKER-MM1 trial. Comparing linvoseltamab to SOC treatment, the ORR was 70% versus 32% (odds ratio [OR] 5.4), median PFS was 20 months versus 3 months (hazard ratio [HR]: 0.23), and median OS was not reached versus 12 months (HR: 0.40).

In the U.S., linvoseltamab has been granted Fast Track Designation and was accepted for Priority Review for the treatment of R/R MM by the U.S. Food and Drug Administration with a target action date of August 22, 2024. Linvoseltamab is also under review for R/R MM by the European Medicines Association.

The Phase 3 confirmatory trial (LINKER-MM3) for linvoseltamab in patients with R/R MM is ongoing. Linvoseltamab is currently under clinical development, and its safety and efficacy have not been fully evaluated by any regulatory authority.

About Multiple Myeloma
As the second most common blood cancer, there are over 176,000 new cases of MM diagnosed globally, and 35,000 cases are diagnosed in the U.S. every year. In the U.S., there are approximately 8,000 people who have MM that has progressed after three lines of therapy, and 4,000 whose disease has progressed after four or more therapies. The disease is characterized by the proliferation of cancerous plasma cells (MM cells) that crowd out healthy blood cells in the bone marrow, infiltrate other tissues and cause potentially life-threatening organ injury. Despite treatment advances, MM is not curable and while current treatments are able to slow progression of the cancer, most patients will ultimately experience cancer progression and require additional therapies.

About the Linvoseltamab Phase 1/2 Trial and Clinical Development Program
The ongoing, open-label, multicenter Phase 1/2 dose-escalation and dose-expansion LINKER-MM1 trial is investigating linvoseltamab in 282 enrolled patients with relapsed/refractory MM. The Phase 1 dose-escalation portion of the trial – which is now complete – primarily assessed safety, tolerability and dose-limiting toxicities across nine dose levels of linvoseltamab and explored different administration regimens. The ongoing Phase 2 dose expansion portion is assessing the safety and anti-tumor activity of linvoseltamab, with the primary endpoint of ORR. Key secondary endpoints include DoR, PFS, rate of minimum residual disease (MRD) negative status and OS.

Eligibility in the Phase 2 portion requires patients to have received at least three prior lines of therapy or have triple-class refractory MM. Linvoseltamab is administered with an initial step-up dosing regimen followed by the full 200 mg dose administered weekly. At week 16, all patients transition to every two-week dosing. A response-adapted regimen further enables patients to shift to every four-week dosing if they achieve a VGPR or better and have completed at least 24 weeks of therapy. The regimen requires a total of two 24-hour hospitalizations for safety monitoring.

The broader linvoseltamab clinical development program includes additional trials in earlier lines of therapy and stages of disease that are planned or underway. They include a Phase 1/2 trial in first-line MM, a Phase 2 trial in high-risk smoldering MM, and a Phase 2 trial in monoclonal gammopathy of undetermined significance. A Phase 1 trial of linvoseltamab in combination with a Regeneron CD38xCD28 costimulatory bispecific in MM is also planned. For more information, visit the Regeneron clinical trials website, or contact via [email protected] or 844-734-6643.